Research Articles

Title: A case of pachyonychia congenita with a hotspot variant at Arg127 in KRT16: Disease severity assessment using AlphaMissense technology
Journal: J Dermatol
Authors: Tatsuhiro Noda, Takuya Takeichi, Kana Tanahashi, Yoshinao Muro, Masashi Akiyama
Volume: 51, Issue: 8, Pages: 1134-1136

Title: Prevalence and Patient Characteristics of Pachyonychia Congenita
Journal: JAMA Dermatol
Authors: Sara Rønde Andersen, Laura Krogh Herlin, Sigrun A J Schmidt, Mette Sommerlund
Volume: 160, Issue: 12, Pages: 1364-1366

Title: Successful treatment of pachyonychia congenita with simvastatin
Journal: J Eur Acad Dermatol Venereol
Authors: Mariam Iqneibi, Sara Al-Khawaga, Omar Wafi, Martin Steinhoff
Volume: 38, Issue: 4, Pages: e356-e358

Title: Living With Pachyonychia Congenita: Patient Perspectives and Activism
Journal: Dermatology Times
Authors: Kaitlyn Bader, Janice Schwartz

Title: Defining patient-centered research priorities in pediatric dermatology
Journal: Pediatr Dermatol
Authors: Holly Neale, Suz Schrandt, Becky M Abbott, Jennifer Austin, Callista Brand, Karen Camp, Katherine Devenport, Michelle Hall, Lauren Isbell, Charlene Miciano, Sarah Pry, Paula Quinn, James Rittle, Francesca Tenconi, Julia Terrell, Meredith Weiss, Sam Zavitz, Michael Siegel
Volume: 40, Issue: 2, Pages: 250-257

Abstract:

Background/objectives: Patient and caregiver perspectives are critical in understanding dermatologic disease impact, presentation, and management in children. The Pediatric Dermatology Research Alliance (PeDRA) Patient Advisory Committee (PtAC), a group of patient representatives and parents of children with cutaneous disease, pursued a multistep, iterative, consensus-building process to identify comprehensive, high-priority research needs. Methods: Building on discussions at the 2020 PeDRA Annual Conference, a research prioritization survey was developed and completed by PtAC members. Survey themes were aggregated and workshopped by the PtAC through a series of facilitated calls. Emerging priorities were refined in collaboration with additional PeDRA patient community members at the 2021 PeDRA Annual Conference. Subsequently, a final actionable list was agreed upon. Results: Fourteen PtAC members (86.7% female) representing patients with alopecia areata, atopic dermatitis, vascular birthmarks, congenital melanocytic nevi, ectodermal dysplasias, epidermolysis bullosa, Gorlin syndrome, hidradenitis suppurativa, ichthyosis, pemphigus, psoriasis, Sturge-Weber syndrome, and pachyonychia congenita completed the survey. Following serial PtAC meetings, 60 research needs were identified from five domains: psychosocial challenges, health care navigation/disease management, causes/triggers, treatments to preserve or save life, and treatments to preserve or save quality of life. Conclusions: Many pediatric dermatology research priorities align across affected communities and may drive meaningful, patient-centric initiatives and investigations.

Title: Mutation p.Arg127Pro in the 1A Domain of KRT16 Causes Pachyonychia Congenita in Chinese Patient: A Case Report of PC Associated with Acral Melanoma
Journal: Clin Cosmet Investig Dermatol
Authors: Wei-Wei Ge, Zai-Ming Chen, Meng-Wei Chou, Ferina Ismail, Guang Chen, Li-Ming Wu, Jian-Qiang Yang
Volume: 17, Pages: 1111-1116

Abstract:

Pachyonychia congenita (PC) is a group of rare hereditary disorders, characterised by hypertrophic nails and palmoplantar keratoderma (PPK), particularly localised to the pressure areas of the feet. At a molecular level, it is caused by mutations in genes encoding KRT6A, KRT6B, KRT6C, KRT16, or KRT17. To identify the underlying gene mutation in a Chinese family with PC presenting with disabling palmoplantar keratoderma and subsequent associated acral melanoma. Genomic DNA was extracted from peripheral blood samples of three available individuals in the Chinese family, which included the patient and his two unaffected sisters. The index patient presented with severe palmoplantar keratoderma as well as a newly diagnosed acral malignant melanoma (MM). Whole-exome sequencing (WES) was carried out with amplification of exon 1 of KRT16 by polymerase chain reaction (PCR). PCR products were then sequenced to identify potential mutations. We identified the proline substitution mutation p.Arg127Pro (c.380G>C) in our patient's 1A domain of KRT16. The same mutation was not found in his sisters or unrelated healthy controls. The mutation (p.Arg127Pro (c.380G>C)) in KRT16 has been reported in Dutch patients with PC. However, it is the first such report of a patient with a PC of Chinese origin. In addition, the acral MM occurred under the background of genetic PPK caused by KRT16 mutation in this patient.

Title: Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma
Journal: J Neurosci
Authors: Rachel L Weinberg, Suyeon Kim, Zixuan Pang, Sandy Awad, Tyger Hanback, Baohan Pan, Leonie Bettin, Dennis Chang, Michael J Polydefkis, Lintao Qu, Michael J Caterina
Volume: 44, Issue: 28, Pages: e0260232024

Abstract:

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.

Title: A novel heterozygous frameshift mutation in the KRT6A gene responsible for an uncommon phenotype of pachyonychia congenita: One case report and review of literature
Journal: Heliyon
Authors: Jiali Liang, Ronghua Li, Chenmei Liu, Yan Cai, Yifei Liu, Pingjiao Chen, Kang Zeng, Changxing Li
Volume: 10, Issue: 5, Pages: e27195

Abstract:

Pachyonychia congenita is an uncommon autosomal dominant skin disorder characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and cutaneous cysts. And fissured tongue is rarely reported in patients with pachyonychia congenita. The disease is primarily associated with mutations in five keratin genes, namely KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Herein we report a 9-year-old Chinese girl who has thickened nails, keratinized plaques, and fissured tongue since birth. To investigate the underlying genetic cause, whole-exome sequencing and Sanger sequencing were performed in this patient and her family members. We identified a candidate variant c.1460-2_1460del (p.S487Lfs*21) in the KRT6A gene (NM_005554.4) by whole-exome sequencing. Sanger sequencing revealed the absence of the mutation in both parents, indicating that it is a de novo variant. Thus, the novel heterozygous frameshift mutation c.1460-2_1460del (p.S487Lfs*21) within exon 9 of KRT6A was identified as the genetic cause of the patient. Our study identified a rare de novo heterozygous frameshift mutation in the KRT6A gene in a patient with pachyonychia congenita presenting fissured tongue. Our findings expand the KRT6A gene mutation spectrum of Pachyonychia congenita, and will contribute to the future genetic counseling and gene therapy for this disease.

Title: Posttranslational modifications of keratins and their associated proteins as therapeutic targets in keratin diseases
Journal: Curr Opin Cell Biol
Authors: Pei Li, Katrin Rietscher, Henriette Jopp, Thomas M Magin, M Bishr Omary
Volume: 85, Pages: 102264

Abstract:

The keratin cytoskeleton protects epithelia against mechanical, nonmechanical, and physical stresses, and participates in multiple signaling pathways that regulate cell integrity and resilience. Keratin gene mutations cause multiple rare monoallelic epithelial diseases termed keratinopathies, including the skin diseases Epidermolysis Bullosa Simplex (EBS) and Pachyonychia Congenita (PC), with limited available therapies. The disease-related keratin mutations trigger posttranslational modifications (PTMs) in keratins and their associated proteins that can aggravate the disease. Recent findings of drug high-throughput screening have led to the identification of compounds that may be repurposed, since they are used for other human diseases, to treat keratinopathies. These drugs target unique PTM pathways and sites, including phosphorylation and acetylation of keratins and their associated proteins, and have shed insights into keratin regulation and interactions. They also offer the prospect of testing the use of drug mixtures, with the long view of possible beneficial human use coupled with increased efficacy and lower side effects.

Title: The variant c.274A>G (p.Asn92Asp) in KRT17 in a patient with pachyonychia congenita and a novel clinical feature of acne inversa
Journal: Front Genet
Authors: Huaiyu Wang, Changhua Zhu, Linxin Dong, Baofeng Wu, Jingjing Liu, Lihang Lin, Daoyao Lin, Xiangqi Chen, Xuemin Xiao
Volume: 15, Pages: 1365581

Abstract:

Introduction: The occurrence of pachyonychia congenita (PC) and acne inversa (AI) may be related to gene mutations. The aim of this study is to identify the genetic cause in a patient with PC and AI, and to explore the possible molecular mechanism of their co-occurrence.   Methods: The clinical data of the proband were collected, and the genomic DNA of the proband and unaffected parents were extracted. The variant sites of the proband were identified by whole-exome sequencing, and then the variant sites of the proband and his parents were verified by Sanger sequencing.   Results: A heterozygous variant in KRT17 gene was found in the patient, resulting in a missense amino acid variant (p.N92D). The variant was not found in his parents or 100 unrelated healthy controls. In addition, this variant was not found in the gnomad v4 database. The three-dimensional structure analysis of the protein suggested that the polarity of amino acids changed after the variant. After lentiviral plasmid transfection into HaCaT cells, the expression level of NOTCH signaling decreased in the constructed c.274A>G (p.Asn92Asp) of KRT-17 mutant cells compared to that in the wild-type. Subsequent verification confirmed that differences in the expression levels of p-PI3K, AKT and p-AKT between the groups were not statistically significant.   Discussion: Although this variant has been reported previously, our findings could expand the spectrum of co-occurrence of PC and AI with KRT17 gene variants, and elucidated the possible pathogenesis at the protein level, thereby laying a foundation for the genetic diagnosis and genetic counseling provided to individuals with PC.

Title: Evaluation of the Foot Function Index in pachyonychia congenita
Journal: Br J Dermatol
Authors: Jaimie Oldham, Beth L Stuart, Rebecca L McCarthy, Janice Schwartz, Holly Evans, David Hansen, Edel A O'Toole
Volume: 192, Issue: 5, Pages: 947-948

Title: Proteomic profiling reveals KRT6C as a probable hereterodimer partner for KRT9: New insights into re-classifying epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c) as a group of genetic cutaneous disorders
Journal: J Proteomics
Authors: Peiyao Li, Jialin Qi, Yuhui Zhong, Aoli Ding, Heng Xiao
Volume: 287,

Abstract:

Epidermolytic palmoplantar keratoderma (EPPK), a highly penetrant autosomal dominant genodermatosis, is characterized by diffuse keratoses on palmplantar epidermis. The keratin 9 gene (KRT9) is responsible for EPPK. To date, phenotypic therapy is the primary treatment for EPPK. Because KRT9 pairs with a type II keratin-binding partner to function in epidermis, identifying the interaction partner is an essential first step in revealing EPPK pathogenesis and its fundamental treatment. In this study, we proved that keratin 6C (KRT6C) is a probable hereterodimer partner for KRT9. In silico model for KRT6C/KRT9 shows a typical coiled-coil structure in their 2B domains. Proteomics analysis shows that KRT6C/KRT9 pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating cytoskeleton organization and keratinization. This study shows that co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis provide a sensitive approach, which compensates for inevitable inadequacies of anti-keratin 6C antibody and helps discover the probable hereterodimer partner KRT6C for KRT9. The acknowledgement of KRT6C/KRT9 pairwise relationship may help re-classify EPPK and PC-K6c (a milder form of pachyonychia congenita, caused by KRT6C) as a group of hereditary defects at a molecular-based level, and lay foundation for deciphering the keratin network contributing to EPPK and PC-K6c. SIGNIFICANCE OF THE STUDY: What is already known about this topic? KRT9 and KRT6C are disease-causing factors for epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c), respectively. EPPK and PC-K6c have some symptom similarities. Keratins are the major structural proteins in epithelial cells. Each of the type I keratin is matched by a particular type II keratin to assemble a coiled-coil heterodimer. The hereterodimer partner for KRT9 is unknown. What does this study add? We discovered and proved that KRT6C is a probable hereterodimer partner for KRT9 in palmplantar epidermis in a native endogenous environment by using co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis, etc. The proteomics analysis shows that KRT6C/KRT9 keratin pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating intermediate filament-based cytoskeleton organization and keratinization processes. What are the implications of this work? The new understanding of probable KRT6C/KRT9 pairwise correlation may help re-classify the genetic cutaneous disorders EPPK and PC-K6c as a group of hereditary defects at a molecular-based level, and lay foundation for pathogenic mechanism research in EPPK and PC-K6c. The densely related network components derived from the proteomic data using Metascape in the study and pairwise regulation fashion of specific keratin pairs should attract more attention in the further explorations when investigators concern the physiological functions of keratins and the pathogenesis of related skin diseases.

Title: Inhibiting EGFR Signaling Holds Promise for Treating Palmoplantar Keratodermas
Journal: J Invest Dermatol
Authors: Pierre A Coulombe, Amanda Orosco
Volume: 143, Issue: 2, Pages: 185-188

Abstract:

PC and related disorders involving PPK PC is a rare condition (w10 thousand cases worldwide) featuring anomalies that affect ectoderm-derived appendages, including nail dystrophy, sebaceous cysts, natal teeth, oral leukokeratosis, and PPK (Leachman et al., 2005). PPK consists of extreme thickening of the skin of palms and especially soles and develops primarily in areas of skin experiencing high pressure or compression stress. Histologically, there is a dramatic thickening of the living and stratum corneum compartments, known as acanthosis and hyperkeratosis, respectively, in the palmar and especially the plantar epidermis in PC (Cao et al., 2015). Very severe pain emanate from PC-associated PPK, on a daily basis, making routine tasks and activities very challenging. PC does not impact lifespan but dramatically impacts QOL (Leachman et al., 2005). The basis for the chronic and intense pain that occurs in PC-associated PPK or other forms of painful PPK is largely unknown (Weinberg et al., 2020). As detailed below, there is as of yet no effective treatment for PC aside from palliative measures that provide short-term and partial relief (Leachman et al., 2005). Individuals suffering from PC benefit from transformative support provided by the Pachyonychia Congenita Project, a highly effective patient advocacy organization founded nearly 20 years ago by Mary Schwartz, a mother in-law and grandmother to PC sufferers (see www.pachyonychia.org). ..... Efforts made to date toward exploring the effectiveness of various drugs and approaches to treat PC-associated PPK have been vigorous but have yielded modest success owing to a combination of factors. Such approaches have included the use of keratin-mutant allele-specific small interfering RNAs, drugs that target mTOR signaling (rapamycin), cholinergic signaling (Botox) or retinoic acid signaling, and statins (see Zieman and Coulombe [2020] for a recent review). The study by Basset et al. (2022) using erlotinib thus provides a most welcome and exciting advance in this field. Intriguingly, as mentioned earlier, these findings build on a comparable outcome when using oral erlotinib in individuals with OS (Greco et al., 2020; Kenner-Bell et al., 2010; Zhang et al., 2020), thereby highlighting the possibility that enhanced EGFR signaling may be a molecular trait that is shared across PPK disorders of distinct etiologies. Yet, many issues need to be addressed going forward. EGFR is a prominent receptor tyrosine kinase (RTK) capable of activating multiple cellular pathways, including the Ras/Raf/MAPK, phosphoinositide-3 kinase/PTEN/protein kinase B, and Jak/signal transducer and activator of transcription kinase cascades, which respectively exert a significant impact on cell proliferation, metabolism, and differentiation (Wee andWang, 2017). Given that EGFR is highly expressed in skin and also gastrointestinal epithelial cells, it comes as no surprise that the most prominent side effects of oral erlotinib are cutaneous lesions and rashes and diarrhea. As part of the next steps, the role of EGFR signaling in the genesis, character, and/or maintenance of PPK; its role in giving rise to significant pain; and the systemic and long-term effects of inhibiting an RTK using orally administered drugs should be carefully assessed as erlotinib (and related drugs) is tested on a larger scale in individuals with PC.

Title: Nail Whispers Revealing Dermatological and Systemic Secrets: An Analysis of Nail Disorders Associated With Diverse Dermatological and Systemic Conditions
Journal: Cureus
Authors: Mansi Satasia, Amita H Sutaria
Volume: 15, Issue: 9,

Abstract:

Background and objective Nail disorders encompass a wide spectrum of conditions, spanning congenital, developmental, infectious, neoplastic, degenerative, dermatological, and systemic diseases. A comprehensive exploration of their clinical manifestations, incidence, and associations is crucial for precise diagnosis and effective management. Methods This observational cross-sectional study conducted at B.J. Medical College and Civil Hospital, Ahmedabad involved 300 consecutive patients with nail changes from July 2017 to June 2019 reporting diverse dermatological and systemic conditions. The inclusion criteria involved patients of both genders and all age groups displaying nail changes associated with dermatological and systemic diseases. Data collection entailed a comprehensive clinical history, systemic and dermatological examinations, nail assessment using Dermoscope (DermLite 3, 10x), and supplementary tests. Analyses were performed on Microsoft Excel 2007 software. The study was approved by the Institute Ethics Committee. Results Among the 300 cases, females had a higher prevalence of nail involvement (57%), with a female-to-male ratio of 1.3:1. The most affected age group was 21-40 years, with 6-10 nails typically affected. Notably, housewives showed a higher prevalence. The most frequent nail condition was onychomycosis (24.33%) followed by psoriatic nail changes (20%). Less frequent nail changes involved eczema (5.7%), paronychia (5%), drug-induced (4.3%), lichen planus (3.7%), trauma-induced (3%), twenty nail dystrophy (2.33%), Darier's disease (2%), pemphigus vulgaris (2%), alopecia areata (1.67%), median Heller dystrophy (1.33%), atopic dermatitis (1%), epidermolysis bullosa (1%), racquet nail (1%), leprosy (1%), pityriasis rubra pilaris (0.67%), vitiligo (0.67%), secondary syphilis (0.67%), pachyonychia congenita (0.67%), as well as a case each of total leukonychia, subungual warts, Koenen tumor, and periungual fibroma(0.33%). Systemic autoimmune connective tissue disorders (CTD) accounted for 9%; the most common nail finding observed was nail fold erythema (48.1%) followed by nail fold telangiectasis (44.4%). In systemic sclerosis (SS), the most common finding was nail fold telangiectasia, and in systemic lupus erythematosus (SLE), the most common was nail fold erythema. Scleroderma capillary pattern on nail fold capillaroscopy was found in seven patients with SS, two patients with dermatomyositis, and only one patient with SLE. Nail changes observed in systemic diseases include onychomycosis in diabetes mellitus and chronic renal failure patients, splinter hemorrhages in ischemic heart disease and hypertension, longitudinal melanonychia in HIV, and koilonychia and platynychia in iron deficiency anemia. Other systemic diseases, such as Addison's disease and renal failure, also exhibited various nail changes. Conclusions Beyond their cosmetic importance, nails hold a vital pathologic role. Proficiency in nail terminology and classification is key for skillful evaluation. Understanding normal and abnormal nail variants, along with their disease associations, benefits diagnosis and tailored management. Nails, often overlooked but accessible, serve as a window into patients' general health and should be an integral part of thorough examinations. This study highlights an intricate clinical panorama of nail disorders, highlighting their significant role in both dermatological and systemic contexts.

Title: EGFR Signaling is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib
Journal: J Invest Dermatol
Authors: Justine Basset, Lucile Marchal, Alain Hovnanian
Volume: 143, Issue: 2, Pages: 294-304

Abstract:

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is caused by dominant mutations in keratin (K) K6A, K6B, K6C, K16, or K17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive. In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. Abnormal late terminal keratinization was associated with elevated TGM1 activity. In addition, the calcium ion permeable channel TRPV3 was significantly increased in PC-lesional skin, suggesting a predominant role of the TRPV3/EGFR signaling complex in PC. We hypothesized that this complex contributes to promoting TGM1 activity and induces the expression and shedding of EGFR ligands. To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL. Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC.

Title: Phenotype and genotype features of Vietnamese children with pachyonychia congenita
Journal: Pediatr Neonatol
Authors: Ha Thi Chu, Tung Anh Dinh Duong, Doanh Huu Le, Thieu Van Le, Binh Bui Nguyen, Chuc Van Dang, Quang Van Vu
Volume: 64, Issue: 4, Pages: 405-410

Abstract:

Background: Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). PC is an extremely rare condition. To our knowledge, this is the largest genotype-phenotype study of PC in a Vietnamese population to date. Materials and methods: We investigated keratin gene mutations and clinical features of seven Vietnamese children with PC. Results: The seven Vietnamese patients were from six different families (two patients in the same family) from across Northern, Central, and Southern Vietnam. All children displayed PC symptoms before 1 year of age, but diagnosis was delayed in 4/7 patients. Thick fingernails, thick toenails, oral leukokeratosis, and follicular hyperkeratosis were the most common features recorded by all seven patients. Plantar keratoderma and thick fingernails were the clinical features associated with the most significant effect on daily function. All patients had mutations in KRT6A (PC-K6a) focused on the 1A and 2B domains. We found three distinct types of mutations (K6a R466P, K6a N171K, and K6a N172del). One mutation (N172del) was common to 5/7 (71.4%) of the patients. Conclusions: Individuals displaying nail dystrophy, oral leukokeratosis, follicular hyperkeratosis, and plantar keratoderma should be referred for genetic testing given the high likelihood of a PC-K6a-related mutation in patients with this constellation of clinical signs.

Title: Early-onset Pachyonychia Congenita with Oral and Cutaneous Manifestations
Journal: Ann Afr Med
Authors: Shambhavi Singh, Ajay Kumar, Kalyan Dalave, Nishtha Mishra

Abstract:

An 11-year-old girl presented with painful plantar hyperkeratosis and nail dystrophy, evident since infancy. Examination revealed hyperkeratotic plaques on the soles, wedge-shaped nail hypertrophy, follicular hyperkeratosis over the extremities, and oral leukokeratosis. A positive maternal history suggested autosomal dominant inheritance with variable expressivity, consistent with pachyonychia congenita. Fungal infection was excluded via KOH mount; genetic testing was unavailable due to financial constraints. Despite prior treatments with keratolytics and emollients, improvement was minimal. This case highlights the early onset, classical features, and psychosocial burden associated with pachyonychia congenita, emphasizing the importance of early diagnosis, genetic counseling, and supportive care.

Title: Congenital nail abnormalities
Journal: Hand Surg Rehabil
Authors: Lorie Nahmani, Franck Fitoussi
Volume: 43S, Pages: 101527

Abstract:

Congenital nail disorders are an uncommon presenting symptom which can be difficult to diagnose and manage. Nail diseases in the pediatric population differ from those in adults in terms of diagnosis, approach and management. In most cases, they do not require treatment and resolve with growth. Physicians need to be able to recognize them, to reassure the parents. The most frequently encountered pathologies associated with nail disorder are syndactyly, acrosyndactyly, symbrachydactyly, macrodactyly, Wassel I thumb duplication, Kirner's deformity and congenital onychodysplasia of the index finger. Treatment usually consists in surgical correction of the deformity. Nail malformation can also be an aspect of a systemic disease. It may provide a clue for screening, and should not be overlooked. Nail conditions can be the first sign of nail-patella syndrome, ectodermal dysplasia, dyskeratosis congenita, epidermolysis bullosa, pachyonychia congenita or lung disease. Medical treatment is therefore discussed on a case-by-case basis.

Title: Pachyonychia Congenita: A Rare Disorder of Keratinization
Journal: Indian Pediatr
Authors: Tavneet Kaur Makkar, Sonia Agrawal, Chander Grover
Volume: 16, Issue: 10, Pages: 1001

Title: Surgical Management of Pachyonychia Congenita in a 3-Year-Old
Journal: Arch Plast Surg
Authors: Jack D Sudduth, Christopher Clinker, Matthew Holdaway, Jessica L Marquez, Jacob Veith, Thomas Wright, W Bradford Rockwell
Volume: 50, Issue: 6, Pages: 573-577

Abstract:

Pachyonychia congenita is a rare genetic disorder characterized by hypertrophic nail plates, hyperkeratotic nail beds, and thickened hyponychium of the fingers and toes, impairing manual dexterity and resulting in poor aesthetics. The current body of literature describes various treatment modalities, but no singular approach has been defined as the gold standard. In this case, the authors employed different surgical techniques for treating pachyonychia congenita to evaluate the most effective approach. A 3-year-old boy presented with hypertrophic nail growth involving all digits of both hands and feet. Three surgical procedures were performed on the patient's fingers and toes using germinal matrix excision (GME) alone, GME plus partial sterile matrix excision (pSME), or GME plus complete sterile matrix excision (cSME). The digits treated with GME + cSME exhibited no recurrence of nail growth. Those treated with GME alone exhibited recurrence of hypertrophic nail growth, although their growth slowed. Excision of GME + cSME prevented recurrence of hypertrophic nails, while GME alone or with pSME led to slower-growing hypertrophic nails. Complete excision of the germinal and sterile matrices with skin graft closure may be a definitive treatment for pachyonychia congenita, but further studies are needed to validate these findings.

Title: Pachyonychia congenita: pathogenesis of pain and approaches to treatment
Journal: Clin Exp Dermatol
Authors: Rebecca L McCarthy, Marianne de Brito, Edel A O'Toole
Volume: 49, Issue: 12, Pages: 1510-1517

Abstract:

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma, and hypertrophic nail dystrophy. Plantar pain can be debilitating and have a profound impact on quality of life. Current therapeutic options for pain in PC are limited to lifestyle adjustment and mechanical techniques, with a small subgroup of patients benefiting from oral retinoids. This review investigates the pathogenesis of pain in PC and provides a summary of the current and future therapeutic options.

Title: Syndromic epidermal differentiation disorders: New classification towards pathogenesis-based therapy
Journal: Br J Dermatol
Authors: Amy S Paller, Joyce Teng, Juliette Mazereeuw-Hautier, Angela Hernandez-Martin, Celine Granier Tounier, Alain Hovnanian, Mandy Aldwin-Easton, Gianluca Tadini, Janice Schwartz, Eli Sprecher, Kiril Malovitski, Akemi Ishida-Yamamoto, Keith Choate, Masashi Akiyama, Edel A O'Toole, Judith Fischer, Christine Bodemer, Antoni Gostynski, Matthias Schmuth

Abstract:

Title: Nonsyndromic epidermal differentiation disorders: New classification and nomenclature based on disease-associated genes leading to targeted therapy
Journal: Br J Dermatol
Authors: Masashi Akiyama, Keith Choate, Angela Hernandez-Martin, Mandy Aldwin-Easton, Christine Bodemer, Antoni Gostynski, Alain Hovnanian, Akemi Ishida-Yamamoto, Kiril Malovitski, Edel A. O'Tolle, Amy S. Paller, Matthias Schmuth, Janice Schwartz, Eli Sprecher, Joyce M C Teng, Celine Granier Tournier, Juliette Mazereeuw-Hautier, Gianluca Tadini, Judith Fischer

Abstract:

Epidermal differentiation disorders (EDDs) encompass inherited conditions characterized by abnormal epidermal differentiation, including nonsyndromic and syndromic subtypes with more extensive cutaneous involvement or palmoplantar keratodermas. Nonsyndromic EDDs (nEDDs) are defined as disorders that primarily affect large areas of skin and adnexal structures without alterations in extracutaneous tissues resulting from the underlying genetic change. To facilitate the development of targeted therapies and provide clinicians with clearer therapeutic guidance, we have recently developed a new nomenclature for EDDs that includes the causative altered gene and the nEDD subgroup designation, sometimes with a clinical or histological descriptor or acronym. Historically, many nEDDs have been named on the basis of phenotypic characteristics or associations that are now considered outdated or inappropriate. For example, the term "harlequin ichthyosis" evokes potentially stigmatizing images. Similarly, the word "ichthyosis" is derived from the Greek "ichthys", meaning fish, and the Greek "hystrix", meaning porcupine, further emphasizing the need to abandon derogatory terminology. As a result, the clinical relevance of the previous classification, which included eponymous and/or descriptive titles, has diminished. In the new, gene-based classification, old terms considered pejorative, such as ichthyosis, vulgaris, hystrix, and harlequin have been eliminated and eponyms have been replaced. Among the 53 genetically distinct nEDDs are conditions formerly known as autosomal recessive congenital ichthyosis, erythrokeratodermia variabilis et progressiva, Hailey-Hailey disease, and Darier-White disease. This review outlines the updated nomenclature and classifications of nEDDs, linked to detailed clinical descriptions and representative photographs to guide practitioners.

Title: Palmoplantar epidermal differentiation disorders: a new classification towards pathogenesis-based therapy
Journal: Br J Dermatol
Authors: Eli Sprecher, Akemi Ishida-Yamamoto, Janice Schwartz, Masashi Akiyama, Mandy Aldwin-Easton, Keith Choate, Judith Fischer, Antonio Gostynski, Celine Granier Tournier, Angela Hernandez-Martin, Alain Hovnanian, Kiril Malovitski, Juliette Mazereeuw-Hautier, Amy S Paller, Matthias Schmuth, Gianluca Tadini, Joyce Teng, Christine Bodemer, Edel A O'Toole

Abstract:

More than 50 palmoplantar epidermal differentiation disorders (pEDDs) have been reported in the literature. Various descriptors have been used to name these conditions including clinical features often designated as acronyms or evocative terms, names of clinicians and of geographical locations. Not only has this nomenclature been criticized for its lack of methodological consistency, it has progressively lost its clinical relevance. Indeed, the advent of a wide range of pathogenesis-targeting therapeutic solutions for these disorders has raised the need for a novel classification of pEDDs, based on their causative genetic defects, to provide clinicians with genuine therapeutic guidance. Here, we present a novel classification scheme for pEDDs and its application in the form of a practical algorithm for the rapid diagnosis of pEDDs.

Title: Plantar Skin Exhibits Altered Physiology, Constitutive Activation of Wound-Associated Phenotypes, and Inherently Delayed Healing
Journal: J Invest Dermatol
Authors: Christiane Fuchs, Katherine J Stalnaker, Clifton L Dalgard, Gauthaman Sukumar, Daniel Hupalo, Jonathan M Dreyfuss, Hui Pan, Ying Wang, Linh Pham, Xunwei Wu, Ivan Jozic, R Rox Anderson, Sunghun Cho, John H Meyerle, Joshua Tam
Volume: 144, Issue: 7, Pages: 1633-1648

Abstract:

Wound research has typically been performed without regard for where the wounds are located on the body, despite well-known heterogeneities in physical and biological properties between different skin areas. The skin covering the palms and soles is highly specialized, and plantar ulcers are one of the most challenging and costly wound types to manage. Using primarily the porcine model, we show that plantar skin is molecularly and functionally more distinct from nonplantar skin than previously recognized, with unique gene and protein expression profiles, broad alterations in cellular functions, constitutive activation of many wound-associated phenotypes, and inherently delayed healing. This unusual physiology is likely to play a significant but underappreciated role in the pathogenesis of plantar ulcers as well as the last 25+ years of futility in therapy development efforts. By revealing this critical yet unrecognized pitfall, we hope to contribute to the development of more effective therapies for these devastating nonhealing wounds

Title: Pachyonychia Congenita: Sporadic Onset with Mutation Analysis
Journal: Indian Dermatol Online J
Authors: Kavitha Athota, Smitha S Prabhu
Volume: 14, Issue: 5, Pages: 703-705

Title: The Pachyonychia Congenita Virtual Support Group Meeting: Patient Insights and Pearls
Journal: J Am Podiatr Med Assoc
Authors: Shari R Lipner, Julianne M Falotico
Volume: 113, Issue: 5, Pages: 22-078

Abstract:

Pachyonychia congenita (PC) is an autosomal dominant disease characterized by heterozygous mutations in keratin genes present in the mucosa, palmoplantar epidermis, and nail bed. Common clinical findings include palmoplantar keratoderma and nail dystrophy, with significant impacts on quality of life (QoL) secondary to both pain and emotional distress. Pachyonychia congenita is a rare disease, with an estimated prevalence of 0.9 cases per 1 million people and 5,000 to 10,000 cases globally. The PC Project (www.pachyonychia.org) was established in 2003 to support PC patients, provide resources, and promote and fund research efforts. Patient support group meetings have become an integral part of the organization to connect those suffering from the disease with each other and with professionals from the medical and scientific community on an international level. Our objectives were to examine the demographic profile of participants who attended the Virtual PC Patient Support Meeting in 2021, report on common areas of concern in the PC population, and share treatment tips provided by PC patients for managing symptoms.

Title: Walking a day in a pachyonychia congenita patient's shoes: Impact on plantar pain and activity levels measured with wristband activity trackers
Journal: Indian J Dermatol Venereol Leprol
Authors: Shari R Lipner, Julianne M Falotico, Justin T Matushansky, Holly Evans, Janice Schwartz, C David Hansen
Volume: 89, Issue: 6, Pages: 850-853

Abstract:

Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain reporting in pachyonychia congenita clinical studies, it is difficult to evaluate the efficacy of treatment outcomes for painful plantar keratodermas. Objectives To objectively analyse associations between plantar pain and activity levels in pachyonychia congenita patients using a wristband tracker. Methods Pachyonychia congenita patients and matched normal controls wore wristband activity trackers and completed a daily digital survey to record their highest and total pain scores (0-10 scale) each day for 28 consecutive days during four different seasons. Results Twenty four participants (12 pachyonychia congenita patients and 12 matched normal controls) completed the study. Pachyonychia congenita patients walked 1801.30 fewer steps/day (95% CI, -3666.4, 64.1) than normal controls (P = 0.072) and had greater average total [5.26; SD, 2.10] and highest (6.92; SD, 2.35) daily pain than normal controls [0.11 (SD, 0.47), 0.30 (SD, 0.22), respectively] (P < 0.001, both). On average, for each one unit increase in daily highest pain level, pachyonychia congenita activity decreased 71.54 steps/day (SE, 38.90, P = 0.066). Limitation The study had a small number of participants, limiting statistical power. Only pachyonychia congenita patients, ages 18 years or older, with keratin 6a, keratin 16, and keratin 17 mutations were included, limiting generalizability. Conclusion Pachyonychia congenita patients were less active with significantly higher pain than normal controls. There was an inverse correlation between pain and activity. Our findings suggest that wristband tracker technology may be used to evaluate treatment efficacy in future trials on severe plantar pain; therapeutic interventions that decrease plantar pain should correlate with significant increases in activity using wristband trackers.

Title: A Rare Case of Pachyonychia Congenita and the Need for Awareness
Journal: Balkan Med J
Authors: Hami Kork, Gurbuz Yildirim, Zeynep Altan Ferhatoglu
Volume: 41, Issue: 4, Pages: 317-318

Abstract:

I am writing to share an extraordinary case of pachyonychia congenita (PC) that recently came to our attention. PC, a group of rare keratin disorders inherited in an autosomal dominant manner, is characterized by palmoplantar keratoderma, dystrophic nail changes, and oral leukokeratosis. Distinguishing the five different keratin mutations is crucial as they result in varied symptoms. This letter aims to raise awareness about the challenges faced by individuals with PC and advocate for a greater understanding of this condition within the medical community.

Title: Shifts in keratin isoform expression activate motility signals during wound healing
Journal: Dev Cell
Authors: Benjamin A Nanes, Kushal Bhatt, Evgenia Azarova, Divya Rajedran, Sabahat Munawar, Tadamoto Isogai, Kevin M Dean, Gaudenz Danuser
Volume: 59, Issue: 20, Pages: 2759-2771

Abstract:

Keratin intermediate filaments confer structural stability to epithelial tissues, but the reason this simple mechanical function requires a protein family with 54 isoforms is not understood. During skin wound healing, a shift in keratin isoform expression alters the composition of keratin filaments. If and how this change modulates cellular functions that support epidermal remodeling remains unclear. We report an unexpected effect of keratin isoform variation on kinase signal transduction. Increased expression of wound-associated keratin 6A, but not of steady-state keratin 5, potentiated keratinocyte migration and wound closure without compromising mechanical stability by activating myosin motors to increase contractile force generation. These results substantially expand the functional repertoire of intermediate filaments from their canonical role as mechanical scaffolds to include roles as isoform-tuned signaling scaffolds that organize signal transduction cascades in space and time to influence epithelial cell state.

Title: Celebrating 20 Years of the International Pachyonychia Congenita Consortium
Journal: J Invest Dermatol
Authors: Pierre A Coulombe, David Hansen, Robyn Hickerson, Alain Hovnanian, Edel A O'Toole, David P Kelsell, Holly Evans, Janice Schwartz, Eli Sprecher
Volume: 145, Issue: 4, Pages: 725-727

Abstract:

Pachyonychia Congenita Project hosted the International Pachyonychia Congenita Consortium symposium as part of the annual meeting of the Society for Investigative Dermatology (SID), held on May 15- 18 in Dallas, TX. Holding a pachyonychia congenita (PC) focused symposium ahead of the main SID meeting has been a long-standing tradition of Pachyonychia Congenita Project. However, this year, the occasion was special for 2 reasons: first, the event provided an opportunity to celebrate the 20th anniversary of Pachyonychia Congenita Project, a remarkable accomplishment, and second, for the first time, the PC-focused meeting was paired with another satellite symposium focused on distinct rare diseases affecting primarily the skin (Darier’s and Hailey-Hailey diseases). Similar to PC, these 2 conditions are rare and clinically significant, and although their genetic etiology is known, individuals suffering from them are eagerly awaiting the development of therapies that positively impact their daily lives. Several clinical, translational, and basic science researchers participated in both events, setting the stage for the sharing of ideas and, potentially, the development of collaborations for the benefit of these patients with PC, Darier, and HaileyeHailey diseases. In this paper, we report on the symposium focused on PC.

Title: Non-pachyonychia congenita conditions in the International Pachyonychia Congenita Research Registry
Journal: Int J Dermatol
Authors: Ashley N. Wittmer, Cassidy M Nguyen, Edel O'Toole, Janice Schwartz, Holly Evans, David Hansen
Volume: 64, Issue: 7, Pages: 1285-1287

Abstract:

Pachyonychia congenita (PC) is a rare disorder characterized by palmoplantar keratoderma, hypertrophic nail dystrophy, steatocystoma, pilosebaceous cysts, oral leukokeratosis, and pain. Prevalence is estimated at up to 10,000 cases globally. As a result of a lack of awareness and access to standardized genetic testing worldwide, these numbers likely underestimate the true prevalence of PC.2 There are five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17. PC Project established the International PC Research Registry (IPCRR) in 2004 (WIRB Study #20040468), a physician-verified registry that not only collects data about PC but also serves as a diagnostic pathway for patients worldwide who are often undiagnosed or misdiagnosed. There are now over 2700 individuals in the registry, and over 1100 are fully enrolled with a genetic diagnosis. While manifestations including hypertrophic nails, palmoplantar keratoderma, and plantar pain may support a clinical PC diagnosis, genetic testing is the key to an accurate diagnosis. The IPCRR collects patient reported data and provides free genetic testing to patients with clinical features of PC. However, among this population, genotyping has revealed that a substantial number of these individuals do not have PC. Through the exploration of data from the IPCRR, a list of genes with pathogenic variants was compiled (Figure 1). These genes included variants not in the five keratin genes known to cause PC. Further review yielded clinical information on these skin disorders with similar PC phenotypes but not caused by a PC variant. An updated count of all non-PC gene variants in the IPCRR was performed. The IPCRR now houses data from other rare skin disorders with variants in approximately 10 genes (Figure 1). Most of the conditions identified in the registry had phenotypic features similar to PC’s, which were difficult to distinguish from PC without genetic confirmation. Specifically, plantar keratoderma occurs in most of these conditions, closely resembling the plantar calluses seen in PC (Figure 2). The three most commonly encountered non-PC conditions in the IPCRR are Clouston syndrome (OMIM 129500), Olmsted syndrome (OMIM 614594), and striate palmoplantar keratoderma (OMIM 148700) (SPPK). Clouston syndrome is caused by a variant in the GJB6 gene that encodes the gap junction protein, connexin 30. Clouston syndrome characteristics similar to PC include nail dystrophy and palmoplantar keratoderma. Key features also include reduced or loss of hair to the scalp and/or eyebrows, which is a finding not found in PC. SPPK occurs because of desmoglein-1 (DSG1) gene variants, which play a role in cell–cell adhesion. These individuals typically present with palmoplantar keratoderma, which may have striate or diffuse patterns in areas subjected to high friction.4 Variants in GJB6 or DSG1 genes generally cause less painful keratoderma than that observed in PC. Olmsted syndrome occurs because of variants in the TRPV3 gene and is characterized by very painful bilateral palmoplantar keratoderma and periorificial plaques. Many individuals also suffer from nail involvement, eye lesions, and inflamed lacrimal glands.5 Early recognition of these syndromes is important, given that they can require different clinical management.

Title: Pachyonychia Congenita: Spectrum of cutaneous disease
Journal: J Am Acad Dermatol
Authors: Kaya J Curtis, Janice Schwartz, Holly Evans, Shari R Lipner
Volume: 91, Issue: 5, Pages: 1021-1025

Abstract:

Pachyonychia congenita is a group of rare keratinization disorders primarily characterized by the triad of palmoplantar keratoderma, nail hypertrophy, and plantar pain (Figs 1-8).1 Estimated prevalence is 5000 to 10,000 patients worldwide, though true prevalence is likely higher due to underdiagnosis of milder subtypes.2 Plantar pain is often debilitating and significantly affects quality of life.3,4 Most cases are inherited in an autosomal dominant fashion, though around 30% are due to de novo mutations.3 There are 5 types of pachyonychia congenita caused by mutations in keratin genes KRT6A, KRT6B, KRT6C, KRT16, and KRT17.

Title: Pachyonychia Congenita Project: Advancing Research and Drug Development through Collaboration
Journal: Keio J Med
Authors: Janice N Schwartz, Holly A Evans, Edel A O'Toole, C. David Hansen
Volume: 74, Issue: 1, Pages: 61-66

Abstract:

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.

Title: Pachyonychia Congenita: Clinical Features and Future Treatments
Journal: Keio J Med
Authors: Rebecca McCarthy, Marianne de Brito, Edel O'Toole
Volume: 74, Issue: 1, Pages: 52-60

Abstract:

Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.

Title: The Importance of Shared Patient Voices in Advancing Science for Genodermatoses on a Global Scale
Journal: J Invest Dermatol
Authors: Fauve CAP van Veen, Eli Sprecher, Janice Schwartz, Tom Baker, Edel A O'Toole, Karin Veldman, Mandy Aldwin-Easton, Antoine Gliksohn, Ncoza Dlova, Fernando Larcher, Nuria Tarrats, Neil Rajan, Antoni H Gostynski
Volume: 25, Pages: 00553-6

Abstract:

The European Society for Dermatological Research (ESDR) hosted an inaugural patient symposium to amplify the patient voice in shaping skin research at its 53rd annual meeting in Lisbon, Portugal on September 4, 2024. The new initiative led by Prof. Eli Sprecher and Prof. Neil Rajan on behalf of the ESDR executive and cochaired with Dr. Antoni Gostynski aimed to create a shared stage of patient and scientist to highlight existing partnerships and opportunities for learning from each other. The conversation focused on the presence and importance of patient participation in scientific research agenda setting as well as strategies to improve partnerships. PALMOPLANTAR EPIDERMAL DIFFERENTIATION DISORDERS (pEDDs)- PACHYONYCHIA CONGENITA The symposium opened with a presentation by David Schwartz, who described the establishment of the International Pachyonychia Congenita Consortium (IPCC) and its exemplar role in promoting collaboration between patients, researchers, clinicians, and the pharmaceutical industry (Coulombe et al, 2025). The International Pachyonychia Congenita Research Registry is a patient-driven initiative that captures clinical and genetic data of epidermal differentiation disorder - pachyonychia congenita (pEDD-PC) (Sprecher et al, 2025) and other rare skin conditions with painful palmoplantar keratoderma. It demonstrates how merging patient cohorts through registry development could drive scientific advancement and clinical trials. Tom and Tim Baker, father and son, both having pEDD-PC, shared their personal experiences, notably the significant pain experienced in the soles of their feet. They discussed their daily challenges, such as walking distances at work or school. Prof. Edel A. O’Toole talked about research projects in collaboration with the IPCC and the importance of sharing knowledge internationally. These projects aim to discover targetable pathways in pachyonychia congenita and develop effective therapies. Among the approaches explored, nucleic acid therapy has emerged as a promising avenue for further investigation.

Title: Pachyonychia Congenita: Clinical Features and Future Treatments
Journal: Keio J Med
Authors: McCarthy RL, De Brito M, O'Toole E

Abstract:

Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.

Title: Genotype‒Structurotype‒Phenotype Correlations in Patients with Pachyonychia Congenita
Journal: J Invest Dermatol
Authors: Wu TT, Eldirany SA, Bunick CG, Teng JMC
Volume: 141, Issue: 12, Pages: 2876-2884

Abstract:

Pachyonychia congenita (PC) is a genetic disorder of keratin that presents with nail dystrophy, painful palmoplantar keratoderma, and other clinical manifestations. We investigated the genotype‒structurotype‒phenotype correlations seen with mutations in keratin genes (keratin [K]6A, K6B, K6C, K16, K17) and utilized protein structure modeling of high-frequency mutations to examine the functional importance of keratin structural domains in PC pathogenesis. Participants of the International PC Research Registry underwent genetic testing and completed a standardized survey on their symptoms. Our results support previous reports associating oral leukokeratosis with K6A mutations and cutaneous cysts, follicular hyperkeratosis, and natal teeth with K17 mutations. Painful keratoderma was prominent with K6A and K16 mutations. Nail involvement was most common in patients with K6A mutation and least common in those with K6C mutation. Across keratin subtypes, patients with coil 2B mutations had the greatest impairment in ambulation, and patients with coil 1A mutations reported more emotional issues. Molecular modeling demonstrated that hotspot missense mutations in PC largely disrupted hydrophobic interactions or surface charge. The former may destabilize keratin dimers/tetramers, whereas the latter likely interferes with higher-order keratin filament formation. Understanding the pathologic alterations in keratin structure improves our knowledge of how PC genotype correlates with clinical phenotype, advancing insight into disease pathogenesis and therapeutic development.

Title: Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches
Journal: Journal of Investigative Dermatology
Authors: O'Toole EA, Kelsell DP, Caterina MJ, de Brito M, Hansen D, Hickerson RP, Hovnanian A, Kaspar R, Lane EB, Paller AS, Schwartz J, Shroot B, Teng J. Titeux M, Coulombe PA, Sprecher E.

Abstract:

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.

Title: Patient Perspectives Column: The Pachyonychia Congenita Project
Journal: Journal of the Dermatology Nurses’ Association
Authors: Schwartz, Janice; Brickley, Sylvana
Volume: 15, Issue: 5, Pages: 242-246

Abstract:

In this edition of the Patient Perspectives column, Janice Schwartz, who serves as the executive director for the Pachyonychia Congenita (PC) Project and is also a patient with PC, writes about her experience with PC and provides pearls to dermatology nurses on PC treatment. PC Project has many resources available to patients, including the opportunity for free diagnostic genetic testing for patients with clinical signs of PC. Nurses can join the International Pachyonychia Congenita Consortium (IPCC), which collaborates with PC Project, to stay updated on PC.

Title: A systematic review of reported cases of pachyonychia congenita tarda
Journal: Clinical and Experimental Dermatology
Authors: Tatiane A, Slape D, Lawless R, Frew JW
Volume: 44, Pages: 606-612

Abstract:

Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenita tarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.

Title: Coexistence of Hidradenitis Suppurativa and Steatocystoma Multiplex: Is It a New Variant of Hidradenitis Suppurativa?
Journal: Journal of Cutaneous Medicine and Surgery
Authors: Fletcher J, Los Rios CP, Jambrosic J, Alavi A
Volume: 25, Issue: 6, Pages: 586-590

Abstract:

Hidradenitis suppurativa and steatocystoma multiplex may coexist in the same patient. The overlap of these 2 conditions could be suggestive of an unrecognized defect in follicular proliferation mutual in the pathogenesis of both conditions. Here we present 5 patients with both hidradenitis suppurativa and steatocystoma multiplex. Recognizing the overlap between these 2 conditions is important for accurate diagnosis, management, and identification of potential surgical candidates, as well as future basic science research.

Title: Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases
Journal: Pharmaceutics
Authors: Sogaard P, Lind M, Christiansen CR, Petersson K, Clauss A, Caffarel-Salvador E
Volume: 13,

Abstract:

Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.

Title: Highly branched poly(B-amino ester)s for gene delivery in hereditary skin diseases
Journal: Advanced Drug Delivery Reviews
Authors: Zeng M, Xu Q, Zhou D, Sigen A, Alshehri F, Lara-Saez I, Zheng Y, Li M, Wang W
Volume: 176,

Abstract:

Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease – recessive dystrophic epidermolysis bullosa (RDEB) – based on highly branched poly(b-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.

Title: Painful thickened skin on the soles of the feet
Journal: JAAD Case Reports
Authors: Nicholson LT, Topham C, Curtis J, Madigan L

Title: Ocular manifestations of skin diseases with pathological keratinization abnormalities
Journal: Adv Dermatol Allergol
Authors: Zdebik A, Zdebik N, Fischer M
Volume: XXXVIII, Issue: 1, Pages: 14-20

Abstract:

Keratinization means cytodifferentiation of keratinocytes turning into corneocytes in the stratum corneum. Disorders of keratinization (hyperkeratosis, parakeratosis and dyskeratosis) are causing many dermatological diseases, including various types of ichthyoses, pachyonychia congenita, pityriasis rubra pilaris, all subtypes of psoriasis, pityriasis lichenoides, dyskeratosis congenita, leukoplakia and keratosis follicularis, which apart from skin lesions may affect the eye’s adnexae causing ectropion, entropion, blepharitis, madarosis, and trichiasis, the ocular surface causing keratitis, conjunctivitis, corneal ulceration and episcleritis, which in turn cause uveitis and various fundoscopic changes (proliferative retinopathy, retinal vasculopathy, macular oedema and birdshot chorioretinopathy). Knowledge of ocular symtoms associated with pathological keratinization is crucial, preventing sight-threatening complications such as corneal perforation, lagophthalmus, phthisis bulbi, retinal neovascularization, retinal vasculopathy and optic nerve atrophy. This review encourages dermatologists to monitor patients for ocular symptoms and encourage ophthalmologists to monitor patients for dermatological symptoms.

Title: A KRT6A and a Novel KRT16 Gene Mutations in Chinese Patients with Pachyonychia Congenita
Journal: International Journal of General Medicine
Authors: Gong L, Guo S, Wang D, Wang T, Ren X, Yuan Y, Cui H
Volume: 14, Pages: 903-907

Abstract:

Background: Pachyonychia congenita (PC) is a rare, autosomal dominant genodermatosis characterized by palmoplantar keratoderma, nail dystrophy, cystic lesions, follicular hyperkeratosis, mucosal leukokeratoses, hyperhidrosis, hoarseness, and, rarely, natal teeth. Five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 and KRT17, have been found to be associated with PC. Methods: Using polymerase chain reaction and Sanger sequencing techniques, the purpose of the present study was to investigate the clinical features associated with PC and discover disease-associated variants. The KRT6A, KRT16, KRT17, and KRT6B exonic and flanking region sequences were amplified and directly sequenced to detect mutations. Results: Across two independent instances of PC, we identified a previously reported c.1393T>C (p.Tyr465His) mutation in exon 7 of KRT6A, and a novel c.1237G>C (p.Glu413Gln) heterozygous missense mutation in exon 6 of the KRT16 gene. Conclusion: Through phenotype-genotype analysis among PC pedigrees, confirmed diagnoses of PC-K6a and PC-K16 were made in the two patients who presented with symptoms of PC. A new pathogenic mutation site in PC-K16 was potentially discovered.

Title: A KRT6A mutation p.Ile462Asn in a Chinese family with pachyonychia congenita, and identification of maternal mosaicism: a case report
Journal: BMC Medical Genomics
Authors: Li Y, Wang Y, Ming Y, Chaolan P, Jia Z, Cheng N, Qiaoyu C, Li M, Tianyi X
Volume: 14,

Abstract:

Background: Pachyonychia congenita (PC, OMIM #167200, #167210, #615726, #615728, and #615735) is a rare autosomal dominant disorder caused by keratin gene mutations in KRT6A,KRT6B,KRT6C, KRT16 or KRT17. It is characterized with nail dystrophy and palmoplantar keratoderma (PPK). The most prominent manifestation is plantar pain. This is a further unusual case of parental mosaicism in PC. Although very rare, germ cell mosaicism should be considered when providing genetic counselling for unaffected parents of a child with PC. Case presentation: We report the case of a 5-year-old boy with thickening nails and oral leukokeratosis at birth. He began to develop palmoplantar keratoderma at 2 years old and his sister has similar clinical manifestation characterized with nail discoloration and thickening. A previously reported heterozygous mutation, p.Ile462Asn, was identified in KRT6A in the proband and his affected sister. SNaPshot sequencing revealed mosaicism at a level of 2.5% and 4.7% in DNA from blood and hair bulbs from the unaffected mother. HiSeq deep sequencing demonstrated low-grade mosaicism in the patient’s younger sister and parents. Conclusion: These findings indicate the ability of WES and SNaP shot sequencing to detect low-frequency mosaic mutations. Although very rare, germinal mosaicism should be considered when genetic counseling is given to families with presumed spontaneous cases of PC.

Title: Distinctions in the Management, Patient Impact, and Clinical Profiles of Pachyonychia Congenita Subtypes
Journal: Skin Appendage Discord
Volume: 7, Pages: 194-202

Abstract:

Introduction: Pachyonychia congenita (PC) is a rare dermatosis that confers lifelong physical and emotional morbidities in affected patients. However, the clinical findings, treatments, and psychosocial impact of this disease have not been adequately described. The International PC Research Registry (IPCRR), a multinational initiative to collect data on PC patients, has allowed an opportunity to distinguish the salient features of this disease. We aimed to characterize the breadth and extent of nail disease, treatments, and quality of life in PC patients, and to describe any significant differences in clinical presentation or treatment of PC subtypes. Methods: The most recent IPCRR patient survey data consisting of an 857-response questionnaire and a 102-response addendum were analyzed in a retrospective analysis. The survey data were collected as part of a multinational, multicenter initiative and comprise the largest representative population of PC to date. Participants (survey respondents) were included in the study based on questionnaire responses and a genetic confirmation of having a PC subtype. Results: A total of 857 survey responses were collected. Genetic variations among PC subtypes influence nail disease onset and severity of symptoms. Nail disease negatively impacts patients’ emotional health, especially during the adolescent and young adult years. Nail treatment tools vary little in terms of effectiveness and acquired infection rates. Conclusion and Discussion: Patients with different PC subtypes have distinct clinical nail presentations and psychosocial impact. Genetic testing should be used to confirm PC diagnoses. Further characterization of PC, especially the rarer subtypes, may allow for more individualized patient education.

Title: EGFR Signaling is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib
Journal: Journal of Investigative Dermatology
Authors: Basset J, Marchal L, Hovnanian A

Abstract:

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is caused by dominant mutations in keratin (K) K6A, K6B, K6C, K16, or K17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive. In this study, we show overexpression of EGFR ligands epiregulin and TGF-a as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. Abnormal late terminal keratinization was associated with elevated TGM1 activity. In addition, the calcium ion permeable channel TRPV3 was significantly increased in PC-lesional skin, suggesting a predominant role of the TRPV3/EGFR signaling complex in PC. We hypothesized that this complex contributes to promoting TGM1 activity and induces the expression and shedding of EGFR ligands. To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL. Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC.

Title: Japanese guidelines for the management of palmoplantar keratoderma
Journal: Japanese Journal of Dermatology
Authors: Yoneda K, Kubo A, Nomura T, Ishida-Yamamoto A, Suga Y, Akiyama M, Kanazawa N, Hashimoto T
Pages: e353-e367

Abstract:

Palmoplantar keratoderma (PPK) is a collective term for keratinizing disorders in which the main clinical symptom is hyperkeratosis on the palms and soles. To establish the first Japanese guidelines approved by the Japanese Dermatological Association for the management of PPKs, the Committee for the Management of PPKs was founded as part of the Study Group for Rare Intractable Diseases. These guidelines aim to provide current information for the management of PPKs in Japan. Based on evidence, they summarize the clinical manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment, and treatment recommendations. Because of the rarity of PPKs, there are only few clinical studies with a high degree of evidence. Therefore, several parts of these guidelines were established based on the opinions of the committee. To further optimize the guidelines, periodic revision in line with new evidence is necessary.

Title: Capitulo 17: Percepcao da dor no paciente de paquioniquia congenita (PC)
Journal: Biomedicina e Farmacia Aproximacoes 3
Authors: Lopes DL, Oliveira Santos LW, Souza Carneiro VM, Matos Silva MVC, Matos Silva CDC
Pages: 170-181

Abstract:

Pachyonychia Congenita (PC) is an atypical genetic disorder of the skin aroused by a mutation in one of the four genes known as responsible for the formation of keratin: K6a, K6b, K16 or K17. These are heterozygous Biomedicina e Farmácia: Aproximações 3 Capítulo 17 171 mutations of the unwise sense of exclusion that hinder the function of cytoskeleton via dominant-negative interference and leads to epithelial fragility cell, thus leaving the callus fragile and sore, increasing the risk of entry of pathogens due to trauma. Aiming to analyze the causes and levels of pain of PC, through a systematic review through the databases PubMed, SciELO, AEP and Brazilian Journal of Science and Health. The data from the 22 articles were reported, with 4 studies presenting as Immunohistochemistry methodology, 1 the routine hematoxylin and eosin staining in epithelial tissue, 3 genomic DNA samples, 1 molecular classification for PC subtypes, 3 Histopathology, 2 biopsy, 1 multidisciplinary physical examination, 1 mechanism of action on the release of acetylcholine, 1 psychophysical method, 3 reviews of scientific articles, 1 study of neurological bases and 1 record of international PC research. The primary indication of PC is onychdystrophy, it relates to fragility and, it is possible that other factors, both genetic and environmental, are involved in the determination of the general clinical phenotype. One obstacle found in this study was to verify the inclusion of the level/cause of pain in patients with PC, while a positive point is to provide sufficient information for this perception of pain. Paquioníquia congênita (PC) é uma atípica desordem genética da pele suscitada por uma mutação em um dos quatro genes conhecidos como responsáveis pela formação da queratina: K6a, K6b, K16 ou K17. São mutações do tipo heterozigotas, de sentido insensato de exclusão que atrapalham a função de citoesqueleto via interferência dominantenegativa e leva a célula fragilidade epitelial, deixando assim os calos frágeis e doloridos, aumentando o risco de entrada de patógenos por trauma. Objetivando analisar as causas e níveis de dor da PC, através de uma revisão sistemática por meio das bases de dados PubMed, SciELO, AEP e Revista Brasileira de Ciência e Saúde. Foram relatados os dados dos 22 artigos, sendo que 4 trabalhos apresentam como metodologia a imunohistoquímica, 1 a coloração de rotina hematoxilina e eosina em tecido epitelial, 3 amostras de DNA genômico, 1 classificação molecular para subtipos de PC, 3 histopatológico, 2 biópsia, 1 exame físico multidisciplinar, 1 mecanismo de ação sobre a liberação da acetilcolina, 1 método psicofísico, 3 revisões de artigos científicos, 1 estudo de bases neurológicas e 1 registro de pesquisa internacional de PC. O indício primordial de PC é o onicodistrofia, ela relaciona-se a fragilidade e, é possível que outros fatores, tanto genéticos como ambientais, estejam envolvidos na determinação do fenótipo clínico geral. Um obstáculo encontrado nesse trabalho foi verificar a inclusão do nível/causa da dor nos pacientes com PC, enquanto, um ponto positivo é proporcionar informações suficientes para tal percepção da dor.

Title: Pachyonychia Congenita Type PC-K6a: The first report in the Vietnamese population
Journal: Biomedical Research and Therapy
Authors: Chu HT, Le DH, Le TV, Nguyen BB, Schwartz J, Quang VV
Volume: 8, Issue: 6, Pages: 4434-4438

Abstract:

Background: Pachyonychia congenita (PC) comprises a group of rare autosomal dominant genetic disorders. It is characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma, follicular keratosis, and oral leukokeratosis. It is associated with mutations in five differentiation specific keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The case is being reported for its rarity. To the best of our knowledge, this is the first report of PC, from Vietnam, confirmed by genetic analysis. Case presentation: A four-year-old Vietnamese girl presented with a thickened nail and oral leukokeratosis soon after birth. She was diagnosed with onychomycosis and chronic oral candidiasis and was treated with systemic anti-fungals in children's hospitals and dermatology departments multiple times; however, no treatments were effective. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), the clinical features were consistent with a diagnosis of PC type PC-K6a. The genetic testing, performed through the IPCRR, shows a K6a N171K mutation. Conclusions: The IPCRR helps screen PC's clinical features and confirm a diagnosis at the molecular level, which is beneficial and crucial for validating the condition's clinical impression.

Title: Management of Plantar Keratoderma: Lessons from Pachyonychia Congenita
Journal: Journal of the American Podiatric Medical Association
Authors: Porter RM, Bravo AA, Smith FJD
Volume: 107, Issue: 5, Pages: 428-429

Abstract:

Plantar keratodermas can arise due to a variety of genetically inherited mutations. The need to distinguish between different plantar keratoderma disorders is becoming increasingly apparent because there is evidence that they do not respond identically to treatment. Diagnosis can be aided by observation of other clinical manifestations, such as palmar keratoderma, more widespread hyperkeratosis of the epidermis, hair and nail dystrophies, or erythroderma. However, there are frequent cases of plantar keratoderma that occur in isolation. This review focuses on the rare autosomal dominant keratin disorder pachyonychia congenita, which presents with particularly painful plantar keratoderma for which there is no specific treatment. Typically, patients regularly trim/pare/file/grind their calluses and file/grind/clip their nails. Topical agents, including keratolytics (eg, salicylic acid, urea) and moisturizers, can provide limited benefit by softening the skin. For some patients, retinoids help to thin calluses but may lead to increased pain. This finding has stimulated a drive for alternative treatment options, from gene therapy to alternative nongenetic methods that focus on novel findings regarding the pathogenesis of pachyonychia congenita and the function of the underlying genes. (J Am Podiatr Med Assoc 107(5): 428-435, 2017)

Title: Treatment of Keratin 16 Palmoplantar Keratoderma With Topical Erlotinib
Journal: JAMA Dermatol
Authors: Lee G, Lowe PM
Volume: 158, Issue: 2, Pages: 216-217

Abstract:

Hereditary palmoplantar keratoderma (PPK) is a rare inherited disorder characterized by marked hyperkeratosis of the palms and soles. Resultant painful fissuring severely limits mobility, and despite substantial advances in determining PPK genetic defects, therapeutic options remain limited. Case reports of patients with Olmsted syndrome (TRPV3 variation) treated with systemic erlotinib, an epidermal growth factor (EGF) receptor inhibitor, demonstrated improvement in their PPK.1,2 Given its adverse effect profile,3 clinicians may be hesitant about administering erlotinib systemically for PPK alone. With knowledge that EGF signaling regulates the expression of keratin 16,4,5 we report our experience of treatment with topical erlotinib for 2 patients (mother and son) with hereditary PPK due to a pathogenic keratin 16 variation (c.379C>T, p.[Arg127Cys]).

Title: Genotype-phenotype correlations of neurovascular structures on the feet in patients with pachyonychia congenita: A cross-sectional study.
Journal: J Am Acad Dermatol
Authors: Tan XL, Thomas BR, Steele L, Schwartz J, Hansen CD, O'Toole EA
Volume: 87, Issue: 5, Pages: 1172-1174

Abstract:

Pachyonychia congenita (PC) is a rare skin disorder caused by an autosomal dominant mutation in 1 of 5 keratin genes. In the diagnostic triad of PC, plantar pain has the most significant impact on the quality of life.1,2 A potential contributor to this pain is the development of putative neurovascular structures (NVSs), previously referred to as ‘‘capillary thromboses,’’ a feature identified through a patient-focused drug development meeting with the Food and Drug Administration.3 NVSs in patients with plantar keratoderma are characterized by 1- 2emm blood-red or dark-red spots, occurring alone or in clusters, with associated extreme pain, suggesting the presence of an adjacent nerve. NVSs may also bleed while paring calluses and can fluctuate in size. NVSs are bigger than the capillary thromboses seen in verrucae and do not have a verrucous surface. Understanding the prevalence of NVSs, their association with PC genotype, and their impact on the quality of life will be important in improving the future management of PC.

Title: Treatment of Painful Palmoplantar Keratoderma Related to Pachyonychia Congenita Using EGFR Inhibitors
Journal: Biomedicines
Authors: Greco C, Ponsen AC, Leclerc-Mercier S, Schlatter J, Cisternino S, Boucheix C, Bodemer C
Volume: 10, Issue: 4, Pages: 841

Abstract:

Pachyonychia congenita (PC) is a genodermatosis associated with severe painful palmoplantar keratoderma (PPK) and thickened dystrophic nails caused by autosomal dominant-negative mutations in five genes encoding keratins 6A-B-C, 16, and 17. The mechanical, surgical, or medical options for painful PC are inefficient. Given ErbB/Her family members’ role in epidermal homeostasis, this study sought to investigate the possibility of treating PC patients with PPK by blocking signaling either with EGFR (Her1) inhibitor erlotinib or lapatinib, a dual EGFR(Her1)/Her2. After 1 month of therapy with oral erlotinib treatment at 75 mg/day, the pain disappeared for patient #1, with partially reduced hyperkeratosis, while increasing the dose to 100 mg/day resulted in painful skin fissures. Therapy replacement with erlotinib cream at 0.2% was inconclusive, and substitution with oral lapatinib at alternating doses of 500 and 750 mg/day achieved a good compromise between pain reduction, symptom improvements, and side effects. Patient #20s treatment with erlotinib cream failed to display significant improvements. Oral erlotinib started at 75 mg/day then reduced to 25 mg/day because of the formation of an acneiform rash. Treatment considerably improved the patient’s condition, with an almost complete disappearance of pain. Oral Her1 or 1/2 inhibitors reduced pain, improved two PC patients’ quality of life, and offered promising therapeutic perspectives.

Title: Therapeutic Use of Botulinum Neurotoxins in Dermatology: Systemic Review
Journal: Toxins
Authors: Martina E, Diotallevi F, Radi G, Campanati A, Offidani A
Volume: 13, Pages: 120

Abstract:

Botulinum toxin is a superfamily of neurotoxins produced by the bacterium Clostridium Botulinum with well-established efficacy and safety profile in focal idiopathic hyperhidrosis. Recently, botulinum toxins have also been used in many other skin diseases, in off label regimen. The objective of this manuscript is to review and analyze the main therapeutic applications of botulinum toxins in skin diseases. A systematic review of the published data was conducted, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Botulinum toxins present several label and off-label indications of interest for dermatologists. The best-reported evidence concerns focal idiopathic hyperhidrosis, Raynaud phenomenon, suppurative hidradenitis, Hailey–Hailey disease, epidermolysis bullosa simplex Weber–Cockayne type, Darier’s disease, pachyonychia congenita, aquagenic keratoderma, alopecia, psoriasis, notalgia paresthetica, facial erythema and flushing, and oily skin. Further clinical trials are still needed to better understand the real efficacy and safety of these applications and to standardize injection and doses protocols for off label applications.

Title: Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence
Journal: Br J Dermatol
Authors: Pavlovsky M, Peled A, Sarig O, Astman N, Malki L, Meijers O, Assaf S, Schwartz J, Malovitski K, Hansen D, Sprecher E, Samuelov L
Volume: 187, Issue: 3, Pages: 392-400

Abstract:

Background The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. Objectives To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. Methods We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. Results Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HS associated clinical features (25
9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). Conclusions The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS.

Title: Pachyonychia Congenita with a Novel Variant in the KRT16 Gene, c.348_379delinsAA
Journal: Ann Dermatol
Authors: Hur K, Ko JM, Mun JH
Volume: 34, Issue: 6, Pages: 490-492

Abstract:

Korean adolescent presented with painful plantar hyperkeratosis and nail changes has novel pachyonychia congenita variant in the KRT16 gene, c.348_379delinsAA

Title: Walking a day in a pachyonychia congenita patient's shoes: Impact on plantar pain and activity levels measured with wristband activity trackers
Journal: Indian J Dermatol Venerol Leprol
Authors: Lipner SR, Falotico JM, Matushanky JT, Evans H, Schwartz J, Hansen CD
Volume: doi:10.25259/IJDVL_939_2022,

Abstract:

Background: Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain reporting in pachyonychia congenita clinical studies, it is difficult to evaluate the efficacy of treatment outcomes for painful plantar keratodermas. Objectives: To objectively analyse associations between plantar pain and activity levels in pachyonychia congenita patients using a wristband tracker. Methods: Pachyonychia congenita patients and matched normal controls wore wristband activity trackers and completed a daily digital survey to record their highest and total pain scores (0–10 scale) each day for 28 consecutive days during four different seasons. Results: Twenty four participants (12 pachyonychia congenita patients and 12 matched normal controls) completed the study. Pachyonychia congenita patients walked 1801.30 fewer steps/day (95% CI, −3666.4, 64.1) than normal controls (P = 0.072) and had greater average total [5.26; SD, 2.10] and highest (6.92; SD, 2.35) daily pain than normal controls [0.11 (SD, 0.47), 0.30 (SD, 0.22), respectively] (P < 0.001, both). On average, for each one unit increase in daily highest pain level, pachyonychia congenita activity decreased 71.54 steps/day (SE, 38.90, P = 0.066). Limitations: The study had a small number of participants, limiting statistical power. Only pachyonychia congenita patients, ages 18 years or older, with keratin 6a, keratin 16, and keratin 17 mutations were included, limiting generalizability. Conclusion: Pachyonychia congenita patients were less active with significantly higher pain than normal controls. There was an inverse correlation between pain and activity. Our findings suggest that wristband tracker technology may be used to evaluate treatment efficacy in future trials on severe plantar pain; therapeutic interventions that decrease plantar pain should correlate with significant increases in activity using wristband trackers.

Title: Prevalence and Characterization of Itch in Pachyonychia Congenita
Journal: JAMA Dermatology
Authors: Steele L, Schwartz J, Hansen CD, O'Toole EA
Volume: 157, Issue: 11, Pages: 1378-1380

Abstract:

This survey study examines the prevalence and characteristics of itch in pachyonychia congenita.

Title: Genotype-phenotype correlations of neurovascular structures on the feet in patients with pachyonychia congenita: A cross-sectional study.
Journal: J Am Acad Dermatol
Authors: Tan XL, Thomas BR, Steele L, Schwartz J, Hansen CD, O'Toole EA
Volume: S0190-9622, Issue: 22, Section: 00364-4,

Abstract:

Genotype-phenotype correlations of neurovascular structures on the feet in patients with pachyonychia congenita: A cross-sectional study.

Title: Prevalence of Diagnosed/Highly Symptomatic Pachyonychia Congenita (PC) Patients Managed Annually by US Dermatologists-National Real World Occurrence (RWO) Physician Study
Journal: J Dermatol Dis
Authors: Jack R Gallagher, David Lapidus, Kaylee Heap, Susan Carroll
Volume: 6, Issue: 1,

Abstract:

Background: Pachyonychia Congenita (PC) is a chronically debilitating and lifelong genetic disease that typically causes constant, disabling pain. PC appears to be rare, but its prevalence is unsubstantiated by large-scale epidemiologic studies. We conducted the first national prevalence study of a cohort of PC patients, those managed annually by US dermatologists. Methods: Potential study participants were randomly selected from a national panel of patient-care dermatologists and invited to participate in a brief study of a patient condition that would be disclosed at the study website. Results: Of the 423 dermatologists contacted, 400 participated, of whom 53% reported managing at least one PC patient during the past 12 months, an annual prevalence of 6.4/10,000 patients (extrapolated to 8,900 to 9,800 nationally), according to the study model. Conclusions: Study findings indicate PC is likely to be far more prevalent than previous estimates in the literature and that the frequency and level of disability caused by pain-related symptoms may be under-recognized by the treating dermatologist. Additional research is needed to determine the extent to which PC diagnosis has been or could be genetically confirmed.

Title: A systematic review of reported cases of pachyonychia congenita tarda
Journal: Clin Exp Dermatol
Authors: Tatiane A, Slape D, Lawless R, Frew JW
Volume: 44, Issue: 6, Pages: 606-612

Abstract:

Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenita tarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.

Title: Genetic and developmental disorders of the oral mucosa: Epidemiology; molecular mechanisms; diagnostic criteria; management
Journal: Periodontal 2000
Authors: Pinna R, Cocco F, Campus G, Conti G, Milia E, Sardella A, Cagetti MG
Volume: 80, Issue: 1, Pages: 12-27

Abstract:

A large number of disorders may affect the oral cavity, including genetic diseases, infections, cancers, blood diseases, skin diseases, endocrine and metabolic disorders, autoimmune and rheumatologic diseases, local lesions, to name a few. Oral mucosa shows a considerable variation in its normal structure and a wide range of conditions may affect it. Such conditions are often harmless or minor and could be primary or secondary to systemic disease. Several of them are quite rare and, hence, the diagnosis is not easy. Clinically, lesions may appear as ulcers, discoloration of the oral mucosa and alterations in size and configuration of oral anatomy. Genetic disorders have specific manifestations and can be caused by a derangement of one or more components of the tissue. Many of them follow the skin or systemic signs of the underlying genetic disease, but in a few cases oral signs could be the first manifestation of the disorder. Among them genodermatoses are prominent. They are inherited disorders characterized by a multisystem involvement. This review describes chondro-ectodermal dysplasia, dyskeratosis congenita, Ehlers-Danlos syndrome, hereditary benign intraepithelial dyskeratosis, keratosis follicularis, lipoid proteinosis, multiple hamartoma syndrome, pachyonychia congenita, Peutz-Jeghers syndrome, tuberous sclerosis and white sponge nevus. Other genetic disorders not included in the genodermatosis group and reported in the present review are: acanthosis nigricans, angio-osteo-hypertrophic syndrome, encephalotrigeminal angiomatosis, familial adenomatous polyposis, focal dermal hypoplasia, focal palmoplantar and oral mucosa hyperkeratosis syndrome, gingival fibromatosis, Maffucci's syndrome, neurofibromatosis (type 1) and oro-facial-digital syndrome (type 1). Disorders during embryonic development might lead to a wide range of abnormalities in the oral cavity; some of them are quite common but of negligible concern, whereas others are rare but serious, affecting not only the oral mucosa, but also other structures of the oral cavity (ie palate, tongue and gingiva). Fordyce's granules, leukoedema, cysts of the oral mucosa in newborns, retrocuspid papilla, geographic tongue, fissured tongue, median rhomboid glossitis, hairy tongue, lingual varices and lingual thyroid nodule are described. This review may help dentists, dental hygienists, but also general internists and pediatricians to diagnose different disorders of the oral mucosa, to understand the pathogenesis and to schedule a treatment plan.

Title: Follicular occlusion tetrad in a male patient with pachyonychia congenita: clinical and genetic analysis
Journal: J Eur Acad Dermatol Venereol
Authors: Musumechi ML, Florentini F, Bianchi L, Cascella R, Giardina E, Caputo V, Micali G
Volume: 33 Suppl 6, Pages: 36-39

Abstract:

The case of a 24-year-old male patient affected by follicular occlusion tetrad (acne conglobata, hidradenitis suppurativa, pilonidal cyst and dissecting cellulitis of the scalp) associated with clinical signs of pachyonychia congenita (PC)-2 (focal palmoplantar keratoderma, plantar pain, onycodystrophy and multiple cysts) is reported. The diagnosis was supported by genetic analysis that showed heterozygous mutation within the exon 1 of KRT17 gene. This case may reflect different expressions of a phenotypic spectrum induced by a common genetic alteration. Received: 7 April 2019; Accepted: 16 July 2019

Title: Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma
Journal: Hum Mol Genet
Authors: Zieman AG, Poll BG, Ma J, Coulombe PA
Volume: 28, Issue: 13, Pages: 2255-2270

Abstract:

The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.

Title: Steatocystoma Multiplex Suppurativa Associated With Hidradenitis Suppurativa Successfully Treated With Adalimumab
Journal: J Eur Acad Dermatol Venereol
Authors: Atori L, Zanniello R, Pilloni L, Rongioletti F
Volume: 33 Suppl 6, Pages: 42-44

Abstract:

Steatocystoma multiplex (SM) is a rare autosomal dominant disease characterized by multiple asymptomatic intradermal true sebaceous cysts of variable size. These lesions may occasionally rupture, become inflamed, painful and heal with scarring [SM suppurativa (SMS)], thus sharing overlapping features with hidradenitis suppurativa (HS). The question of whether SMS simply mimics HS or if the two diseases may be associated remains open. We report three patients (2 M/1 F; age: 47, 27 and 40 years) affected by SMS showing inflammatory lesions on the areas typically affected by HS. Repeated skin biopsy from each patient showed true sebaceous cysts in some specimens and findings compatible with HS, without sebaceous glands evidence in others, supporting coexistence of the two diseases. Adalimumab at the initial dose of 160 mg (day 1), followed by 80 mg (day 15), and maintained at the dose of 40 mg every week from day 29 on, improved both HS and SMS lesions, including also non-inflammatory cystic lesions.

Title: Topical Cholesterol/Lovastatin for the Treatment of Porokeratosis: A Pathogenesis-Directed Therapy
Journal: J Am Acad Dermatol
Authors: Atzmony L, Lim YH, Hamilton C, Leventhal JS, Wagner A, Paller A, Choate K
Volume: 82, Issue: 1, Pages: 123-131

Abstract:

Title: Symptomatic Mucosal Involvement in Pachyonychia Congenita: Challenges in Infants and Young Children
Journal: Br J Dermatol
Authors: Goldberg I, Mashiah J, Kutz A, Derowe A, Warshauer E, Schwartz ME, Smith F, Sprecher E, Hansen CD
Volume: 182, Issue: 3, Pages: 708-713

Abstract:

Background: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. Objectives: To characterize patients with PC with symptomatic mucosal involvement. Methods: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. Conclusions: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

Title: A Treatment Protocol for Botulinum Toxin Injections in the Treatment of Pachyonychia Congenita-Associated Keratoderma
Journal: Br J Dermatol
Authors: Koren A, Sprecher E, Reider E, Artzi O
Volume: 182, Issue: 3, Pages: 671-677

Abstract:

Background: Severely debilitating plantar keratoderma pain is the most distressing clinical feature of pachyonychia congenita (PC). Several earlier publications have reported therapeutic success with plantar injections of botulinum toxin (Btx). Objectives: To describe our 4-year experience during which we administered a total of 30 plantar Btx injections to five patients with PC following an optimized protocol. Methods: Five patients with PC (age 21-54 years) who were treated at our medical centre from April 2015 to June 2018 were included in the study. After an ultrasound-guided nerve block performed by an anaesthesiologist, the patients received plantar intradermal injections of Btx A. To ascertain the effect of the treatment, we used a dedicated quality-of-life questionnaire for patients with PC (PCQoL) and asked the patients to evaluate the intensity of eight parameters pertaining to their symptoms at baseline and before every treatment session. At study closure, patients were asked to evaluate the maximal improvement in the same eight parameters throughout the study period. Results: All patients demonstrated a decrease in PCQoL scores during the follow-up period. All patients showed a significant improvement in PCQoL after the first treatment session and at the last evaluation (P = 0·043). The scores with the best improvement concerned morning feet burning and long-distance walking (> 500 m). The scores were significantly lower if the intervals between Btx injections were <100 days. Conclusions: Btx treatment of PC-associated keratoderma following an optimized protocol leads to a major change in patients' quality of life. What's already known about this topic? Plantar pain is considered by patients to be the most severe and debilitating manifestation of pachyonychia congenita (PC). Over the past few years, a number of reports have shown that plantar injections of botulinum toxin (Btx) reduce or even eliminate pain, blistering and callosities in patients with PC. However, the injection technique, doses of Btx and methods of anaesthesia varied between reports and patients. What does this study add? Here we report our 4-year experience in providing 30 treatments to five patients following an optimized protocol. Btx was found to provide a quantifiable improvement in all patients treated. What is the translational message? Btx treatment of PC-associated keratoderma using a structured approach, which includes the use of a sufficient dose of Btx (200-400 U of onabotulinumtoxinA or 500-1000 U of abobotulinumtoxinA), and regular intervals between treatment sessions (of < 100 days), leads to a major change in patients' quality of life.

Title: The Histopathological Features of the Nail Plate in Pachyonychia Congenita
Journal: J Cutan Pathol
Authors: Stewart CL, Takeshita J, Hansen CD, Rubin AI
Volume: 47, Issue: 4, Pages: 357-362

Title: Management of Symptomatic Mucosal Involvement in Paediatric Pachyonychia Congenita
Journal: Br J Dermatol
Authors: Youssefian L, Vahidnezhad H
Volume: 182, Issue: 3, Pages: 536-537

Title: Sharing (Data) Is Caring for Patients With Pachyonychia Congenita
Journal: Br J Dermatol
Authors: Mordaunt DA
Volume: 182, Issue: 3, Pages: 537

Title: Old Mitochondria Accumulate in Pachyonychia Congenita
Journal: Br J Dermatol
Authors: Vetter A, Magin TM
Volume: 182, Issue: 3, Pages: 529-530

Title: Pachyonychia Congenita: A Case Report of a Successful Treatment With Rosuvastatin in a Patient With a KRT6A Mutation
Journal: Br J Dermatol
Authors: Abdollahimaid F, Rajabi F, Shahidi-Dadras M, Saket S, Youssefian L, Vahidnezhad H, Uitto J
Volume: 181, Issue: 3, Pages: 584-586

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by nail dystrophy and palmoplantar keratoderma with severe plantar pain affecting quality of life. There is no effective treatment. Heterozygous mutations in the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17 have been reported as a cause of PC. Herein we present a female patient with an amino acid substitution mutation in KRT6A (c.1381G>A, p.Glu461Lys in exon 7) and classic features of PC associated with oral leucokeratosis and follicular hyperkeratosis. We also demonstrate successful treatment of the patient with rosuvastatin. A 3.6-mm reduction in plantar callosity thickness was demonstrated by sonography. Our patient also experienced significant pain relief that allowed her to increase physical activity (Children's Dermatology Life Quality Index score dropped nine points following treatment). Collectively, these improvements suggest that rosuvastatin may offer a promising treatment for PC. What's already known about this topic? Pachyonychia congenita (PC) is an autosomal dominant disease characterized by nail dystrophy and painful plantar keratoderma. Keratolytics, emollients, retinoids and steroids have been used for treatment but with limited benefits. What does this study add? A patient with PC who had a KRT6A mutation was treated with rosuvastatin with significant improvement in plantar hyperkeratosis and pain. Statins could be a promising treatment for PC with long-term safety, but further studies are needed.

Title: Current Mysteries of Pachyonychia Congenita
Journal: Br J Dermatol
Authors: Leube RE, Schwartz N
Volume: 182, Issue: 3, Pages: 525-526

Title: Revisiting Pachyonychia Congenita: A Case-Cohort Study of 815 Patients
Journal: Br J Dermatol
Authors: Samuelov L, Smith FJD, Hansen CD, Sprecher E
Volume: 182, Issue: 3, Pages: 738-746

Abstract:

Background: Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. Objectives: To harness the same resource to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. Methods: In total, 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry were surveyed for clinical findings associated with PC. Data were analysed using various statistical methods, including the Student's t-test, χ² -test and anova tests for differences in means/proportions. Spearman correlation and logistic regression were used for phenotype-genotype correlations. Results: KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids. KRT17 mutations were most commonly associated with cysts and natal teeth. Using logistic regression, we found that oral leucokeratosis was correlated with earlier toenail involvement, walking aids, nursing difficulties and hoarseness. Cysts were correlated with oral leucokeratosis, natal teeth and ear wax. Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation. Hoarseness was correlated with an increased number of involved fingernails. Conclusions: Here, we establish phenotype-genotype correlations in the largest cohort of patients with PC described to date and reveal novel and clinically useful predictors of disease course and manifestations. What's already known about this topic? Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. The establishment of an international registry containing the clinical and molecular data of patients with PC led to the development of a disease classification based on the mutant gene and associated features. What does this study add? Data were collected via an international registry to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. This is the largest cohort of patients with PC described to date. The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years. Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function. Linked Editorial: Steele and O'Toole. Br J Dermatol 2020; 182:521-522. Linked Comment: Mordaunt. Br J Dermatol 2020; 182:537.

Title: Update on Pachyonychia Congenita Research
Journal: Br J Dermatol
Authors: Funk T, Hansen CD, Paller A, O'Toole EA
Volume: 182, Issue: 3, Pages: 788-789

Title: Pathophysiology of Pachyonychia Congenita-Associated Palmoplantar Keratoderma: New Insights Into Skin Epithelial Homeostasis and Avenues for Treatment
Journal: Br J Dermatol
Authors: Zieman AG, Coulombe PA
Volume: 182, Issue: 3, Pages: 564-573

Abstract:

Background: Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy and very painful palmoplantar keratoderma (PPK). PC dramatically impacts quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound-repair-associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature. Objectives: This review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms. Methods: We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK. Results: There are three main stages of progression of PPK-like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1-Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis. Conclusions: The progress made suggests new avenues to explore for the treatment of PC-based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16 and KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.

Title: Pachyonychia Congenita, a Paradigm for Rare Skin Disorders
Journal: Br J Dermatol
Authors: Steele L, O'Toole EA
Volume: 182, Issue: 3, Pages: 521-522

Title: Pachyonychia Congenita Responding Favorably to a Combination of Surgical and Medical Therapies
Journal: Dermatol Ther
Authors: Daroach M, Dogra S, Bhattacharjee R, Tp A, Smith F, Mahajan R
Volume: 32, Issue: 5, Pages: e13045

Abstract:

Pachyonychia congenital (PC) is a rare genetic disorder of cornification and is classified into five types on the basis of keratin gene involved. There are no established treatment options available for PC. Sirolimus in both topical and oral form has been studied in management of PC. We report a young female with a novel genetic mutation in KRT6A gene who presented with painful palmoplantar hyperkeratosis and onychogryphosis, which was cosmetically disfiguring. She was prescribed oral sirolimus after all investigations. There was significant improvement in pain within a week. Pain relief was sustained at 1 year follow-up with topical treatment only. Serial nail avulsion surgeries were also done with showed significant cosmetic improvement in the nails. Medical therapies can be combined with surgery for a better cosmetic outcome and improvement in patient quality of life.

Title: Pachyonychia Congenita and Botulinum Toxin
Journal: Br J Dermatol
Authors: Thomas BR, Sahota A
Volume: 182, Issue: 3, Pages: 531-532

Title: Stopping Pachyonychia Congenita Plantar Pain With a Statin?
Journal: Br J Dermatol
Authors: Theocharopoulos I, O'Toole E.A.
Volume: 181, Issue: 3, Pages: 446-447

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant disorder classified into five subtypes based on mutations in keratin genes (KRT6A, KRT6B, KRT6C, KRT16 and KRT17).1 The main clinical features include the triad of severe debilitating plantar pain, plantar keratoderma and hypertrophic nail dystrophy usually apparent by the age of 10. At present, there are limited treatment options for PC and the majority of patients perform mechanical debridement of calluses to manage their disease. As there is no cure for PC, novel treatment strategies are necessary to relieve pain and improve patient’s quality of life. Current treatment options under investigation include topical sirolimus, botulinum toxin injections, small

Title: Report of the 16th Annual International Pachyonychia Congenita Consortium (IPCC) Symposium
Journal: IPCC Newsletter
Authors: Funk T; Hansen C.D; Paller AS; O'Toole EA
Volume: 16, Issue: 3, Pages: 5-8

Abstract:

Summary The International Pachyonychia Congenita Consortium (IPCC) is a global group of scientists and physicians working to develop therapies for pachyonychia congenita, a rare genetic skin disorder. The research reported at the 16th Annual Re-search Symposium of the IPCC, held on 7-8 May 2019 in Chicago, IL, U.S.A is summarised here. What’s already known about this topic?

• Pachyonychia congenita (PC) is a rare genetic skin condition caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17).
• PC is characterized clinically by the triad of plantar keratoderma, plantar pain and variable nail dystrophy. Patients may also have other findings such as oral leukokeratosis, follicular hyperkeratosis and/or cutaneous cysts.
• Plantar pain is severe and is out of proportion to that of non-syndromic callus formation, and it is the major symp-tom of concern for PC patients.

• We report on progress by scientists and clinicians from around the world who are working to understand the patho-physiology of PC and other keratinopathies.
• We discuss ongoing scientific efforts to understand the role of inflammation in PC and work to translate that infor-mation into therapeutic treatments for PC.
• We provide an update on the most recent advances in gene suppression or the modification of genetic expression as a treatment approach in PC.
• We discuss the status of current therapeutic trials in PC as well as the need for collaboration between scientists, clini-cians, patients, and industry to further advance PC treatment.

Title: Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.
Journal: Br J Dermatol
Authors: Zieman AG, Coulombe PA

Abstract:

BACKGROUND:

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSIONS:

Title: Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma.
Journal: Hum Mol Genet
Authors: Zieman AG, Poll BG, Ma J, Coulombe PA
Volume: 28, Issue: 13, Pages: 2255-2270

Abstract:

The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.

Title: Painful Callosities in a young boy
Journal: Pediatr Dermatol
Authors: Arake Zanatta D, Taniguchi Abagge K, Franca Souza Gomes Vial I
Volume: 35, Issue: 4, Pages: 509-510

Title: Novel mutations in desmoglein 1: focal palmoplantar keratoderma in milder phenotypes
Journal: Br J Dermatol
Authors: Zamiri M, Wilson NJ, O'Toole EA, Smith FJD

Title: Keratin 17 in disease pathogenesis: from cancer to dermatoses
Journal: J Pathol
Authors: Yang L, Zhang S, Wang G
Volume: 247, Issue: 2, Pages: 158-165

Abstract:

Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of biological processes, including cell proliferation and growth, skin inflammation and hair follicle cycling. Aberrant overexpression of K17 is found in various diseases ranging from psoriasis to malignancies such as breast, cervical, oral squamous and gastric carcinomas. Moreover, genetic mutation in KRT17 is related to tissue-specific diseases, represented by steatocystoma multiplex and pachyonychia congenita. In this review, we summarize our findings concerning the regulatory mechanisms of K17 overexpression in psoriasis and compare them to the literature relating to other diseases. We discuss data that proinflammatory cytokines, including interleukin-17 (IL-17), IL-22, interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-β) and transcription factors glioma-associated oncogene homolog 1/2 (Gli1/2), Nrf2 and p53 can regulate K17 by transcriptional and translational control. Moreover, post-translational modification, including phosphorylation and ubiquitination, is involved in the regulation of K17 stability and biological functions. We therefore review the current understanding of the K17 regulatory mechanism and its pathogenic role in diseases from dermatoses to cancer. Prospects for anti-K17 therapy in diagnosis, prognosis and disease treatment are also discussed.

Title: A KRT16 mutation in the first Chinese pedigree with Pachyonychia congenita and review of the literatures
Journal: J Cosmet Dermatol
Authors: Xu Q, Zhang Q, Tang L, Jin L, Wang X, Kan L, Zheng X, Yang S

Abstract:

BACKGROUND:

AIMS:

PATIENTS/METHODS:

RESULTS:

CONCLUSIONS:

Title: A recurrent mutation in the KRT17 gene responsible for severe steatocystoma multiplex in a large Chinese family.
Journal: Clin Exp Dermatol
Authors: Wang J, Li J, Li X, Lei D, Xiao W, Li Z, Zhang S, Li M
Volume: 43, Issue: 2, Pages: 205-208

Title: Striate palmoplantar keratoderma resulting from a missense mutation in DSG1
Journal: Br J Dermatol
Authors: Vodo D, O'Toole EA, Malchin N, Lahav A, Adir N, Sarig O, Green KJ, Smith FJD, Sprecher E
Volume: 179, Issue: 3, Pages: 755-757

Title: Novel treatment of painful plantar keratoderma in pachyonychia congenita using topical sirolimus.
Journal: Clin Exp Dermatol
Authors: Teng JMC, Bartholomew FB, Patel V, Sun G
Volume: 43, Issue: 8, Pages: 968-971

Title: A systematic review of reported cases of pachyonychia congenita tarda.
Journal: Clin Exp Dermatol
Authors: Tatiane A, Slape D, Lawless R, Frew JW
Volume: 44, Issue: 6, Pages: 606-612

Abstract:

Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenitatarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.

Title: Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma.
Journal: Clin Exp Dermatol
Authors: Smith FJD, Kreuser-Genis IM, Jury CS, Wilson NJ, Terron-Kwiatowski A, Zamiri M
Volume: 44, Issue: 5, Pages: 528-534

Abstract:

Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell-fragility disorders, and are the genetic basis of many inherited palmoplantar keratodermas (PPKs). Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1. Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. We report four unrelated cases (one with sporadic EI and three with autosomal dominant PPK), due to two novel and two recurrent KRT1 mutations. Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern.

Title: Keratin 6b variant p.Gly499Ser reported in delayed-onset pachyonychia congenita is a non-pathogenic polymorphism.
Journal: J Dermatol
Authors: Smith FJD, McLean WHI
Volume: 44, Issue: 12, Pages: e312

Title: Genetic and developmental disorders of the oral mucosa: Epidemiology; molecular mechanisms; diagnostic criteria; management.
Journal: Periodontol 2000
Authors: Pinna R, Cocco F, Campus G, Conti G, Milia E, Sardella A, Cagetti MG
Volume: 80, Issue: 1, Pages: 12-27

Abstract:

A large number of disorders may affect the oral cavity, including genetic diseases, infections, cancers, blood diseases, skin diseases, endocrine and metabolic disorders, autoimmune and rheumatologic diseases, local lesions, to name a few. Oral mucosa shows a considerable variation in its normal structure and a wide range of conditions may affect it. Such conditions are often harmless or minor and could be primary or secondary to systemic disease. Several of them are quite rare and, hence, the diagnosis is not easy. Clinically, lesions may appear as ulcers, discoloration of the oral mucosaand alterations in size and configuration of oral anatomy. Genetic disorders have specific manifestations and can be caused by a derangement of one or more components of the tissue. Many of them follow the skin or systemic signs of the underlying genetic disease, but in a few cases oralsigns could be the first manifestation of the disorder. Among them genodermatoses are prominent. They are inherited disorders characterized by a multisystem involvement. This review describes chondro-ectodermal dysplasia, dyskeratosis congenita, Ehlers-Danlos syndrome, hereditary benign intraepithelial dyskeratosis, keratosis follicularis, lipoid proteinosis, multiple hamartoma syndrome, pachyonychia congenita, Peutz-Jeghers syndrome, tuberous sclerosis and white sponge nevus. Other genetic disorders not included in the genodermatosis group and reported in the present review are: acanthosis nigricans, angio-osteo-hypertrophic syndrome, encephalotrigeminal angiomatosis, familial adenomatous polyposis, focal dermal hypoplasia, focal palmoplantar and oral mucosa hyperkeratosis syndrome, gingival fibromatosis, Maffucci's syndrome, neurofibromatosis (type 1) and oro-facial-digital syndrome (type 1). Disorders during embryonic development might lead to a wide range of abnormalities in the oral cavity; some of them are quite common but of negligible concern, whereas others are rare but serious, affecting not only the oral mucosa, but also other structures of the oralcavity (ie palate, tongue and gingiva). Fordyce's granules, leukoedema, cysts of the oral mucosa in newborns, retrocuspid papilla, geographic tongue, fissured tongue, median rhomboid glossitis, hairy tongue, lingual varices and lingual thyroid nodule are described. This review may help dentists, dental hygienists, but also general internists and pediatricians to diagnose different disorders of the oral mucosa, to understand the pathogenesis and to schedule a treatment plan.

Title: Skin fragility, woolly hair syndrome with a desmoplakin mutation - a case from India.
Journal: Int J Dermatol
Authors: Peter DCV, Thomas M, Wilson NJ, Smith FJD
Volume: 57, Issue: 9, Pages: e73-e75

Title: Nociceptin/orphanin FQ opioid peptide-receptor expression in pachyonychia congenita.
Journal: J Peripher Nerv Syst
Authors: Pan B, Schroder W, Jostock R, Schwartz M, Rosson G, Polydefkis M
Volume: 23, Issue: 4, Pages: 241-248

Abstract:

Nociceptin/orphanin FQ opioid peptide (NOP)-receptor (NOP-R) is a member of the opioid receptor family. NOP-R activation has demonstrated analgesic effects in preclinical pain models without the addiction risks associated with other opiate targets. Pachyonychia congenita (PC) is a palmoplantar keratoderma characterized by neuropathic pain in affected skin. A cohort of KRT6A gene mutation PC patients with no other explanation for their neuropathic pain offered a unique opportunity to assess potential of NOP-R as a therapeutic target. Plantar biopsies from 10 PC patients and 10 age/gender matched controls were performed at the ball (PC-affected) and the arch (PC-unaffected) of the foot. NOP-R expression was assessed by immunohistochemistry. Localization of NOP-R in subsets of epidermal nerve fibers was investigated using the pan-neuronal marker PGP9.5, markers for unmyelinated peptidergic fibers (calcitonin gene-related peptide [CGRP] and substance P [SP]), as well as for myelinated Aδ and Aβ fibers (neurofilament H [NFH]). Robust NOP-R expression was detected in epidermal keratinocytes and in a subset of PGP9.5+ fibers in both epidermis and dermis, confirmed by western blot and absorption experiments with NOP-R peptide. NOP-R expression in keratinocytes was significantly reduced in PC-affected plantar skin compared with PC-unaffected skin. In addition, NOP-R expression occurred in dermal NFH+ myelinated fibers in all groups, although few CGRP+ fibers co-expressed NOP-R. Furthermore, most SP+ fibers also co-expressed NOP-R. These findings indicate that NOP-R is expressed on epidermal keratinocytes, as well as on epidermal and dermal nerve fibers and has potential as a promising target to treat neuropathic pain in PC.

Title: A novel APC mutation identified in a large Chinese family with familial adenomatous polyposis and a brief literature review
Journal: Mol Med Rep
Authors: Pang M, Liu Y, Hou X, Yang J, He X, Hou N, Liu P, Liang L, Fu J, Wang K, Ye Z, Gong B
Volume: 18, Issue: 2, Pages: 1423-1432

Abstract:

Familial adenomatous polyposis (FAP), an autosomal dominant disease, is a colon cancer predisposition syndrome that manifests as a large number of adenomatous polyps. Mutations in the Adenomatous polyposis coli (APC) gene are responsible for the majority of cases of FAP. The purpose of the present study was to report the clinical features of a Chinese family with FAP and screen for novel mutations using the targeted next‑generation sequencing technology. Among the 29 familymembers, 12 were diagnosed of FAP. Based on an established filtering strategy and data analyses, along with confirmation by Sanger sequencing and co‑segregation, a novel frameshift mutationc.1317delA (p.Ala440LeufsTer14) in exon 10 of the APC gene was identified. To the best of our knowledge, this mutation has not been reported prior to the present study. In addition, it was correlated with extra‑colonic phenotypes featuring duodenal polyposis and sebaceous cysts in this family. This novel frameshift mutation causing FAP not only expands the germline mutation spectrum of the APCgene in the Chinese population, but it also increases the understanding of the phenotypic and genotypic correlations of FAP, and may potentially lead to improved genetic counseling and specific treatment for families with FAP in the future.

Title: Keratin 6a mutations lead to impaired mitochondrial quality control.
Journal: Br J Dermatol
Authors: Lehmann SM, Leube RE, Schwarz N

Abstract:

BACKGROUND:

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSIONS:

Title: Laryngeal manifestations of pachyonychia congenita: a clinical case and discussion on management for the otolaryngologist.
Journal: J Laryngol Otol
Authors: O'Kane AM, Jackson CP, Mahadevan M, Barber C
Volume: 131, Issue: 52, Pages: S53-S56

Abstract:

BACKGROUND:

METHODS:

RESULTS:

CONCLUSION:

Title: Plantar pain in pachyonychia congenita
Journal: Br J Dermatol
Authors: Krupiczojc MA, O'Toole EA
Volume: 179, Issue: 1, Pages: 11-12

Abstract:

Comment on

• Chronic pain in pachyonychia congenita: evidence for neuropathic origin.

Title: The non-neuronal and nonmuscular effects of botulinum toxin: an opportunity for a deadly molecule to treat disease in the skin and beyond.
Journal: Br J Dermatol
Authors: Grando SA, Zachary CB.
Volume: 178, Issue: 5, Pages: 1011-1019

Abstract:

There is growing evidence that botulinum neurotoxins (BoNTs) exhibit biological effects on various human cell types with a host of associated clinical implications. This review aims to provide an update on the non-neuronal and nonmuscular effects of botulinum toxin. We critically analysed recent reports on the structure and function of cellular signalling systems subserving biological effects of BoNTs. The BoNT receptors and intracellular targets are not unique for neurotransmission. They have been found in both neuronal and non-neuronal cells, but there are differences in how BoNT binds to, and acts on, neuronal vs. non-neuronal cells. The non-neuronal cells that express one or more BoNT/A-binding proteins, and/or cleavage target synaptosomal-associated protein 25, include: epidermal keratinocytes; mesenchymal stem cells from subcutaneous adipose; nasal mucosal cells; urothelial cells; intestinal, prostate and alveolar epithelial cells; breast cell lines; neutrophils; and macrophages. Serotype BoNT/A can also elicit specific biological effects in dermal fibroblasts, sebocytes and vascular endothelial cells. Nontraditional applications of BoNT have been reported for the treatment of the following dermatological conditions: hyperhidrosis, Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita, multiple eccrine hydrocystomas, eccrine angiomatous hamartoma, eccrine sweat gland naevi, congenital eccrine naevus, Raynaud phenomenon and cutaneous leiomyomas. Experimental studies have demonstrated the ability of BoNT/A to protect skin flaps, facilitate wound healing, decrease thickness of hypertrophic scars, produce an anti-ageing effect, improve a mouse model of psoriasiform dermatitis, and have also revealed extracutaneous effects of BoNT arising from its anti-inflammatory and anticancer properties. BoNTs have a much wider range of applications than originally understood, and the individual cellular responses to the cholinergic impacts of BoNTs could provide fertile ground for future studies.

Title: Facial cystic lesions and onychodystrophy
Journal: Pediatr Dermatol
Authors: Sabogal Gomez MV, Gozalez V, Martin JM
Volume: 35, Issue: 4, Pages: 517-518

Title: Identification of a novel substitution mutation (R103C) in the rod domain of the keratin 17 gene associated with pachyonychia congenita type 2.
Journal: Int J Dermatol
Authors: Ghazawi FM, Hassani-Ardakani K, Henriques L, Jafarian F.
Volume: 58, Issue: 2, Pages: 233-236

Title: Enamel Anomalies in a Pachyonychia Congenita Patient with a Mutation in KRT16
Journal: J Invest Dermatol
Authors: Duverger O, Cross MA, Smith FJD, Morasso MI.
Volume: 139, Issue: 1, Pages: 238-241

Title: First Report of Pachyonychia Congenita Type PC-K6a in the Romanian Population
Journal: Maedica (Buchar)
Authors: Chiriac A, Rusu C, Murgu A, Chiriac AE, Wilson NJ, Smith FJD.
Volume: 12, Issue: 2, Pages: 123-126

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder, with unknown prevalence, although it is estimated there are between 2,000 and 10,000 cases of PC worldwide. The International PC Research Registry (IPCRR) has currently identified (as of November 2016) 746 individuals (in 403 families) with genetically confirmed PC. Heterozygous mutations, predominantly missense mutations, in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17 cause PC. The predominant clinical findings include plantar keratoderma, plantar pain and variable dystrophy of some or all toenails and/ or fingernails. Oral leukokeratosis, follicular hyperkeratosis, cysts of various types and natal teeth may also be present. We report the first case of genetically confirmed PC from Romania due to a mutation in KRT6A, p.Arg466Pro.

Title: Pachyonychia congenita: a case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation
Journal: British Journal of Dermatology
Authors: Abdollahimajd F, Rajabi F, Shahidi-Dadras M, Saket S, Youssefian L, Vahidnezhad H, Uitto J.

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by nail dystrophy and palmoplantar keratoderma with severe plantar pain affecting quality of life. There is no effective treatment. Heterozygous mutations in the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17 have been reported as a cause of PC. Herein we present a female patient with an amino acid substitution mutation in KRT6A (c.1381G>A, p.Glu461Lys in exon 7) and classic features of PC associated with oral leucokeratosis and follicular hyperkeratosis. We also demonstrate successful treatment of the patient with rosuvastatin. A 3.6-mm reduction in plantar callosity thickness was demonstrated by sonography. Our patient also experienced significant pain relief that allowed her to increase physical activity (Children's Dermatology Life Quality Index score dropped nine points following treatment). Collectively, these improvements suggest that rosuvastatin may offer a promising treatment for PC.

Title: Pachyonychia Congenita (updated 2018)
Journal: Gene Reviews
Authors: FJD Smith, CD Hansen, PR Hull, RL Kaspar, WHI McLean, E O'Toole, E Sprecher

Abstract:

CLINICAL CHARACTERISTICS:

DIAGNOSIS/TESTING:

MANAGEMENT:

GENETIC COUNSELING:

Title: The keratin 16 null phenotype is modestly impacted by genetic strain background in mice.
Journal: Exp Dermatol.
Authors: Abagail Zieman and Pierre A. Coulombe

Abstract:

The type I intermediate filament keratin 16 (K16) is constitutively expressed in ectoderm-derived appendages and is inducibly expressed in the epidermis upon barrier-compromising challenges. Dominantly acting missense alleles in KRT16 are causative for pachyonychia congenita (PC), a genodermatosis involving debilitating palmoplantar keratoderma (PPK), nail dystrophy, oral lesions and, frequently, alterations in glands and hair. C57Bl/6;Krt16^-/- micedevelop oral lesions early after birth and PC-like PPK lesions as young adults. These PPK lesions have a marked dysregulation of skin barrier-related genes and innate immunity effectors (eg danger-associated molecular patterns) and are preceded by oxidative stress secondary to hypoactive Nrf2 signalling. These molecular features are present in PPK lesions of PC patients. Here, we report that all components of the C57Bl/6;Krt16^-/- mouse phenotypeoccur as well in the FVB strain background, albeit less severely so, a significant observation in the light of variations in the clinical presentation of individuals harbouring disease-causing mutations in the KRT16 gene.

Title: Long-Range Polymerase Chain Reaction for Speci¢c Full-Length Ampli¢cation of the Human Keratin 14 Gene andN ovel Keratin 14 Mutations in Epidermolysis Bullosa Simplex Patients
Journal: J Invest Dermatol.
Authors: P. Wood, D.U. Baty, E.B. Lane, W.H. McLean
Volume: 120, Issue: 3, Pages: 495-497

Title: Mutations in POGLUT1 in Galli–Galli/Dowling– Degos disease
Journal: Br J Dermatol.
Authors: N.J. Wilson, C. Cole, K. Kroboth, W.N. Hunter, J.A. Mann, W.H. McLean, K. Lang Kerland, H. Beltraminelli, R.A. Sabroe, N. Tiffin, G.J. Sobey, L. Borradori, E. Simpson, F.J. Smith
Volume: 176, Issue: 1, Pages: 270-274

Title: Striate palmoplantar keratoderma resulting from a missense mutation in DSG1
Journal: Br J Dermatol.
Authors: D. Vodo, E.A. O’Toole, N. Malchin, A. Lahav, N. Adir, O. Sarig, K. Green, F. J.D. Smith, E. Sprecher

Title: Keratin 6b variant p.Gly499Ser reported in delayed-onset pachyonychia congenita is a non-pathogenic polymorphism
Journal: J Dermatol.
Authors: F.J.D. Smith, W.H.I. McLean
Volume: 44, Issue: 12, Pages: e312

Title: Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium
Journal: Br J Dermatol.
Authors: L. Rittie, R.L. Kaspar, E. Sprecher and F.J.D. Smith
Volume: 176, Issue: 5, Pages: 1144-1147

Abstract:

The International Pachyonychia Congenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for pachyonychiacongenita, a rare autosomal dominant skin disorder. The research presented at the 13thAnnual Research Symposium of the IPCC, held on 10-11 May 2016, in Scottsdale, AZ, U.S.A., is reported here.

Title: Proteomic profiling of Pachyonychia congenita plantar callus
Journal: J Proteomics.
Authors: Robert H. Rice, Blythe P. Durbin-Johnson, Michelle Salemi, Mary E. Schwartz, David M. Rocke, Brett S. Phinney
Volume: 165, Pages: 132-137

Abstract:

Callus samples from the ball and the arch of the foot, collected on tape circles, were compared by shotgun proteomic profiling. Pachyonychia congenita subjects were sampled who exhibited a mutation in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, and the proteins were digested and analyzed by tandem mass spectrometry. In comparison with samples from unaffected control subjects, those from subjects with KRT6A or KRT16 mutations displayed the most differences in profile from normal, while those from subjects with KRT6C or KRT17 mutations showed few differences from normal. The profiles from subjects with KRT6B mutations were intermediate in protein profile differences. Degree of departure from the normal profile could be estimated by expression of numerous proteins in callus from the ball of the foot that were consistently different. By contrast, the protein profile from the arch of the foot was hardly affected. The results provide a foundation for noninvasive monitoring of the efficacy of treatments with quantitative assessment of departure from the normal phenotype.

SIGNIFICANCE:

Title: RNA-based therapies for genodermatoses.
Journal: Exp Dermatol.
Authors: Olivier Bornert, Patricia Peking, Jeroen Bremer, Ulrich Koller, Peter C. van den Akker, Annemieke Aartsma-Rus, Anna M. G. Pasmooij, Eva M. Murauer, Alexander Nyström
Volume: 26, Issue: 1, Pages: 3-10

Abstract:

Genetic disorders affecting the skin, genodermatoses, constitute a large and heterogeneous group of diseases, for which treatment is generally limited to management of symptoms. RNA-based therapies are emerging as a powerful tool to treat genodermatoses. In this review, we discuss in detail RNA splicing modulation by antisense oligonucleotides and RNA trans-splicing, transcript replacement and genome editing by in vitro-transcribed mRNAs, and gene knockdown by small interfering RNA and antisense oligonucleotides. We present the current state of these therapeutic approaches and critically discuss their opportunities, limitations and the challenges that remain to be solved. The aim of this review was to set the stage for the development of new and better therapies to improve the lives of patients and families affected by a genodermatosis.

Title: Pachyonychia Congenita in a Toddler
Journal: Plast Reconstr Surg Glob Open.
Authors: M Mandelbaum, JW Chao, GF Rogers
Volume: 5, Issue: 5, Pages: e1325

Title: First Report of Pachyonychia Congenita Type PC-K6a in the Romanian Population
Journal: Maedica (Buchar).
Authors: Anca CHIRIAC, Cristina RUSU, Alina MURGU, Anca E CHIRIAC, Neil J WILSON, Frances J D SMITH
Volume: 12, Issue: 2, Pages: 123-126

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder, with unknown prevalence, although it is estimated there are between 2,000 and 10,000 cases of PC worldwide. The International PC Research Registry (IPCRR) has currently identified (as of November 2016) 746 individuals (in 403 families) with genetically confirmed PC. Heterozygous mutations, predominantly missense mutations, in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17 cause PC. The predominant clinical findings include plantar keratoderma, plantar pain and variable dystrophy of some or all toenails and/ or fingernails. Oral leukokeratosis, follicular hyperkeratosis, cysts of various types and natal teeth may also be present. We report the first case of genetically confirmed PC from Romania due to a mutation in KRT6A, p.Arg466Pro.

Title: Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening
Journal: Br J Dermatol.
Authors: M.L. Lovgren, M.A. McAleer, A.D. Irvine, N.J. Wilson, S. Tavadia, M.E. Schwartz, C. Cole, A. Sandilands, F.J.D. Smith and M. Zamiri
Volume: 176, Issue: 5, Pages: 1345-1350

Abstract:

The inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis - striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene.

Title: Sex Matters: Interfering with the Oxidative Stress Response in Pachyonychia Congenita
Journal: J Invest Dermatol.
Authors: RE Leube, N Schwarz
Volume: 138, Issue: 5, Pages: 1019-1022

Abstract:

Pachyonychia congenita is an incurable and often debilitating genodermatosis. Topical application of the antioxidative response inducer sulforaphane, however, alleviates disease symptoms in a murine pachyonychia congenita model, forecasting clinical benefits. The Coulombe laboratory now reports sex-dependent differences in sulforaphane responsiveness of pachyonychia congenita mice, thereby dampening treatment expectations but also unveiling novel aspects of sex-specific oxidative stress reactivity in the epidermis.

Title: Pachyonychia Congenita: Brief Appraisal of History and Current Classification
Journal: Indian Dermatol Online J.
Authors: NK Kansal
Volume: 8, Issue: 4, Pages: 287

Title: The x-ray crystal structure of the keratin 1–keratin 10 helix 2B heterodimer reveals molecular surface properties and biochemical insights into human skin disease
Journal: J Invest Dermatol.
Authors: Christopher G. Bunick, Leonard M. Milstone
Volume: 137, Issue: 1, Pages: 142-150

Abstract:

Keratins 1 (K1) and 10 (K10) are the primary keratins expressed in differentiated epidermis. Mutations in K1/K10 are associated with human skin diseases. We determined the crystalstructure of the complex between the distal (2B) helices of K1 and K10 to better understand how human keratin structure correlates with function. The 3.3 Å resolution structure confirms many features inferred by previous biochemical analyses, but adds unexpected insights. It demonstrates a parallel, coiled-coil heterodimer with a predominantly hydrophobic intermolecular interface; this heterodimer formed a higher order complex with a second K1-K10-2B heterodimer via a Cys401^K10 disulfide link, although the bond angle is unanticipated. The molecular surface analysis of K1-K10-2B identified several pockets, one adjacent to the disulfide linkage and conserved in K5-K14. The solvent accessible surface area of the K1-K10 structure is 20-25% hydrophobic. The 2B region contains mixed acidic and basic patches proximally (N-terminal), whereas it is largely acidic distally (C-terminal). Mapping of conserved and nonconserved residues between K1-K10 and K5-K14 onto the structure demonstrated the majority of unique residues align along the outer helical ridge. Finally, the structure permitted a fresh analysis of the deleterious effects caused by K1/K10 missense mutations found in patients with phenotypic skin disease.

Title: Delayed-onset pachyonychia congenita caused by a novel mutation in the V2 domain of keratin 6b
Journal: J Dermatol.
Authors: K Guo, S Xiao, S Geng, Y Feng, D Zhang, P Zhou, Y Zhang
Volume: 41, Issue: 1, Pages: 108-109

Title: Cutaneous Cysts with Nail Dystrophy in a Young Female: A Classical Association
Journal: Indian J Dermatol.
Authors: Romana Ghosh, Kingshuk Chatterjee, Jayanta Kumar Barua, and Anupam Roy
Volume: 62, Issue: 6, Pages: 661-664

Abstract:

Pachyonychia Congenita (PC) refers to a group of autosomal dominant disorders with variable clinical presentations. While nail dystrophy and plantar keratoderma are the most consistent features in all the variants, a myriad of other manifestations has been observed. This report highlights a case of young female presenting with multiple asymptomatic cutaneous cystsassociated with plantar kearatoderma and nail dystrophy. Similar nail changes were evident in her son also. Such clinical presentation, in corroboration with histopathological evaluation of the cutaneous cyst prompted us to make a diagnosis of Pachyonychia Congenita type II.

Title: Early severe pachyonychia congenita subtype PC-K6a with a novel mutation in the KRT6A gene
Journal: J Eur Acad Dermatol Venereol.
Authors: F Cammarata-Scalisi, K Natsuga, E Toyonaga, W Nishie, H Shimizu, A Avendano, G Da Silva, E Bellacchio, M Callea
Volume: 31, Issue: 2, Pages: e94-e96

Title: Chronic pain in Pachyonychia Congenita: evidence for neuropathic origin
Journal: Br J Dermatol.
Authors: S Brill, E Sprecher, FJD Smith, N Geva, H Gruener, H Nahman-Averbuch, R Defrin

Abstract:

BACKGROUND:

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSIONS:

Title: Keratin 17 Mutations in Four Families from India with Pachyonychia Congenita
Journal: Indian J Dermatol.
Authors: Manoj Agarwala, Pankaj Salphale, Dincy Peter, Neil J Wilson, Susanne Pulimood, Mary E Schwartz, and Frances J D Smith
Volume: 62, Issue: 4, Pages: 422-426

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The main features are palmoplantar keratoderma, plantar pain, and nail dystrophy. Cysts of various types, follicular hyperkeratosis, oral leukokeratosis, hyperhidrosis, and natal teeth may also be present. Four unrelated Indian families presented with a clinical diagnosis of PC. This was confirmed by genetic testing; mutations in KRT17 were identified in all affected individuals.

Title: PCQoL: A Quality of Life Assessment Measure for Pachyonychia Congenita
Journal: J Cutan Med Surg
Authors: Mariam Abbas, Mary E. Schwartz, Frances J.D. Smith, W.H. Irwin McLean, and Peter R. Hull
Volume: 19, Issue: 1, Pages: 57-65

Abstract:

BACKGROUND:

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSION:

Title: Genetic variants in pachyonychia congenita: associated keratins increase susceptibility to tooth decay
Journal: PLoS Genet
Authors: O Duverger, Jc Carlson, CM Karacz, ME Schwartz, MA Cross, ML Marazita, JR Shaffer, MI Morasso
Volume: 14, Issue: 1,

Abstract:

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in toothenamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.

Title: Nail removal in pachyonychia congenita: Patient-reported survey outcomes
Journal: J Am Acad Dermatol
Authors: CMC DeKlotz, ME Schwartz, LM Milstone
Volume: 76, Issue: 5, Pages: 990-992

Title: Proteomic profiling of Pachyonychia congenita plantar callus
Journal: J Proteomics
Authors: Robert H. Rice, Blythe P. Durbin-Johnson, Michelle Salemi, Mary E. Schwartz, David M. Rocke, Brett S. Phinney
Volume: 165, Pages: 132-137

Abstract:

Callus samples from the ball and the arch of the foot, collected on tape circles, were compared by shotgun proteomic profiling. Pachyonychia congenita subjects were sampled who exhibited a mutation in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, and the proteins were digested and analyzed by tandem mass spectrometry. In comparison with samples from unaffected control subjects, those from subjects with KRT6A or KRT16 mutations displayed the most differences in profile from normal, while those from subjects with KRT6C or KRT17 mutations showed few differences from normal. The profiles from subjects with KRT6B mutations were intermediate in protein profile differences. Degree of departure from the normal profile could be estimated by expression of numerous proteins in callus from the ball of the foot that were consistently different. By contrast, the protein profile from the arch of the foot was hardly affected. The results provide a foundation for noninvasive monitoring of the efficacy of treatments with quantitative assessment of departure from the normal phenotype.

SIGNIFICANCE:

Title: Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita.
Journal: J Invest Dermatol
Authors: Michelle L. Kerns, Jill M.C. Hakim, Abigail Zieman, Rosemary G. Lu, and Pierre A. Coulombe
Volume: 138, Issue: 5, Pages: 1094-1100

Abstract:

Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita is caused by mutations in keratin genes and typified by dystrophic lesions affecting nails, glands, oral mucosa, and palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK) severely impairs mobility in pachyonychia congenita. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in pachyonychia congenita, develop pachyonychia congenita-like PPK. In male Krt16^-/- mice, oxidative stress associated with impaired glutathione synthesis and nuclear factor erythroid-derived 2 related factor 2 (NRF2)-dependent gene expression precedes PPK onset, which can be prevented by topical sulforaphane-mediated activation of NRF2. We report here that sulforaphane treatment fails to activate NRF2 and prevent PPK in female Krt16^-/- mice despite a similar set of molecular circumstances. Follow-up studies reveal a temporal shift in PPK onset in Krt16^-/- females, coinciding with sex-specific fluctuations in footpad skin glutathione levels. Dual treatment with sulforaphane and diarylpropionitrile, an estrogen receptor beta selective agonist, results in NRF2 activation, normalization of glutathione levels, and prevention of PPK in female Krt16^-/-mice. These findings point to a sex difference in NRF2 responsiveness that needs be considered when exploring NRF2 as a therapeutic target in skin disorders.

Title: The keratin 16 null phenotype is modestly impacted by genetic strain background in mice.
Journal: Exp Dermatol
Authors: Abigail Zieman and Pierre A. Coulombe

Abstract:

Title: Longitudinal Assessment of Small Fiber Neuropathy: Evidence of a Non–Length-Dependent Distal Axonopathy
Journal: JAMA Neurology
Authors: Mohammad A. Khoshnoodi, MD; Shaun Truelove, BA; Ahmet Burakgazi, MD; Ahmet Hoke, MD, PhD; Andrew L. Mammen, MD, PhD; Michael Polydefkis, MD, MHS

Title: Author's Reply: Pachyonychia Congenita Type 1: Case Report and Review of the Literature
Journal: Indian Journal of Dermatology
Authors: Anupam Das

Title: A novel KRT6A mutation in a case of pachyonychia congenita from India
Journal: Indian Journal of Dermatology
Authors: Anup Kumar Tiwary, Neil J. Wilson, Mary E. Schwartz, Frances J. D. Smith
Volume: 83, Issue: 1,

Title: Pachyonychia congenita with late onset (PC tarda)
Journal: Indian Dermatology Online Journal
Authors: A. Sravanthi, P. Srivalli, K. V. T. Gopal, T. Narayana Rao
Volume: 7, Issue: 4,

Title: Peripheral neuropathic changes in pachyonychia congenita
Journal: PAIN
Authors: Baohan Pan, Kelly Byrnes, Mary Schwartz, C. David Hansen, Claudia M. Campbell, Malvina Krupiczojc, Michael J. Caterina, Michael Polydefkis

Title: Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo
Journal: Oncogene
Authors: RP Hobbs, AS Batazzi, MC Han, PA Coulombe

Abstract:

Despite preventive human papilloma virus (HPV) vaccination efforts, cervical cancer remains a leading cause of death in women worldwide. Development of therapeutic approaches for cervical cancer are hampered by a lack of mechanistic insight during tumorigenesis. The cytoskeletal protein Keratin 17 (KRT17;K17) is robustly expressed in a broad array of carcinomas, including in cervical tumors, where it has both diagnostic and prognostic value. In this study, we have established multiple functional roles for K17 in the promotion of cervical tumorigenesis in vivo using the established HPV16tg mouse model for cervical squamous cell carcinoma. In HPV16tg/+;Krt17-/-relative to HPV16tg/+ reference female mice, onset of cervical lesions is delayed and closely paralleled by marked reductions in hyperplasia, dysplasia and vascularization. In addition, loss of Krt17 is associated with a cytokine polarization and recruitment of effector immune cells to lesion-prone cervical epithelia. Further, we observed marked enhancement of terminal differentiation in HPV16tg/+;Krt17-/-cervical epithelium accompanied by a stimulation and expansion in the expression of p63, a known basal/reserve cell marker in this tissue. Altogether, the data suggest that the loss of Krt17 may foster an overall protective environment for lesion-prone cervical tissue. In addition to providing new insights into the immunomodulatory and cellular mechanisms of cervical tumorigenesis, these findings may help guide the development of future therapies including vaccines.Oncogene advance online publication, 11 April 2016; doi:10.1038/onc.2016.102.

Title: Pachyonychia Congenita: New Classification and Diagnosis
Journal: Indian J Dermatol
Authors: M.K. Agarwala, M.E. Schwartz, F.J.D. Smith
Volume: 61, Section: 5, Pages: 567

Abstract:

We read with interest the article “Pachyonychia congenita Type 1: Case report and review of the literature,” by Rathore et al.[1]
We would like to emphasize the importance of genetic testing to confirm a clinical diagnosis, draw your attention to the revised classification of pachyonychia congenita (PC) and provide further information regarding this rare skin disorder. Historically, PC was subdivided, with the two major clinical forms being PC‑1 and PC‑2. With an improvement in the understanding of the disease based on detailed clinical and molecular data collected by the International PC Research Registry (IPCRR), a new
classification system was proposed, that divides PC into five subtypes based on the keratin gene affected.[2] The authors referred to this publication, but they did not mention the new classification, which is more scientific and has mutational analysis as the discriminator. Reference of the disease as PC‑1 and PC‑2 is obsolete and should be revised in the published literature. Analysis of the IPCRR dataset showed considerable phenotypic overlap between cases classified as PC‑1 and PC‑2.

Title: Keratins Are Going Nuclear
Journal: Dev Cell
Authors: RP Hobbs, JT Jacob, PA Coulombe
Volume: 38, Section: 3, Pages: 227-33

Abstract:

Previously thought to reside exclusively in the cytoplasm, the cytoskeletal protein keratin 17 (K17) has been recently identified inside the nucleus of tumor epithelial cells with a direct impact on cell proliferation and gene expression. We comment on fundamental questions raised by this new finding and the associated significance.

Title: Keratins Are Going Nuclear
Journal: Dev Cell
Authors: R.P. Hobbs, J.T. Jacob, P.A. Coulombe
Volume: 38, Section: 3, Pages: 227-33

Abstract:

Previously thought to reside exclusively in the cytoplasm, the cytoskeletal protein keratin 17 (K17) has been recently identified inside the nucleus of tumor epithelial cells with a direct impact on cell proliferation and gene expression. We comment on fundamental questions raised by this new finding and the associated significance.

Title: Treatment of symptomatic epidermolysis bullosa simplex with botulinum toxin in a pediatric patient
Journal: JAAD Case Rep
Authors: H.M. Holahan, R.S. Farah, N.N. Ferguson, A.S. Paller, A.A. Legler
Volume: 2, Section: 3, Pages: 259-60

Abstract:

Keywords: EBS, epidermolysis bullosa simplex; botulinum toxin; bullous disease; disport;epidermolysis bullosa simplex; hyperhidrosis; pediatric; symptomatic

Title: Semidominant Inheritance in Olmstead Syndrome
Journal: J Invest Dermatol
Authors: X. Cao, H. Wang, Y. Li, M. Lee, L, Jiang, Y. Zhou, C. Feng, Z. Lin, Y. Yang
Volume: 136, Section: 8, Pages: 1722-5

Abstract:

Olmsted syndrome is a hereditary disorder characterized predominantly by palmoplantar keratoderma and periorificial keratosis. Frequent additional features include intolerant itching on palms and/or soles, diffuse alopecia, keratosis pilaris, onychodystrophy, and digital autoamputation. Recently, mutations in transient receptor potential vanilloid type 3 (TRPV3) and membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with autosomal-dominant and X-linked OS, respectively. In TRPV3-associated OS, we previously demonstrated that certain missense mutations led to overactivation of the TRPV3 channel, as an underlying pathogenesis of OS. In addition to the autosomal-dominant trait, autosomal-recessive OS caused by homozygous or compound heterozygous mutations in TRPV3 has been described in two families. Herein we report a TRPV3-associated OS family of semidominant inheritance.

Title: Early severe pachyonychia congenita subtype PC-K6a with a novel mutation in KRT6A gene.
Journal: J Eur Acad Dermatol Venereol
Authors: F. Cammarata-Scalisi, K. Natsuga, E. Toyonaga, W. Nishie, H. Shimizu, A. Avendano, D. Arague, G. Da Silva, E. Bellacchio, M. Callea

Title: Pachyonychia Congenita: A Case Report and Review of a Genetic Disorder with No Known Cure
Journal: Podiatry Institute Update Book
Authors: Thomas Merrill, Jamie Dermatis, Hani Badahdah

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis with an estimated incidence of only 5,000 to 10,000 reported cases worldwide (1). This disorder is most often caused by heterozygous mutations in any one of the genes encoding the differentiation-specifi c keratins K6a, K6b, K6c, K16, or K17. The most common clinical findings of PC include hypertrophic nail dystrophy, palmoplantar keratoderma, plantar pain, oral leukokeratosis, and epidermal cysts (2). This article reports a patient presenting with genetically confirmed PC who was treated conservatively. A thorough review of the most recent literature and findings of PC will also be presented.

Title: Two familial cases of Olmsted-like syndrome with a G573V mutation of the TRPV3 gene
Journal: Clin Exp Dermatol
Authors: YP Zhi, J Liu, JW Han, YP Huang, ZQ Gao, Y Yang, RN Wu
Volume: 41, Section: 5, Pages: 510-3

Abstract:

Olmsted syndrome (OS) is a rare disease, characterized by symmetrical, sharply defined, hyperkeratotic, mutilating plaques on the palms and soles, which are associated with periorificial keratotic plaques. Other clinical manifestations of OS include diffuse alopecia, leucokeratosis of the oral mucosa, onychodystrophy, hyperkeratotic linear streaks, follicular hyperkeratosis and constriction of the digits. A recent study identified de novo mutations in the gene for transient receptor potential vanilloid 3 (TRPV3), causing constitutive activation of the TRPV3 channel, as a cause of OS. We report familial inheritance of OS in a family from Mongolia, which was caused by a previously undescribed G573V point mutation in TRPV3. To date, mutations in the G573 residue of TRPV3 have been reported in seven cases of OS: G573S in five cases, and G573C and G573A mutations in one case each. We present a Mongolian familial case of G573V point mutation in TRPV3.

Title: Hereditary palmoplantar keratoderma "clinical and genetic differential diagnosis"
Journal: J Dermatol
Authors: Sakiyama T, Kubo A
Volume: 43, Section: 3, Pages: 264-74

Abstract:

Hereditary palmoplantar keratoderma (PPK) is a heterogeneous group of disorders characterized by hyperkeratosis of the palm and the sole skin. Hereditary PPK are divided into four groups - diffuse, focal, striate and punctate PPK - according to the clinical patterns of the hyperkeratotic lesions. Each group includes simple PPK, without associated features, and PPK with associated features, such as involvement of nails, teeth and other organs. PPK have been classified by a clinically based descriptive system. In recent years, many causative genes of PPK have been identified, which has confirmed and/or rearranged the traditional classifications. It is now important to diagnose PPK by a combination of the traditional morphological classification and genetic testing. In this review, we focus on PPK without associated features and introduce their morphological features, genetic backgrounds and new findings from the last decade.

KEYWORDS:
diffuse; focal; punctate; striate; transgrediens

Title: Chronic Foot Pain due to Pachyonychia Congenita in a Pediatric Patient: A Successful Management Strategy
Journal: A A Case Rep
Authors: Tariq S, Schmitz ML, Kanjia MK
Volume: 6, Section: 10, Pages: 305-7

Abstract:

We report the case of an 11-year-old girl who presented to our multidisciplinary pain center with the chief complaint of chronic bilateral foot pain because of a rare congenital keratin disorder. This patient had been diagnosed with pachyonychia congenita, an extremely rare genetic disorder primarily affecting the skin and nails. The child had bilateral foot pain for years because of the characteristic blisters and calluses on the soles of her feet. Chronic pain was negatively impacting her quality of life; she was severely limited in her activities of daily living secondary to pain. Furthermore, she reported absenteeism from school, lack of social activities, and frequent nighttime awakenings. We discuss the successful management of her chronic foot pain using a multimodal, multidisciplinary approach.

Title: A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome.
Journal: Sci Rep
Authors: Ni C, Yan M, Zhang J, Cheng R, Liang J, Deng D, Wang Z, Li M, Yao Z
Volume: 6,

Abstract:

Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks-mutilating palmoplanter and periorificial keratoderma. However, there's a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease.

Title: Pachyonychia Congenita Type 1: Case Report and Review of the Literature
Journal: Indian J Dermatol
Authors: Rathore PK, Khullar V, Das A
Volume: 61, Section: 2, Pages: 196-9

Abstract:

The case of an 8-year-old boy is hereby reported, who presented with nail dystrophy, subungual hyperkeratosis, oral leukokeratosis, and numerous follicular papules all over the body. The features were consistent with a diagnosis of pachyonychia congenita type 1. The case is being reported for its rarity. We also discuss in a nutshell, the literature till date.

KEYWORDS:
Follicular papules; leukokeratosis; nail dystrophy; subungual hyperkeratosis

Title: p53 Is a Direct Transcriptional Repressor of Keratin 17: Lessons from a Rat Model of Radiation Dermatitis
Journal: J Invest Dermatol
Authors: Liao C, Xie G, Zhu L, Chen X, Li X, Lu H, Xu B, Ramot Y, Paus R, Yue Z
Volume: 136, Section: 3, Pages: 680-9

Abstract:

The intermediate filament protein keratin 17 (Krt17) shows highly dynamic and inducible expression in skin physiology and pathology. Because Krt17 exerts physiologically important functions beyond providing structural stability to keratinocytes whereas abnormal Krt17 expression is a key feature of dermatoses such as psoriasis and pachyonychia congenita, the currently unclear regulation of Krt17 expression needs to be better understood. Using a rat model of radiation dermatitis, we report here that Krt17 expression initially is down-regulated but later is strongly up-regulated by ionizing radiation. The early down-regulation correlates with the activation of p53 signaling. Deletion of p53 abolishes the initial down-regulation but not its subsequent up-regulation, suggesting that p53 represses Krt17 transcription. Because previous work reported up-regulation of Krt17 by ultraviolet irradiation, which also activates p53 signaling, the effect of ultraviolet radiation was reexamined. This revealed that the initial down-regulation of Krt17 is conserved, but the up-regulation comes much faster. Chromatin immunoprecipitation analysis in vivo and electromobility shift assay in vitro identified two p53-binding sites in the promoter region of Krt17. Thus, p53 operates as a direct Krt17 repressor, which invites therapeutic targeting in dermatoses characterized by excessive Krt17 expression.

Title: [Congenital pachyonychia: A new case associated with the KRT17 gene]
Journal: An Pediatr (Barc)
Authors: Micol-Mart
Volume: 84, Section: 3, Pages: 174-6

Abstract:

Pachyonychia congenita ([PC], OMIM #167200 and #167210) is a rare genodermatosis, with 1000 cases in patients from 270 families described to date. It has a pattern of autosomal dominant inheritance (40% de novo mutations), with complete penetrance and a variable expression.1 Its historical classification includes two types: type 1 (PC-1 or Jadassohn- Lewandowsky syndrome) and type 2 (PC-2 or Jackson-Lawler syndrome).1---3 At present, it is classified based on the gene involved in keratin synthesis where the mutation is found: PC-K6a (caused by mutations in the KRT6A gene, identified in 44% of the families), PC-K6b (KRT6B, 5% of families), PCK6c (KRT6C, 2% of families) at the 12q13.13 locus, PC-K16 (KRT16, 25% of families) and PC-K17 (KRT17, remaining 24% of families) at the 17q21.2 locus.1,3 Mutations in the KRT6A and KRT16 genes correspond to the clinical features of PC-1; while mutations in the KRT6B and KRT17 correspond to PC-2. We present the case of a boy that received a diagnosis of PC associated with a mutation in the KRT17 gene (c.284T>C; p.Leu95Pro; L95P) at age 14 months.

Title: Palmoplantar keratodermas: clinical and genetic aspects
Journal: J Dtsch Dermatol Ges
Authors: Has C, Technau-Hafsi K
Volume: 14, Section: 2, Pages: 123-39

Abstract:

Palmoplantar keratodermas comprise a diverse group of acquired and hereditary disorders marked by excessive thickening of the epidermis of palms and soles. Early onset and positive family history suggest a genetic cause. While hereditary forms of palmoplantar keratoderma (PPK) may represent the sole or dominant clinical feature, they may also be associated with other ectodermal defects or extracutaneous manifestations. In recent years, much progress has been made in deciphering the genetic basis of PPK, which has led to the emergence of new disorders and syndromes. The elucidation of disease mechanisms has opened new avenues for specific therapies, increasingly sparking interest in this field. Given the high heterogeneity with respect to clinical features, genetic defects, and disease mechanisms, the classification of PPK is based on various criteria. These include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis. Though not always feasible, the clinical distinction of various PPK entities is based on fine-tuned criteria or clues. Remarkably, apparently distinct disorders have been shown to be allelic, as they are caused by mutations in the same gene. By contrast, similar clinical pictures may result from mutations in different genes. Because of this complexity, mutation analysis is required to determine the precise type of PPK. The best-defined entities are described in this review.

Title: Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes.
Journal: J Clin Invest
Authors: Kerns ML, Hakim JM, Lu RG, Guo Y, Berroth A, Kaspar RL, Coulombe PA

Abstract:

Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.

Title: First bite syndrome: Our experience with intraparotid injections with botulinum toxin type A
Journal: Laryngoscope
Authors: Ghosh A, Mirza N
Volume: 126, Section: 1, Pages: 104-7

Abstract:

OBJECTIVES/HYPOTHESIS:
First bite syndrome is the sudden onset of acute and severe pain in the parotid region at the initiation of mastication. Although it generally lasts less than a minute, it is disabling for these individuals and leads to a fear of oral intake. It is typically seen after parapharyngeal or deep parotid space surgery. Intraparotid injection of botulinum toxin A (BTA) has been suggested as a treatment for this condition, but there is little supporting literature to this effect. The purpose of this study is to document our experience using this treatment method for first bite syndrome.

STUDY DESIGN:
Retrospective case review.

METHODS:
Five patients with first bite syndrome, developed after parapharyngeal space surgery, were treated by multisite injection of BTA into the parotid gland. Between 17.5 and 50 total U of BTA were injected into four or more sites in the parotid region. The patients were then followed up every 4 months.

RESULTS:
Three of five patients reported a significant improvement in symptoms at the 4-month follow-up visit, although complete resolution was not reported. One patient reported only moderate improvement, and despite two series of injections there was no improvement in one patient, leading us to question our initial diagnosis.

CONCLUSIONS:
Unilateral BTA injection into the affected parotid gland produces a decrease in the severity of symptoms. It is a safe and viable noninvasive treatment for this difficult to treat condition and may lead to permanent resolution of symptoms in some patients.

Title: Realizing Our Potential in Biobanking: Disease Advocacy Organizations Enliven Translational Research.
Journal: Biopreserv Biobank
Authors: Edwards KA, Terry SF, Gold D, Horn E, Schwartz M, Stuart M, Vernon S

Abstract:

Biobanks are increasingly powerful tools used in translational research, and disease advocacy organizations (DAOs) are making their presence known as research drivers and partners. We examined DAO approaches to biobanking to inform how the enterprise of biobanking can grow and become even more impactful in human health. In this commentary, we outline overarching approaches from successful DAO biobanks. These lessons learned suggest principles that can create a more participant-centric approach and illustrate the key roles DAOs can play as partners in research initiatives. DAO approaches to biobanking for translational research include the following: be outcome driven; forge alliances that are unexpected-build bridges to enhance translation; come ready for success; be nimble, flexible, and adaptable; and remember that people matter. Each of these principles led to particular practices that have increased the translational impact of biobank collections. The research practices discussed can inform partnerships in all sectors going forward.

Title: Pachyonychia Congenita: A Spectrum of KRT6a Mutations in Australian Patients
Journal: Pediatr Dermatol
Authors: Forrest CE, Casey G, Mordaunt DA, Thompson EM, Gordon L.
Volume: 33, Section: 3, Pages: 337-42

Abstract:

BACKGROUND:
Pachyonychia congenita (PC) is a rare inherited disorder of keratinization characterised by hypertrophic nail dystrophy, painful palmoplantar blisters, cysts, follicular hyperkeratosis and oral leukokeratosis. It is associated with mutations in five differentiation-specific keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17.

OBJECTIVES:
Living with Pachyonychia Congenita can be isolating. The aim of this paper is to document a single patient's experience within a national context.

METHOD:
We report the case of a 2 year old female with an atypical presentation of PC due to a mutation in KRT6A with severely hypertrophic follicular keratoses, skin fragility, relative sparing of nail hypertrophy on one hand and failure to thrive in early infancy. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), a database search was performed using Australian residency and KRT6A mutation as inclusion criteria. The IPCRR database was also searched for a matching KRT6A mutation. Six Australian patients were identified in addition to one patient with an identical mutation residing in the United States. The detailed standardized patient questionnaire data was manually collated and analysed.

RESULTS:
Fingernail hypertrophy and oral leukokeratosis were the most common features. There was no recording of asymmetric distribution in any other Australian patient. Trouble nursing as an infant and follicular hyperkeratosis also occurred in the American patient, however they did not have asymmetric distribution and the oral leukokeratosis appeared later in life.

CONCLUSION:
This case has unique features. Sharing information can assist patients navigating life with this condition.

Title: Non-Invasive Intravital Imaging of siRNA-Mediated Mutant Keratin Gene Repression in Skin
Journal: Mol Imaging Biol
Authors: R. Hickerson; T. Speaker; M. Lara; E. Gonzalez-Gonzalez; M. Flores; C. Contag; R. Kaspar
Volume: 18, Section: 1, Pages: 34-42

Abstract:

PURPOSE:
Small interfering RNAs (siRNAs) specifically and potently inhibit target gene expression. Pachyonychia congenita (PC) is a skin disorder caused by mutations in genes encoding keratin (K) 6a/b, K16, and K17, resulting in faulty intermediate filaments. A siRNA targeting a single nucleotide, PC-relevant mutation inhibits K6a expression and has been evaluated in the clinic with encouraging results.
PROCEDURES:
To better understand the pathophysiology of PC, and develop a model system to study siRNA delivery and visualize efficacy in skin, wild type (WT) and mutant K6a complementary DNAs (cDNAs) were fused to either enhanced green fluorescent protein or tandem tomato fluorescent protein cDNA to allow covisualization of mutant and WT K6a expression in mouse footpad skin using a dual fluorescence in vivo confocal imaging system equipped with 488 and 532 nm lasers.
RESULTS:
Expression of mutant K6a/reporter resulted in visualization of keratin aggregates, while expression of WT K6a/reporter led to incorporation into filaments. Addition of mutant K6a-specific siRNA resulted in inhibition of mutant, but not WT, K6a/reporter expression.
CONCLUSIONS:
Intravital imaging offers subcellular resolution for tracking functional activity of siRNA in real time and enables detailed analyses of therapeutic effects in individual mice to facilitate development of nucleic acid-based therapeutics for skin disorders.
KEYWORDS:
Gene regulation; Gene therapy; Genodermatosis; In vivo confocal fluorescence microscopy

Title: Discovery of keratin function and role in genetic diseases: the year that 1991 was
Journal: Mol Biol Cell
Authors: Pierre A. Coulombe
Volume: 27, Section: 18, Pages: 2807-10

Abstract:

In 1991, a set of transgenic mouse studies took the fields of cell biology and dermatology by storm in providing the first credible evidence that keratin intermediate filaments play a unique and essential role in the structural and mechanical support in keratinocytes of the epidermis. Moreover, these studies intimated that mutations altering the primary structure and function of keratin filaments underlie genetic diseases typified by cellular fragility. This Retrospective on how these studies came to be is offered as a means to highlight the 25th anniversary of these discoveries.

Title: Transdermal Delivery of siRNA through Microneedle Array.
Journal: Sci Rep
Authors: Y. Deng, J. Chen, Y. Zhao, X. Yan, L. Zhang, K. Choy, J. Hu, H. Sant, B.K. Gale, T. Tang
Volume: 6,

Abstract:

Successful development of siRNA therapies has significant potential for the treatment of skin conditions (alopecia, allergic skin diseases, hyperpigmentation, psoriasis, skin cancer, pachyonychia congenital) caused by aberrant gene expression. Although hypodermic needles can be used to effectively deliver siRNA through the stratum corneum, the major challenge is that this approach is painful and the effects are restricted to the injection site. Microneedle arrays may represent a better way to deliver siRNAs across the stratum corneum. In this study, we evaluated for the first time the ability of the solid silicon microneedle array for punching holes to deliver cholesterol-modified housekeeping gene (Gapdh) siRNA to the mouse ear skin. Treating the ear with microneedles showed permeation of siRNA in the skin and could reduce Gapdh gene expression up to 66% in the skin without accumulation in the major organs. The results showed that microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively.

Title: Expanding the Phenotypic Spectrum of Olmsted Syndrome
Journal: J Invest Dermatol
Authors: N. Wilson; C. Cole; L. Milstone; A. Kiszewski; C. Hansen; E. OToole; M. Schwartz; W. McLean; F. Smith
Volume: 135, Section: 11, Pages: 2879-93

Abstract:

Palmoplantar keratodermas (PPKs) are a group of genetically heterogeneous genodermatoses. Recently mutations in TRPV3 were identified as a cause of the rare form of PPK, Olmsted syndrome. OS was first reported in 1927 in an Italian American boy with painful palmoplantar keratoderma, deep fissures, pseudoainhum, curved thickened nails, and periorificial hyperkeratosis with fissuring (Olmsted, 1927). About 50 clinical cases of OS have been described, and all generally exhibit the features described by Olmsted as well as some additional features. In this study, we report the case of six families, referred to the Pachyonychia Congenita Project for the evaluation of painful plantar keratoderma, but lacking pseudoainhum or significant periorificial keratoderma. In each case, after no mutations were identified in the PC associated keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17, and in some cases, after other candidate genes including GJB6,DSP, DSG1, KRT5, and KRT14 had been screened, we identified heterozygous missense mutations in TRPV3

Title: Imaging Functional Nucleic Acid Delivery to Skin
Journal: Methods in Molecular Biology-RNA Imaging: Methods & Protocols
Authors: R.L. Kaspar, R.P. Hickerson, E. Gonzalez-Gonzalez, M.A. Flores, T.P. Speaker, F.A. Rogers, L.M. Milstone, C.H. Contag
Volume: Chapter 1, Pages: 1-24

Abstract:

Monogenic skin diseases arise from well-defi ned single gene mutations, and in some cases a single point mutation. As the target cells are superfi cial, these diseases are ideally suited for treatment by nucleic acidbased therapies as well as monitoring through a variety of noninvasive imaging technologies. Despite the accessibility of the skin, there remain formidable barriers for functional delivery of nucleic acids to the target cells within the dermis and epidermis. These barriers include the stratum corneum and the layered structure of the skin, as well as more locally, the cellular, endosomal and nuclear membranes. A wide range of technologies for traversing these barriers has been described and moderate success has been reported for several approaches. The lessons learned from these studies include the need for combinations of approaches to facilitate nucleic acid delivery across these skin barriers and then functional delivery across the cellular and nuclear membranes for expression (e.g., reporter genes, DNA oligonucleotides or shRNA) or into the cytoplasm for regulation (e.g., siRNA, miRNA, antisense oligos). The tools for topical delivery that have been evaluated include chemical, physical and electrical methods, and the development and testing of each of these approaches has been greatly enabled by imaging tools. These techniques allow delivery and real time monitoring of reporter genes, therapeutic nucleic acids and also triplex nucleic acids for gene editing Optical imaging is comprised of a number of modalities based on properties of light-tissue interaction (e.g., scattering, autofl uorescence, and refl ectance), the interaction of light with specifi c molecules (e.g., absorbtion, fl uorescence), or enzymatic reactions that produce light (bioluminescence). Optical imaging technologies operate over a range of scales from macroscopic to microscopic and if necessary, nanoscopic, and thus can be used to assess nucleic acid delivery to organs, regions, cells and even subcellular structures. Here we describe the animal models, reporter genes, imaging approaches and general strategies for delivery of nucleic acids to cells in the skin for local expression (e.g., plasmid DNA) or gene silencing (e.g., siRNA) with the intent of developing nucleic acid-based therapies to treat diseases of the skin.

Title: Steatocystoma multiplex is associated with the R94C mutation in the KRTl7 gene.
Journal: Mol Med Rep
Authors: Q. Liu, W. Wu, J. Lu, P. Wang, F. Qiao
Volume: 12, Section: 4, Pages: 5072-6

Abstract:

Steatocystoma multiplex (SM) is an uncommon disorder, characterized by numerous skin‑colored subcutaneous cysts. A number of SM pedigrees have been identified with mutations in the keratin 17 (KRT17) gene. The present study examined a four‑generation Chinese pedigree with an autosomal dominant mode of inheritance and examined its genetic basis. A review of the literature on KRT17 gene mutations in the SM pedigree was also performed to investigate the KRT17 gene mutation and genotype‑phenotype correlation. Exon 1 of the KRTl7 gene was amplified using polymerase chain reaction (PCR) from genomic DNA obtained, which was obtained from 25 family members in the selected Chinese pedigree and from 100 unrelated control individuals. The DNA was then subjected to automatic DNA sequencing. Genealogical investigations demonstrated an autosomal dominant pattern, and direct sequencing of the PCR product revealed a heterozygous mutation, c.280C/T (R94C), which was located in exon 1 of the KRT17 gene in all 10 affected family members. The mutation was not identified in the 15 unaffected family members or in the 100 unrelated control individuals. Therefore, the present study identified a causative mutation in the KRT17 gene in a large Chinese SM pedigree, exhibiting autosomal dominance. A review of the literature suggested that, in addition to the mutation factor, other modifying factors contribute to the phenotype of familial SM.

Title: Alitretinoin: treatment for refractory palmoplantar keratoderma
Journal: Br J Dermatol
Authors: H.K. Park, E.J. Kim, J.Y. Ko

Abstract:

Mal de Meleda (MDM) is an autosomal recessive form of palmoplantar keratoderma caused by mutations in the ARS gene, encoding SLURP-1.1 It has been reported that etretinate and acitretin, which are aromatic retinoids, are effective treatment modalities for MDM.2 However, early and long-term use of these retinoids are associated with several well-known adverse effects, such as dryness, teratogenicity and liver toxicity. 

Title: Keratins K2 and K10 are essential for the epidermal integrity of plantar skin
Journal: J Dermatol Sci
Authors: H. Fischer, L. Langbein, J. Reichelt, M. Buchberger, E. Tschachler, I. Eckhart

Abstract:

BACKGROUND:

K1 and K2 are the main type II keratins in the suprabasal epidermis where each of them heterodimerizes with the type I keratin K10 to form intermediate filaments. In regions of the ears, tail, and soles of the mouse, only K2 is co-expressed with K10, suggesting that these keratins suffice to form a mechanically resilient cytoskeleton.

OBJECTIVE:

To determine the effects of the suppression of both main keratins, K2 and K10, in the suprabasal plantar epidermis of the mouse.

METHODS:

Krt2(-/-) Krt10(-/-) mice were generated by crossing Krt2(-/-) and Krt10(-/-) mice. Epidermalmorphology of soles of hind-paws was examined macroscopically and histologically. Immunofluorescence analysis and quantitative PCR analysis were performed to analyze the expression of keratins in sole skin of wildtype and Krt2(-/-) Krt10(-/-) mice. Highly abundant proteins of the sole stratum corneum were determined by electrophoretic and chromatographic separation and subsequent mass spectrometry.

RESULTS:

K2 and K10 are the most prominent suprabasal keratins in normal mouse soles with the exception of the footpads where K1, K9 and K10 predominate. Mice lacking both K2 and K10 were viable and developedepidermal acanthosis and hyperkeratosis in inter-footpad epidermis of the soles. The expression of keratinsK1, K9 and K16 was massively increased at the RNA and protein levels in the soles of Krt2(-/-) Krt10(-/-) mice.

CONCLUSIONS:

This study demonstrates that the loss of the main cytoskeletal components of plantarepidermis, i.e. K2 and K10, can be only partly compensated by the upregulation of other keratins. The thickening of the epidermis in the soles of Krt2(-/-) Krt10(-/-) mice may serve as a model for pathomechanistic aspects of palmoplantar keratoderma.

Title: Genetics of human isolated hereditary nail disorders
Journal: Br J Dermatol
Authors: S Khan, S Basit, R. Habib, A Kamal, N Muhammad, W. Ahmad
Volume: 173, Section: 4, Pages: 922-9

Abstract:

Human hereditary nail disorders constitute a rare and heterogeneous group of ectodermal dysplasias. They occur as isolated and/or syndromic ectodermal conditions where other ectodermal appendages are also involved, and can occur associated with skeletal dysplasia. 'Nail disorder, nonsyndromic congenital' (OMIM; Online Mendelian Inheritance in Man) is subclassified into 10 different types. The underlying genes identified thus far are expressed in the nail bed and play important roles in nail development and morphogenesis. Here, we review the current literature on nail disorders and present a coherent review on the genetics of nail disorders. This review will pave the way to identifying putative genes and pathways involved in naildevelopment and morphogenesis.

Title: Can skin disease cause neuropathic pain? A study in pachyonychia congenita
Journal: Clinical and Experimental Dermatology CED
Authors: T. Wallis, C.D. Poole, B. Hoggart

Abstract:

Introduction. Pachyonychia congenita (PC) is a rare skin disorder caused by an autosomal dominant mutation in one of five genes encoding keratin (K6a, K6b, K6c, K16 or K17; each defining one PC subtype). Pain is a prominent symptom, but its severity and type are poorly characterized.
Methods. In total, 35 genotyped US patients with PC consented to clinical assessment including the quality of life (QoL) questionnaire EQ-5D-3L, the Brief Pain Inventory (BPI) and painDETECT. Abbreviated quantitative sensory testing (QST) was also performed, and included mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up pain ratio (WUR) and vibration detection threshold (VDT).
Results. Significant pain in patients with PC was confirmed, as indicated by mean BPI severity and interference of 4.2
1.7 and 4.4
2.2, respectively, as well as QoL impairment, as indicated by mean EQ-5D index of 0.69
0.18. PD identified neuropathic pain in 62% of patients, the remainder being nociceptive. The pain- DETECT score was most significantly related to EQ-5D index (R2 = 0.26, P = 0.02).
The K17 and K6a subtypes exhibited significantly worse QoL (0.584 and 0.613 respectively) than the K16 and K6b subtypes (P = 0.02). In QST analysis, abnormal pressure pain (assessed as MPT) was frequently observed, with more than half of patients with PC affected (54%), and 57% of patients with K17 also exhibiting abnormality in minimum touch threshold (assessed as MDT, P < 0.05). Very few patients were receiving analgesic therapy appropriate for neuropathic pain. 
Conclusion. Significant neuropathic pain was observed in PC, which warrants appropriate treatment. The health states observed in this sample are at a level that the average US citizen would forfeit one-third of their remaining lifespan to avoid.

Title: Pachyonychia Congenita Type II: A Case Report
Journal: Indian Journal of Mednodent and Allied Sciences
Authors: V. Sindhuri Reddy, M. Madhavi Latha, D. Masthan Saheb
Volume: 2, Section: 2, Pages: 204-209

Abstract:

Pachyonychia congenita type II is an autosomal dominant inherited rare genodermatosis characterized by dystrophic wedge shaped thickened nails with subungual hyperkeratosis, symmetric palmoplantar keratoderma, steatocystoma multiplex. Here we report a 23-year-old male with characteristic features of dystrophic nails, palmoplantar keratoderma, steatocystoma multiplex, follicular hyperkeratotic papules and history of natal teeth at birth.
KEYWORDS: Dystrophic nails, Palmoplantar keratoderma, Natal teeth, Steatocystoma multiplex

Title: A novel H1 mutation in keratin 6a in an infant with pachyonychia congenita
Journal: Indian Journal of Dermatology, Venerology and Leprology
Authors: S. Luo, Q. Luo, H. Zhang, C. Wan
Volume: 81, Section: 4, Pages: 385-387

Abstract:

Pachyonychia congenita (PC) is a rare genetic disorder which is inherited in an autosomal dominant pattern. We report a sporadic novel H1 mutation in the KRT6A gene (c. 428G>AJp. Ser143Asn S143N) in a Chinese infant patient. The mutation is concurrent with a single-nucleotide polymorphism and resulted in a serine for asparagine substitution in H1 subdomain of KRT6A chain next to the rod domain. The infant showed the classic symptoms of pachyonychia congenita. Conclusion: The heterozygous missense mutation c. 428G >  Jp.Ser143Asn in KRT6A exon 1 may cause severe disease.

Title: Generic and Personalized RNAi-Based Therapeutics for a Dominant-Negative Epidermal Fragility Disorder
Journal: Journal of Investigative Dermatology JID
Authors: D. M. Leslie Pedrioli, D. Jack Fu, E. Gonzalez-Gonzalez, C. H. Contag, R. L. Kaspar, F. J.D. Smith, W. H. I. McLean
Volume: 132, Pages: 1627-1635

Abstract:

Epidermolytic palmoplantar keratoderma (EPPK) is one of 430 autosomal-dominant human keratinizing disorders that could benefit from RNA interference (RNAi)-based therapy. EPPK is caused by mutations in the keratin 9 (KRT9) gene, which is exclusively expressed in thick palm and sole skin where there is considerable keratin redundancy. This, along with the fact that EPPK is predominantly caused by a few hotspot mutations, makes it an ideal proof-of-principle model skin disease to develop gene-specific, as well as mutation-specific, short interfering RNA (siRNA) therapies. We have developed a broad preclinical RNAi-based therapeutic package for EPPK containing generic KRT9 siRNAs and allele-specific siRNAs for four prevalent mutations. Inhibitors were systematically identified in vitro using a luciferase reporter gene assay and validated using an innovative dual-Flag/Strep-TagII quantitative immunoblot assay. siKRT9-1 and siKRT9-3 were the most potent generic K9 inhibitors, eliciting 485% simultaneous knockdown of wild-type and mutant K9 protein synthesis at picomolar concentrations. The allele-specific inhibitors displayed similar potencies and, importantly, exhibited strong specificities for their target dominant-negative alleles with little or no effect on wild-type K9. The most promising allele-specific siRNA, siR163Q-13, was tested in a mouse model and was confirmed to preferentially inhibit mutant allele expression in vivo.

Title: In vivo gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation
Journal: J Control Release
Authors: V. Hegde, R.P. Hickerson, S. Nainamalai, P.A. Campbell, F. J. Smith, W.H. McLean, D. M. Pedrioli
Volume: 196, Pages: 355-362

Abstract:

Therapeutics based on short interfering RNAs (siRNAs), which act by inhibiting the expression of target transcripts, represent a novel class of potent and highly specific next-generation treatments for human skin diseases. Unfortunately, the intrinsic barrier properties of the skin combined with the large size and negative charge of siRNAs make epidermal delivery of these macromolecules quite challenging. To help evaluate the in vivo activity of these therapeutics and refine delivery strategies we generated an innovative reporter mouse model that predominantly expresses firefly luciferase (luc2p) in the paw epidermis--the region of murine epidermis that most closely models the tissue architecture of human skin. Combining this animal model with state-of-the-art live animal imaging techniques, we have developed a real-time in vivo analysis work-flow that has allowed us to compare and contrast the efficacies of a wide range nucleic acid-based gene silencing reagents in the skin of live animals. While inhibition was achieved with all of the reagents tested, only the commercially available "self-delivery" modified Accell-siRNAs (Dharmacon) produced potent and sustained in vivo gene silencing. Together, these findings highlight just how informative reliable reporter mouse models can be when assessing novel therapeutics in vivo. Using this work-flow, we developed a novel clinically-relevant topical formulation that facilitates non-invasive epidermaldelivery of unmodified and "self-delivery" siRNAs. Remarkably, a sustained >40% luc2p inhibition was observed after two 1-hour treatments with Accell-siRNAs in our topical formulation. Importantly, our ability to successfully deliver siRNA molecules topically brings these novel RNAi-based therapeutics one-step closer to clinical use.

KEYWORDS:

Filaggrin; Luciferase reporter mouse model; Propylene glycol (PubChem CID: 1030); RNAi-based therapeutics; Topical formulation; Transepidermal siRNA delivery

Title: Keratins and disease at a glance
Journal: J Cell Sci
Authors: R.L. Haines, E.B. Lane
Volume: 125, Section: 17, Pages: 3923-8

Title: Efficacy of botulinum toxin in pachyonychia congenita type 1: report of two new cases
Journal: Dermatol Ther
Authors: J. Gonz

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis caused by a mutation in keratin genes, which can lead to hypertrophic nail dystrophy and focal palmoplantar keratoderma (predominantly plantar), amongst other manifestations. Painful blisters and callosities, sometimes exacerbated by hyperhidrosis, are major issues that can have a significant impact on patient quality of life. Many alternative treatments for this condition have been applied with variable and partial clinical response, but a definitive cure for this disease has yet to be discovered. After obtaining informed consent, two patients with genetically confirmed PC type 1 were treated with plantar injections of botulinum toxintype A. Both patients showed a marked improvement in pain and blistering with an average response time of one week, a six-month mean duration of effectiveness, and a lack of any side effects or tachyphylaxis.

botulinum toxin; hyperhidrosis; pachyonychia congenita

Title: Steatocystoma multiplex is associated with the R94C mutation in the KRTl7 gene
Journal: Mol Med Rep
Authors: Q. Liu, W. Wu, J. Lu, P. Wang, F. Qiao
Volume: 12, Section: 4, Pages: 5072-6

Abstract:

Steatocystoma multiplex (SM) is an uncommon disorder, characterized by numerous skin‑colored subcutaneous cysts. A number of SM pedigrees have been identified with mutations in the keratin 17 (KRT17) gene. The present study examined a four‑generation Chinese pedigree with an autosomal dominant mode of inheritance and examined its genetic basis. A review of the literature on KRT17 gene mutations in the SM pedigree was also performed to investigate the KRT17 genemutation and genotype‑phenotype correlation. Exon 1 of the KRTl7 gene was amplified using polymerase chain reaction (PCR) from genomic DNA obtained, which was obtained from 25 family members in the selected Chinese pedigree and from 100 unrelated control individuals. The DNA was then subjected to automatic DNA sequencing. Genealogical investigations demonstrated an autosomal dominant pattern, and direct sequencing of the PCR product revealed a heterozygousmutation, c.280C/T (R94C), which was located in exon 1 of the KRT17 gene in all 10 affected family members. The mutation was not identified in the 15 unaffected family members or in the 100 unrelated control individuals. Therefore, the present study identified a causative mutation in the KRT17 gene in a large Chinese SM pedigree, exhibiting autosomal dominance. A review of the literature suggested that, in addition to the mutation factor, other modifying factors contribute to the phenotype of familial SM.

Title: Jadassohn Lewandowsky Syndrome: A Rare Entity
Journal: Indian J. Dermatol
Authors: A.M. Prasad, Y. Inakanti, S. Kumar
Volume: 60, Section: 5, Pages: 524

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis, and cystic lesions. It is classically subdivided into two major variants, PC-1 (Jadassohn-Lewandowski syndrome) and PC-2 (Jackson-Lawler syndrome), according to the localization of the mutations in the KRT6A/KRT16 or KRT6B/KRT17 genes, respectively. We report a 9-year-old male patient with a history of thickened, discolored nails, raised spiny skin lesions all over the body since birth with focal plantar keratoderma and absence of natal teeth.

KEYWORDS:

Jadassohn–Lewandowski syndrome; keratins; nails; pachyonychia congenita; palmoplantar keratoderma

Title: Nucleic acid delivery into skin for the treatment of skin disease: Proofs-of-concept, potential impact, and remaining challenges
Journal: J Control Release
Authors: M. Zakrewsky, S. Kumar, S. Mitragotri
Volume: 219, Pages: 445-56

Abstract:

Nucleic acids (NAs) hold significant potential for the treatment of several diseases. Topical deliveryof NAs for the treatment of skin diseases is especially advantageous since it bypasses thechallenges associated with systemic administration which suffers from enzymatic degradation, systemic toxicity and lack of targeting to skin. However, the skin's protective barrier function limits the delivery of NAs into skin after topical application. Here, we highlight strategies for enhancingdelivery of NAs into skin, and provide evidence that translation of topical NA therapies could have a transformative impact on the treatment of skin diseases.

KEYWORDS:

Dermal drug delivery; Nucleic acids; Skin disease

Title: Pachyonychia Congenita (K16) with Unusual Features and Good Response to Acitretin
Journal: Case Rep Dermatol
Authors: F. Almutawa, T. Thusaringam, K. Watters, T. Gayden, N. Jabado, D. Sasseville
Volume: 7, Section: 2, Pages: 220-6

Abstract:

BACKGROUND:

Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new classification is based on genetic variants with mutations in keratin KRT6A, KRT6B, KRT6C, KRT16, KRT17, and an unknown mutation. Here, we present a case of PC with unusual clinical and histological features and a favorable response to oral acitretin.

CASE:

A 49-year-old male presented with diffuse and striate palmoplantar keratoderma, thickened nails, knuckle pads, and pseudoainhum. Histology showed compact hyperkeratosis, prominent irregular acanthosis, and extensive epidermolytic hyperkeratosis, suggestive of Vörner's palmoplantar keratoderma. However, keratin 9 and 1 were not mutated, and full exome sequencing showed heterozygous missense mutation in type I keratin K16.

CONCLUSION:

To our knowledge, epidermolytic hyperkeratosis has not been previously described with PC. Our patient had an excellent response, maintained over the last 5 years, to a low dose ofacitretin. We wish to emphasize the crucial role of whole exome sequencing in establishing the correct diagnosis.

KEYWORDS:

Exome sequencing; Pachyonychia congenita; Palmoplantar keratoderma

Title: A case of pachyonychia congenita with unusual manifestations: an unusual type or a new syndrome?
Journal: International Journal of Dermatology
Authors: M. Gonul; U. Gul; A. Kilic; S. Soylu; O. Kocak; M. Demiriz
Volume: 54, Pages: 334-337

Abstract:

A 30-year-old man presented with lesions on his oral mucosa and soles. There were nosimilar complaints in his family members. The dermatological examination revealedfollicular hyperkeratosis on his trunk and upper extremities and flesh-colored, firm cysticlesions on his axillae. He had focal, painful, hyperkeratotic areas sited particularly on bothhis soles and palms. In addition to these, leukokeratosis and ulcerative areas on buccal,labial mucosa, tongue, and at corners of the mouth, and complete loss of teeth wasobserved. The proximal layering was revealed on all of his nails. The laboratoryinvestigations produced normal results except the deficiency of immunoglobulin A. Thepsychiatric examination revealed mild mental retardation. Keratin gene (KRT6a, KRT6b,KRT16, and KRT17) mutations for pachyonychia congenita were negative. He gotremovable dental prosthesis because of inadequate alimentation. Squamous cell cancerdeveloped on lower lip mucosa during follow-up. We present an individual who haddifferent nail dystrophy, epidermal cysts, mental retardation, blepharitis, complete loss ofteeth, and negative keratin gene mutations for pachyonychia congenita and developedsquamous cell cancer on the oral leukokeratosis lesions. We think that the present casemay be an unusual new type of pachyonychia congenita.

Title: Novel and recurrent mutations in the 1B domain of keratin 1 in palmoplantar keratoderma with tonotubules
Journal: British Journal of Dermatology
Authors: G. Grimberg; I. Hausser; F.B. Muller; K. Wodecki; C. Schaffrath; T. Krieg; V. Oji; H. Traupe; M.J. Arin
Volume: 160, Pages: 446-449

Title: Mutation S233L in the 1B Domain of Keratin 1 Causes Epidermolytic Palmoplantar Keratoderma with "Tonotubular" Keratin
Journal: Journal of Investigative Dermatology
Authors: A. Terron-Kwiatkowski, M. van Steensel, M. van Geel, E. B. Lane, W.H.I. McLean, P.M. Steijlen
Volume: 126, Pages: 607-613

Abstract:

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis restricted to the palm and sole epidermis. The disorder is normally associated with dominant-negative mutations in the keratin 9 (K9) gene; however, a small number of cases have been reported where causative mutations were identified in the K1 gene. Here, we present two unrelated Dutch EPPK families with striking ultrastructural findings: tubular keratin structures in the cytoplasm of suprabasal cells. Similar structures were reported previously in a German EPPK family and were termed "tonotubular" keratin. After excluding the involvement of the K9 gene by complete sequencing, we identified a novel mutation, S233L, at the beginning of the 1B domain of K1 in both families. Protein expression studies in cultured cells indicated pathogenicity of this mutation. This is the first report of a genetic defect in this domain of K1. The unusual gain-of-function mutation points to a subtle role of the 1B domain in mediating filament–filament interactions with regular periodicity.

Title: Mutations in GJB6 causing phenotype resembling pachyonychia congenita
Journal: British Journal of Dermatology
Authors: G.I. Hale; N.J. Wilson; F.J.D. smith; G. Wylie; M.E. Schwartz; M. Zamiri

Title: Disease Classification Using Clinical and Molecular Features
Journal: The Journal of Dermatology
Authors: E. Sprecher; M.E. Schwartz; D. Hansen; F.J.D. Smith
Volume: 41, Section: 10, Pages: 949

Abstract:

We read with great interest the report by Guo et al.1 on a
patient displaying nail thickening, palmoplantar keratoderma,
corneal hyperemia and alopecia, which they refer to as pachyonychia
(PC) unknown.

Title: Disease Classification Using Clinical and Molecular Features
Journal: The Journal of Dermatology
Authors: E. Sprecher; M.E. Schwartz; D. Hansen; F.J.D. Smith
Volume: 41, Section: 10, Pages: 949

Abstract:

We read with great interest the report by Guo et al.1 on a
patient displaying nail thickening, palmoplantar keratoderma,
corneal hyperemia and alopecia, which they refer to as pachyonychia
(PC) unknown.

Title: Pachyonychia Congenita
Journal: Orphanet
Authors: R. Kaspar; M. Schwartz; F. Smith; E. Sprecher

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and whitish oral mucosa.

The prevalence is not known but approximately 1000 patients have been registered to date worldwide.

For full Article visit: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2309

Title: Pachyonychia Congenita
Journal: Orphanet
Authors: R. Kaspar; M. Schwartz; F. Smith; E. Sprecher

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and whitish oral mucosa.

The prevalence is not known but approximately 1000 patients have been registered to date worldwide.

For full Article visit: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2309

Title: Visualization of plasmid delivery to keratinocytes in mouse and human epidermis
Journal: Scientific Reports
Authors: E. Gonzalez; Y.C. Kim; T.J. Speaker; R.P. Hickerson; R. Spitler; J.C. Birchall; M.F. Lara; R.H. Hu; Y. Liang; N. Kirkiles-Smith; M.R. Prausnitz; L.M. Milstone; C.H. Contag; R.L. Kaspar
Volume: 1, Section: 158,

Abstract:

The accessibility of skin makes it an ideal target organ for nucleic acid-based therapeutics; however, effective patient-friendly delivery remains a major obstacle to clinical utility. A variety of limited and inefficient methods of delivering nucleic acids to keratinocytes have been demonstrated; further advances will require well-characterized reagents, rapid noninvasive assays of delivery, and well-developed skin model systems. Using intravital fluorescence and bioluminescence imaging and a standard set of reporter plasmids we demonstrate transfection of cells in mouse and human xenograft skin using intradermal injection and two microneedle array delivery systems. Reporter gene expression could be detected in individual keratinocytes, in real-time, in both mouse skin as well as human skin xenografts. These studies revealed that non-invasive intravital imaging can be used as a guide for developing gene delivery tools, establishing a benchmark for comparative testing of nucleic acid skin delivery technologies.

Title: Gene Expression Profiling in Pachyonychia Congenita Skin
Journal: Journal of Dermatological Science
Authors: Y. Cao, R.P. Hickerson, B.L. Seegmiller, D. Grapov, M.M. Gross, M.R. Bessette, B.S. Phinney, M.A. Flores, T.J. Speaker, A. Vermeulen, A.A. Bravo, A.L. Bruckner, L.M. Milstone, M.E. Schwartz, R.H. Rice, R.L. Kaspar

Abstract:

BACKGROUND:

Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear.

OBJECTIVE:

To better understand PC pathogenesis.

METHODS:

RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples.

RESULTS:

A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis.

CONCLUSION:

Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics

Title: Pachyonychia Congenita
Journal: Genodermatoses
Authors: J. Spitz
Pages: 294-296

Title: Pachyonychia Congenita
Journal: Genetic Skin Disorders
Authors: V. Sybert
Pages: 248

Abstract:

Chapter from Textbook.

Title: From patients to partners: participant-centric initiatives in biomedical research
Journal: Nature Reviews Genetics
Authors: J. Kaye; L. Curren; N. Anderson; K. Edwards; S.M. Fullerton; N. Kanellopoulou; D. Lund; D.G. MacArthur; D. Mascalzoni; J. Shepherd; P.L. Taylor; S.F. Terry and S.F. Winter
Volume: 13, Section: 5, Pages: 371-6

Abstract:

Advances in computing technology and bioinformatics mean that medical research is increasingly characterized by large international consortia of researchers that are reliant on large data sets and biobanks. These trends raise a number of challenges for obtaining consent, protecting participant privacy concerns and maintaining public trust. Participant-centred initiatives (PCIs) use social media technologies to address these immediate concerns, but they also provide the basis for long-term interactive partnerships. Here, we give an overview of this rapidly moving field by providing an analysis of the different PCI approaches, as well as the benefits and challenges of implementing PCIs.

Title: The National Registry for Ichthyosis and Related Disorders Will Cease Operation after 2012
Journal: Journal of Investigative Dermatology
Authors: P. Fleckman
Volume: 132, Section: 7, Pages: 1745

Title: In Vivo Assessment of Gene Delivery to Keratinocytes by Lentiviral Vectors
Journal: Journal of Virology
Authors: U. Kuhn; A. Terunuma; W. Pfutzner; R.A. Foster; and J.C. Vogel
Volume: 76, Section: 3, Pages: 1496-1504

Abstract:

For skin gene therapy, introduction of a desired gene into keratinocyte progenitor or stem cells could overcome the problem of achieving persistent gene expression in a significant percentage of keratinocytes. Although keratinocyte stem cells have not yet been completely characterized and purified for gene targeting purposes, lentiviral vectors may be superior to retroviral vectors at gene introduction into these stem cells, which are believed to divide and cycle slowly. Our initial in vitro studies demonstrate that lentiviral vectors are able to efficiently transduce nondividing keratinocytes, unlike retroviral vectors, and do not require the lentiviral accessory genes for keratinocyte transduction. When lentiviral vectors expressing green fluorescent protein (GFP) were directly injected into the dermis of human skin grafted onto immunocompromised mice, transduction of dividing basal and nondividing suprabasal keratinocytes could be demonstrated, which was not the case when control retroviral vectors were used. However, flow cytometry analysis demonstrated low transduction efficiency, and histological analysis at later time points provided no evidence for progenitor cell targeting. In an alternative in vivo method, human keratinocytes were transduced in tissue culture (ex vivo) with either lentiviral or retroviral vectors and grafted as skin equivalents onto immunocompromised mice. GFP expression was analyzed in these human skin grafts after several cycles of epidermal turnover, and both the lentiviral and retroviral vector-transduced grafts had similar percentages of GFP-expressing keratinocytes. This ex vivo grafting study provides a good in vivo assessment of gene introduction into progenitor cells and suggests that lentiviral vectors are not necessarily superior to retroviral vectors at introducing genes into keratinocyte progenitor cells during in vitro culture.

Title: The Majority of Keratinocytes Incorporate Intradermally Injected Plasmid DNA Regardless of Size but Only a Small Proportion of Cells Can Express the Gene Product
Journal: Journal of Investigative Dermatology
Authors: D. Sawamura; K. Yasukawa; K. Kodama; K. Yokota; K.C. Sato-Matsumura; T. Toshihiro; and H. Shimizu
Volume: 118, Section: 6, Pages: 967-971

Abstract:

The expression of intradermally injected DNA by keratinocytes is found mainly in the upper and middle layers of the epidermis. To investigate the mechanism of this selective expression, we observed the sequential changes in the distribution of interleukin-6-expressing keratinocytes after the introduction of the interleukin-6 gene. Transgene expression first occurred in basal keratinocytes and subsequently expanded to all epidermal layers and then remained in the upper layers. Semiquantitative analysis indicated that keratinocytes in the lower layers incorporated and lost DNA earlier than those in the upper layers. In order to examine the effect of the DNA size on the transgene expression, we constructed a plasmid containing a full-length 9 kb cDNA of type VII collagen and introduced it into keratinocytes. The expression pattern of type VII collagen in the epidermis was the same as those for smaller genes. This suggests that plasmid size has little or no effect on the expression pattern of the transfected gene. To trace the introduced plasmid, we intradermally injected a green fluorescence protein expression plasmid coupled with a rhodamine flag. Almost all keratinocytes in the injected areas showed rhodamine fluorescence. Furthermore, some cells also expressed green fluorescence protein. A lack of rhodamine fluorescence in the nucleus suggested an impairment of plasmid DNA transport from the cytoplasm to the nucleus. Collectively, our results show that the majority of keratinocytes take up the intradermally injected DNA regardless of its size, but that the transfer of DNA from the cytoplasm to the nucleus is limiting the transgene expression.

Title: Promoter/Enhancer Cassettes for Keratinocyte Gene Therapy
Journal: Journal of Investigative Dermatology
Authors: D. Sawamura; X. Meng; S. Ina; H. Nakano; K. Tamai; K. Nomura; K. Hanada; J.I. Miyazaki; I. Hashimoto
Volume: 112, Section: 5, Pages: 828-830

Title: Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo
Journal: PNAS
Authors: W. Pfutzner; A. Terunuma; C.L. Tock; E.K. Snead; T.M. Kolodka; M.M. Gottesman; L. Taichman; and J.C. Vogel
Volume: 99, Section: 20, Pages: 13096-13101

Abstract:

In gene therapy, a clinically relevant therapeutic effect requires long-term expression of the desired gene at a level sufficient to correct or at least alleviate the underlying gene defect. One approach to achieve persistent as well as high-level transgene expression in a significant percentage of target cells would be to select cells expressing both the desired transgene and a linked selectable gene--such as the human multi-drug resistance (MDR1) gene--in a bicistronic vector. Because of its accessibility, the skin is a very attractive target tissue to select genetically modified cells, allowing topical application of a selecting agent, thus minimizing potential toxic side effects. Among the potential selecting drugs, agents that block cell division, such as colchicine, are of particular interest because the use of anti-mitotic drugs takes advantage of the rapid keratinocyte (KC) turnover in the epidermis and the need for continued proliferation to substitute the KC lost due to selection. Before assessing the therapeutic benefit of such an approach, several key questions need to be answered in preclinical models: (1) Does topical colchicine application achieve the desired in vivo effect by blocking KC mitosis without eliciting unwanted toxic side effects? (2) Are MDR-transduced (MDR+) human KC still able to proliferate and differentiate when treated with colchicine? (3) Can MDR+ KC be enriched by topical selection? (4) Does topical selection result in persistent transgene expression by selecting KC stem cells expressing MDR? To answer these questions and to test the feasibility of such an approach both an in vitro skin equivalent and an in vivo human skin graft model were developed in which MDR+ KC were treated with different dosages of colchicine. Quantitative and qualitative analyses of MDR expression in human KC showed that topical colchicine treatment selects high-level transgene expression in a high percentage of KC. Moreover, determination of transgene copy numbers demonstrated that MDR+ KC progenitor cells were enriched by topical selection resulting in long-term expression of the transgene in the skin. Thus, in summary, these models demonstrate that topical selection of MDR+ KC is a safe approach to efficiently enhance long-term gene expression in the skin and holds future promise for clinical gene therapy applications.

Title: Immune-Mediated Loss of Transgene Expression in Skin: Implications for Cutaneous Gene Therapy
Journal: Molecular Therapy
Authors: S. Ghazizadeh; R.S. Kalish; and L.B. Taichman
Volume: 7, Section: 3, Pages: 296-303

Abstract:

A clearer understanding of the immune-mediated loss of transgene from cutaneous epithelium is necessary for development of effective clinical gene therapy protocols for patients who carry null mutations in the target gene. We have used retrovirus-mediated transfer of lacZ to mouse skin as a model to investigate the mechanism of immune-mediated transgene loss in skin. Transduction of C57Bl/6 mouse skin resulted in elicitation of both humoral and cellular immune responses. Antibody responses did not play a major role in the loss of transgene. Infiltration of the transduced skin with CD4(+) and CD8(+) cells and induction of transgene-specific cytotoxic T lymphocytes implied a role for T-cell-mediated responses. Transduction of mice deficient in either major histocompatibility complex (MHC) class I or class II molecules resulted in transient transgene expression. Only in MHC(-/-) mice lacking expression of both class I and class II MHC molecules was persistent transgene expression seen. These data indicate a primary role for T-cell-mediated responses in the immune-mediated loss of transgene expression. Furthermore, CD4 and CD8 T cells have overlapping roles and either population can effectively eliminate transduced cells. Therefore, long-term cutaneous gene therapy may require development of strategies to interfere with activation or function of both T cell populations

Title: Direct injection of naked DNA and cytokine transgene expression: implications of Keratinocyte gene therapy
Journal: Clinical and Experimental Dermatology
Authors: D. Sawamura; M. Akiyama; and H. Shimizu
Volume: 27, Pages: 480-484

Abstract:

Intradermally injected DNA diffuses into the epidermis and can then enter keratinocytes and become expressed by these cells. Using this method, plasmids containing cytokine genes that have been introduced into keratinocytes can induce a level of cytokine expression sufficient to provide biological effects in the treated skin. Furthermore, transgenic cytokines released from the transduced keratinocytes can also enter the circulation and have downstream effects on other target organs. Thus far, naked DNA injection appears to be a safe, simple, and relatively efficient method that enables genes to be expressed in transplanted human skin on immunosuppressed animals. In humans, keratinocyte gene therapy using the cytokine gene DNA injection method has the potential to become a powerful therapeutic tool for dermatologists in the management of certain inflammatory and other dermatoses.

Title: cDNA Cloning, Expression, and Assembly Characteristics of Mouse Keratin 16
Journal: Journal of Biological Chemistry
Authors: R.M. Porter; A.M. Hutcheson; E.L. Rugg; R.A. Quinlan; and E.B. Lane
Volume: 273, Section: 48, Pages: 32265-32272

Abstract:

There has been speculation as to the existence of the mouse equivalent of human type I keratin 16 (K16). The function of this keratin is particularly intriguing because, in normal epidermis, it is usually confined to hair follicles and only becomes expressed in the suprabasal intrafollicular regions when the epidermis is traumatized. Previous studies suggested that K16 is highly expressed in the skin of mice carrying a truncated K10 gene. We therefore used the skin of heterozygous and homozygous mice to create a cDNA library, and we report here the successful cloning and sequencing of mouse K16. Recent in vitro studies suggested that filaments formed by human K16 are shorter than those formed by other type I keratins. One hypothesis put forward was that a proline residue in the 1B subdomain of the helical domain was responsible. The data presented here demonstrate that this proline is not conserved between mouse and human, casting doubt on the proposed function of this proline residue in filament assembly. In vitro assembly studies showed that mouse K16 produced long filaments in vitro. Also, in contrast to previous observations, transfection studies of PtK2 cells showed that mouse K16 (without the proline) and also human K16 (with the proline) can incorporate into the endogenous K8/K18 network without detrimental effect. In addition, K16 from both species can form filaments de novo when transfected with human K5 into immortalized human lens epithelial cells, which do not express keratins. These results suggest that reduced assembly capabilities due to unusual sequence characteristics in helix 1B are not the key to the unique function of K16. Rather, these data implicate the tail domain of K16 as the more likely protein domain that determines the unique functions.

Title: Keratinocyte gene therapy: inducible promoters and in vivo control of transgene expression
Journal: Clinical and Experimental Dermatology
Authors: K. Itai; D. Sawamura; X. Meng; I. Hashimoto
Volume: 26, Pages: 531-535

Abstract:

Modulation of transgene expression by exogenous agents is an optimal goal in gene therapy. Successful keratinocyte gene therapy requires a promoter-enhancer cassette to regulate expression of the therapeutic gene in vivo. In this study, we first transferred plasmids, constructed by introducing inducible promoters fused to the beta-galactosidase gene (LAC Z), into keratinocytes in vitro. Metallothionein (MT) and 1,24-vitamin D(3)(OH)(2) dehydroxylase (VDH) promoters responded to the inducing agents, Cadmium and 1,25-vitamin D(3)(OH)(2) (VitD(3)), respectively. The plasmids were then introduced in vivo using a naked DNA method and the inducible promoters were evaluated by measuring beta-gal activity in rat keratinocytes. Zinc induced the transferred MT promoter activity by approximately 2-fold or 10-fold when administered systemically and topically, respectively. In addition, VitD(3) induced the transferred VDH promoter activity approximately 10-fold when administered topically. These data are useful for developing inducible promoters for keratinocyte gene therapy.

Title: Diffuse Nonepidermolytic Palmoplantar Keratoderma Caused by a Recurrent Nonsense Mutation in DSG1
Journal: Arch Deratol
Authors: H. Keren; R. Bergman; M. Mizrachi; Y. Kashi; E. Sprecher
Volume: 141, Pages: 625-628

Title: Reaction of Keratinocytes to Exogenous DNA
Journal: Cells Tissues Organs
Authors: A. Mirmohammadsadegh; J. Maschke; E. Basner-Tschakarjan; A. Bar; U.R. Hengge
Volume: 172, Pages: 86-95

Abstract:

Keratinocytes have the ability to take up oligonucleotides (ODN) and plasmid DNA probably by receptor-mediated endocytosis or macropinocytosis. Despite the use of DNA for antisense and gene therapy, little is known about the regulation of genes following exposure to nucleic acids. To systematically identify gene regulation in keratinocytes upon exposure to ODN, we screened human cytokine DNA arrays containing 383 different genes and found interleukin-1 alpha (IL-1 alpha), IL-1 beta, integrin beta1, alpha tubulin and follistatin greatly induced, while most genes were unaffected. The time course and concentration dependence for IL-1 alpha and follistatin was confirmed by the standard Northern blot technique and found to be induced by picomolar or femtomolar concentrations of ODN. ODN of different length and sequence induced comparable amounts of IL-1 alpha and follistatin. Their induction was independent of the negative charge and of several proinflammatory compounds and proteins such as lipopolysaccharides, IL-1 beta or IFN-gamma, but was partly inhibited by activin A. In summary, our study revealed several genes of the acute phase protein family that were induced in a non-sequence specific manner following the exposure of normal human keratinocytes to ODN. Therefore, it is tempting to speculate that, upon internalization, ODN bind to an intracellular receptor (e.g. Toll like receptor 9), which mediates signaling.

Title: Mutations in the desmoglein 1 gene in five Pakistani families with striate palmoplantar keratoderma
Journal: Journal of Dermatological Science
Authors: M.B. Dua-Awereh; Y. Shimomura; L. Kraemer; M. Wajid; A.M. Christiano
Volume: 53, Pages: 192-197

Abstract:

Background: Striate palmoplantar keratoderma (SPPK; OMIM #148700) is a rare autosomal dominant genodermatosis characterized by linear hyperkeratosis on the digits and hyperkeratosis on the palms and soles. SPPK is known to be caused by heterozygous mutations in either the desmoglein 1 (DSG1), desmoplakin (DSP), or keratin 1 (KRT1) genes.

Title: Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma
Journal: European Journal of Human Genetics
Authors: D.M. Hunt; L. Rickman; N.V. Whittock; R.A. Eady; D. Simrak; P.J. Dopping-Hepenstal; H.P. Stevens; D.K.B. Armstrong; H.C. Hennies; W. Kuster; A.E. Hughes; J. Arnemann; I.M.Leigh; J.A. McGrath; D.P.Kelsell; R.S. Buxton
Volume: 9, Pages: 197-203

Abstract:

The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon.

Title: Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome
Journal: British Journal of Dermatology
Authors: J.E. Lai-Cheong; G. Sethuraman; M. Ramam; K. Stone; M.A. Simpson; and J.A. McGrath
Volume: 167, Pages: 440-442

Abstract:

Olmsted syndrome (OS) is a rare genodermatosis characterized by extensive palmoplantar and periorificial keratoderma, alopecia in most cases, and itching. t Other clinical featnres can include autoamputation of digits , oral leucoplakia and onychodystrophy. The condition is often difficult to diagnose because of its rarity (fewer than 50 published cases), its clinical overlap with various ectodermal dysplasias and disorders of kerati nization (e. g. keratosis-ichthyosis-cieafness syndrome), 2 and an uncertain mode of inheritance (autosomal dominant, X-linked dominant or recessive, and sporadic) . Moreover, the lack of a clear clinical and genetic basis to OS has meant that UJ1[il recently did not have lacks an Online Mendelian Inheri· tance in Man (OMIM) reference number. However, Olmsted syndrome is now recognised as a discrete entity (OMIM 6 14594). Here, we describe a further clinical case of OS as well as delineation of the tmderlying generic patll010gy.
 

Title: Pachyonychia congenita with involvement of the larynx
Journal: Acta Otorrinolaringologica Espanola
Authors: H. Rodriguez; G. Cuestas; A. Zanetta; Z. Balbarrey

Abstract:

Paciente de sexo masculino de 2 a˜nos, con hiperqueratosis subungueal y engrosamiento y decoloración marrón-amarillento de la lámina ungueal de sus 20 u˜nas y leucoplasia lingual desde los primeros meses de vida, consulta al Servicio de Endoscopia Respiratoria por presentar disfonía desde los 10 meses de edad (fig. 1). Su bisabuela materna, abuela materna, madre, tío y hermana presentan paquioniquia congénita (PC). El paciente es el más joven de los 6 miembros de la familia con este trastorno que abarca 4 generaciones.

Title: Report of the 10th Annual International Pachyonychia Congenita Consortium Meeting
Journal: Journal of Investigative Dermatology
Authors: M.A.M. van Steensel; P.A. Coulombe; R.L. Kaspar; L.M. Milstone; I.W.H. McLean; D.R. Roop; F.J.D. Smith; E. Sprecher; M.E. Schwartz
Volume: 134, Pages: 588-591

Title: New Described Dermatological Disorders.
Journal: BioMed Research International
Authors: Gonul M, Cevirgen Cemil B, Keseroglu HO, Kaya Akis H.
Volume: 2014, Pages: 13

Abstract:

Many advances in dermatology have been made in recent years. In the present review article, newly described disorders from the last six years are presented in detail. We divided these reports into different sections, including syndromes, autoinflammatory diseases, tumors, and unclassified disease. Syndromes included are "circumferential skin creases Kunze type" and "unusual type of pachyonychia congenita or a new syndrome"; autoinflammatory diseases include "chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome," "pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome," and "pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) syndrome"; tumors include "acquired reactive digital fibroma," "onychocytic matricoma and onychocytic carcinoma," "infundibulocystic nail bed squamous cell carcinoma," and "acral histiocytic nodules"; unclassified disorders include "saurian papulosis," "symmetrical acrokeratoderma," "confetti-like macular atrophy," and "skinspicules," "erythema papulosa semicircularis recidivans."

Title: Pachyonychia congenita with corneal dystrophy
Journal: The Journal of Dermatology
Authors: Guo H, Liu D, Wu J, Liao Q, Bai Y
Volume: 40, Section: 8, Pages: 681-682

Title: Pachyonychia Congenita Cornered: Report on the 11th Annual International Pachyonychia Congenita Consortium Meeting.
Journal: British Journal of Dermatology
Authors: E.A. O'Toole, R.L. Kaspar, E. Sprecher, M.E. Schwartz, L. Rittie

Abstract:

The 11th annual meeting of the International Pachyonychia Congenita Consortium (IPCC) was held on May 6th, 2014 in Albuquerque, NM, USA. The consortium regroups physicians and scientists who contribute their expertise and time to developing therapeutics for the rare orphan disease pachyonychia congenita (PC), an autosomal dominant genodermatosis caused by mutations in keratin (K)6a, K6b, K6c, K16, or K17. PC's main clinical features include highly debilitating pain accompanying plantar keratoderma, hypertrophic nail dystrophy, oral leukokeratosis, and epidermal cysts.

This article is protected by copyright. All rights reserved.

Title: Response to the Commentary
Journal: Journal of Investigative Dermatology
Authors: Liz Horn, Marin Aurand, Mary E. Schwartz and Sharon F. Terry
Volume: 133, Section: 5, Pages: 1361

Abstract:

Response to the commentary "Significance of patient registries for dermatological disorder".

Title: First case of pachyonychia congenita in the Czech Republic
Journal: Dermatologic Therapy
Authors: Anna Jirakova, Lucie Rajska, Filip Rob, Martina Dzambova, Zuzana Sec nikova, Dana Gopfertova, Mary Schwartz, Frances Smith, Torello Lotti & Jana Hercogova

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by hypertrophic nail dystrophy, oral leukokeratosis, and painful palmoplantar keratoderma. It is associated with a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The International PC Research Registry (IPCRR) confirms that as of January 2014 there have been 547 cases of PC genetically confirmed. It is estimated that there are between 2000 and 10,000 cases of PC in the world. However, the exact prevalence of PC is not yet established. We report a case of PC-K6a, p.Arg164Pro, in a 40-year-old man. Initially he was diagnosed with onychomycosis and was treated with systemic antifungals. This is the first genetically confirmed case of PC in the Czech Republic.

© 2014 Wiley Periodicals, Inc.

Title: Familial pachyonychia congenita with steatocystoma multiplex and multiple abcesses of the scalp due to the p.Asn92Ser mutation in keratin 17
Journal: British Journal of Dermatology
Authors: J. Ofaiche; S. Duchatelet; S. Fraitag; A. Nassif; J. Nougue; A. Hovnanian

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis transmitted as an autosomal dominant trait, caused by mutations in the differentiation-specific keratin genes KRT6a (52%), KRT6b (3%), KRT16 (28%) or KRT17 (17%) which are expressed in the nails, skin, oral mucosa, larynx, hair and teeth. Approximately 1000 patients with PC have been identified, of which 400 have been confirmed genetically. Two sub-types have been classically described: PC-1 (Jadassohn-Lewandowsky type, OMIM#167200), caused by KRT6a or KRT16 mutations, with predominant oral leucokeratosis and palmoplantar keratoderma, and PC-2 (Jackson-Lawler type, OMIM#167210) resulting from KRT6b or KRT17 mutations, with neonatal teeth, pili torti and multiple cysts.2,3 The presence of multiple sebaceous cysts (steatocystoma multiplex (SM)) at puberty has been proposed to differentiate PC-2 from PC-12,3 , but it is now recognized that there is a considerable overlap between the two classical sub-types of PC, and a new classification based on the mutated keratin gene has now been proposed (PC-6a, PC-6b, PC-16 and PC-17). This article is protected by copyright. All rights reserved.

Title: The molecular genetic analysis of the expanding pachyonychia congenita case collection
Journal: Br J Dermatol
Authors: N.J. Wilson; E. O'Toole; L.M. Milston; C.D. Hansen; A.A. Shepherd; E. Ali-Asadi; M.E. Schwartz; W.H. McLean; E. Sprecher; F.J. Smith
Volume: [Epub ahead of ,

Abstract:

Abstract

BACKGROUND:

Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma (PPK) and nail dystrophy, often accompanied by oral leukokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes; KRT6A, KRT6B, KRT6C, KRT16 or KRT17.

OBJECTIVES:

To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry (IPCRR) during the last few years.

METHODS:

Genomic DNA isolated from saliva or peripheral blood leukocytes was amplified using primers specific for the PC associated keratin genes and PCR products were directly sequenced.

RESULTS:

Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105.

CONCLUSIONS:

This study has confirmed at the molecular level the clinical diagnosis of PC in these families, by identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved. keratin mutation, keratins, nail dystrophy, pachyonychia congenita, palmoplantar keratoderma, plantar pain

Title: Impaired wound healing and cheilitis in a Pachyonychia Congenita K6a family
Journal: J Eur Acad Dermatol Venereol
Authors: M.C. Winge; M. Bradley; E. Bjorck
Volume: [Epub ahead of ,

Abstract:

Pachyonycia Congenita (PC) is a rare autosomal dominant keratinization
disorder, where the majority of disease causing mutations has been detected in the keratin genes KRT6A/B, KRT16 and KRT17. These mutations lead to extreme fragility of the cells where mutated keratins are expressed.

Title: Report of the 10th Annual International Pachyonychia Congenita Consortium Meeting
Journal: J Invest Dermatol
Authors: M.A. van Steensel; P.A. Coulombe; R.L. Kaspar; L.M. Milstone; W.H. McLean; D.R. Roop; F.J. Smith; E. Sprecher; M.E. Schwartz
Volume: 134, Section: 3, Pages: 588-91

Abstract:

Report of the 10th Annual International Pachyonychia Congenita Consortium (IPCC) Symposium held in Park City, Utah in Feb 2013.

Title: Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy
Journal: J Dermatol Sci
Authors: N.J. Wilson; C.D. Hansen; D. Azkur; C.N. Kocabas; A. Metin; Z. Coskun; M.E. Schwartz; P.R. Hull; W.H. McLean; F.J. Smith
Volume: 70, Section: 1, Pages: 58-60

Abstract:

Nail dystrophy is a hallmark of the autosomal dominant
disorder pachyonychia congenita (PC), accompanied by keratoderma
and other ectodermal defects [1]. We recently analysed
three cases initially diagnosed as PC, but who presented with nail
dysplasia only. None had mutations in any of the four keratin genes
associated with PC (KRT6A, KRT6B, KRT16 & KRT17) [2] or in KRT6C
(associated with keratoderma and trivial changes) nor in GJB6
(Clouston syndrome is in the differential diagnosis for PC). The
frizzled 6 gene (FZD6) was analysed because mutations in this gene
were shown to cause autosomal recessive nail dysplasia [3,4]. FZD6
mutations were identified in these three unrelated families with
clinically similar nail dystrophy, where all fingernails and toenails
were discoloured and thickened from birth.

Title: Pachyonychia congenita tarda: A rare case report
Journal: Contemp Clin Dent
Authors: Ganapathi Moger; M.C. Shashikanth; K.T. Chandrashekar; Sophia Kurein
Volume: 4, Section: 3, Pages: 409-11

Abstract:

Pachyonychia congenita is a rare, but well-characterized autosomal dominant disorder of keratinization. It usually begins within the first few months of life. Here, we are presenting a rarecase, which started at the age of 10 years of life and is known as pachyonychia congenita tarda. The case is being reported for its rarer occurrence as the patient had oral leukokeratosis and angular cheilosis present in the same type of the syndrome (Jadassohn-Lewandowsky syndrome), which is still uncommon. Angular cheilosis, nails, oral leukokeratosis, pachyonychia congenita

Note: Onset by age 10 is typical in some types of Pachyonychia Congenita. Also, there is no genetic testing information in this article.

Title: A new KRT16 mutation associated with a phenotype of pachyonychia congenita
Journal: Exp Dermatol
Authors: F. Paris; C. Hurtado; A. Azon; L. Aguado; J.L. Vizmanos
Volume: 22, Section: 12, Pages: 838-9

Abstract:

Pachyonychia congenita is a rare, autosomal dominant genetic disease characterized by painful palmoplantar keratoderma and hypertrophic nail dystrophy. This disorder is caused by mutations in any one of five cytoskeletal keratin proteins, K6a, K6b, K6c, K16 and K17. Here, we describe anew p.Leu421Pro (c.1262T>C) mutation in the highly conserved helix termination motif of K16 in a large Spanish family. Bioinformatic analyses as well as previous descriptions in the literature of homologous mutations in other keratin-coding genes show that this mutation is probably causative of the disease.KRT16, PC, keratin

Title: Pachyonychia Congenita with involvement of the larynx
Journal: Acta Otorrinolaringol Esp
Authors: Hugo Rodriguez; Giselle Cuestas; Adrian Zanetta; Ziomara Balbarrey
Volume: 65, Section: 3, Pages: 208-210

Title: Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma
Journal: J Dermatol
Authors: A. Kubo; Y. Oura; T. Hirano; Y. Aoyama; S. Sato; K. Nakamura; Y. Takae; M. Amagai
Volume: 40, Section: 7, Pages: 553-7

Abstract:

Focal palmoplantar keratoderma (PPK) with severe pain is a hallmark of pachyonychia congenita, a rare autosomal dominant disorder involving PPK and hypertrophic nail dystrophy. Some families present focal PPK with either minimal or no nail changes. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16 or KRT17, lead to pachyonychia congenita. However, the majority of families with focal PPK showing minimal or no nail changes do not harbor mutations in these genes. Recently, mutations of KRT6C were identified in families withfocal PPK alone. Here, we report a 26-year-old Japanese man with focal plantar hyperkeratosis that developed at approximately 10 years of age with no palmar involvement and no nail alterations. We identified a missense KRT6C mutation c.1414G>A resulting in an p.Glu472Lys substitution, as reported in other Japanese patients. When the mutant keratin 6c protein is exogenously expressed in human HaCaT cells, a collapse of the keratin filament network isobserved in a dose-dependent manner, suggesting the mutation has a dominant-negative effect onkeratin filament network formation. The mutated residue is located at the helix termination motif ofkeratin 6c. The peptide sequence around this residue is highly conserved among type II, III and IV intermediate filament proteins. Glu to Lys mutations of the equivalent residue have been reported in a variety of inherited diseases, including neurodegenerative diseases, corneal dystrophy and skin disorders, suggesting that this residue is vital to keratin function. KRT6C, intermediate filament proteins, keratin 6c, pachyonychia congenita, palmoplantarkeratoderma

Title: Keratin 16 regulates innate immunity in response to epidermal barrier breach
Journal: Proc Natl Acad Sci USA
Authors: J.C. Lessard; S. Pina-Paz; J.D. Rotty; R.P. Hickerson; R.L. Kaspar; A. Balmain; P.A. Coulombe
Volume: 110, Section: 26, Pages: 19537-42

Abstract:

Mutations in the type I keratin 16 (Krt16) and its partner type II keratin 6 (Krt6a, Krt6b) cause pachyonychia congenita (PC), a disorder typified by dystrophic nails, painful hyperkeratotic calluses in glabrous skin, and lesions involving other epithelial appendages. The pathophysiology of these symptoms and its relationship to settings in which Krt16 and Krt6 are induced in response toepidermal barrier stress are poorly understood. We report that hyperkeratotic calluses arising in the glabrous skin of individuals with PC and Krt16 null mice share a gene expression signature enriched in genes involved in inflammation and innate immunity, in particular damage-associated molecular patterns. Transcriptional hyper-activation of damage-associated molecular pattern genes occurs following de novo chemical or mechanical irritation to ear skin and in spontaneously arising skin lesions in Krt16 null mice. Genome-wide expression analysis of normal mouse tail skin and benign proliferative lesions reveals a tight, context-dependent coregulation of Krt16 and Krt6 with genes involved in skin barrier maintenance and innate immunity. Our results uncover a role for Krt16 in regulating epithelial inflammation that is relevant to genodermatoses, psoriasis, and cancer and suggest a avenue for the therapeutic management of PC and related disorders.

Title: Resolution of the plantar hyperkeratosis of pachyonychia congenita during chemotherapy for Ewing sarcoma
Journal: Br J Dermatol
Authors: E. Higgins; M. Capra; M.E. Schwartz; F.J. Smith; W.H. McLean; A.D. Irvine
Volume: 169, Section: 6, Pages: 1357-60

Abstract:

A 15-year-old girl with pachyonychia congenita (PC) confirmed by genetic testing presented with pain and a localized subcutaneous swelling on her right back. Biopsy confirmed Ewing sarcoma of the posterior 10th rib. Preoperative tumour-reduction chemotherapy was commenced as per the Euro EWING 99 protocol, with vincristine, ifosfamide, doxorubicin and etoposide.1 Ifosfamide was subsequently replaced by cyclophosphamide, as per protocol, due to potential renal tubule toxicity (Table 1).1 Surgical resection was performed followed by radiotherapy to the primary site.... patient experienced a dramatic resolution of her symptoms during chemotherapy, we are aware of other patients with PC on different chemotherapy regimens (for breast cancer) who have not experienced this dramatic benefit (IPCRR, unpublished data), so the response may be regimen specific. Clearly such a regimen is too toxic to be applied to patients with PC in the broader sense, but our hope is that this observation may stimulate thinking as to how to harness this positive effect in a safe and localized fashion.

Title: Novel mutation (p.L91P, c.272T>C) of keratin 17 in a case with pachyonychia congenita
Journal: J Dermatol
Authors: M. Ichimiya; M. Yamaguchi; K. Nemoto; M. Muto
Volume: 40, Section: 9, Pages: 757-8

Title: Double trouble: homozygous dominant mutations and hair loss in pachyonychia congenita
Journal: J Invest Dermatol
Authors: A. D. Irvine
Volume: 132, Issue: 7, Pages: 1757-1759

Abstract:

In this issue, Wilson et al. report the first case of homozygous dominant negative mutations in KRT17 in pachyonychia congenita (PC). Homozygous dominant negative mutations are a rare occurrence in keratin disorders and this is a first report in PC. These mutations cause a distinct sub-phenotype of PC that is more severe in the offspring of affected parents and has associated alopecia.

Title: Pachyonychia congenita: A rare genodermatosis
Journal: Indian Dermatology Online Journal
Authors: Puneet Agarwal, Mahendra K. Chhaperwal, Apurva Singh, Arvind Verma, Manisha Nijhawan, Kishore Singh, Dinesh Mathur
Volume: 4 - Issue 3, Pages: 225-227

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis with only 450 cases reported since 1906. It is of two types, type I due to mutation in genes 6a and 16, and 6b and 17 in type II with an autosomal dominant inheritance in both types. A 22 yr old female patient presented in our OPD with hypertrophy of finger and toe nails, palmoplantar keratoderma, oral punctuate leukokeratosis, hyperhidrosis in palms and soles with maceration and malodour since childhood. She had a positive family history with father and grandfather affected but less severely. Microscopy and culture of nail clippings and scrapping were done to rule out fungal infection. On biopsy acanthotic epidermis, parakeratosis, orthokeratosis were seen. No evidence of any associated malignancy was found after thorough workup. She was diagnosed as PC Type 1. She was put on topical steroids and orally on acetretin 25 mg OD. Paring of the nails was done to reduce the thickness of nails & to provide symptomatic relief. She was on a regular treatment for 3-4 months and showed some improvement in the form of reduced palmoplantar hyperkeratosis and reduced oral punctate keratosis but was later lost on followup. She showed no adverse effect to therapy during this period. This case is being reported because of its rarity.

Title: Pachyonychia Congenita
Journal: J Paediatr Child Health
Authors: B. S. Menon;S. B. Ibrahim;E. Juraida;M. Mohamed;H. Ibrahim;
Issue: 44, Pages: 386

Title: Significance of Patient Registries for Dermatological Disorders
Journal: Journal of Investigative Dermatology
Authors: M.P. de Souza;V.R. Miller
Volume: 132, Issue: 7, Pages: 1749-1752

Abstract:

Patient registries for dermatological disorders are important sources of data for researchers, clinicians, and patients. The majority of registries are maintained by academic investigators with funding from federal agencies. However, these registries are fragmented and are maintained only as long as federal funding exists. Patient organizations and companies can serve as alternative sources of funding for registries.

Title: Pachyonychia Congenita Project: A Partnership of Patient and Medical Professional
Journal: Journal of the Dermatology Nurses' Association
Authors: M. E. Schwartz;G. M. Zimmerman;F. J. D. Smith;E. Sprecher
Volume: 5, Issue: 1, Pages: 42-47

Abstract:

ABSTRACT: A rare disease like pachyonychia congenita (PC) poses barriers to the patient, medical professional, and scientist. The patient has challenges connecting to information, the medical professional has challenges connecting to patient experience, and the scientist has challenges connecting to a sufficient number of patients to do meaningful research. Recent collaboration between these groups has transformed our understanding of PC and its symptoms and method of diagnosis. PC Project is at the center of this collaboration and is providing new insights for the dermatologist and dermatology nurse, enabling better diagnosis of PC and counseling of a PC patient. The PC patient, medical professional, and scientist have an international advocate in PC Project, a patient-led, nonprofit project committed to connecting all these communities to the tools they need to improve the lives of those living with PC.

Title: Best treatment practices for pachyonychia congenita
Journal: Journal of the European Academy of Dermatology and Venereology
Authors: I. Goldberg;D. Fructer;A. Meilick;M. E. Schwartz;E. Sprecher

Abstract:

BACKGROUND:Numerous therapeutic modalities have been proposed to treat the manifestations of pachyonychia congenita (PC). While research hopes lie with molecular therapies, patients are in need of answers regarding the efficacy of conventional treatments. AIM OF THE STUDY: To determine patients' experience and preferences regarding conventional treatments for PC. METHODS: The study population included 120 PC patients from 20 countries. The study was based on a patient survey developed by physicians and researchers from the International Pachyonychia Congenita Consortium and conducted via the internet. Using an effectiveness scale of 1 to 5, the patients were asked to grade treatments for different manifestations, including keratoderma, cysts, follicular hyperkeratosis, fingernail and toenail involvement. RESULTS: Patients reported surgical treatments being most effective for cysts and mechanical treatments the most effective conventional therapeutic approach for all other investigated manifestations. The other conventional medical treatments were found to be non-effective to only slightly effective. Among patients with keratoderma, older people were more likely to report beneficial effect from mechanical treatments (P = 0.04), topical retinoids (P = 0.04) and topical steroids (P = 0.02). Likewise, females were more inclined to report filing and grinding beneficial than males (P = 0.02). Finally, carriers of KRT16 and KRT6a were more likely to benefit from keratolytics than carriers of mutations in KRT17 (P = 0.04). CONCLUSIONS: None of the currently available therapeutic options for PC are ideal, although they provide some relief, with mechanical/surgical options being preferred over medical therapies. These results emphasize the need for more efficient and targeted therapies.

Title: What is Pachyonychia Congenita?
Journal: The Institute of Chiropodists and Podiatrists Chiropody Review
Volume: 62, Issue: 6, Pages: 4-7

Title: Pachyonychia Congenita (MIM:167200, 167210)
Journal: Genetic Skin Disorders
Authors: V. P. Sybert
Pages: 248 - 253

Title: Oral manifestations of pachyonychia congenita
Journal: Dermatol Online J.
Authors: P. S. da Silva Santos;F. Mannarino;R. F. Lellis;L. H. Osorio
Volume: 16, Issue: 10, Pages: 3

Abstract:

Pachyonychia congenita is a rare genetic disorder characterized mainly by hypertrophy of the nails and hyperkeratosis of the skin and mucosae. Fifty percent of all patients have oral leukokeratosis, which is often painful. The case reported here is of a 41-year-old patient who had white lesions in the form of irregular plaques; these affected multiple regions of the oral mucosa and were sensitive to touch. Histological examination revealed acanthosis, parakeratosis and ballooning of the epithelial cells, consistent with oral leukokeratosis. After therapy including topical steroids and prosthetic rehabilitation, the symptoms resolved.

Title: Disadhesion of epidermal keratinocytes: a histologic clue to palmoplantar keratodermas caused by DSG1 mutations
Journal: J Am Acad Dermatol
Authors: R. Bergman;D. Hershkovitz;D. Fuchs;M. Indelman;Y. Gadot;E. Sprecher
Volume: 62, Issue: 1, Pages: 107-113

Abstract:

BACKGROUND: Recent developments in molecular genetics may lead to re-examination of the histopathology of inherited palmoplantar keratodermas (PPKs) based on more precise groupings of the various entities and syndromes. OBJECTIVE: We sought to characterize the histopathological findings in PPKs associated with mutations in DSG1, which encodes desmoglein 1. METHODS: We studied the histopathology of 3 cases of keratosis palmoplantaris striata type I and one case of diffuse PPK, all associated with autosomal-dominant mutations in DSG1. Our cases for comparison included 4 cases with Mal de Meleda PPK associated with autosomal-recessive SLURP1 mutations, one case with pachyonychia congenita type II PPK associated with an autosomal-dominant KRT17 mutation, and one case with focal PPK associated with an autosomal-dominant KRT16 mutation. RESULTS: The distinguishing histopathological features of the 3 keratosis palmoplantaris striata type I cases and the diffuse PPK case associated with DSG1 mutation were: varying degrees of widening of the intercellular spaces and partial disadhesion of keratinocytes in the mid and upper epidermal spinous cell layers, often extending to the granular cell layer. These findings, which are associated with haploinsufficiency of desmoglein 1, were not observed in any of the other 6 PPK cases. Mild perinuclear eosinophilic condensations and cytoplasmic vacuolizations were observed in the spinous cell layer keratinocytes of the pachyonychia congenita type II PPK and the nonspecified focal PPK cases. LIMITATIONS: There were a limited number of patients and control patients with hereditary PPKs. CONCLUSION: Widening of the intercellular spaces and disadhesion of epidermal keratinocytes may serve as a histologic clue to PPKs caused by DSG1 mutations.

Title: Pachyonychia congenita: report of two cases and mutation analysis
Journal: Dermatologica Sinica
Authors: J. Yeh;C. Huang;S. Chao
Volume: 1, Issue: 4, Pages: 1-7

Abstract:

Pachyonychia congenita (PC) comprises a group of rare autosomal dominant genetic disorders thatinvolve ectodermal dysplasia. It is characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma, follicular keratoses, and oral leukokeratosis. Historically, PC has been subdivided into two subtypes, PC-1 or PC-2, on the basis of clinical presentation. However, differential diagnosis based on clinical grounds, especially in young and/or not fully penetrant patients, can be difficult. In addition, clinical analysis of the large case series has shown that there is considerable phenotypic overlap between these two subtypes recently. Based on the advent of molecular genetics and the identification of the genes causing PC, more specific nomenclature has been adopted. Therefore, diagnosis at the molecular level is useful and important to confirm the clinical impression. In this report, we describe two typical cases of PC with mutation analysis revealed a small deletion (514_516delACC, Asn172del) and a point mutation (487 G > A, GAG / AAG, Glu163Lys) in the KRT6A gene.

Title: A novel mutation (p.Arg94Gly) of keratin 17 in a Chinese family with steatocystoma multiplex
Journal: Eur J Dermatol
Authors: D.Zang;C. Zhou;M. He;X. Ma;J. Zhang
Volume: 21, Issue: 1, Pages: 142-144

Title: Homozygous Dominant Missense Mutation in Keratin 17 Leads to Alopecia in Addition to Severe Pachyonychia Congenita
Journal: J Invest Dermatol
Authors: N. J. Wilson;M. L. Cardenas Perez;A. Vahlquist;M. E. Schwartz;C. D. Hansen;W. H. I. McLean; F. J. D. Smith
Section: Feb, Pages: 1-4

Abstract:

Homozygosity for dominant mutations in keratin genes is rare and has only been reported for epidermolysis bullosa simplex (EBS; Stephens et al., 1995; Hu et al., 1997; Oldak et al., 2011). The majority of pathogenic variants reported in 23 keratin genes are heterozygous missense or small in-frame insertion/deletion mutations inherited in an autosomal dominant manner (http://www.interfil.org;Szeverenyi et al., 2008). A small number of recessive cases have been reported, mostly due to nonsense mutations (Yiasemides et al., 2008). Here, we report homozygosity for dominant missense mutations in keratin 17 that modify the pachyonychia congenita (PC) phenotype. PC is an autosomal dominant skin disorder caused by heterozygous mutations in any one of the genes encoding keratins K6a, K6b, K16, or K17 (McLean et al., 2011). The main characteristics are palmoplantar keratoderma, plantar pain, and nail dystrophy. Additionally, oral leukokeratosis, follicular keratoses, and epidermal cysts often occur. PC due to mutations in K17 (termed PC-17) is more frequently associated with neonatal teeth and widespread pilosebaceous cysts in adults.

Title: Pachyonychia congenita type 1 with skeletal abnormalities
Journal: Eur J Dermatol
Authors: J. J., Van der Velden;M. A. Van Steensel
Volume: 19, Issue: 3, Pages: 274-275

Title: Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita
Journal: Br J Dermatol
Authors: C. Swartling;M. Karlqvist;K. Hymnelius;J. Weis;A. Vahlquist
Volume: 163, Issue: 5, Pages: 1072-1076

Abstract:

BACKGROUND: Painful foot blistering is a common problem in patients with epidermolysis bullosa simplex (EBS) and pachyonychia congenita (PC). Hyperhidrosis, a condition which can be effectively blocked by plantar injections of botulinum toxin (Btx), often exacerbates the blistering. OBJECTIVES: A retrospective evaluation of the effects of Btx injections in 14 patients with EBS and PC with foot blisters and painful callosities. METHODS: After informed consent, patients with EBS (n = 6) and PC (n = 8), aged 7-66 years, who had received Btx therapy at our centre since 2003, were included. The treatment consisted of multiple plantar injections of Btx A or Btx B after prior regional or general anaesthesia. Patients were interviewed about the treatment effect and were asked to score the improvement from 0 to 5, where 5 is 'excellent'. One patient with PC with painful callosities was studied by magnetic resonance (MR) spectroscopic microimaging before and after Btx injections to disclose any underlying blisters. RESULTS: In total, 76 treatments were evaluated (one to 19 sessions per patient). Thirteen patients (93%) reported reduced plantar blistering and pain; the improvement score was

Title: Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16
Journal: Br J Dermatol
Authors: K. M. Spaunhurst;A. M. Hogendorf;F. J. Smith;B. Lingala;M. E. Schwartz;A. Cywinska-Bernasp;K. J. Zeman;J. Tang
Volume: 166, Issue: 4, Pages: 875-878

Abstract:

BACKGROUND: Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type). OBJECTIVES: To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16. METHODS: In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations. RESULTS: Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P < 0

Title: Marathon of eponyms: 10 Jadassohn-Lewandowsky syndrome (Pachyonychia congenita)
Journal: Oral Dis
Authors: C. Scully;J. Langdon;J. Evans
Volume: 16, Issue: 3, Pages: 310-311

Abstract:

The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Jadassohn-Lewandowsky syndrome.

Title: Pachyonychia congenita type 2
Journal: J Dtsch Dermatol Ges
Authors: I. M. Scholz;P. Helmbold
Volume: 9, Issue: 2, Pages: 144-145

Title: Comparative Study of High-Resolution Multifrequency Ultrasound of the Plantar Skin in Patients with Various Types of Hereditary Palmoplantar Keratoderma
Journal: Dermatology
Authors: I. Goldberg E. Sprecher M.E. Schwartz D. Gaitini
Pages: 365

Abstract:

Background: High-variable-frequency ultrasound is used as an imaging tool for various cutaneous disorders. We utilized this tool in pachyonychia congenita (PC) patients, who typically present with plantar hyperkeratosis and often severely debilitating pain, compared to patients with epidermolytic palmoplantar keratoderma (EPPK) and mal de Meleda (MDM). Objective: To ascertain the feasibility of ultrasound technology for the diagnosis of PC. Methods: The study included a total of 16 patients, 7 with PC, 5 with EPPK and 4 with MDM, who underwent ultrasound examination of the plantar skin with high-resolution multifrequency ultrasound equipment. Results: Ultrasound scans performed over the proximal and distal plantar foot calluses in PC patients demonstrated hyperechoic dots and lines within the epidermis compatible with hyperkeratosis, engorged varicose veins in the dermis and an anechoic layer interposed between the epidermis and the dermis, corresponding to blister fluid below the calluses. In contrast to PC patients, patients with MDM and EPPK demonstrated no blisters. Conclusion: PC patients, as opposed to a group of patients with MDM and EPPK, displayed subepidermal blistering beneath their calluses. This finding may help in the diagnosis of PC and in partially explaining plantar pain as part of PC symptomatology.

Title: Building models for keratin disorders
Journal: J Invest Dermatol
Authors: M. I. Koster
Volume: 132, Issue: 5, Pages: 1324-1326

Abstract:

Palmoplantar keratoderma is a hallmark of pachyonychia congenita (PC) and focal non-epidermolytic palmoplantar keratoderma (FNEPPK). By generating keratin 16 (Krt16)-deficient mice, Lessard and Coulombe, as described in this issue, have generated a mouse model to replicate these palmoplantar lesions. Studies using this model may provide novel insights into the molecular mechanisms responsible for the formation of palmoplantar lesions in PC and FNEPPK patients.

Title: Visualization of plasmid delivery to keratinocytes in mouse and human epidermis
Journal: Sci Rep
Authors: E. Gonzalez-Gonzalez;Y. C. Kim;T. J. Speaker;R. P. Hickerson;R. Spitler;J. C. Birchall;M. F. Lara;R. H. Hu;Y. Liang;N. Kirkiles-Smith;M. R. Prausnitz;L. M. Milstone;C. H. Contag;R. L. Kaspar
Volume: 158, Issue: 1, Pages: 1-9

Abstract:

The accessibility of skin makes it an ideal target organ for nucleic acid-based therapeutics; however, effective patient-friendly delivery remains a major obstacle to clinical utility. A variety of limited and inefficient methods of delivering nucleic acids to keratinocytes have been demonstrated; further advances will require well-characterized reagents, rapid noninvasive assays of delivery, and well-developed skin model systems. Using intravital fluorescence and bioluminescence imaging and a standard set of reporter plasmids we demonstrate transfection of cells in mouse and human xenograft skin using intradermal injection and two microneedle array delivery systems. Reporter gene expression could be detected in individual keratinocytes, in real-time, in both mouse skin as well as human skin xenografts. These studies revealed that non-invasive intravital imaging can be used as a guide for developing gene delivery tools, establishing a benchmark for comparative testing of nucleic acid skin delivery technologies.

Title: Steatocystoma multiplex, oligodontia and partial persistent primary dentition associated with a novel keratin 17 mutation
Journal: Br J Dermatol
Authors: J. K. Gass;N. J. Wilson;F. J. Smith;E. B. Lane,W. H. McLean;E. Rytina;I. Salvary;N. P. Burrows
Volume: 161, Issue: 6, Pages: 1396-1398

Title: Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders
Journal: J Invest Dermatol
Authors: J. C. Lessard;P. A. Coulombe
Volume: 132, Issue: 5, Pages: 1384-1391

Abstract:

Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis upon wounding and other stressors. Mutations altering the coding sequence of KRT16 cause pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, oral leukokeratosis, and palmoplantar keratoderma (PPK). PPK associated with PC is extremely painful and compromises patient mobility, making it the most debilitating PC symptom. In this study, we show that, although inherited in a recessive manner, the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk. Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms.

Title: A novel frameshift mutation in keratin 16 underlies pachyonychia congenita with focal palmoplantar keratoderma
Journal: Br J Dermatol
Authors: L. H. Cao;Y. Luo;W. Wen;W. L. Liu;L. Jiang;C. Chen;C. Y. Ji;X. Zhang
Volume: 165, Issue: 5, Pages: 1145-1147

Title: Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation
Journal: Br J Dermatol
Authors: E. Akasaka;H. Nakano;A. Nakano;Y. Toyomaki;N. Takiyoshi;D. Rokunohe;Y. Nishikawa;A. Korekawa;Y. Matsuzaki;Y. Mitsuhashi;D. Sawamura
Volume: 165, Issue: 6, Pages: 1290-2

Abstract:

The palmoplantar keratodermas (PPKs) are a large group of genodermatoses comprising nearly 60 genetically distinct diseases. They are characterized by hyperkeratosis on the palms and soles with or without extrapalmoplantar hyperkeratotic lesions. Focal PPK is one of the hallmarks of pachyonychia congenita, a rare autosomal dominant disorder resulting from mutations in the keratin genes KRT6A, KRT6B, KRT16 or KRT17. Recently, in-frame deletion mutations of KRT6C have been identified in three families with focal PPK with slight or no nail changes. We report here a novel KRT6C mutation identified in a Japanese family with PPK with phenotypic heterogeneity, presenting with not only focal but also diffuse hyperkeratosis. The proband had diffuse hyperkeratosis on the soles and small focal hyperkeratoses on the palms, while the two other affected individuals showed focal hyperkeratoses on the soles. All three patients were heterozygotes for c.1414G>A in KRT6C, predicted to result in p.Glu472Lys. These findings strongly suggest that screening of patients with nonepidermolytic diffuse PPK, in whom the pathogenic mutations are yet to be determined, might identify mutations in KRT6C.

Title: Pachyonychia congenita patients with mutations in K6a have more extensive disease compared to patients with mutations in K16.
Journal: British Journal of Dermatology
Authors: K. M. Spaunhurst;A. M. Hogendorf;F. J. D. Smith;B. Lingala;M. E. Schwartz;A. Cywinska-Bernas;K. J. Zeman;J. Y. Tang
Pages: ahead of print

Abstract:

Background: Pachyonychia Congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16, or KRT17) which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in K6a and K16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowski type) and K6b and K17 to PC-2 (Jackson-Lawler type). Objectives: To describe clinical heterogeneity among PC patients with genetic mutations in K6a and K16. Methods: In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for PC patients. All subjects reported here underwent genetic testing and responded to a standardized, validated survey on their PC symptoms. We report results from 89 subjects with K6a mutations and 68 subjects with K16 mutations. Results: PC patients with K6a and K16 mutations have distinct phenotypic differences. PCK6a patients experience earlier onset, more extensive nail disease, and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leukokeratosis (P<0.001), cysts (P<0.001), and follicular hyperkeratosis (P<0.001) compared to their PC-K16 counterparts. Conclusion: Phenotypic differences between patients with K6a and K16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.

Title: Mutations in Frizzled 6 Cause Isolated Autosomal-Recessive Nail Dysplasia
Journal: The American Journal of Human Genetics
Authors: A. Frojmark;J. Schuster;M. Sobol;M. Entesarian;M. Kilander;D. Gabrikova;S. Nawaz;S. Baig;G. Shulte;J. Klar;N. Dahl
Volume: 88, Pages: 852-860

Abstract:

Inherited and isolated nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated nail dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD6, the gene encoding Frizzled 6. FZD6 belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways.We expressed the FZD6 missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A andWNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd6
mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus,our combined results show that FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD6 levels and several nonfunctional WNT-FZD pathways.

Title: Keratin disorders: from gene to therapy
Journal: Human Molecular Genetics
Authors: W. H. I. McLean;C. B. T. Moore
Volume: 20, Issue: 2, Pages: R189-R197

Abstract:

The term

Title: Pachyonychia Congenita: Cast in Translation
Journal: Journal of Investigative Dermatology
Authors: J. A. McGrath
Volume: 131, Pages: 995

Title: Toward a Treatment for Pachyonychia Congenita: Report on the 7th Annual International Pachyonychia Congenita Consortium Meeting
Journal: Journal of Investigative Dermatology
Authors: R. L. Kaspar;S. A Leachman;W. H. I. McLean;M. E. Schwartz
Volume: 131, Pages: 1011-1014

Title: Transgrediens pachyonychia congenita (PC): case series of a nonclassical PC presentation
Journal: British Journal of Dermatology
Authors: K. Harris;P. R. Hull;C. D. Hansen;F. J. D. Smith;W. H. I. McLean;J. L. Arbiser;S. A. Leachman
Volume: 166, Pages: 124-128

Abstract:

Background Pachyonychia congenita (PC) is a rare keratin disorder that typicallypresents with nail dystrophy and focal plantar keratoderma. We present seven cases of PC with transgrediens involvement of the dorsal feet. Objectives To document the extension of their disease to the dorsum of the feet in patients with mutation-confirmed PC, to report the natural history of PC with such transgrediens involvement, to generate hypotheses regarding aetiology, and to suggest prevention and treatment modalities. Methods Genetically confirmed cases of PC with transgrediens foot involvement were verified through the International Pachyonychia Congenita Research Registry (IPCRR) and characterized via telephone survey and photography. Results Seven patients with PC in the IPCRR were confirmed to have transgrediens lesions on the dorsal feet (six KRT6A mutations; one KRT16 mutation). Six cases had pre-existing nontransgrediens keratoderma and all cases reported standing, wearing shoes, foot moisture, and ⁄or infection as exacerbating or predisposing factors. Improvement, reported in six cases, was attributed to use of antibiotics or gentian violet, or improved footwear. Conclusions Transgrediens involvement of the dorsal feet is a rare manifestation of mutation-confirmed PC and may be more common in patients who carry a KRT6A mutation. Trauma, friction, infection and wound healing may exacerbate or predispose toward transgrediens lesions. It remains to be proven whether transgrediens associated infection is causal or represents a primary or secondary process. Patients with PC who develop transgrediens lesions may benefit from fungal and bacterial cultures, followed by appropriate antimicrobial treatments. Efforts to decrease skin friction and moisture may also improve and ⁄or prevent transgrediens spread.

Title: Pachyonychia Congenita with Laryngeal Obstruction
Journal: Pediatric Dermatology
Authors: R. M. Haber;D. Drummond
Pages: 1-4

Abstract:

Pachyonychia congenita is a rare genodermatosis that can affect the larynx. Laryngeal obstruction is very unusual with only a few cases reported. A 2-year-old girl presented with typical clinical features of pachyonychia congenita shortly after birth. At age 9 months, following an upper respiratory infection, she developed stridor and hoarseness and was found to have severe laryngeal obstruction, which was felt to be secondary to pachyonychia congenita based on direct laryngoscopy and laryngeal biopsy. Leukokeratosis of her larynx was treated with CO2 laser on three occasions, with improvement in her respiratory distress after each treatment. This report is the first case of pachyonychia congenita with laryngeal obstruction in which the gene mutation has been established (a deletional mutation in K6a), confirming that laryngeal obstruction can occur in PC-1.

Title: Josef Jadassohn (1863-1936), Felix Lewandowsky (1979-1921), and their syndrome
Journal: Dove Press Clinical, Cosmetic and Investigational Dermatology
Authors: A. Al Abound; K. Al Abound
Volume: 4, Pages: 179-182

Abstract:

Abstract: Josef Jadassohn (1863–1936) and his assistant, Felix Lewandowsky (1879–1921), were eminent German dermatologists who had several dermatology conditions linked eponymously.
One such condition is Jadassohn–Lewandowsky syndrome, which is a type of pachyonychia congenita – a disease that is characterized by severe thickening of the nail due to massive nail hyperkeratosis. This report describes Jadassohn–Lewandowsky syndrome and the men behind this disease. 

Title: An appraisal of oral retinoids in the treatment of pachyonychia congenita
Journal: J Am Acad Derm
Authors: R. Gruber; M. Edlinger; R. L. Kaspar; C. D. Hansen; S. Leachman; L. M. Milstone; F. J. D. Smith; A. Sidoroff; P. O. Fritsch; M. Schmuth

Abstract:

Background: Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused bymutations in keratin genes KRT6A/B, KRT16, or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. Objective: We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. Methods: In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. Results: In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from e3 to 13) (95% confidence interval 1.2-1.9, P .001). In all, 14% observed amelioration of their pachyonychia; 79% did not experience any nail change. The self-reported overall satisfaction score with oral retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (#25 mg/d) over a longer time period ([5 months), compared with higher doses ([25 mg/d) for a shorter time (#5 months). Limitations: The retrospective, cross-sectional study design is prone to a recall bias. Conclusion: Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects. ( J Am Acad Dermatol 10.1016/j.jaad.2011.02.003.)

Title: A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita
Journal: Journal of the American Academy of Dermatology
Authors: M. J. Eliason;S. A. Leachman;B. Feng;M. E. Schwartz;C. D. Hansen
Volume: ISSN 0190-9622,

Abstract:

BackgroundPachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from case series and case reports. Most patients in these reports were not genetically tested for PC. Objective We sought to clarify the prevalence of clinical features associated with PC. Methods We surveyed 254 individuals with confirmed keratin mutations regarding their experience with clinical findings associated with PC. Statistical comparison of the groups by keratin mutation was performed using logistic regression analysis. Results Although the onset of clinical symptoms varied considerably among our patients, a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years. Plantar pain had the most profound impact on quality of life. Other clinical findings reported by our patients included fingernail dystrophy, oral leukokeratosis, palmar keratoderma, follicular hyperkeratosis, hyperhidrosis, cysts, hoarseness, and natal teeth. We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation. Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2. Limitations Data were obtained through questionnaires, not by direct examination. Patients were self- or physician-referred. Conclusions We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development.

Title: Keratin gene mutations in disorders of human skin and its appendages
Journal: Archives of Biochemistry and Biophysics
Authors: J. Chamcheu; I.A. Siddiqui; D.N. Syed; V.M. Adhami; M. Liovic; H. Mukjtar
Volume: 508, Pages: 123-137

Abstract:

Keratins, the major structural protein of all epithelia are a diverse group of cytoskeletal scaffolding proteins that form intermediate filament networks, providing structural support to keratinocytes that maintain the integrity of the skin. Expression of keratin genes is usually regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Amongst the 54 known functional keratin genes in humans, about 22 different genes including, the cornea, hair and hair follicle-specific keratins have been implicated in a wide range of hereditary diseases. The exact phenotype of each disease usually reflects the spatial expression level and the types of mutated keratin genes, the location of the mutations and their consequences at sub-cellular levels as well as other epigenetic and/or environmental factors. The identification of specific pathogenic mutations in keratin disorders formed the basis of our understanding that led to re-classification, improved diagnosis with prognostic implications, prenatal testing and genetic counseling in severe keratin genodermatoses. Molecular defects in cutaneous keratin genes encoding for keratin intermediate filaments (KIFs) causes keratinocytes and tissue-specific fragility, accounting for a large number of genetic disorders in human skin and its appendages. These diseases are characterized by keratinocytes fragility (cytolysis), intra-epidermal blistering, hyperkeratosis, and keratin filament aggregation in severely affected tissues. Examples include epidermolysis bullosa simplex (EBS; K5, K14), keratinopathic ichthyosis (KPI; K1, K2, K10) i.e. epidermolytic ichthyosis (EI; K1, K10) and ichthyosis bullosa of Siemens (IBS; K2), pachyonychia congenita (PC; K6a, K6b, K16, K17), epidermolytic palmo-plantar keratoderma (EPPK; K9, (K1)), monilethrix (K81, K83, K86), ectodermal dysplasia (ED; K85) and steatocystoma multiplex. These keratins also have been identified to have roles in apoptosis, cell proliferation, wound healing, tissue polarity and remodeling. This review summarizes and discusses the clinical, ultrastructural, molecular genetics and biochemical characteristics of a broad spectrum of keratin-related genodermatoses, with special clinical emphasis on EBS, EI and PC. We also highlight current and emerging model tools for prognostic future therapies. Hopefully, disease modeling and in-depth understanding of the molecular pathogenesis of the diseases may lead to the development of novel therapies for several hereditary cutaneous diseases.

Title: Paternal Germ Cell Mosaicism in Autosomal Dominant Pachyonychia Congenita
Journal: Arch Dermatol
Authors: L.N. Pho;F.J.D. Smith;D. Konecki;S. Bale;W.H.I. McLean;B. Cohen;M.J. Eliason;S.A. Leachman

Abstract:

Background: Pachyonychia congenita (PC) is a genodermatosis caused by mutations in 1 of 4 known keratin genes, including KRT6A, KRT6B, KRT16, or KRT17. The most common mode of inheritance is autosomal dominant. Families with an affected parent are routinely counseled about the 50% transmission risk to each offspring. In some cases, families with a rare disorder like PC can initially present with an affected child while both parents are unaffected. This is usually the result of a spontaneous in utero mutation, and the risk of subsequent offspring being affected with the same condition is negligible (but may be increased above the general population

Title: A Modified Surgical Technique for Steatocystoma Multiplex
Journal: J Cutan Aestehet Surg
Authors: S. Choudhary; S. Koley; A. Salodkar
Volume: 3, Issue: 1, Pages: 25-28

Abstract:

BACKGROUND: Steatocystoma multiplex (SM) is a disorder of the pilosebaceous unit characterized by multiple sebum-containing dermal cysts. Different surgical modalities like cryosurgery, aspiration, surgical excision, incision with a surgical blade or sharp-tipped cautery followed by expression of cyst contents and forceps-assisted removal of the cyst wall and carbon dioxide laser have been used in the past. AIMS: To study the efficacy of a modified surgical technique in the treatment of steatocystoma multiplex. MATERIALS AND METHODS: We have used a simple modified surgical technique using a radiofrequency instrument as the incision tool for the treatment of SM in two patients. RESULTS: The results were cosmetically excellent with no complications developing during or after the procedure. No recurrences were observed after five and half months of follow-up. CONCLUSIONS: This is a simple, easy, fast office-based procedure that is associated with minimal blood loss and post inflammatory hypo or hyperpigmentation and scarring are practically absent.

Title: The Vein Hook Successfully Used for Eradication of Steatocystoma Multiplex
Journal: Dermatol Surg
Authors: S.J. Lee; Y.S. Choe; B.C. Park; W.J. Lee; D.W. Kim
Volume: 33, Issue: 1, Pages: 82-84

Abstract:

BACKGROUND: Steatocystoma multiplex is characterized by the formation of the numerous cutaneous cysts in the exposed area leaving some cosmetic problems for the patients. Only surgical excision has been effective, and its several variations were done with limited success. Because the patients usually have many cysts, excision of cysts was tedious for the doctors and left scars on the patients. METHOD: Five patients agreeing to participate in this experiments were selected. The vein hook used for ambulatory phlebectomy was employed to eradicate the cysts. The skin was incised approximately 2 to 3 mm in length. Then the mosquito forceps removed the cysts by gently squeezing or hooking the inner or outer cyst wall. By completely removing tissue around the cyst, recurrence was able to be prevented. RESULT: It took approximately 1 minute to excise one cyst completely, it left no hypertrophic scars except for transient postinflammatory hyperpigmentation, and it had no recurrences for 14 to 30 months on five patients. CONCLUSION: The use of this instrument is very simple and time-saving, providing excellent success rate with favorable cosmetic results. It can be a good alternative for eradication of the cysts in steatocystma multiplex. The authors have indicated no significant interest with commercial supporters.

Title: Surgical Pearl: Mini-incisions for the extraction of steatocystoma multiplex
Journal: J Am Acad Dermatol
Authors: T. Schmook;G. Burg;J. Hafner
Volume: 44, Pages: 1041-2

Title: Tackling the Challenge of Nucleic Acid Delivery: Progress & New Approaches
Journal: Drug Development & Delivery
Authors: J.J. Cunningham; L.S. Crocker; A. Leone
Volume: 11, Issue: 2, Pages: 36-40

Abstract:

It is broadly accepted that nucleic acid delivery, particularly targeted intracellular delivery following systemic administration, remains one of the most difficult challenges facing pharmaceutical scientists today. Nucleic acids are large, hydrophilic, charged molecules, and as such, are not easily transported across the cell membrane. Add to this the poor stability of unmodified nucleic acids in circulation, and the desire to direct delivery to specific cell types in specific tissues, and the complexity multiplies. Efforts to achieve such delivery have enjoyed a resurgence of interest following the discovery and development and provide an entirely new theraputic modality. Despite the significant challenges facing this endeavor, major progress has been made throughout the past several years, and the following aims to highlight some of the most promising approaches.

Title: The Phenotypic and Molecular Genetic Features of Pachyonychia Congenita
Journal: J Invest Dermatol
Authors: W.H.I. McLean;C.D. Hansen;M.J. Eliason;F.J.D. Smith
Volume: 131, Issue: 5, Pages: 1015-1017

Abstract:

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis caused by heterozygous mutations in any one of the genes encoding the differentiation-specific keratins K6a, K6b, K16, or K17. The main clinical features of the condition include painful and highly debilitating plantar keratoderma, hypertrophic nail dystrophy, oral leukokeratosis, and a variety of epidermal cysts. Although the condition has previously been subdivided into PC-1 and PC-2 subtypes, the phenotypic characterization of 1,000 mutation-verified PC patients enrolled in the International PC Research Registry, coordinated by the patient advocacy group PC Project, shows that there is considerable overlap between these subtypes. Thus, a new genotypic nomenclature is proposed, in which PC-6a represents a patient carrying a mutation in the K6a gene, etc. Although a rare disorder, PC represents a good model for therapy development, and international efforts are ongoing to develop and deliver siRNA, gene, correction, small molecule, and other strategies to treat this painful, disabling skin condition. The special relationship between PC Project and the PC research community has greatly accelerated the development pathway from gene identification to clinical trials in only a few years and represents a paradigm of hope for other orphan diseases.Journal of Investigative Dermatology advance online publication, 24 March 2011; doi:10.1038/jid.2011.59. [epub ahead of print]

Title: Mutations in a keratin 6 isomer (K6c) cause a type of focal palmoplantar keratoderma
Journal: J Invest Dermatol
Authors: P.E. Bowden
Volume: 130, Issue: 2, Pages: 336-8

Abstract:

Twenty years have elapsed since keratin mutations were linked to cutaneous genodermatoses, and we now know that they cause 40 different genetic disorders. In this issue, Wilson et al. have identified KRT6C mutations in patients with focal palmoplantar keratoderma (FPPK), but debate concerning overlapping phenotypes between FPPK and pachyonychia congenita (PC) will continue because only one family has nail involvement. Furthermore, screening of control DNA samples identified 3 in 335 individuals (1%) who had a mutation (K6c p.Asn172del), but the phenotype was not ascertained. However, this raises the question as to whether individuals with sensitive feet bear specific KRT6C mutations and whether a general population screen should be considered.

Title: Drug giants turn their backs on RNA interference - A once much-touted technique faces a difficult transition to the clinic.
Journal: Nature
Authors: H. Ledford
Volume: 468, Pages: 487

Title: Persistent hoarseness in a patient with pachyonychia congenita: an early sign of laryngeal involvement.
Journal: Int J Dermatology
Authors: A.M. Ceyhan; M. Yildirim; V.B. Akkaya; H. Yasan
Volume: 48, Issue: 12, Pages: 1346-8

Title: The Allergy Gene - How a mutation in a skin protein revealed a link between eczema and asthma
Journal: The Scientist
Authors: W.H.I. McLean
Volume: 24, Issue: 12, Pages: 34

Title: Development of Quantitative Molecular Clinical End Points for siRNA Clinical Trials
Journal: J Invest Dermatol
Authors: R.P. Hickerson; S.A. Leachman; L.N. Pho; E.G. Gonzalez; F.J. Smith; W.H.I. McLean; C.H. Contag; D. Leake; L.M. Milstone; R.L. Kaspar

Abstract:

RNA interference (RNAi) is an evolutionarily conserved mechanism that results in specific gene inhibition at the mRNA level. The discovery that short interfering RNAs (siRNAs) are selective, potent, and can largely avoid immune surveillance has resulted in keen interest to develop these inhibitors as therapeutics. A single nucleotide-specific siRNA (K6a_513a.12, also known as TD101) was recently evaluated in a phase 1b clinical trial for the rare skin disorder, pachyonychia congenita (PC). To develop a clinical trial molecular end point for this type of trial, methods were developed to: (1) isolate total RNA containing amplifiable mRNA from human skin and callus material; (2) quantitatively distinguish the single-nucleotide mutant mRNA from wild-type K6a mRNA in both patient-derived keratinocytes and patient callus; and (3) demonstrate that repeated siRNA treatment results in sustained inhibition of mutant K6a mRNA in patient-derived keratinocyte cultures. These methods allow noninvasive sampling and monitoring of gene expression from patient-collected shavings and may be useful in evaluating the effectiveness of RNAi-based therapeutics, including inhibitors that specifically target single-nucleotide mutations.Journal of Investigative Dermatology advance online publication, 30 December 2010; doi:10.1038/jid.2010.372. [epub ahead of print]

Title: Use of Self-Delivery siRNAs to Inhibit Gene Expression in an Organotypic Pachyonychia Congenita Model
Journal: J Invest Dermatol
Authors: R.P. Hickerson; M.A. Flores; D. Leake; M.F. Lara; C.H. Contag; S.A. Leachman; R.L. Kaspar

Abstract:

Although RNA interference offers therapeutic potential for treating skin disorders, delivery hurdles have hampered clinical translation. We have recently demonstrated that high pressure, resulting from intradermal injection of large liquid volumes, facilitated nucleic acid uptake by keratinocytes in mouse skin. Furthermore, similar intradermal injections of small interfering RNA (siRNA; TD101) into pachyonychia congenita (PC) patient foot lesions resulted in improvement. Unfortunately, the intense pain associated with hypodermic needle administration to PC lesions precludes this as a viable delivery option for this disorder. To investigate siRNA uptake by keratinocytes, an organotypic epidermal model, in which pre-existing endogenous gene or reporter gene expression can be readily monitored, was used to evaluate the effectiveness of "self-delivery" siRNA (i.e., siRNA chemically modified to enhance cellular uptake). In this model system, self-delivery siRNA treatment resulted in reduction of pre-existing fluorescent reporter gene expression under conditions in which unmodified controls had little or no effect. Additionally, treatment of PC epidermal equivalents with self-delivery "TD101" siRNA resulted in marked reduction of mutant keratin 6a mRNA with little or no effect on wild-type expression. These results indicate that chemical modification of siRNA may overcome certain limitations to transdermal delivery (specifically keratinocyte uptake) and may have clinical utility for inhibition of gene expression in the skin.Journal of Investigative Dermatology advance online publication, 20 January 2011; doi:10.1038/jid.2010.426. [epub ahead of print]

Title: In Vivo Imaging of Human and Mouse Skin with a Handheld Dual-Axis Confocal Fluorescence Microscope
Journal: J Invest Dermatol
Authors: H. Ra; W. Piyawattanametha; E.G. Gonzalez; M.J. Mandella; G.S. Kino; O. Solgaard; D. Leake; R.L. Kaspar; A. Oro; C.H. Contag

Abstract:

Advancing molecular therapies for the treatment of skin diseases will require the development of new tools that can reveal spatiotemporal changes in the microanatomy of the skin and associate these changes with the presence of the therapeutic agent. For this purpose, we evaluated a handheld dual-axis confocal (DAC) microscope that is capable of in vivo fluorescence imaging of skin, using both mouse models and human skin. Individual keratinocytes in the epidermis were observed in three-dimensional image stacks after topical administration of near-infrared (NIR) dyes as contrast agents. This suggested that the DAC microscope may have utility in assessing the clinical effects of a small interfering RNA (siRNA)-based therapeutic (TD101) that targets the causative mutation in pachyonychia congenita (PC) patients. The data indicated that (1) formulated indocyanine green (ICG) readily penetrated hyperkeratotic PC skin and normal callused regions compared with nonaffected areas, and (2) TD101-treated PC skin revealed changes in tissue morphology, consistent with reversion to nonaffected skin compared with vehicle-treated skin. In addition, siRNA was conjugated to NIR dye and shown to penetrate through the stratum corneum barrier when topically applied to mouse skin. These results suggest that in vivo confocal microscopy may provide an informative clinical end point to evaluate the efficacy of experimental molecular therapeutics.Journal of Investigative Dermatology advance online publication, 30 December 2010; doi:10.1038/jid.2010.401.[epub ahead of print]

Title: A Large Mutational Study in Pachyonychia Congenita
Journal: J Invest Dermatol
Authors: N.J. Wilson; S.A. Leachman; C.D. Hansen; A.C. McMullan; L.M. Milstone; M.E. Schwartz; W.H.I. McLean; P.R. Hull; F.J. Smith

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC.Journal of Investigative Dermatology advance online publication, 17 February 2011; doi:10.1038/jid.2011.20. [epub ahead of print]

Title: Statins Downregulate K6a Promoter Activity: A Possible Therapeutic Avenue for Pachyonychia Congenita
Journal: J Invest Dermatol
Authors: Y. Zhao; U. Gartner; F.J.D. Smith; W.H.I. McLean

Abstract:

Pachyonychia congenita (PC) is a keratinizing disorder predominantly caused by mutations in keratin 6a (K6a) (∼50% of cases) or K6b, K16, or K17. One means of treating PC is identification of small-molecule inhibitors of PC-related keratins. Here, we cloned the human K6a promoter, and using a cell-based reporter gene assay, a chemical library was screened for K6a inhibitors. One compound, compactin, the precursor of all cholesterol-lowering statins, was of particular interest. We found that, surprisingly, simvastatin and other statins inhibit K6a promoter activity and K6a protein expression. Further investigation showed that this effect works through cholesterol/mevalonate pathway inhibition rather than an off-target effect. Inhibition of both basal and IFN-γ-inducible K6a expression by statins was demonstrated. Both these K6a inhibitory effects were found to be mediated by Stat1 transcription factor, but only the IFN-γ-inducible promoter activity was controlled via the Stat/JAK pathway. The repressive effect of statins was found to be mediated by the isoprenoid pathway downstream of mevalonate (the intermediate following 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) but upstream of cholesterol, specifically the geranylgeranylation pathway. These data set the scene for further unraveling signaling pathways that control the K6a promoter, as well as facilitating clinical trials for statins in PC patients.Journal of Investigative Dermatology advance online publication, 10 March 2011; doi:10.1038/jid.2011.41. [epub ahead of print]

Title: Development of Skin-Humanized Mouse Models of Pachyonychia Congenita
Journal: J Invest Dermatol
Authors: M. Garcia;F. Larcher;R.P. Hickerson;E. Baselga;S.A. Leachman;R.L. Kaspar;M. Del Rio
Issue: Epub,

Abstract:

Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p.Asn171Lys mutation of the keratin 6a gene (KRT6A), we were able to regenerate PC-derived human skin that appeared phenotypically normal, but developed sustained PC features after the use of an acute hyperproliferative stimulus (i.e., tape stripping). In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p.Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease.Journal of Investigative Dermatology advance online publication, 9 December 2010; doi:10.1038/jid.2010.353.

Title: Genotype-Phenotype Correlations among Pachyonychia Congenita Patients with K16 Mutations
Journal: J Invest Dermatol
Authors: T. Fu;S.A. Leachman;N.J. Wilson;F.J.D. Smith;M.E. Schwartz;J.Y. Tang
Issue: Epub,

Abstract:

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management. Journal of Investigative Dermatology advance online publication, 16 December 2010; doi:10.1038/jid.2010.373.

Title: RXi Pharmaceuticals Continues String of Sensible RNAi Delivery Collaborations
Journal: RNAITherapeutics.blogspot.com
Authors: D. Haussecker

Abstract:

http://rnaitherapeutics.blogspot.com/2010/09/rxi-pharmaceuticals-continues-string-of.html

Title: Expediting RNA Delivery with small parcels
Journal: Genetic Engineering & Biotechnology News
Authors: C. Potera
Pages: 18-19

Abstract:

Nanosized particles use molecular motor from Bacteriophage to slip into cells and drop off cargo.

Title: Shoestring Gene Therapy
Journal: The Scientist
Authors: A. Rowe
Volume: 24, Issue: 8, Pages: 20

Title: Silencing of Reporter Gene Expression in Skin Using siRNAs and Expression of Plasmid DNA Delivered by a Soluble Protrusion Array Device (PAD)
Journal: Molecular Therapy
Authors: E.G. Gonzalez; T.J. Speaker; R.P. Hickerson; R. Spitler; M.A. Flores; D. Leake; C.H. Contag; R.L. Kaspar
Volume: 18, Issue: 9, Pages: 1667-1674

Abstract:

Despite rapid progress in the development of potent and selective small interfering RNA (siRNA) agents for skin disorders, translation to the clinic has been hampered by the lack of effective, patient-friendly delivery technologies. The stratum corneum poses a formidable barrier to efficient delivery of large and/or charged macromolecules including siRNAs. Intradermal siRNA injection results in effective knockdown of targeted gene expression but is painful and the effects are localized to the injection site. The use of microneedle arrays represents a less painful delivery method and may have utility for the delivery of nucleic acids, including siRNAs. For this purpose, we developed a loadable, dissolvable protrusion array device (PAD) that allows skin barrier penetration. The PAD tips dissolve upon insertion, forming a gellike plug that releases functional cargo. PAD-mediated delivery of siRNA (modified for enhanced stability and cellular uptake) resulted in effective silencing of reporter gene expression in a transgenic reporter mouse model. PAD delivery of luciferase reporter plasmids resulted in expression in cells of the ear, back, and footpad skin as assayed by intravital bioluminescence imaging. These results support the use of PADs for delivery of functional nucleic acids to cells in the skin with an efficiency that may support clinical translation.

Title: Broken bricks and cracked mortar- epidermal diseases resulting from genetic abnormalities
Journal: Drug Discov Today:Dis Mech
Authors: E.B. Lane; W.H.I. McLean
Volume: doi:10.1016/j, Issue: ddmec-289, Pages: e1-e9

Abstract:

The epidermis is an attractive organ system for therapydevelopment since it is completely accessible for both the application of new cutaneous therapeutics and subsequent monitoring of safety and efficacy. The molecular basis of a large number of hereditary epidermal diseases has now been elucidated. Many of the gene products involved in these disorders are structural molecules, including the multigene family of keratins, cell junction proteins and cytoskeletal modifying proteins. Building on this knowledge base, the causative genes contributing to complex traits of the epidermis are now emerging, such as the keratin-associated protein filaggrin in atopic eczema. As well as recent developments in ex vivo gene replacement therapy in skin blistering disorders, gene silencing methods based on RNA interference technology are currently the centre of attention in the field, as well as small molecule screening campaigns targeting proteins and pathways identified through human genetics studies.

Title: Pachyonychia Congenita: A Case Report
Journal: Cutis
Authors: N. Kohli
Volume: 84, Issue: 5, Pages: 269-271

Abstract:

A 21-year-old man presented with hypertrophic nail dystrophy and subungual debris of all 20 nails, hyperkeratotic plaques on the heels of both feet, and oral leukokeratosis. he had an extensive faimily history of similar clinical findings. The patient's clinical presentation and history were consistent with pachyonychia congenita (PC), an autosomal dominant genodermatosis caused by mutations in the genes for keratin 6, K6a and K6b; keratin 16, K16; and keratin 17, K17.

Title: Identification of a CAST Mutation in a Cohort Previously Misdiagnosed as Having Autosomal Recessive Pachyonychia Congenita
Journal: JAMA Dermatol
Authors: R.M. Haber, T.H. Rose
Volume: 151, Section: 12, Pages: 1393-1394

Abstract:

To the Editor This letter corrects our diagnosis from1986, documents the CAST mutation in our patients fromthat time, and adds to the list of genodermatoses that may mimic pachyonychia congenita (PC).
The gold standard for diagnosis of genetic skin diseases is the demonstration of the causative gene mutation. The dominantly inherited genodermatosis PC is caused by a mutation in K6a, K6b, K6c, K16, or K17. Pachyonychia congenita can be clinically misdiagnosed, with reports of Clouston syndrome mimicking PC, and the correct diagnosis can only bemade by gene mutational analysis.
In 1986, prior tothe establishmentof the causativePCkeratin gene  mutations,we reported PCwith autosomal recessive inheritance. When one of our original patients was eventually contacted for genetic assessment in 2015 and tested negative for any of the knownkeratin mutations causing PC, he underwent whole-exome sequencing, which established the correct diagnosis of PLACK syndrome (peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads)
in our cohort. PLACKsyndrome was recently described by Lin et al4 as a
newtype of autosomal recessive generalized peeling skin  syndromecaused by mutations in theCAST gene. The authors describe
Chinese and Nepalese patients as well as our “autosomal recessive PC” family. By whole-exome sequencing, Lin et al found that all affected individuals had loss-of-function mutations in theCAST gene that encodes for the protein calpastatin. The CAST mutation in our patients was a homozygous frameshift mutation, c.1750delG, p.Val584Trpfs*37. Different homozygous mutationswere identified in the Chinese and Nepalese families. Similar to the other families with PLACKsyndrome,
our patients had peeling skin, leukonychia, acral punctate keratoses, and angular cheilitis. Our patients differed from the other families with PLACKsyndromein that they had extensive oral leukokeratosis, more diffuse plantar keratoderma, and no knuckle pads.To our knowledge, the only other report of autosomal recessive PC was in 1977, a Malaysian girl
whose parents were first cousins. This case was never supported by a molecular diagnosis.
All genetically documented cases of PC in the Pachyonychia Congenita Research Registry are dominantly inherited (personal communication with Mary E. Schwartz at the Pachyonychia Congenita Project, 2015). To our knowledge, there are no knowncases of autosomal recessive PC with confirmed genetic analysis.

Title: Pachyonychia Congenita in Pediatric Patients Natural History, Features, and Impact
Journal: JAMA Dermatol
Authors: S Shah; M Boen; B Kenner-Bell; M Schwartz; A Rademaker; AS Paller

Abstract:

Among patients with a detectable mutation, PC manifests with nail thickening and plantar keratoderma before school age in more than three-quarters of affected children, allowing early diagnosis. The highly visible nail changes and painful plantar thickening exert a psychosocial effect on most affected adolescents. Phenotype-genotype correlations in children with PC validate the new classification based on the affected gene.

Title: Hedgehog Signaling, Keratin 6 Induction, and Sebaceous Gland Morphogenesis
Journal: Am J Pathol.
Authors: L.H. Gu; P.A. Coulombe
Volume: 173, Issue: 3, Pages: 752-761

Abstract:

Keratins 6a and b (K6a, K6b) belong to a subset of keratin genes with constitutive expression in epithelial appendages, and inducible expression in additional epithelia, when subjected to environmental challenges or disease. Mutations in K6a or K6b cause a broad spectrum of epithelial lesions that differentially affect nail, hair, and glands in humans. Some lesions reflect a loss of the structural support function shared by K6, other keratins, and intermediate filament proteins. The formation of sebaceous gland-derived epithelial cysts does not fit this paradigm, raising the question of the unique functions of different K6 isoforms in this setting. Here, we exploit a mouse model of constitutively expressed Gli2, a Hedgehog (Hh) signal effector, to show that K6a expression correlates with duct fate in sebaceous glands (SGs). Whether in the setting of Gli2 transgenic mice skin, which develops a prominent SG duct and additional pairs of highly branched SGs, or in wild-type mouse skin, K6a expression consistently coincides with Hh signaling in ductal tissue. Gli2 expression modestly transactivates a K6a promoter-driven reporter in heterologous systems. Our findings thus identify K6 as a marker of duct fate in SGs, partly in response to Hh signaling, with implications for the pathological expansion of SGs that arises in the context of certain keratin-based diseases and related disorders.

Title: Identification of two recurrent mutations in keratin genes in three cases with pachyonychia congenita
Journal: J Eur Acad Dermatol Venereol
Authors: J.W. Wu; S.X. Xiao; Y. Liu; B. Yu; Z.L. Bai; S.N. Zhou; X.L. Li
Volume: 23, Issue: 2, Pages: 174-176

Abstract:

Pachyonychia congenita (PC) is a group of autosomaldominant ectodermal dysplasias containing two main clinical subtypes: PC-1 and PC-2. PC-1 is caused by mutations in either K16 or K6a, and PC-2 is caused by mutations in K17 or K6b. Here, we reported two mutations: 380G > C resulting in a substitution of Argine for Proline (R127P) in K16 in a sporadic case with PC-1 and 296T > C causing substitution of Leucine for Proline (L99P) in K17 in a family presenting with PC-2.

Title: Pachyonychia congenita and hidradenitis suppurativa: no response to infliximab therapy
Journal: J Eur Acad Dermatol Venereol.
Authors: J. Pedraz; P.F. Pe
Volume: 22, Issue: 12, Pages: 1500-1501

Title: Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco
Journal: Am J Med Genet A.
Authors: R. Mostefai; F. Morice-Picard; F. Boralevi; M. Sautarel; D. Lacombe; M.J. Stasia; J. McGrath; A. Ta
Volume: 146A, Issue: 21, Pages: 2762-2769

Abstract:

Three siblings from Morocco consanguineous family presented with cutaneous poikiloderma following postnatal ichthyosiform lesions, associated with papillomatous lesions, palmoplantar keratoderma, pachyonychia of toenails, fragile carious teeth, and lachrymal duct obstruction. Photosensitivity and blistering improved with age. Atrophic scars were prominent on the limbs. Neutropenia developed in the first year secondary to dysmyelopoiesis affecting the granulocyte lineage, associated with a polyclonal hypergammaglobulinemia. Several broncho-pulmonary infectious episodes complicated the evolution, and cystic fibrosis was first considered on the basis of repeated abnormal sweat chloride tests but not confirmed by molecular analyses. This autosomal recessive disorder matches that described originally as poikiloderma with neutropenia-Clericuzio type in Navajo Indians (OMIM 604173). It is discussed within the group of the major hereditary poikiloderma disorders, that is, Rothmund-Thomson syndrome, dyskeratosis congenita, and Kindler syndrome. Copyright 2008 Wiley-Liss, Inc.

Title: Therapeutic interference: a step closer for pachyonychia congenita?
Journal: J Invest Dermatol.
Authors: E.L. Rugg
Volume: 128, Issue: 1, Pages: 7-8

Abstract:

The identification of mutations in keratin genes as the cause of several inherited skin disorders raised the possibility that molecular-based therapies might be developed to treat these conditions. In this issue, Smith et al. (2007) have identified small interfering RNAs that specifically and potently silence keratin 6a expression. These molecules have great promise as therapeutic agents for the treatment of pachyonychia congenita.

Title: Mice Expressing a Mutant Krt75 (K6hf ) Allele Develop Hair and Nail Defects Resembling Pachyonychia Congenita
Journal: J Invest Dermatol.
Authors: J. Chen; K. Jaeger; Z. Den; P.J. Koch; J.P. Sundberg; D.R. Roop
Volume: 128, Issue: 2, Pages: 270-279

Abstract:

KRT75 (formerly known as K6hf) is one of the isoforms of the keratin 6 (KRT6) family located within the type II cytokeratin gene cluster on chromosome 12 of humans and chromosome 15 of mice. KRT75 is expressed in the companion layer and upper germinative matrix region of the hair follicle, the medulla of the hair shaft, and in epithelia of the nail bed. Dominant mutations in members of the KRT6 family, such as in KRT6A and KRT6B cause pachyonychia congenita (PC) -1 and -2, respectively. To determine the function of KRT75 in skin appendages, we introduced a dominant mutation into a highly conserved residue in the helix initiation peptide of Krt75. Mice expressing this mutant form of Krt75 developed hair and nail defects resembling PC. This mouse model provides in vivo evidence for the critical roles played by Krt75 in maintaining hair shaft and nail integrity. Furthermore, the phenotypes observed in our mutant Krt75 mice suggest that KRT75 may be a candidate gene for screening PC patients who do not exhibit obvious mutations in KRT6A, KRT6B, KRT16, or KRT17, especially those with extensive hair involvement.

Title: Pachyonychia congenita tarda: very late onset
Journal: Int J Dermatol.
Authors: R. Bahhady; O. Abbas; M. Dahdah
Volume: 47, Issue: 11, Pages: 1172-1173

Title: Pachyonychia congenita associated with median rhomboid glossitis
Journal: Dermatol Online J.
Authors: J.K. Karen; J.V. Schaffer
Volume: 13, Issue: 1, Pages: 21

Abstract:

A 3-year-old girl presented with subungual hyperkeratosis and nail plates with increased transverse curvature, distal elevation, yellow-brown discoloration, and mild thickening. The changes, which affected all 20 nails, had developed during the first year of life. Mucocutaneous examination showed the presence of median rhomboid glossitis. The patient's mother had similar nail changes, which had been present since infancy as well as a focal plantar keratoderma and hyperhidrosis. The patient's clinical presentation and history were compatible with a diagnosis of pachyonychia congenita, a rare heritable disease that affects the nails, skin, oral and laryngeal mucosae, teeth, and hair. Dominant-negative mutations in four keratin genes (K6a, K6b, K16, and K17) lead to keratinocyte fragility and the resultant pachyonychia congenita phenotype. Successful targeted therapies are currently lacking for this oftentimes disabling disorder. Although oral manifestations are a common feature of PC, to our knowledge, this represents the first report of median rhomboid glossitis in association with PC.

Title: Milia: a review and classification
Journal: J Am Acad Dermatol.
Authors: D.R. Berk; S.J. Bayliss
Volume: 59, Issue: 6, Pages: 1050-1063

Abstract:

Milia are frequently encountered as a primary or secondary patient concern in pediatric and adult clinics, and in general or surgical dermatology practice. Nevertheless, there are few studies on the origin of milia and, to our knowledge, there is no previous comprehensive review of the subject. We review the various forms of milia, highlighting rare variants including genodermatosis-associated milia, and present an updated classification.

Title: Pachyonychia congenita with unusual dental findings: a case report
Journal: Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
Authors: A.R. Pradeep; C. Nagaraja
Volume: 104, Issue: 1, Pages: 89-93

Title: Pachyonychia congenita: treatment of the thickened nails and palmoplantar circumscribed callosities with urea 40% paste
Journal: J Eur Acad Dermatol Venereol.
Authors: M.A. El-Darouti; S.A. Marzouk; N. Nabil; M.R. Abdel-Halim; M.H. El-Komy; M. Abdel-Latif
Volume: 20, Issue: 5, Pages: 615-617

Title: Pachyonychia congenita type 2, N92S mutation of keratin 17 gene: clinical features, mutation analysis and pathological view
Journal: Eur J Pediatr
Authors: O. Cogulu; H. Onay; A. Aykut; N.J. Wilson; F.J. Smith; T. Dereli; F. Ozkinay
Volume: 168, Issue: 10, Pages: 1269-1272

Abstract:

Pachyonychia congenita (PC) type 2 is a rare inherited genetic disease characterized by hypertrophic nail dystrophy, palmoplantar hyperkeratosis and multiple pilosebaceous cysts. In some cases, natal teeth and hair abnormalities may be present. It is caused by mutations in keratin 17 or its expression partner keratin 6b. Here, an N92S (p.Asn92Ser) germline keratin 17 gene mutation in a pachyonychia congenita type 2 female patient is presented. The pedigree includes the 15 members of a family who showed a severe expression of the phenotype for six generations with a similar clinical picture consisting of sebaceous cysts, nail dystrophy, hyperkeratosis, hair abnormalities, natal teeth, hoarseness and hyperhydrosis. In conclusion, we emphasize the importance of diagnosing and managing pachyonychia congenita in childhood for the assistance of affected children and for the development of potential therapies.

Title: Supernumerary digits associated with pachyonychia congenita type I
Journal: Indian J Dermatol Venereol Leprol
Authors: S. Agarwal; K. Gopal
Volume: 73, Issue: 6, Pages: 431-432

Title: Morphological and genetic analysis of steatocystoma multiplex in an Asian family with pachyonychia congenita type 2 harbouring a KRT17 missense mutation
Journal: Br J Dermatol
Authors: M. Kanda; K. Natsuga; W. Nishie; M. Akiyama; A. Nagasaki; T. Shimizu; H. Shimizu
Volume: 160, Issue: 2, Pages: 465-468

Abstract:

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder. PC can be classified into two main clinical subtypes: PC type 1 (PC-1, OMIM 167200) and PC type 2 (PC-2, OMIM 167210). PC-1 is associated with mutations in KRT6A or KRT16, and PC-2 corresponds to mutations in KRT6B or KRT17.1,2 Almost all mutations detected in patients with PC occur in the helix boundary motifs of each keratin gene.3 Common clinical features of both PC subtypes are hypertrophic nail dystrophy, and focal hyperkeratosis of the palms, soles, knees and elbows.4 Among clinical manifestations in patients with PC, the development of steatocystoma multiplex is one of the most characteristic features for differentiating PC-2 from PC-1. Typically, patients with PC-2 exhibit 100-2000 round or oval cysts widely distributed on the back, anterior trunk, arms, scrotum and thighs. We report an Asian PC-2 family with a missense mutation in KRT17. In this study, we present histological and ultrastructural features of a steatocystoma from the proband. Furthermore, comparative analysis of genomic DNA (gDNA) extracted from steatocystomas and peripheral blood of the family was performed. These observations could provide significant information for understanding the pathomechanisms of cyst formation in patients with PC-2.

Title: Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity
Journal: Human Molecular Genetics
Authors: G.M. Essenfelder; R. Bruzzone; J. Lamartine; A. Charollais; C. Blanchet-Bardon; M.T. Barbe; P. Meda; G. Waksman
Volume: 13, Issue: 16, Pages: 1703-1714

Abstract:

Clouston syndrome or hidrotic ectodermal dysplasia (HED) is a rare dominant genodermatosis characterized by palmoplantar hyperkeratosis, generalized alopecia and nail defects. The disease is caused by mutations in the human GJB6 gene which encodes the gap junction protein connexin30 (Cx30). To gain insight into the molecular mechanisms underlying HED, we have analyzed the consequences of two of these mutations (G11R Cx30 and A88V Cx30) on the functional properties of the connexons they form. Here, we show that the distribution of Cx30 is similar in affected palmoplantar skin and in normal epidermis. We further demonstrate that the presence of the wild-type protein (wt Cx30) improves the trafficking of mutated Cx30 to the plasma membrane where both G11R and A88V Cx30 co-localize with wt Cx30 and form functional intercellular channels. The electrophysiological properties of channels made of G11R and A88V Cx30 differ slightly from those of wt Cx30 but allow for dye transfer between transfected HeLa cells. Finally, we document a gain of function of G11R and A88V Cx30, which form functional hemichannels at the cell surface and, when expressed in HeLa cells, generate a leakage of ATP into the extracellular medium. Such increased ATP levels might act as a paracrine messenger that, by altering the epidermal factors which control the proliferation and differentiation of keratinocytes, may play an important role in the pathophysiological processes leading to the HED phenotype.

Title: Pachyonychia Congenita
Journal: GeneReviews: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pc
Authors: F.J.D. Smith; R.L. Kaspar; M.E. Schwartz; W.H.I. McLean; S.A. Leachman
Volume: ,

Abstract:

Disease characteristics. Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy,focal palmoplantar keratoderma and blistering, oral leukokeratosis, cyst formation, palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities. PC includes two main subtypes,pachyonychia congenita type 1 (PC-1) and pachyonychia congenita type 2 (PC-2). Variants of PC include focal non-epidermolytic palmoplantar keratoderma (FNEPPK), with keratoderma occurring on the palms and soles but usually without nail dystrophy; steatocystoma multiplex (SM) with widespread cysts but with little or no nail involvement or palmoplantar keratoderma; and late-onset PC (PC tarda), which resembles either PC-1 or PC-2 and has onset from late childhood to middle age. Diagnosis/testing. PC is diagnosed by clinical findings and by molecular genetic testing. The two keratin genes known to be associated with PC-1 are KRT6A (encoding keratin, type II cytoskeletal 6a) and KRT16 (encoding keratin, type I cytoskeletal 16). The two keratin genes known to be associated with PC-2 are KRT6B (encoding keratin, type II cytoskeletal 6b) and KRT17 (encoding keratin, type I cytoskeletal 17). Molecular genetic testing of these four genes is available on a clinical basis. Management. Treatment of manifestations: Pain from the palmoplantar keratoderma can be reduced by limiting friction and trauma to the feet by minimizing walking or standing, reducing hydration of the stratum corneum by using wicking socks and ventilated footwear, selecting comfortable shoes, and maintaining ideal body weight. Foot care includes paring down hyperkeratotic areas and topical therapies for hyperkeratosis including emollients and lotions containing keratolyics. Early detection permits treatment of secondary bacterial and yeast/fungal infections on the feet and nails and in the mouth. Care of thickened nails often requires the use of surgical or razor blades or sanders such as a Dremel

Title: Novel and recurrent keratin 6A (KRT6A) mutations in Chinese patients with pachyonychia congenita type 1
Journal: Br J Dermatol
Authors: Y.M. Lv; S. Yang; Z. Zhang; Y. Cui; C. Quan; F.S. Zhou; Q.Y. Fang; W.H. Du; F.R. Zhang; J.M. Chang; X.P. Tao; A.L. Zhang; R.H. Kang; W.D. Du; X.J. Zhang
Volume: 160, Issue: 6, Pages: 1327-1329

Abstract:

Pachyonychia congenita (PC) is a rare autosomal dominant disorder caused by keratin gene mutations. PC clinically presents with hypertrophic nail dystrophy, hyponychial keratosis, painful palmoplantar keratoderma and other ectodermal features.1 The PC classification accepted worldwide includes two clinical subtypes: the Jadassohn-Lewandowsky or PC type 1 (PC-1; OMIM 167200) and the Jackson-Lawler or PC-2 variant (OMIM 167210). PC-1 is characterized by nail dystrophy composed of four helical segments named 1A, 1B, 2A and 2B, respectively.3 It has been reported that all the known keratin mutations in patients with PC-1 are limited to within the conserved helix boundary motifs of either the beginning of 1A or the end of the 2B domain which are encoded by exons 1 and 6 of the keratin 16 gene (KRT16) and exons 1 and 7 of the keratin 6A gene (KRT6A), respectively. 3-5 So far, over 33 mutations in KRT6A ⁄KRT16 have been identified in independently ascertained families with PC-1 (http://www.interfil. org). Here we report three novel mutations and four recurrent missense mutations within the hotspot regions of KRT6A detected in Chinese patients with PC-1.

Title: Pachyonychia congenita with unusual features
Journal: Indian Pediatrics
Authors: S. Balasubramanian; K. Kaarthigeyan; B. Ramnath
Volume: 46, Issue: 10, Pages: 897-899

Abstract:

Pachyonychia congenita is a rare hereditary disorder characterized by gross thickening of all finger and toenails. We report an infant who had clinical features consistent with pachyonychia congenita type II, with unusual features of microcephaly, seizures, electroencephalogram abnormalities, failure to thrive, and heterochromia iridis.

Title: Pachyonychia congenita type 2
Journal: Indian J Dermatol Venereol Leprol
Authors: J.K. Das; S. Sengupta; A. Gangopadhyay
Volume: 75, Issue: 3, Pages: 321-322

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis in which hypertrophy of the nails occurs, in some cases in association with nail bed and hyponychial hyperkeratosis. Autosomal dominant inheritance with incomplete penetrance is the rule, although Haber and Rose described cases with autosomal recessive transmission. The presence of thickened, wedgeshaped nails is the diagnostic clinical feature of PC, but the other clinical characteristics of it usually match with two major patterns. Jadassohn-Lewandowsky syndrome (PC-1) shows focal palmoplantar hyperkeratosis and localized foot blistering, follicular hyperkeratosis and oral leukokeratosis. Jackson- Lawler syndrome (PC-2) shows cutaneous cysts, hair abnormalities and presence of teeth at birth, but less severe nail lesions, and neither oral lesions nor significant keratoderma.

Title: Pachyonychia Congenita Type 1 Presenting with Subtle Nail Changes
Journal: Pediatr Dermatol
Authors: M. Iorizzo;C. Vincenzi;F.J.D. Smith;N.J. Wilson;A. Tosti
Volume: 26, Issue: 4, Pages: 492-3

Abstract:

Pachyonychia congenita type 1 is an autosomal dominant disorder where nail abnormalities are a constant feature and develop during childhood. We report here a family with pachyonychia congenita type 1 and very mild nail changes to underline that this diagnosis should be considered even in the absence of severe nail thickening.

Title: Achieving Successful Delivery of Nucleic Acids to Skin: 6th Annual Meeting of the International Pachyonychia Congenita Consortium
Journal: J Invest Dermatol
Authors: R.L. Kaspar; W.H. Irwin; M.E. Schwartz
Volume: 129, Issue: 9, Pages: 2085-2087

Abstract:

The 2009 Annual Meeting of the International Pachyonychia Congenita Consortium (IPCC)* centered on the need to develop patient-friendly technologies to effectively and efficiently deliver nucleic acids to skin. The IPCC is a group of physicians and scientists who have agreed to work together to develop therapeutics for the rare skin disorder pachyonychia congenita (PC) (a list of IPCC members can be found at http://www.pachyonychia.org). Each year's IPCC meeting is devoted to the most pressing issues related to developing PC therapeutics and to identifying future directions toward achieving realistic goals. The consortium fully recognizes and expects that research success in this realm will be of immediate benefit not only to patients with PC but also to those suffering from other skin disorders. The meeting was divided into four areas: (i) a historical overview highlighting the need for nucleic acid skin delivery, (ii) delivery technologies used in recent clinical trials, (iii) delivery technologies currently under development, and (iv) future directions in the development of nucleic acid skin delivery technologies that will be acceptable and effective.

Title: Acro-osteolysis: A complication of Jadassohn
Journal: International Journal of Dermatology
Authors: S.B. Murugesh; S. Reddy; S. Ragunatha; M.M.Mohammed Faizal; P. Shashikala
Volume: 46, Issue: 2, Pages: 202-205

Abstract:

Pachyonychia congenita (PC) is a group of inherited ectodermal dysplasias whose most prominent feature is hypertrophic nail dystrophy. Muller, in 1904, and Wilson, in 1905, described the first cases of PC. One year later the same condition was described in two siblings by Jadassohn and Lewandowsky.It usually develops in early infancy and the onset of nail changes beyond the first few years after infancy is rare. There are two major types of PC: Jadassohn

Title: Increased pachyonychia Congenita severity in patients with current keratin and filaggrin mutations
Journal: Br J Dermatol
Authors: R. Gruber;N.J. Wilson;F.J.D. Smith;D. Grabher;L. Steinwender;P.O. Fritsch;M. Schmuth
Volume: 161, Issue: 6, Pages: 1391-5

Abstract:

Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A ⁄B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss-of-function mutations in the filaggrin (FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X-linked ichthyosis and alopecia areata. We report a parent-child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC.

Title: Rapamycin selectively inhibits expression of an inductible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients
Journal: J Dermatol Sci
Authors: R.P. Hickerson;D. Leake;L.N. Pho;S.A. Leachman;R.L. Kaspar
Volume: 56, Issue: 2, Pages: 82-8

Abstract:

Background: The macrolide sirolimus (rapamycin) selectively blocks translation of mRNAs containing a terminal 50 oligopyrimidine (TOP) tract by altering the activity of mammalian target of rapamycin (mTOR) and inhibiting downstream mTOR pathway components involved in TOP mRNA translation. The skin disorder pachyonychia congenita (PC) is caused bymutations in the inducible keratins (K) including K6a, K6b, K16 and K17. Published sequence data suggest the 50 untranslated regions of K6a and K6b mRNAs contain 50 TOP motifs and therefore may be sensitive to rapamycin treatment. Objective: Determine if mTOR inhibitors (rapamycin, temsirolimus or everolimus) are viable drug candidates for treatment of PC and other disorders caused by inappropriate expression of K6a and K6b. Methods: 50 RACE analysis was used to map the transcriptional start sites for K5, K6a, K6b, K14, K16 and K17. The sensitivity of these keratins to mTOR inhibitors was determined by Western and qPCR analysis following treatment of a human HaCaT keratinocyte cell line with rapamycin, temsirolimus or everolimus. A small off-label study was undertaken using orally administered rapamycin in three PC patients and the effects were monitored by clinical examination, photography, a validated Dermatology Life Quality Index (DLQI) and a pain and activity diary. Results: Sequence comparison and 50 RACE analysis of the 50 untranslated regions of K6a and K6b revealed putative TOP regulatory elements. Treatment of a human HaCaT keratinocyte cell line with mTOR inhibitors (rapamycin, temsirolimus or everolimus) resulted in selective K6a repression. Furthermore, treatment of this HaCaT cell line with siRNAs targeting components of the mTOR pathway altered the levels of K6a expression. To test the ability of rapamycin to ameliorate PC symptoms, an offlabel study was conducted. PC patient clinical responses to oral rapamycin showed a therapeutic response in callus character as well as subjective improvement. Of particular note, rapamycin greatly reduced the presence of painful cutaneous thromboses after reaching therapeutic serumlevels. The wellknown rapamycin side effects led to the early withdrawal of all of the patients from the study. Conclusion: Rapamycin selectively blocks K6a expression in human keratinocytes. The improvement of symptoms in PC patients following rapamycin treatment suggests rapamycin (or rapamycin analogs) may be a therapeutic option, particularly if topical formulations can be developed that avoid the side effects associated with systemic administration.

Title: A novel missense mutation L468Q of keratin 6a in pachyonychia congenita type 1
Journal: J Eur Acad Dermatol Venereol
Authors: H.L. Zhou; S. Yang; M. Gao; X.Y. Zhu; W. Li; Y.Q. Ren; Y.H. Liang; W.H. Du; X.J.Zhang
Volume: 21, Issue: 3, Pages: 351-355

Abstract:

BACKGROUND: Pachyonychia congenita is an autosomal dominant disorder that usually develops in early infancy. The major features of the syndrome are hypertrophic nail dystrophy, palmoplantar keratoderma and oral leucokeratosis, accompanied by other ectodermal defects, according to subtype. OBJECTIVE: To analyse the K6a gene mutation in a sporadic Chinese patient with pachyonychia congenita type 1 (PC-1) and to explore the relationship between the genotype and phenotype of PC-1. METHODS: Genomic DNA was extracted from peripheral blood of the patient with PC-1 and 100 unrelated controls. The whole coding region of K6a gene was amplified using long-range polymerase chain reaction (PCR); nested PCR was then used to amplify the mutation 'hot-spot' of the K6a gene. The PCR products were directly sequenced to detect the mutation. RESULTS: A novel missense mutation L468Q in the helix 2B domain of the K6a polypeptide was identified in the patient but not in the healthy individuals from the family and 100 unrelated control individuals. CONCLUSIONS: We describe this mutation for the first time, and provide further evidence that the helix boundary motif sequences of K6a are a mutation 'hot-spot'.

Title: A novel mutation in K6b in pachyonychia congenita type 2
Journal: Journal of Investigative Dermatology
Authors: V.M. Sharma; S.L. Stein
Volume: 127, Issue: 8, Pages: 2060-2062

Title: Keratin K6c Mutations Cause Focal Palmoplantar Keratoderma
Journal: J Invest Dermatol
Authors: N.J. Wilson;A.G. Messenger;S.A. Leachman;E.A. O'Toole;E.B. Lane;W.H. McLean;F.J.D. Smith

Abstract:

The palmoplantar keratodermas (PPKs) are a large group of clinically and genetically heterogeneous genodermatoses. The gene defects underlying many PPKs still need to be resolved to facilitate definitive molecular diagnosis and genetic counseling. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16, or KRT17, cause pachyonychia congenita (PC), characterized by hypertrophic nail dystrophy and other ectodermal features. In PC, focal PPK (FPPK) is the most painful and debilitating phenotypic feature. Some families presenting with FPPK alone, or with minimal nail changes, carry mutations in KRT16; however, most FPPK families do not harbor mutations in any of these keratin genes. Here, we report threeunrelated families who presented with familial FPPK with minor or absent nail changes. The four PC/FPPKrelated keratin genes were excluded; however, mutational analysis of the recently identified KRT6C gene, encoding keratin K6c, showed heterozygous in-frame deletion mutations in all three kindreds. Affected members of Families 1 and 2 carried the same mutation, p.Asn172del. In Family 3, the mutation p.Ile462-Glu470del co-segregated with the disease. KRT6C was shown to be expressed in the plantar epidermis using reverse transcription-PCR, consistent with the phenotype observed in this tissue. These data expand the genetic testing repertoire for the PPKs.

Title: Stability Study of Unmodified siRNA and Relevance to Clinical Use
Journal: Oligonucleotides
Authors: R. P. Hickerson; A. V. Vlassov; Q. Wang; D. Leake; H. Ilves; E. Gonzalez-Gonzalez; C. H. Contag; B. H. Johnston; R. L. Kaspar
Issue: ahead of print,

Abstract:

RNA interference offers enormous potential to develop therapeutic agents for a variety of diseases. To assess the stability of siRNAs under conditions relevant to clinical use with particular emphasis on topical delivery considerations, a study of three different unmodified siRNAs was performed. The results indicate that neither repeated freeze/thaw cycles, extended incubations (over 1 year at 21 degrees C), nor shorter incubations at high temperatures (up to 95 degrees C) have any effect on siRNA integrity as measured by nondenaturing polyacrylamide gel electrophoresis and functional activity assays. Degradation was also not observed following exposure to hair or skin at 37 degrees C. However, incubation in fetal bovine or human sera at 37 degrees C led to degradation and loss of activity. Therefore, siRNA in the bloodstream is likely inactivated, thereby limiting systemic exposure. Interestingly, partial degradation (observed by gel electrophoresis) did not always correlate with loss of activity, suggesting that partially degraded siRNAs retain full functional activity. To demonstrate the functional activity of unmodified siRNA, EGFP-specific inhibitors were injected into footpads and shown to inhibit preexisting EGFP expression in a transgenic reporter mouse model. Taken together, these data indicate that unmodified siRNAs are viable therapeutic candidates.

Title: Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity.
Journal: J Dermatol
Authors: S. W. Oh; M. Y. Kim; J. S. Lee; S. C. Kim
Volume: 33, Issue: 3, Pages: 161-4

Abstract:

Pachyonychia congenita type 2 (PC-2) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, focal keratoderma, multiple pilosebaceous cysts, and other features of ectodermal dysplasia. It has been demonstrated that PC-2 is caused by mutations in the keratin 17 and keratin 6b genes. In this report, we describe a missense mutation in the keratin 17 gene, M88T, in a Korean patient whose phenotype included early onset steatocystoma multiplex and Hutchinson-like tooth deformities along with other typical features of PC-2 such as hypertrophic nails, natal teeth and follicular hyperkeratosis.

Title: First-in-human Mutation-targeted siRNA Phase 1b Trial of an Inherited Skin Disorder
Journal: Mol Ther
Authors: S.A. Leachman; R.P. Hickerson; M.E. Schwartz; E.E. Bullough; S.L. Hutcherson; K.M. Boucher; C.D. Hansen; M.J. Eliason; G.S. Srivatsa; D.J. Kornbrust; F.J. Smith; W.H. McLean; L.M. Milstone; R.L. Kaspar

Abstract:

The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient's siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.

Title: The chemical chaperone trimethylamine N-oxide ameliorates the effects of mutant keratins in cultured cells
Journal: Br J Dermatol
Authors: D. Lee;D. Santos;H. Al-Rawi;A.M. McNeill;E. Rugg
Volume: 159, Issue: 1, Pages: 252-5

Title: Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita.
Journal: J Dermatol Sci.
Authors: S. A. Leachman; R. P. Hickerson; P. R. Hull; F. J. Smith; L. M. Milstone; E. B. Lane; S. J. Bale; D. R. Roop; W. H. McLean; R. L. Kaspar
Volume: 51, Issue: 3, Pages: 151-7

Abstract:

The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been genetically defined, but little progress has been made with respect to the clinical application of this knowledge. A notable exception to this exists for pachyonychia congenita (PC), a rare, dominant-negative keratin disorder. The establishment of a non-profit organization, PC Project, has led to an unprecedented coalescence of patients, scientists, and physicians with a unified vision of developing novel therapeutics for PC. Utilizing the technological by-products of the human genome project, such as RNA interference (RNAi) and quantitative RT-PCR (qRT-PCR), physicians and scientists have collaborated to create a candidate siRNA therapeutic that selectively inhibits a mutant allele of KRT6A, the most commonly affected PC keratin. In vitro investigation of this siRNA demonstrates potent inhibition of the mutant allele and reversal of the cellular aggregation phenotype. In parallel, an allele-specific quantitative real-time RT-PCR assay has been developed and validated on patient callus samples in preparation for clinical trials. If clinical efficacy is ultimately demonstrated, this "first-in-skin" siRNA may herald a paradigm shift in the treatment of dominant-negative genetic disorders.

Title: Recurrent mutation in keratin 17 in a large family with pachyonychia congenita type 2
Journal: Arch Dermatol Res.
Authors: C. Oh Adib;B. Jones;H. Liao;F.J. Smith;R. Solomon;C.A. Egan;S. Leachman
Volume: 300, Issue: 5, Pages: 211-4

Title: A novel point mutation of keratin 17 (KRT17) in a Japanese family with pachyonychia congenita type 2: an RNA-based genetic analysis using a single hair bulb.
Journal: Br J Dermatol [Epub ahead of print]
Authors: T. Tsuda;C. Ishikawa;N. Nakagawa;H. Konishi;M. Tarutani;M. Matsuki;K. Yamanishi

Abstract:

Pachyonychia congenita type 2 (PC-2) (MIM 167210; Jackson?Lawler syndrome) is an autosomal dominant keratin disorder characterized by hypertrophic nail dystrophy with multiple pilosebaceous cysts. Genetic defects in PC-2 have been correlated with two different keratin genes: keratin 17 (KRT17) and keratin 6b (KRT6B).1,2 We report here a novel missense mutation, methionine at codon 88 to lysine (p.M88K), of KRT17, which was detected using RNA from only an individual hair bulb.

Title: Pachyonychia congenita type 2: abnormal dentition extending into adulthood.
Journal: Br J Dermatol
Authors: M. Zamiri;W.H. McLean;M.B. Hodgins;C.S. Munro
Volume: 159, Issue: 2, Pages: 500-1

Title: Challenges in Developing Therapies for Rare Diseases Including Pachyonychia Congenita
Journal: J Investig Dermatol Symp Proc
Authors: Kaspar RL.
Volume: 10, Issue: 1, Pages: 62-6

Abstract:

The ability to attract sufficient resources to effectively develop therapeutics for rare diseases is a daunting task. This review summarizes existing resources for rare diseases and discusses some of the challenges and strategies associated with developing therapies for small patient populations with an emphasis on pachyonychia congenita. PMID: 16250210 [PubMed - indexed for MEDLINE]

Title: Mutations of KRT6A are more frequent than those of KRT16 in pachyonychia congenita type 1: report of a novel and a recently reported mutation in two unrelated Chinese families.
Journal: Br J Dermatol
Authors: Z.L. Bai;Y.G. Feng;S.S. Tan;X.Y. Wang;S.X. Xiao;H. Wang;H.Q. Jia;J.W. Wu;D.L. He;R.H. Kang
Volume: 159, Issue: 1, Pages: 238-40

Title: Insights into Genotype-Phenotype Correlation in Pachyonychia Congenita from the Human Intermediate Filament Mutation Database.
Journal: J Investig Dermatol Symp Proc
Authors: McLean WH, Smith FJ, Cassidy AJ.
Volume: 10, Issue: 1, Pages: 31-6

Abstract:

Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes that are differentially expressed in specific epithelial structures of the body, many of which involve the epidermis and its appendages. Pachyonychia congenita (PC) is a group of autosomal dominant genodermatoses affecting the nails, thick skin and other ectodermal structures, according to specific sub-type. The major clinical variants of the disorder (PC-1 and PC-2) are known to be caused by dominant-negative mutations in one of four differentiation-specific keratins: K6a, K6b, K16, and K17. A total of 20 human keratin genes are currently linked to single-gene disorders or are predisposing factors in complex traits. In addition, a further six intermediate filament genes have been linked to other non-epithelial genetic disorders. We have established a comprehensive mutation database that catalogs all published independent occurrences of intermediate filament mutations (http://www.interfil.org), with details of phenotypes, published papers, patient support groups and other information. Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved.

Title: Mouse Models in Preclinical Studies for Pachyonychia Congenita.
Journal: J Investig Dermatol Symp Proc
Authors: Chen J, Roop DR.
Volume: 10, Issue: 1, Pages: 37-46

Abstract:

The similarities between the human and mouse genomes often allow researchers to make accurate predictions about the roles of their human counterparts. Because of the similar physiology between these two mammals, mice are used extensively in the laboratory to investigate the mechanisms of human diseases. Furthermore, mice provide us with the option of testing the toxicity of drugs and the safety of therapeutic approaches prior to human application. Here, we review the existing mouse models involving the keratin genes (K6a, K6b, K16, and K17) that cause the human genetic disorder pachyonychia congenita (PC). We also suggest methods to more accurately model this autosomal dominant skin condition in the mouse in order to better understand the pathophysiological processes underlying PC and importantly, provide a test-bed for testing emerging therapies in vivo.

Title: Gene Therapy for Autosomal Dominant Disorders of Keratin.
Journal: J Investig Dermatol Symp Proc
Authors: Lewin AS, Glazer PM, Milstone LM.
Volume: 10, Issue: 1, Pages: 47-61

Abstract:

Dominant mutations that interfere with the assembly of keratin filaments cause painful and disfiguring epidermal diseases like pachyonychia congenita and epidermolysis bullosa simplex. Genetic therapies for such diseases must either suppress the production of the toxic proteins or correct the genetic defect in the chromosome. Because epidermal skin cells may be genetically modified in tissue culture or in situ, gene correction is a legitimate goal for keratin diseases. In addition, recent innovations, such as RNA interference in animals, make an RNA knockdown approach plausible in the near future. Although agents of RNA reduction (small interfering RNA, ribozymes, triplex oligonucleotides, or antisense DNA) can be delivered as nucleotides, the impermeability of the skin to large charged molecules presents a serious impediment. Using viral vectors to deliver genes for selective inhibitors of gene expression presents an attractive alternative for long-term treatment of genetic disease in the skin. PMID: 16250209 [PubMed - indexed for MEDLINE]

Title: Clinical and Pathological Features of Pachyonychia Congenita.
Journal: J Investig Dermatol Symp Proc
Authors: Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJ, McLean WH, Lunny DP, Milstone LM, van Steensel MA, Munro CS, O'Toole EA, Celebi JT, Kansky A, Lane EB.
Volume: 10, Issue: 1, Pages: 3-17

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

Title: Treatment of Pachyonychia Congenita.
Journal: J Investig Dermatol Symp Proc
Authors: Milstone LM, Fleckman P, Leachman SA, Leigh IM, Paller AS, van Steensel MA, Swartling C.
Volume: 10, Issue: 1, Pages: 18-20

Abstract:

There are currently no specific treatments for pachyonychia congenita (PC). Available treatments generally are directed at specific manifestations of the disorder, and an effective treatment plan must recognize that different patients are more or less troubled by different manifestations of the disease. Treatment for all aspects of PC has been less than completely satisfactory. Very few studies have compared different approaches to treatment, and fewer still have given longitudinal follow-up of efficacy and patient acceptance. This review is essentially a compilation of anecdotes. It was collected from physicians' reports in the literature, from direct communication with physicians currently following patients with PC and from patients who answered a questionnaire on the Pachyonychia Congenita Project web page (http://www.pachyonychia.org/Registry.html).

Title: The Genetic Basis of Pachyonychia Congenita.
Journal: J Investig Dermatol Symp Proc
Authors: Smith FJ, Liao H, Cassidy AJ, Stewart A, Hamill KJ, Wood P, Joval I, van Steensel MA, Björck E, Callif-Daley F, Pals G, Collins P, Leachman SA, Munro CS, McLean WH.
Volume: 10, Issue: 1, Pages: 21-30

Abstract:

In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 2B domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.

Title: Treatment of pachyonychia congenita with plantar injections of botulinum toxin.
Journal: Br J Dermatol
Authors: C. Swartling;A. Vahlquist
Volume: 154, Issue: 4, Pages: 763-5

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis which may be associated with painful, focal hyperkeratosis on the soles. Plantar sweating at high ambient temperatures increases the blistering of the callosities. We report three patients with PC who had great problems in walking, especially during summer time. They were treated with intracutaneous plantar injections of botulinum toxin type A (Dysport
, 100 U mL)1; Ipsen, Slough, U.K.) after prior intravenous regional anaesthesia of the foot with a low tourniquet and 25 mL prilocaine (5 mg mL)1). Within a week all three patients experienced dryness and a remarkable relief of pain from plantar pressure sites. The effect duration was 6 weeks to 6 months. Repeated injections over a 2-year period confirmed the good results, with no side-effects or tachyphylaxis noted.

Title: Development of Therapeutic siRNAs for Pachyonychia Congenita.
Journal: J Invest Dermatol.
Authors: F. J. Smith;R.P. Hickerson;J. M. Sayers;R. E. Reeves;C. H. Contag;D. Leake;R.L. Kaspar;W. H.McLean

Abstract:

Pachyonychia congenita (PC) is an autosomal-dominant keratin disorder where the most painful, debilitating aspect is plantar keratoderma. PC is caused by mutations in one of four keratin genes; however, most patients carry K6a mutations. Knockout mouse studies suggest that ablation of one of the several K6 genes can be tolerated owing to compensatory expression of the others. Here, we have developed potent RNA interference against K6a as a paradigm for treating a localized dominant skin disorder. Four small interfering RNAs (siRNAs) were designed against unique sequences in the K6a 3'-untranslated region. We demonstrated near-complete ablation of endogenous K6a protein expression in two keratinocyte cell lines, HaCaT and NEB-1, by transient transfection of each of the four K6a siRNAs. The siRNAs were effective at very low, picomolar concentrations. One potent lead K6a inhibitor, which was highly specific for K6a, was tested in a mouse model where reporter gene constructs were injected intradermally into mouse paw and luciferase activity was used as an in vivo readout. Imaging in live mice using the Xenogen IVIS system demonstrated that the K6a-specific siRNA strongly inhibited bicistronic K6a-luciferase gene expression in vivo. These data suggest that siRNAs can specifically and very potently target mutated genes in the skin and support development of these inhibitors as potential therapeutics.

Title: SiRNA-mediated selective inhibition of mutant keratin mRNAs responsible for the skin disorder pachyonychia congenita.
Journal: Ann N Y Acad Sci.
Authors: R. P. Hickerson;F. J. Smith;W. H. McLean;M. Landthaler;R. E. Leube;R. L. Kaspar
Issue: 1082, Pages: 56-61

Abstract:

RNA interference offers a novel approach for treating genetic disorders including the rare monogenic skin disorder pachyonychia congenita (PC). PC is caused by mutations in keratin 6a (K6a), K6b, K16, and K17 genes, including small deletions and single nucleotide changes. Transfection experiments of a fusion gene consisting of K6a and a yellow fluorescent reporter (YFP) resulted in normal keratin filament formation in transfected cells as assayed by fluorescence microscopy. Similar constructs containing a single nucleotide change (N171K) or a three-nucleotide deletion (N171del) showed keratin aggregate formation. Mutant-specific small inhibitory RNAs (siRNAs) effectively targeted these sites. These studies suggest that siRNAs can discriminate single nucleotide mutations and further suggest that "designer siRNAs" may allow effective treatment of a host of genetic disorders including PC.

Title: A spectrum of mutations in keratins K6a, K16 and K17 causing pachyonychia congenita.
Journal: J Dermatol Sci.
Authors: H. Liao;J. M. Sayers;N. J. Wilson;A. D. Irvine;J. E. Mellerio;E. Baselga;S. J. Bayliss;V. Uliana;M. Fimiani;E. B. Lane;W. H. McLean;S. A. Leachman;F. J. Smith

Abstract:

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant keratin disorder, subdivided into two major variants, PC-1 and PC-2. Predominant characteristics include hypertrophic nail dystrophy, focal palmoplantar keratoderma and oral leukokeratosis. Multiple steatocystomas that develop during puberty are a useful feature distinguishing PC-2 from PC-1. At the molecular level it has been shown that mutations in keratin K6a or K16 cause PC-1 whereas those in K6b or K17 lead to PC-2. OBJECTIVE: To identify mutations in 22 families presenting with clinical symptoms of either PC-1/focal non-epidermolytic palmoplantar keratoderma (FNEPPK) or PC-2. METHODS: Mutation analysis was performed on genomic DNA from PC patients by direct sequencing. RESULTS: Here, we report four new missense and five known mutations in K6a; one new deletion and three previously identified missense mutations in K16; plus one known mutation in K17. CONCLUSION: With one exception, all these heterozygous mutations are within the highly conserved helix boundary motif regions at either end of the keratin rod domain. In one sporadic case, a unique mutation in K16 resulting in deletion of 24bp was found within the central rod domain, in a child with a phenotype predominantly consisting of focal plantar keratoderma. The identification of mutations in cases of PC is prerequisite for future development of gene-specific and/or mutation-specific therapies. PMID: 17719747 [PubMed - indexed for MEDLINE]

Title: Single-Nucleotide-Specific siRNA Targeting in a Dominant-Negative Skin Model
Journal: J Invest Dermatol
Authors: R.P. Hickerson;F.J.Smith;R.E. Reeves;C.H.Contag;D. Leake;S.A. Leachman;L. M. Milstone;W. H. McLean;R.L. Kaspar

Abstract:

RNA interference offers a novel approach for developing therapeutics for dominant-negative genetic disorders. The ability to inhibit expression of the mutant allele without affecting wild-type gene expression could be a powerful new treatment option. Targeting the single-nucleotide keratin 6a (K6a) N171K mutation responsible for the rare monogenic skin disorder pachyonychia congenita (PC), we demonstrate that small interfering RNAs (siRNAs) can potently and selectively block expression of mutant K6a. To test whether lead siRNAs could discriminate mutant mRNA in the presence of both wild-type and mutant forms, a dominant-negative PC cell culture model was developed. As predicted for a dominant-negative disease, simultaneous expression of both wild-type and mutant K6a resulted in defective keratin filament formation. Addition of mutant-specific siRNAs allowed normal filament formation, suggesting selective inhibition of mutant K6a. The effectiveness of our siRNA in skin was tested by co-delivering a firefly luciferase/mutant K6a bicistronic reporter construct and mutant-specific siRNAs to mouse footpads. Potent inhibition of the fluorescent reporter was demonstrated using the Xenogen IVIS200 in vivo imaging system. Additionally, wild type-specific siRNAs knocked down the expression of pre-existing endogenous K6a in human keratinocytes. These results suggest that efficient delivery of these "designer siRNAs" may allow effective treatment of numerous genetic disorders including PC.

Title: Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion.
Journal: Genes Dev.
Authors: X. Tong;P.A. Coulombe
Volume: 20, Issue: 10, Pages: 1353-64.

Title: Pachyonychia congenita with woolly hair in a ten month old infant
Journal: Indian J Dermatol Venereol Leprol.
Authors: A. Ehsani; F. Moeineddin; A. Rajaee
Volume: 74, Issue: 5, Pages: 485-486

Abstract:

A 10-month-old female presented with severe progressive wedge-shaped thickening and discoloration of all twenty nails. Further evaluations revealed palmoplantar keratoderma along with recurrent acral blisters causing residual crusted ulcers which were present during the past six months. Other findings included scalp kinky hair and dental caries. Past medical and family history had remarkable findings such as natal teeth and similar skin lesions in her older brother since his infancy. The patients' clinical presentations and history are compatible with pachyonychia congenita presenting with concomitant features of both subtypes 1 and 2.

Title: Keratin 17 modulates hair follicle cycling in a TNF{alpha}-dependent fashion
Journal: Genes Dev.
Authors: Tong X; Coulombe PA
Volume: 20, Pages: 1353-64

Title: A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth
Journal: Nature
Authors: Kim S; Wong P; Coulombe PA
Volume: 441, Pages: 362-65

Title: Pachyonychia congenita with only nail involvement.(Letter to the Editor)
Journal: The Journal of Dermatology
Authors: Arika BANSAL; Gomathy SETHURAMAN; Vinod K SHARMA;
Volume: 33, Issue: 6, Pages: 437-8

Title: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis
Journal: Nat Genet.
Authors: Palmer CN; Irvine AD; Terron-Kwiatkowski A; Zhao Y; Liao H; Lee SP; Goudie DR; Sandilands A; Campbell LE; Smith FJ; O'Regan GM; Watson RM; Cecil JE; Bale SJ; Compton JG; DiGiovanna JJ; Fleckman P; Lewis-Jones S; Arseculeratne G; Sergeant A; Munro CS; El Houate B; McElreavey K; Halkjaer LB; Bisgaard H; Mukhopadhyay S; McLean WH
Volume: 38, Issue: 4, Pages: 441-6

Title: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris
Journal: Nat Genet.
Authors: Smith FJ; Irvine AD; Terron-Kwiatkowski A; Sandilands A; Campbell LE; Zhao Y; Liao H; Evans AT; Goudie DR; Lewis-Jones S; Arseculeratne G; Munro CS; Sergeant A; O'Regan G; Bale SJ; Compton JG; DiGiovanna JJ; Presland RB; Fleckman P; McLean WH
Volume: 38, Issue: 3, Pages: 337-42

Abstract:

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization. PMID: 16444271 [PubMed - indexed for MEDLINE]

Title: Hereditary Familial Dystrophy of the Nails
Journal: JAMA
Authors: Tobias, N.
Volume: 84, Pages: 1588-1569

Abstract:

Affections of the nails are frequent in dermatologic practice, but the hereditary conditions are relatively uncommon.

Title:
Journal: Nucleic Acids Res
Authors: F. Nagatsugi; S. Sasaki; P. S. Miller; M. M. Seidman
Volume: 31, Issue: 6, Pages: e31

Abstract:

The specific recognition of homopurine-homopyrimidine regions in duplex DNA by triplex-forming oligonucleotides (TFOs) proavides an attractive strategy for genetic manipulation. Alkylation of nucleobases with functionalized TFOs would have the potential for site-directed mutagenesis. Recently, we demonstrated that a TFO bearing 2-amino-6-vinylpurine derivative.I.achieves triplex-mediated reation with high selectivity toward the cytosine of the G-C target site. In this report, we have investigated the use of this reagent to target mutations to a specific site in a shuttle vector plasmid which replicates in mamalian cells. TFOs bearing I produced adducts at the complementary position of I and thereby introduced mutations at that site during replication/repaire of the plasmid in mamalian cells. Reagents that produce vovalent cytocine modifications are relatively rare. These TFOs enable the preparation of templates carrying targeted cytosine adducts for in vitro and in vivo sutdies. The ability to target mutations may prove useful as a tool for styding DNA repair, and as technique for gene therapy and genetic engineering.

Title: Keratins and Skin Disorders
Journal: J Path
Authors: E. B. Lane; W.H.I. McLean
Volume: 204, Pages: 355-366

Abstract:

The association of keratin mutations with genetic skin fragility disorders is now one of the best-established examples of cytoskeleton disorders. It has served as a paradigm for many other diseases and has been highly informative for the study of intermediate filaments and their associated components, in helping to understand the functions of this large family of structural proteins. The keratin diseases have shown unequivocally that, at least in the case of the epidermal keratins, a major function of intermediate filaments is to provide physical resilience for epithelial cells. This review article reflects on the variety of phenotypes arising from mutations in keratins and the reasons for this variation.

Title: Reconstruction of a functional and esthetic nail
Journal: Hand Clin
Authors: E. G. Zook;R. C. Russell
Volume: 6, Issue: 1, Pages: 59-68

Abstract:

The most common cause of nail bed deformity is trauma, but other causes are infection, tumor, ischemia, or congenital anomalies. This article includes discussions of nonadherence, split nail, reconstruction of the eponychium, crooked and hooked nail, bony irregularity, pachyonychia, ischemic deformities, and absence of the nail. New problems are encountered daily and other deformities have no method of correction recorded in the literature. For these cases, we provide suggested treatments based on the anatomy and physiology of the nail.

Title: Repair of triplex-directed DNA alkylation by nucleotide excision repair
Journal: Nucleic Acids Res
Authors: A. Ziemba;L. C. Derosier;R. Methvin;C. Y. Song;E. Clary;W. Kahn;D. Milesi;V. Gorn;M. Reed;S. Ebbinghaus
Volume: 29, Issue: 21, Pages: 4257-4263

Abstract:

Triplex-forming oligonucleotides (TFOs) are being investigated as highly specific DNA binding agents to inhibit the expression of clinically relevant genes. So far, they have been shown to inhibit transcription from the HER-2 neu gene in vitro, whereas their use in vivo has been studied to a limited extent. This study uses a TFO-chlorambucil (chl) conjugate capable of forming site-specific covalent guanine adducts within the HER-2 neu promoter. We demonstrate that nucleotide excision repair (NER) represents a mechanism of cellular resistance to TFO-directed DNA alkylation. In vitro repair assays demonstrate that triplex-directed chl-guanine adducts are substrates for repair by NER competent cell extracts but not XP12BE cell extracts deficient in NER. The degree of repair is estimated by a ligation-mediated polymerase chain reaction with a pre-formed triplex in a plasmid transfected into repair competent cells, indicating that approximately 25% of the guanine adducts are removed after 24 h. These data indicate that guanine adducts from TFO-directed alkylation are a substrate for NER and that DNA repair is a significant barrier to the intracellular persistence of target gene binding by TFOs.

Title: A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia
Journal: J Dermatol Sci
Authors: X. J. Zhang;J. J. Chen;S. Yang;Y. Cui;X. Y. Xiong;P. P. He;P. L. Dong;S. J. Xu;Y. B. Li;Q. Zhou;Y. Wang;W. Huang
Volume: 32, Issue: 1, Pages: 11-17

Abstract:

BACKGROUND: hidrotic ectodermal dysplasia (HED) or Clouston syndrome is a rare autosomal dominant disorder affecting the skin and its derivatives. It is characterized by the triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis. To date, all mutations have been involving in three codons: G11R, A88V and V37E in the connexin 30 (Cx30) gene have been shown to cause this disorder. OBJECTIVE: in order to analyze the mutations of the Cx30 gene in Chinese Han patients with HED. METHODS: we collected a large Chinese HED family consisting of a total of 81 individuals including 28 HED patients (14 males and 14 females). The whole coding region of Cx30 was amplified by polymerase chain reaction and products analyzed by direct sequencing, then further confirmed at the mRNA level by RT-PCR. RESULTS: we detected a transition, 31(G-->A), leading to a missense mutation (G11R) in genomic DNAs of 18 patients, and the point mutation was not found in 16 normal individuals in this HED family and in 188 unrelated, population-match control individuals. The transcription of mutated allele was confirmed by RT-PCR of Cx30 mRNA. CONCLUSION: our data suggests that a G11R missense mutation in the Cx30 gene can cause HED in Chinese Han population and emphasizes the importance of screening for this as well as other Cx30 gene mutations in the HED.

Title: The longitudinal nail biopsy
Journal: J Invest Dermatol
Authors: N. J. Zaias
Volume: 49, Issue: 4, Pages: 406-408

Title: Signal transduction for proliferation and differentiation in keratinocytes
Journal: Ann N Y Acad Sci
Authors: S. H. Yuspa;H. Hennings;R. W. Tucker;S. Jaken;A. E. Kilkenny;D. R. Roop
Volume: 548, Pages: 191-196

Abstract:

In mouse and human epidermis, the Ca2+ environment of the basal cell layer is substantially below serum Ca2+, while that of the granular cell layer is unusually high. Reduction of extracellular Ca2+ concentration (Cao) in the medium of keratinocyte cultures maintains a basal cell phenotype while serum Ca2+ concentrations induce terminal differentiation. Measurements of intracellular Ca2+ (Cai) by the use of Fura 2 and digital imaging technology reveal that Cai increases 10-20-fold in response to an increase in Cao and remains elevated. Concomitant with the rise in Cai is an increase in the metabolism of phosphatidylinositol (PI) to yield inositol phosphates and diacylglycerol. PI metabolism is also stimulated by calcium ionophores suggesting that a rise in Cai is directly responsible. The consequent increase in diacylglycerol and Cai would activate protein kinase C, an event known to trigger epidermal differentiation. Specific Cao and Cai determine the expression of individual markers of keratinocyte differentiation in vitro. These findings may account for the importance of the Ca2+ gradient for maintaining regulated growth and differentiation of the epidermis in vivo.

Title: Pachyonychia congenita. A long-term evaluation of associated oral and dermal lesions
Journal: Oral Surg Oral Med Oral Pathol
Authors: L. L. Young;J. A. Lenox
Volume: 36, Issue: 5, Pages: 663-666

Title: Pairwise assembly determines the intrinsic potential for self-organization and mechanical properties of keratin filaments
Journal: Mol Biol Cell
Authors: S. Yamada;D. Wirtz;P. A. Coulombe
Volume: 13, Issue: 1, Pages: 382-391

Abstract:

Most type I and II keratin genes are spatially and temporally regulated in a pairwise manner in epithelial tissues, where they represent the major structural proteins. Epithelia can be partitioned into simple (single-layered) and complex (multilayered) types. We compared the structural and mechanical properties of natural keratin polymers occurring in complex (K5-K14) and simple (K8-K18) epithelia. The intrinsic properties of these distantly related keratin filaments, whether dispersed or bundled in vitro, were surprisingly similar in all respects when at high polymer concentration. When type I and II assembly partners were switched to give rise to mismatched polymers (K5-K18; K8-K14), the interfilament interactions, which determine the structural and mechanical properties of keratin polymers, were significantly altered. We also show that a K5-K16 polymer exhibits lesser elasticity than K5- K14, which may help explain the inability of K16 to fully rescue the skin blistering characteristic of K14 null mice. The property of self-interaction exhibited by keratin filaments is likely to assist their function in vivo and may account for the relative paucity of cytoplasmic and keratin-specific cross-linkers. Our findings underscore the fundamental importance of pairwise polymerization and have implications for the functional significance of keratin sequence diversity.

Title: A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2
Journal: J Invest Dermatol
Authors: S. X. Xiao;Y. G. Feng;X. R. Ren;S. S. Tan;L. Li;J. M. Wang;Y. Z. Shi
Volume: 122, Issue: 4, Pages: 892-895

Abstract:

Pachyonychia congenita type 2 (PC-2), also known as Jackson-Lawler type PC, is an autosomal dominant disorder characterized by hypertrophic nail dystrophy associated with focal keratoderma and multiple pilosebaceous cysts. We report a large Chinese pedigree of typical delayed-onset PC-2 that includes 19 affected members. Direct sequencing of PCR products revealed a novel heterozygous 325A-->G mutation in the affected members. This mutation predicts the substitution of asparagine by aspartic acid in codon 109 (N109D) located in the second half of the keratin 17 1A domain, where similar mutation in keratin 5 is associated with the mild Weber-Cockayne form of epidermolysis bullosa simplex.

Title: Diagnosis and management of laryngeal obstruction in childhood pachyonychia congenita
Journal: Int J Pediatr Otorhinolaryngol
Authors: S. A. Wudy;H. Lenders;W. Pirsig;W. Mohr;W. M. Teller
Volume: 31, Issue: 1, Pages: 109-115

Abstract:

Pachyonychia congenita is a genetic syndrome of epithelial dysplasia. In infants and young children, laryngeal involvement can present a life threatening complication: obstruction of the patient's airway due to leukokeratosis can lead to severe respiratory distress. This report concentrates on the diagnosis and successful microsurgical management of laryngeal obstruction in the first female case, a 19-month-old girl with pachyonychia congenita.

Title: Part of two letters from the Reverend Dr. Rich Wroe, Warden of Manchester College, to Dr. Hans Sloane, S.R.S. concernign horn-like excresences growing on the fingers
Journal: Phil Trans R Soc Lond
Authors: R. Wroe
Volume: 24, Pages: 1899-1900

Title: Pachyonychia congenita: Report of two cases, with studies on therapy
Journal: Arch Dermatol Syphilol
Authors: C. S. Wright, J. P. Guequierre
Volume: 55, Pages: 819-830

Title: The developmental nature of pachyonychia congenita; a twenty year study of a case
Journal: Int Rec Med Gen Pract Clin
Authors: C. S. Wright
Volume: 169, Issue: 6, Pages: 368-370

Title: Congenital ectodermal dysplasia: Pachyonychia congenita?
Journal: Arch Dermatol Syphilol
Authors: C. S. Wright
Volume: 47, Pages: 435

Title: Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair
Journal: J Cell Biol
Authors: P. Wong;P. A. Coulombe
Volume: 163, Issue: 2, Pages: 327-337

Abstract:

The ability to heal wounds is vital to all organisms. In mammalian tissues, alterations in intermediate filament (IF) gene expression represent an early reaction of cells surviving injury. We investigated the role of keratin IFs during the epithelialization of skin wounds using a keratin 6alpha and 6beta (K6alpha K6beta)-null mouse model. In skin explant culture, null keratinocytes exhibit an enhanced epithelialization potential due to increased migration. The extent of the phenotype is strain dependent, and is accompanied by alterations in keratin IF and F-actin organization. However, in wounded skin in vivo, null keratinocytes rupture as they attempt to migrate under the blood clot. Fragility of the K6alpha K6beta-null epidermis is confirmed when applying trauma to chemically treated skin. We propose that the alterations in IF gene expression after tissue injury foster a compromise between the need to display the cellular pliability necessary for timely migration and the requirement for resilience sufficient to withstand the rigors of a wound site.

Title: Introducing a null mutation in the mouse K6alpha and K6beta genes reveals their essential structural role in the oral mucosa
Journal: J Cell Biol
Authors: P. Wong;E. Colucci-Guyon;K. Takahashi;C. Gu;C. Babinet;P. A. Coulombe
Volume: 150, Issue: 4, Pages: 921-928

Abstract:

Mammalian genomes feature multiple genes encoding highly related keratin 6 (K6) isoforms. These type II keratins show a complex regulation with constitutive and inducible components in several stratified epithelia, including the oral mucosa and skin. Two functional genes, K6alpha and K6beta, exist in a head-to-tail tandem array in mouse genomes. We inactivated these two genes simultaneously via targeting and homologous recombination. K6 null mice are viable and initially indistinguishable from their littermates. Starting at two to three days after birth, they show a growth delay associated with reduced milk intake and the presence of white plaques in the posterior region of dorsal tongue and upper palate. These regions are subjected to greater mechanical stress during suckling. Morphological analyses implicate the filiform papillae as being particularly sensitive to trauma in K6alpha K6beta null mice, and establish the complete absence of keratin filaments in their anterior compartment. All null mice die about a week after birth. These studies demonstrate an essential structural role for K6 isoforms in the oral mucosa, and implicate filiform papillae as being the major stress bearing structures in dorsal tongue epithelium.

Title: Pachyonychia congenita. Immunohistologic findings
Journal: Zentralbl Pathol
Authors: U. Wollina;H. Schaarschmidt;V. Funfstuck;B. Knopf
Volume: 137, Issue: 4, Pages: 372-375

Abstract:

Pachyonychia congenita (PC) is a very rare hereditary disorder of keratinization. Immunohistological findings has so far been lacking. Reported in this paper is a case of Jadassohn-Lewandowsky type PC in a woman aged 18 years on which immunohistological investigations could be performed. Several monoclonal antibodies to filaggrin and keratin were used to stain tissue sections of lesional plantar skin, with a view to studying impairment of epidermal differentiation. While staining patterns comparable to those of normal skin were exhibited by anti-filaggrin and some antikeratins (RPN 1161, A51-B H4), substantially altered immunostaining was recordable from other anti-keratins. Only superficial vital keratinocytes were stained by RKSE 60 against keratin 10 and K 8.12 against keratins 13 and 16. The authors, in other words, obtained information on expression of keratin 10, normally occurring in all suprabasal keratinocytes, as well as of the basal proliferation keratin 16 in the uppermost vital cell positions of PC lesion. The above results are likely to suggest impairment of keratin expression in cases of PC.

Title: Discovery of a novel murine keratin 6 (K6) isoform explains the absence of hair and nail defects in mice deficient for K6a and K6b
Journal: J Cell Biol
Authors: S. M. Wojcik;M. A. Longley;D. R. Roop
Volume: 154, Issue: 3, Pages: 619-630

Abstract:

The murine genome is known to have two keratin 6 (K6) genes, mouse K6 (MK6)a and MK6b. These genes display a complex expression pattern with constitutive expression in the epithelia of oral mucosa, hair follicles, and nail beds. We generated mice deficient for both genes through embryonic stem cell technology. The majority of MK6a b- - mice die of starvation within the first two weeks of life. This is due to a localized disintegration of the dorsal tongue epithelium, which results in the build up of a plaque of cell debris that severely impairs feeding. However, approximately 25% of MK6a b- - mice survive to adulthood. Remarkably, the surviving MK6a b- - mice have normal hair and nails. To our surprise, we discovered MK6 staining both in the hair follicle and the nail bed of MK6a b- - mice, indicating the presence of a third MK6 gene. We cloned this previously unknown murine keratin gene and found it to be highly homologous to human K6hf, which is expressed in hair follicles. We therefore termed this gene MK6 hair follicle (MK6hf). The presence of MK6hf in the MK6a b- - follicles and nails offers an explanation for the absence of hair and nail defects in MK6a b- - animals.

Title: Expression of MK6a dominant-negative and C-terminal mutant transgenes in mice has distinct phenotypic consequences in the epidermis and hair follicle
Journal: Differentiation
Authors: S. M. Wojcik;S. Imakado;T. Seki;M. A. Longley;L. Petherbridge;D. S. Bundman;J. R. Bickenbach;J. A. Rothnagel;D. R. Roop
Volume: 65, Issue: 2, Pages: 97-112

Abstract:

Mouse keratin 6a (MK6a) is constitutively expressed in a single cell layer of the outer root sheath (ORS) of hair follicles, but its synthesis can be induced in interfollicular epidermis including the basal cell layer in response to perturbing stimuli. A basally inducible human K6 (HK6) isoform has not been described, and it is not clear which of the known HK6 isoforms is expressed in the ORS. In this study we show that expression of a dominant-negative MK6a construct (Delta2B-P) in the interfollicular epidermis caused severe blistering and neonatal lethality, suggesting that mutations in a yet to be identified basally expressed HK6 isoform might result in a severe blistering phenotype. Surviving Delta2B-P animals showed transgene expression only in isolated epidermal cells and not in all cells of the ORS, but nevertheless developed severe alopecia. Expression of two different C-terminal mutant transgenes also caused alopecia while a third C-terminal mutant had no phenotypic conse- quences. Electron microscopy revealed that Delta2B-P expression resulted in the collapse of keratin filaments, while destruction of hair follicles in the two phenotypic C-terminal mutant lines occurred in the absence of filament abnormalities. The latter finding indicates that the innermost ORS cells are uniquely sensitive to expression of even slightly altered K6 proteins, suggesting that mutations affecting an HK6 isoform expressed in this cell layer could result in alopecia in humans as well.

Title: Delayed wound healing in keratin 6a knockout mice
Journal: Mol Cell Biol
Authors: S. M. Wojcik;D. S. Bundman;D. R. Roop
Volume: 20, Issue: 14, Pages: 5248-5255

Abstract:

Keratin 6 (K6) expression in the epidermis has two components: constitutive expression in the innermost layer of the outer root sheath (ORS) of hair follicles and inducible expression in the interfollicular epidermis in response to stressful stimuli such as wounding. Mice express two K6 isoforms, MK6a and MK6b. To gain insight into the functional significance of these isoforms, we generated MK6a-deficient mice through mouse embryonic stem cell technology. Upon wounding, MK6a was induced in the outer ORS and the interfollicular epidermis including the basal cell layer of MK6a(+ +) mice, whereas MK6b induction in MK6a(- -) mice was restricted to the suprabasal layers of the epidermis. After superficial wounding of the epidermis by tape stripping, MK6a(- -) mice showed a delay in reepithelialization from the hair follicle. However, the healing of full-thickness skin wounds was not impaired in MK6a(- -) animals. Migration and proliferation of MK6a(- -) keratinocytes were not impaired in vitro. Furthermore, the migrating and the proliferating keratinocytes of full-thickness wounds in MK6a(- -) animals expressed neither MK6a nor MK6b. These data indicate that MK6a does not play a major role in keratinocyte proliferation or migration but point to a role in the activation of follicular keratinocytes after wounding. This study represents the first report of a keratin null mutation that results in a wound healing defect.

Title: Four hereditary mucosal syndromes: comparative histology and exfoliative cytology of Darier-White's disease, hereditary benign intraepithelial dyskeratosis, white sponge nevus, and pachyonychia congenita
Journal: Arch Dermatol
Authors: C. J. Witkop, R. J. Gorlin
Volume: 84, Pages: 762-771

Title: Pachyonychia congenita with keratoderma of palms & soles and leukoplakia oris
Journal: Arch Dermatol Syphilol
Authors: F. Wise
Volume: 58, Pages: 608-609

Title: Pachyonychia Congenita Keratosis Palmaris et Plantaris: Diptrophia Inquirium and Leukoplakia Oris
Journal: Arch Dermatol Syphilol
Authors: F. Wise
Volume: 60, Pages: 846-847

Title: Multiple Congenital Anomalies. A Diagnostic Compendium 1st ed
Authors: R. M. Winter, M. Baraitser

Title: Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix
Journal: Nat Genet
Authors: H. Winter;M. A. Rogers;L. Langbein;H. P. Stevens;I. M. Leigh;C. Labreze;S. Roul;A. Taieb;T. Krieg;J. Schweizer
Volume: 16, Issue: 4, Pages: 372-374

Abstract:

Pathogenic mutations in a large number of human epithelial keratins have been well characterized. However, analogous mutations in the hard alpha-keratins of hair and nail have not yet been described. Monilethrix is a rare autosomal dominant hair defect with variable expression. Hairs from affected individuals show a beaded structure of alternating elliptical nodes and constrictions (internodes). These internodes exhibit a high prospensity to weathering and fracture. Strong evidence that trichocyte keratin defects might underlie this hair disorder was provided by genetic linkage analyses that mapped this disease to the type-II keratin gene cluster on 12q13. All affected individuals from a four-generation British family with monilethrix, previously linked to the type-II keratin gene cluster, as well as three unrelated single monilethrix patients, exhibited a heterozygous point mutation in the gene for type-II hair cortex keratin hHb6, leading to lysine substitution of a highly conserved glutamic acid residue in the helix termination motif (Glu 410 Lys). In a three-generation French family with monilethrix of a milder and variable phenotype, we detected another heterozygous point mutation in the same glutamic acid codon of hHb6, which resulted in a conservative aspartic acid substitution (Glu 410 Asp). These mutations provide the first direct evidence for involvement of hair keratins in hair disease.

Title: A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix
Journal: Hum Genet
Authors: H. Winter;M. A. Rogers;M. Gebhardt;U. Wollina;L. Boxall;D. Chitayat;R. Babul-Hirji;H. P. Stevens;A. Zlotogorski;J. Schweizer
Volume: 101, Issue: 2, Pages: 165-169

Abstract:

Monilethrix is a rare dominant hair disease characterized by beaded or moniliform hair which results from the periodic thinning of the hair shaft and shows a high propensity to excess weathering and fracturing. Several cases of monilethrix have been linked to the type II keratin gene cluster on chromosome 12q13 and causative heterozygous mutations of a highly conserved glutamic acid residue (Glu 410 Lys and Glu 410 Asp) in the helix termination motif of the type II hair keratin hHb6 have recently been identified in monilethrix patients of two unrelated families. In the present study, we have investigated two further unrelated monilethrix families as well as a single case. Affected members of one family and the single patient exhibited the prevalent hHb6 Glu 410 Lys mutation. In the second family, we identified in affected individuals a lysine substitution of the corresponding glutamic acid residue, Glu 403, in the type II hair keratin hHb1, suggesting that this site represents a mutational hotspot in these highly related type II hair keratins. Both hHb1 and hHb6 are largely coexpressed in cortical trichocytes of the hair shaft. This indicates that monilethrix is a disease of the hair cortex.

Title: Ungual affections
Journal: On the diseases of the skin: A system of cutaneous medicine
Authors: Erasmus Wilson
Pages: 708-714

Title: Three cases of hereditary hyperkeratosis of the nailbed
Journal: Arch Dermatol Syphilol
Authors: A. G. Wilson
Volume: 17, Pages: 13-14

Title: Cornoid lamella in pachyonychia congenita
Journal: Arch Dermatol
Authors: J. K. Wilkin;E. W. Rosenberg;T. Kanzaki
Volume: 114, Issue: 12, Pages: 1795-1796

Abstract:

A 13-year-old white girl was admitted with pachyonychia congenita, Kumer and Loos type 1. In addition to all nails being distally elevated, plantar keratoses and bullae, and a scalloped tongue, the patient also had keratotic papules on the elbows and knees. A cornoid lamella was identified in the histologic examination of keratotic papule. The cornoid lamella, widely regarded as pathognomonic for porokeratosis (Mibeli) and its variants, may not be specific. This histologic marker should be sought in other localized disorders of keratinization.

Title: Pachyonychia congenita (Jadassohn-Lewandowski syndrome: case report
Journal: Plast Reconstr Surg
Authors: R. R. th White;R. B. Noone
Volume: 59, Issue: 6, Pages: 855-858

Abstract:

We report an illustrative case of pachyonychia congenita, with a description of the presenting complaints, the associated physical findings, the rationale for surgical treatment, and the technical aspects of the surgical treatment.

Title: Increased levels of keratin 16 alter epithelialization potential of mouse skin keratinocytes in vivo and ex vivo
Journal: Mol Biol Cell
Authors: M. J. Wawersik;S. Mazzalupo;D. Nguyen;P. A. Coulombe
Volume: 12, Issue: 11, Pages: 3439-3450

Abstract:

The process of wound repair in adult skin is complex, involving dermal contraction and epithelial migration to repair the lesion and restore the skin's barrier properties. At the wound edge, keratinocytes undergo many changes that engender an epithelialization behavior. The type II keratin 6 and type I keratins 16 and 17 are induced well before cell migration begins, but the role of these proteins is not understood. Forced expression of human K16 in skin epithelia of transgenic mice has been shown to cause dose-dependent skin lesions concomitant with alterations in keratin filament organization and in cell adhesion. Here we show, with the use of a quantitative assay, that these transgenic mice show a delay in the closure of full-thickness skin wounds in situ compared with wild-type and low-expressing K16 transgenic mice. We adapted and validated an ex vivo skin explant culture system to better assess epithelialization in a wound-like environment. Transgenic K16 explants exhibit a significant reduction of keratinocyte outgrowth in this setting. This delay is transgene dose-dependent, and is more severe when K16 is expressed in mitotic compared with post-mitotic keratinocytes. Various lines of evidence suggest that the mechanism(s) involved is complex and not strictly cell autonomous. These findings have important implications for the function of K16 in vivo.

Title: A proline residue in the alpha-helical rod domain of type I keratin 16 destabilizes keratin heterotetramers
Journal: J Biol Chem
Authors: M. Wawersik;R. D. Paladini;E. Noensie;P. A. Coulombe
Volume: 272, Issue: 51, Pages: 32557-32565

Abstract:

The type I keratins 14 (K14) and 16 (K16) are distinct in their assembly properties and their expression pattern despite a high degree of sequence identity. Understanding K16 function and regulation is of interest, given its strong induction in keratinocytes located at the wound edge after injury to stratified epithelia. We reported previously that, compared with K14, K16 forms unstable heterotetramers with either K5 or K6 as the type II keratin pairing partner (Paladini, R. D., Takahashi, K., Bravo, N. S., and Coulombe, P. A. (1996) J. Cell Biol. 132, 381-397). We show here that yet another related type I keratin, K17, forms stable heterotetramers with a variety of type II keratins, further accentuating the unique nature of K16. Analysis of chimeric K14-K16 proteins in a heterotetramer formation assay indicated that the instability determinant resides in a 220-amino acid segment within the alpha-helical rod domain of K16. Site-directed mutagenesis revealed that Pro188, an amino acid residue located in subdomain 1B of the rod, accounts quantitatively for the instability of K16-containing heterotetramers under denaturing conditions. In vitro polymerization studies suggest that the presence of Pro188 correlates with a reduction in assembly efficiency. In addition to their implications for the stable conformation of the keratin heterotetramers, these findings suggest that the tetramer-forming properties of K16 may influence its partitioning between the soluble and polymer pools, and hence contribute to its regulation in epithelial cells under resting and wound repair conditions.

Title: Forced expression of keratin 16 alters the adhesion, differentiation, and migration of mouse skin keratinocytes
Journal: Mol Biol Cell
Authors: M. Wawersik;P. A. Coulombe
Volume: 11, Issue: 10, Pages: 3315-3327

Abstract:

Injury to the skin results in an induction of keratins K6, K16, and K17 concomitant with activation of keratinocytes for reepithelialization. Forced expression of human K16 in skin epithelia of transgenic mice causes a phenotype that mimics several aspects of keratinocyte activation. Two types of transgenic keratinocytes, with forced expression of either human K16 or a K16-C14 chimeric cDNA, were analyzed in primary culture to assess the impact of K16 expression at a cellular level. High K16-C14-expressing and low K16-expressing transgenic keratinocytes behave similar to wild type in all aspects tested. In contrast, high K16-expressing transgenic keratinocytes show alterations in plating efficiency and calcium-induced differentiation, but proliferate normally. Migration of keratinocytes is reduced in K16 transgenic skin explants compared with controls. Finally, a subset of high K16-expressing transgenic keratinocytes develops major changes in the organization of keratin filaments in a time- and calcium concentration-dependent manner. These changes coincide with alterations in keratin content while the steady-state levels of K16 protein remain stable. We conclude that forced expression of K16 in progenitor skin keratinocytes directly impacts properties such as adhesion, differentiation, and migration, and that these effects depend upon determinants contained within its carboxy terminus.

Title: Identification of a recurrent mutation in keratin 6a in a patient with overlapping clinical features of pachyonychia congenita types 1 and 2
Journal: Clin Exp Dermatol
Authors: K. M. Ward;F. E. Cook-Bolden;A. M. Christiano;J. T. Celebi
Volume: 28, Issue: 4, Pages: 434-436

Abstract:

Pachyonychia congenita is characterized by hypertrophic nail dystrophy and associated ectodermal features. PC-1 subtype is associated with mutations in keratins 6a or 16, whereas PC-2 subtype is linked to mutations in keratins 6b or 17. The correlation between the mutated gene and the type of PC has generally been consistent. In this report, we describe a case with overlapping clinical features of PC-1 and PC-2 in which a mutation in K6a was identified.

Title: [Keratin 17 gene mutation in patients with steatocystoma multiplex]
Journal: Zhonghua Yi Xue Za Zhi
Authors: X. Wang;Y. Shi;Y. Ye;F. Liu;W. Jin;W. Chen;M. Wang;L. Hu;G. Zhao;X. Kong
Volume: 81, Issue: 9, Pages: 540-543

Abstract:

OBJECTIVE: To study the relationship between steatocystoma multiplex (SCM) and keratin 17 gene mutation. METHODS: The keratin 17 gene mutation in the cDNA of cystic tissue of 5 patients of SCM and in the DNA in peripheral blood of 25 patients with SCM from a SCM family was studied by direct sequencing of the RT-PCR products, nested PCR, and restricted fraction length polymorphism (RFLP) analysis. Thirty-nine blood specimens from the unaffected members of that family were collected and tested too. Ten DNA pool specimens and other 2000 DNA pool specimens of normal individuals outside that SCM family were used as controls. RESULTS: In the base 428, 94(th) codon in keratin 17 gene in the cDNA of patients' cystic tissue, R94C mutation, a G-->A mutation, was detected Nested PCR, and restricted enzyme Acil polymorphism analysis showed that in the DNA specimens of peripheral blood of patients a mutated allele lacking enzyme cutting locus was detected, thus causing an uncut band with 200 bp while the corresponding allele was cut and caused two bands with 108 bp and 92 bp. In the DNA pool specimens of normal controls only these two bands with 108 bp and 92 bp were observed. CONCLUSION: The R94C mutation in keratin 17 gene is one of the genetic bases of SCM in Chinese. The results of this study provide scientific data for genetic diagnosis and counseling of SCM.

Title: Nonviral skin gene therapy
Journal: Hum Gene Ther
Authors: J. C. Vogel
Volume: 11, Issue: 16, Pages: 2253-2259

Abstract:

Nonviral skin gene therapy is an effective method to directly deliver and transiently express genes in the skin. Several different nonviral delivery methods have been successfully used and are analyzed here for their efficiency and efficacy in achieving specific therapeutic applications. For one important and frequently used application of nonviral skin gene therapy, genetic immunization, the types of resulting immune responses (Th1 versus Th2) will depend on which delivery method is used. In addition, we discuss the contributions of DNA as an immunostimulatory adjuvant in genetic immunization and how activation of skin dendritic cells and induction of IL-12 expression are mechanistically important in this process. Nonviral skin gene therapy has also been successfully used to enhance tumor regression in animal models, frequently by inducing a specific immune response against the tumor. In the future, nonviral skin gene therapy may be successfully used for the treatment of additional skin diseases if genes can be selectively delivered and expressed in specific skin cells, and if increased level and duration of gene expression can be achieved.

Title: Keratinocyte gene therapy
Journal: Arch Dermatol
Authors: J. C. Vogel
Volume: 129, Issue: 11, Pages: 1478-1483

Abstract:

BACKGROUND: Gene therapy is currently being used in clinical trials to treat a variety of diseases. In keratinocyte gene therapy, the gene that will correct the disease by expressing the normal protein or enzyme is inserted and expressed in keratinocytes. Keratinocytes have significant potential, as a target cell of gene therapy, in the treatment of both systemic diseases as well as skin diseases caused by a genetic defect in keratinocytes. OBSERVATIONS: Although keratinocyte gene therapy is not yet being tested in clinical trials, animal models do exist where keratinocytes are being used to secrete factors such as human growth hormone and factor IX (for hemophilia) into the systemic circulation. Genetic diseases of the skin such as recessive epidermolysis bullosa dystrophica or xeroderma pigmentosum have not yet been treated with keratinocyte gene therapy in animal models. CONCLUSIONS: Keratinocytes have many advantages as a target cell in gene therapy, and progress has been made using animal models. However, the sustained and efficient delivery of factors to the bloodstream by keratinocytes expressing a transgene has not yet been accomplished. Future goals are to obtain adequate levels of the desired factors, hormones, or enzymes for sustained periods of time, either in keratinocytes or in the vascular system.

Title: A direct in vivo approach for skin gene therapy
Journal: Proc Assoc Am Physicians
Authors: J. C. Vogel
Volume: 111, Issue: 3, Pages: 190-197

Abstract:

In vivo gene therapy is a direct and effective way to express genes in the epidermis. Plasmid DNA that contains the desired gene can be injected intradermally, and it is rapidly absorbed and expressed by the epidermis. Because gene expression following plasmid injection is transient, the two principal therapeutic uses of this approach are genetic immunization and the expression of biological response modifiers to treat skin disease.

Title: Pachyonychia congenita: a case report
Journal: Pediatr Dermatol
Authors: M. Vijaikumar;D. M. Thappa;C. Laxmisha
Volume: 18, Issue: 6, Pages: 541-543

Title: Steatocystoma multiplex with pachyonychia congenita. Eight cases in four generations
Journal: Arch Dermatol
Authors: W. R. Vineyard;R. A. Scott
Volume: 84, Pages: 824-827

Title: Sebocystomatosis with congenital pachyonychia
Journal: Int J Dermatol
Authors: J. P. Velasquez;J. Bustamante
Volume: 11, Issue: 2, Pages: 77-81

Title: Hereditary onychogryphosis
Journal: Ann Eugen Lond
Authors: A. Videback
Volume: 14, Pages: 139-141

Title: Clouston Syndrome can mimic Pachyonychia congenita
Journal: Society for Investigative Dermatology
Authors: M. A. van Steensel, Jonkman, M. F., van Geel, M., Steijlen, P. M., McLean, W. H. I. and Smith, F. J. D.
Volume: 121, Issue: 5, Pages: 1035-1038

Abstract:

We studied three families suffering from nail abnormalities who had previously been diagnosed as pachyonychia congenita. No keratin gene mutations were detected. Sequencing of connexin 30 (GJB6 gene) in these patients identified heterozygous missense mutations G11R and A88V that are known to be associated with Clouston syndrome. This unexpected finding expands the Clouston syndrome phenotype and suggests that some patients diagnosed with pachyonychia may in fact be suffering from Clouston syndrome. PMID: 14708603 [PubMed - indexed for MEDLINE]

Title: A new type of pachyonychia congenita
Journal: Eur J Dermatol
Authors: M. A. van Steensel;F. J. Smith;P. M. Steijlen
Volume: 11, Issue: 3, Pages: 188-190

Abstract:

We describe two patients with an apparently unique autosomal dominant ectodermal dysplasia. Symptoms consist of thickening of all nails as seen in pachyonychia congenita and severe generalized hypotrichosis. No other abnormalities were present. Histopathological examination of scalp skin showed a reduction in the number of hair follicles, but other abnormalities were not found. Direct sequencing of the keratins known to be associated with pachyonychia congenita, Krt 6a, 6b, 16 and 17, failed to detect mutations. This suggests that this may be a new type of pachyonychia caused by a mutation in a so-called hard keratin.

Title: Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease
Journal: Cell
Authors: R. Vassar;P. A. Coulombe;L. Degenstein;K. Albers;E. Fuchs
Volume: 64, Issue: 2, Pages: 365-380

Abstract:

To explore the relationship between keratin gene mutations and genetic disease, we made transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia. These mice exhibited abnormalities in epidermal architecture and often died prematurely. Blistering occurred easily, and basal cell cytolysis was evidence at the light and electron microscopy levels. Keratin filament formation was markedly altered, with keratin aggregates in basal cells. In contrast, terminally differentiating cells made keratin filaments and formed a stratum corneum. Recovery of outer layer cells was attributed to down-regulation of mutant keratin expression and concomitant induction of differentiation-specific keratins as cells terminally differentiate, and the fact that these cells arose from basal cells developing at a time when keratin expression was relatively low. Collectively, the pathobiology and biochemistry of the transgenic mice and their cultured keratinocytes bore a resemblance to a group of genetic disorders known as epidermolysis bullosa simplex.

Title: Evidence for posttranscriptional regulation of the keratins expressed during hyperproliferation and malignant transformation in human epidermis
Journal: J Cell Biol
Authors: A. L. Tyner;E. Fuchs
Volume: 103, Issue: 5, Pages: 1945-1955

Abstract:

Keratin K6 is a protein that is expressed in human skin under conditions of hyperproliferation (e.g., wound-healing, psoriasis, and cell culture) and malignant transformation (e.g., squamous cell carcinomas). When induced, the appearance of K6 is rapid: if skin tissue is placed in radiolabeled culture medium, this protein can be detected within an hour. The regulation of K6 seems to be controlled partly by a posttranscriptional mechanism: At least two K6 genes are actively transcribed both in vivo, when the protein is not made, as well as in vitro, when abundant levels of the protein are expressed. Substantial levels of K6a and K6b RNAs can be detected in skin by Northern Blot analysis, and these RNAs are largely, if not fully translatable in vitro. In situ hybridizations reveal that the RNAs are distributed throughout the living layers of the epidermis. The rapid induction of K6 expression through a posttranscriptional regulatory mechanism suggests that this keratin may play an important role in designing a cytoskeletal architecture that is compatible with the hyperproliferative state.

Title: Pachyonychia Congenita Overview: The inherited nail dystrophy is associated with painful plantar keratoderma.
Journal: The Dermatologist
Authors: Mary E. Schwartz; C. David Hansen; Amy S. Paller; Frances J.D. Smith; Eli Sprecher
Volume: 22, Section: 4, Pages: 36-38

Title: Characterization of the human gene encoding cytokeratin 17 and its expression pattern
Journal: European J Cell Biol
Authors: S. M. Troyanovsky, R. E. Leube, W. W. Franke
Volume: 59, Issue: 1, Pages: 127-137

Title: Patterns of expression of keratin 17 in human epithelia: dependency on cell position
Journal: J Cell Sci
Authors: S. M. Troyanovsky, V. I. Guelstein, T. A. Tchipysheva, V. A. Krutovskikh, G. A. Bannikov
Volume: 93, Pages: 419-426

Title: The sequence of a type II keratin gene expressed in human skin: conservation of structure among all intermediate filament genes
Journal: Proc Natl Acad Sci U S A
Authors: A. L. Tyner;M. J. Eichman;E. Fuchs
Volume: 82, Issue: 14, Pages: 4683-4687

Abstract:

We report here the coding sequence of the gene for a 56-kDa type II keratin (designated K6b). Using a subclone specific for a unique 3' noncoding region of the encoded mRNA, we have shown that this gene is one of at least two 56-kDa keratin genes expressed in abundance in human epidermis. Segmenting the coding portion of this gene are eight introns, six of which are identically positioned with those of a distantly related type III intermediate filament gene (vimentin), and five of which are identically positioned with those of a distantly related type I gene (50-kDa keratin). These results indicate a common ancestral origin for all three classes of intermediate filament genes. All of the highly conserved intron positions are located within, but do not demarcate, the four central alpha-helical domains common to all intermediate filament polypeptides, suggesting that these genes were probably not created piecemeal by recombination-mediated linkage of separate structural domains as they presently are known.

Title: Expression of keratins (K10 and K17) in steatocystoma multiplex, eruptive vellus hair cysts, and epidermoid and trichilemmal cysts
Journal: Am J Dermatopathol
Authors: H. Tomkova;W. Fujimoto;J. Arata
Volume: 19, Issue: 3, Pages: 250-253

Abstract:

We compared the patterns of keratin 10 (K10) and keratin 17 (K17) expression in epidermoid cysts, trichilemmal cysts, eruptive vellus hair cysts, and steatocystoma multiplex. Epidermoid cysts expressed K10 and eruptive vellus hair cysts expressed K17, whereas trichilemmal cysts and steatocystoma multiplex showed expression of both K10 and K17. Our findings support the opinion that eruptive vellus hair cysts, which stained negative for K10, and steatocystoma multiplex are distinct entities and not variants of one disorder.

Title: A novel mouse type I intermediate filament gene, keratin 17n (K17n), exhibits preferred expression in nail tissue
Journal: J Invest Dermatol
Authors: X. Tong;P. A. Coulombe
Volume: 122, Issue: 4, Pages: 965-970

Abstract:

Inactivating the type I keratin 17 gene (mK17) causes severe but reversible hair loss in a strain-dependent fashion in mouse (McGowan et al, Genes Dev. 16:1412, 2002). Missense mutations in human K17 give rise to two dominantly inherited disorders apparented to ectodermal dysplasias, pachyonychia congenita (PC), and steatocystoma multiplex (SM). In contrast to the null phenotype in mouse, marked lesions are seen in the nail and nail bed and sebaceous glands of PC and SM patients, respectively. In an effort to understand the lack of nail involvement in mK17 null mice, we discovered that the gene located immediately 5' upstream from mK17 is functional and encodes a type I keratin protein highly analogous to mK17. mRNA and protein localization studies show that the expression of this novel gene is highly restricted and most prevalent in the nail bed and matrix, leading to its designation as mK17n (n stands for nail). Weak expression of mK17n also occurs in vibrissae follicles, in filiform and fungiform papillae of oral mucosa. These findings have direct implications for the mK17 null phenotype. Depending on the existence of a human ortholog or a functional equivalent, our findings may also provide a molecular explanation for several unusual aspects of hK17-based diseases.

Title: Keratin gene expression in mouse skin tumors and in mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate
Journal: Cancer Res
Authors: R. Toftgard;S. H. Yuspa;D. R. Roop
Volume: 45, Issue: 11 Pt 2, Pages: 5845-5850

Abstract:

Alterations in the pattern of epidermal differentiation and proliferation occur during mouse skin carcinogenesis. We have used cDNA clones corresponding to the major keratin subunits synthesized in differentiating epidermal cells (Mr 67,000 and 59,000) and in proliferating epidermal cells (Mr 60,000, 55,000, and 50,000) to study changes in keratin gene transcript levels in mouse epidermis exposed to tumor promoters. The same probes were used to characterize the keratin expression patterns in benign and malignant skin tumors. A single topical treatment with 12-O-tetradecanoylphorbol-13-acetate caused a rapid initial decrease in the epidermal transcript levels corresponding to the Mr 67,000 and 59,000 keratin subunits. By 48 h the transcript level for the Mr 67,000 keratin subunit was restored to control values, whereas the transcript levels for the Mr 59,000 subunit returned to control at a slower rate. In contrast, the transcript level for the Mr 55,000 subunit was increased substantially 12- 48 h after treatment, the Mr 50,000 subunit transcript increased to a lesser extent, and the Mr 60,000 subunit message was transiently decreased at 12 h but returned to the level of solvent-treated skin by 24 h. Single exposure to the incomplete tumor promoters 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate, the ionophore A23187, and mezerein induced changes in keratin gene transcripts similar to those of 12-O-tetradecanoylphorbol-13-acetate. The antipromoter fluocinolone acetonide, administered with 12-O-tetradecanoylphorbol-13-acetate, partially inhibited the decrease in the Mr 59,000 and 67,000 transcripts and completely inhibited the increase in the Mr 55,000 transcript. In skin papillomas produced by initiation and promotion, keratin gene expression was similar to normal skin, with the exception of a two-fold increase in the transcript levels for the Mr 55,000 keratin subunit. However, in carcinomas, the transcript levels for the Mr 67,000 and 59,000 subunits were only 1-3% of those observed in untreated mouse epidermis. In concert with other data, the rapid and selective loss of transcripts for differentiation-related keratins after exposure to both complete and incomplete tumor promoters is most consistent with an accelerated rate of maturation in differentiating keratinocytes, resulting in the rapid production of transcript-depleted fully mature squames. The enhanced level of Mr 55,000 transcripts suggests a concomitant increase in the number of all cells or a subset of cells in the proliferative compartment.(ABSTRACT TRUNCATED AT 400 WORDS)

Title: Novel regulation of keratin gene expression by thyroid hormone and retinoid receptors
Journal: J Biol Chem
Authors: M. Tomic-Canic;D. Day;H. H. Samuels;I. M. Freedberg;M. Blumenberg
Volume: 271, Issue: 3, Pages: 1416-1423

Abstract:

Expression of keratin proteins, markers of epidermal differentiation and pathology, is uniquely regulated by the nuclear receptors for retinoic acid (RAR) and thyroid hormone (T3R) and their ligands: it is constitutively activated by unliganded T3R, but it is suppressed by ligand-occupied T3R or RAR. This regulation was studied using gel mobility shift assays with purified receptors and transient transfection assays with vectors expressing various receptor mutants. Regulation of keratin gene expression by RAR and T3R occurs through direct binding of these receptors to receptor response elements of the keratin gene promoters. The DNA binding "C" domain of these receptors is essential for both ligand-dependent and -independent regulation. However, the NH2-terminal "A B" domain of T3R is not required for either mode of regulation of keratin gene expression. Furthermore, v-ErbA, an oncogenic derivative of cT3R, also activates keratin gene expression. In contrast to the previously described mechanism of gene regulation by T3R, heterodimerization with the retinoid X receptor is not essential for activation of keratin gene expression by unliganded T3R. These findings indicate that the mechanism of regulation of keratin genes by RAR and T3R differs significantly from the mechanisms described for other genes modulated by these receptors.

Title: Codominant regulation of keratin gene expression by cell surface receptors and nuclear receptors
Journal: Exp Cell Res
Authors: M. Tomic-Canic;I. M. Freedberg;M. Blumenberg
Volume: 224, Issue: 1, Pages: 96-102

Abstract:

Epidermal keratinocytes are subject to a large variety of signals that modulate their differentiation in health and their activation in disease. Hormones and vitamins, which act via nuclear receptors, affect the differentiation process, whereas growth factors and cytokines, which act via cell surface receptors, affect keratinocyte activation and related events. Using expression of keratin genes as markers for keratinocyte phenotype, we examined the interaction between the nuclear receptor and cell surface receptor pathways. We expected to find dominance of one of the pathways. Surprisingly, we found that the two pathways are codominant. Specifically, while EGF induces expression of K6 and K16 keratin genes, retinoic acid suppresses their expression, and when both mediators are present simultaneously, the level of expression is intermediate, a product of both signals. Similar codominant effects were found on other keratin genes using interferon gamma, TGF beta, and thyroid hormone signaling molecules. These codominant effects are specific only for genes that are regulated by both pathways. Our results suggest that a judicious combination of hormones, vitamins, growth factors, and cytokines may be used to target specific expression of appropriate genes in the treatment of human epidermal diseases.

Title: Control of plantar blisters in pachyonychia congenita with topical aluminium chloride
Journal: Br J Dermatol
Authors: M. J. Tidman;R. S. Wells
Volume: 118, Issue: 3, Pages: 451-452

Title: Pachyonychia congenita with cutaneous amyloidosis and hyperpigmentation--a distinct variant
Journal: J Am Acad Dermatol
Authors: M. J. Tidman;R. S. Wells;D. M. MacDonald
Volume: 16, Issue: 5 Pt 1, Pages: 935-940

Abstract:

Two kindreds manifesting an unusual form of pachyonychia congenita are described. Clinical involvement consists of nail dystrophy, which tends to improve with age, and moderate palmoplantar hyperkeratosis. In addition, all affected members show a characteristic pattern of cutaneous hyperpigmentation, which resembles macular amyloidosis around the neck and waist, but which confers a dappled appearance to the axillae, popliteal fossae, thighs, buttocks, and lower aspect of the abdomen. With advancing age the pigmentation fades. Histologic and ultrastructural examination of the hyperpigmented skin has revealed pigmentary incontinence and deposition of amyloid within the papillary dermis. These features appear to constitute a distinct variant of pachyonychia congenita.

Title: Pachyonychia congenita complicated by hidradenitis suppurativa: a family study
Journal: Br J Dermatol
Authors: P. Todd;J. Garioch;M. Rademaker;W. Susskind;C. Gemell;J. Thomson
Volume: 123, Issue: 5, Pages: 663-666

Abstract:

A family is described in which five of the six members with the Jackson-Lawler type of pachyonychia congenita also had varying degrees of hidradenitis suppurativa. We suggest an association between this type of pachyonychia congenita and hidradenitis suppurativa.

Title: Pachyonychia congenita. Electron microscopic and epidermal glycoprotein assessment before and during isotretinoin treatment
Journal: Arch Dermatol
Authors: D. R. Thomas;J. L. Jorizzo;M. M. Brysk;J. A. Tschen;J. Miller;E. H. Tschen
Volume: 120, Issue: 11, Pages: 1475-1479

Abstract:

Two patients, a father and son, with pachyonychia congenita were treated with orally administered isotretinoin because the extreme deformity and discomfort associated with their massive keratoderma interfered with their work and school, respectively. While clinical benefits could not be sustained, electron microscopic findings compatible with suppression of abnormal keratinization were observed. In addition, skin biopsy samples were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the gels were then subjected to a lectin overlay technique with concanavalin A labeled with iodine 125. The distribution of specific glycoproteins was found to be different for lesional as against normal epidermis. The procedure was repeated after oral treatment with isotretinoin. The labeled glycoprotein pattern of the lesional epidermis was clearly distinguishable from both the pretreatment lesional and the normal epidermis; it was mostly intermediate between the two. The normal epidermis was virtually unaffected by the retinoid treatment.

Title: Pachyonychia congenita: surgical management of the nail changes
Journal: J Dermatol Surg Oncol
Authors: R. J. Thomsen;R. L. Zuehlke;B. I. Beckman
Volume: 8, Issue: 1, Pages: 24-28

Abstract:

The fingernails of a woman with pachyonychia congenita were ablated by several different methods. The most effective, most rapidly performed, and most acceptable method was vigorous curettage and electrofulguration of the matrices and beds of the nails. The responses to treatment suggest that the matrix, rather than the bed, is the site from which the abnormality of the nails develops in pachyonychia congenita. Removal of the nail beds is not necessary to prevent recurrence of deformed nails, but it may reduce hyperkeratosis in their sites.

Title: Pachyonychia congenita Jadassohn-Lewandowsky: a disorder of keratinization
Journal: Acta Derm Venereol
Authors: J. Thormann;T. Kobayasi
Volume: 57, Issue: 1, Pages: 63-67

Abstract:

A 15-month-old boy with pachyonychia congenita is described. The patient also had follicular keratosis, leukokeratosis of the tongue, and blisters on the soles. Histopathological examination of the follicular keratosis showed hyperkeratosis and acanthosis. Horny plugs were located in sweat pores. By electron microscopy abnormal keratinization was demonstrated.

Title: Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita
Journal: J Invest Dermatol
Authors: A. Terrinoni;F. J. Smith;B. Didona;F. Canzona;M. Paradisi;M. Huber;D. Hohl;A. David;A. Verloes;I. M. Leigh;C. S. Munro;G. Melino;W. H. McLean
Volume: 117, Issue: 6, Pages: 1391-1396

Abstract:

Thirteen patients with pachyonychia congenita types 1 and 2 were studied, two of which had a family history of pachyonychia and 11 of which were sporadic cases. Heterozygous mis-sense or small in-frame insertion deletion mutations were detected in the genes encoding keratins K6a, K16, and K17 in all cases. Three novel mutations, F174V, E472K, and L469R were found in the K6a gene. Two novel mutations, M121T and L128Q were detected in K16. Similarly, three novel mutations, L95P, S97del, and L99P were found in K17. In addition, we identified recurrent mutations N171del (three instances) and F174S in K6a and R94H in K17. Analysis of both phenotype and genotype data led to the following conclusions: (i) K6a or K16 mutations produce the pachyonychia congenita type 1 phenotype, whereas K17 (or K6b) mutations cause pachyonychia congenita type 2; (ii) the presence of pilosebaceous cysts following puberty is the best indicator of pachyonychia congenita type 2; (iii) prepubescent patients are more difficult to classify due to the lack of cysts; and (iv) natal teeth are indicative of pachyonychia congenita type 2, although their absence does not preclude the pachyonychia congenita type 2 phenotype. This study establishes useful diagnostic criteria for pachyonychia congenita types 1 and 2, which will help limit unnecessary DNA analysis in the diagnosis and management of this genetically heterogeneous group of genodermatoses.

Title: Two cases of primarily palmoplantar keratoderma associated with novel mutations in keratin 1
Journal: J Invest Dermatol
Authors: A. Terron-Kwiatkowski;A. S. Paller;J. Compton;D. J. Atherton;W. H. McLean;A. D. Irvine
Volume: 119, Issue: 4, Pages: 966-971

Abstract:

Mutations in keratin 1 were initially described in the classical form of bullous congenital ichthyosiform erythroderma (also known as epidermolytic hyperkeratosis). More recently the range of phenotypes associated with mutations in this gene has been extended to include annular ichthyosiform erythroderma and mild epidermolytic palmoplantar keratoderma. Here we present two novel mutations in the keratin 1 gene (KRT1): a 5' donor splice site mutation in exon 1 (591 + 2T > A) that predicts a 22 amino acid in-frame deletion in the keratin 1 1A domain; and an in-frame deletion in exon 7 (1376del24) that predicts a foreshortened 2B coiled-coil domain of keratin 1. In each case these mutations are associated with palmoplantar keratoderma and mild ichthyosis, largely limited to the flexural areas. These mutations appear to have a less damaging effect than previously reported mis-sense mutations sited in the helix boundary motifs. This report extends the range of phenotypes associated with mutations in KRT1.

Title: Clinical notes, suggestions, and new instruments
Journal: JAMA
Authors: E. B. Tauber, L. Goldman, H. Claassen
Volume: 107, Pages: 29-30

Title: Pachyonychia congenita-associated alopecia. A microscopic analysis using transverse section technique
Journal: Am J Dermatopathol
Authors: S. F. Templeton;S. E. Wiegand
Volume: 19, Issue: 2, Pages: 180-184

Abstract:

Pachyonychia congenita (PC) is a rare genodermatosis with characteristic nail abnormalities and occasional palmoplantar keratoderma and leukokeratosis oris; alopecia may occur (10% of patients). This report is the first microscopic description of a patient with PC-associated alopecia. Transverse section histologic features include diminished follicular density with preservation of follicular units, prominent miniaturization of follicles, dyskeratosis of outer root sheath keratinocytes, and moderate parakeratotic and orthokeratotic follicular hyperkeratosis. These microscopic features may be seen individually in other nonscarring alopecias, but the combination may be unique to PC-associated alopecia. Differential diagnoses include alopecia areata, androgenetic alopecia and traction alopecia trichotillomania.

Title: A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus
Journal: J Invest Dermatol
Authors: A. Terrinoni;P. Puddu;B. Didona;V. De Laurenzi;E. Candi;F. J. Smith;W. H. McLean;G. Melino
Volume: 114, Issue: 6, Pages: 1136-1140

Abstract:

Palmoplantar keratodermas are a group of heterogeneous diseases characterized by thickening, and marked hyperkeratosis, of the epidermis of the palms and soles. Palmoplantar keratodermas can be divided into four major classes: diffuse, focal, punctate, and palmoplantar ectodermal dysplasias. All forms are genetic diseases inherited as autosomal dominant disorders. We studied a patient exhibiting a localized thickening of the skin in parts of the right palm and the right sole, following Blaschko's lines, that does not fit into any classes already described. We sequenced the keratin 16 cDNA derived from skin biopsy material from affected and non affected palms. The keratin 16 cDNA sequence from lesional epidermis showed a 12 base pair deletion (309-320del), which deletes codons 104-107. The mutation is predicted to delete four amino acids, GGFA, from the V1 domain of the keratin 16 polypeptide, close to the 1A domain. Full-length keratin 16 cDNA sequence derived from the unaffected palm was completely normal, consistent with a postzygotic mutation as is suggested by the mosaicism observed. We defined this new clinical entity, "unilateral palmoplantar verrucous nevus", rather than localized or focal epidermolytic palmoplantar keratodermas, as the lesions are present only on one side of the body and follow Blaschko's lines. This study is a report of a mosaic mutation in keratin 16 and also the association of a mutation in the V1 domain of a type I keratin associated with a human disease.

Title: The two functional keratin 6 genes of mouse are differentially regulated and evolved independently from their human orthologs
Journal: Genomics
Authors: K. Takahashi;B. Yan;K. Yamanishi;S. Imamura;P. A. Coulombe
Volume: 53, Issue: 2, Pages: 170-183

Abstract:

The type II keratin 6 (K6) features a complex expression pattern, with a constitutive component in a subset of stratified epithelia and an inducible component following injury and other types of acute challenges. Multiple genes encoding highly related K6 isoforms have been described for human and bovine, a unique feature among mammalian keratin genes. Here we report on the cloning and characterization of two functional genes and their cDNAs encoding the K6 isoforms in mouse and two related pseudogenes. A systematic comparison of the mouse and human K6 genes suggests that they evolved independently after these species diverged. The mK6alpha and mK6beta genes are organized in tandem with the same transcriptional orientation in the mouse genome. Similar to the human isoforms, the coding sequences for mK6alpha and mK6beta isoforms show approximately 95% identity. The two mouse K6 genes are differentially regulated at the mRNA level in several stratified epithelia. The mK6alpha isoform mRNA clearly predominates in intact trunk skin of adult mice, where it is restricted to the outer root sheath of hair follicles. Both mRNAs are induced in epidermis and proximal hair follicles as early as 1 h following acute injury or topical application of phorbol esters and subsequently increase to a comparable extent but with different kinetics. These novel findings have important implications for the evolution, regulation, and function of K6 genes in mammalian species.

Title: Eruptive vellus hair cyst and epidermoid cyst in a patient with pachyonychia congenita
Journal: J Dermatol
Authors: T. Takeshita;H. Takeshita;K. Irie
Volume: 27, Issue: 10, Pages: 655-657

Abstract:

We report the first case of pachyonychia congenita (PC) associated with both eruptive vellus hair cyst (EVHC) and epidermoid cyst. The patient is a 12-year-old Japanese girl who presented with two natal teeth at birth. She had thickening and discoloration of the fingernails and toenails, plantar hyperkeratosis, palmar-plantar hyperhidrosis and multiple cutaneous cysts. Histologic examination revealed EVHC and epidermoid cyst.

Title: Using transgenic models to study the pathogenesis of keratin-based inherited skin diseases
Journal: J Dermatol Sci
Authors: K. Takahashi;P. A. Coulombe;Y. Miyachi
Volume: 21, Issue: 2, Pages: 73-95

Abstract:

In the past decade, the production of transgenic animals whose genome is modified to contain DNA transgenes of interest has significantly contributed to expand our understanding of the molecular etiology and pathobiology of several inherited skin diseases. This technology has led to the discovery that mutations affecting specific keratin genes are responsible for a wide spectrum of inherited bullous diseases, which are collectively characterized by blistering after minor trauma. Type I and type II keratin proteins are restricted to, and very abundant in, epithelial cells, where they occur as a pancytoplasmic network of cytoskeletal filaments. Although it had long been suspected that a primary function of keratin filaments may be to contribute to the physical strength of epithelial sheets, a formal demonstration came from studies of transgenic mouse models and patients suffering from keratin-based blistering diseases. Here we review the basic characteristics of keratin gene and their proteins and relate them to the molecular pathogenesis of relevant inherited skin blistering diseases. A particular emphasis is placed on the role of transgenic mouse models in the past, current, and future studies of these genodermatoses.

Title: Increased expression of keratin 16 causes anomalies in cytoarchitecture and keratinization in transgenic mouse skin
Journal: J Cell Biol
Authors: K. Takahashi;J. Folmer;P. A. Coulombe
Volume: 127, Issue: 2, Pages: 505-520

Abstract:

Injury to epidermis and other stratified epithelia triggers profound but transient changes in the pattern of keratin expression. In postmitotic cells located at the wound edge, a strong induction of K6, K16, and K17 synthesis occurs at the expense of the keratins produced under the normal situation. The functional significance of these alterations in keratin expression is not known. Here, we report that overexpression of a wild-type human K16 gene in a tissue-specific fashion in transgenic mice causes aberrant keratinization of the hair follicle outer root sheath and proximal epidermis, and it leads to hyperproliferation and increased thickness of the living layers (acanthosis), as well as cornified layers (hyperkeratosis). The pathogenesis of lesions in transgenic mouse skin begins with a reorganization of keratin filaments in postmitotic keratinocytes, and it progresses in a transgene level-dependent fashion to include disruption of keratinocyte cytoarchitecture and structural alterations in desmosomes at the cell surface. No evidence of cell lysis could be found at the ultrastructural level. These results demonstrate that the disruption of the normal keratin profile caused by increased K16 expression interferes with the program of terminal differentiation in outer root sheath and epidermis. They further suggest that when present at sufficiently high intracellular levels, K16, along with K6 and K17, appear capable of inducing a reorganization of keratin filaments in the cytoplasm of skin epithelial cells.

Title: Cloning and characterization of multiple human genes and cDNAs encoding highly related type II keratin 6 isoforms
Journal: J Biol Chem
Authors: K. Takahashi;R. D. Paladini;P. A. Coulombe
Volume: 270, Issue: 31, Pages: 18581-18592

Abstract:

The human type II keratin 6 (K6; 56 kDa) is expressed in a heterogeneous array of epithelial tissues under normal conditions, but is better known for its strong induction in stratified epithelia that feature an enhanced cell proliferation rate or abnormal differentiation. Previous work has established the existence of two functional genes encoding K6 protein isoforms in the human genome, although only a partial cDNA clone is available for K6a, the dominant human K6 isoform in skin epithelial tissues (Tyner, A., and Fuchs, E. (1986) J. Cell Biol. 103, 1945-1955). We screened human genomic and skin cDNA libraries with probes derived from the K6b gene, and isolated clones containing the full-length gene and cDNA predicted to encode K6a. A thorough characterization of a large number of genomic (57) as well as cDNA (64) clones further revealed the existence of as many as six different human K6 protein isoforms that are highly related at the gene structure, nucleotide sequence, and predicted amino acid sequence levels. Based on the information accumulated to date we propose an evolutionary model in which the multiplicity of human K6 genes is explained by successive gene duplication events. We further demonstrate that K6a is clearly the dominant K6 isoform in skin tissue samples and cultured epithelial cell lines and that the various isoforms are differentially regulated within and between epithelial tissue types. Our findings have direct implications for an understanding of the regulation and function of K6 during hyperproliferation in stratified epithelia and the search for disease-causing mutations in K6 sequences in the human population.

Title: Congenital deformity of the nails (onychogryphosis)
Journal: Lancet
Authors: Sympson
Volume: 1, Pages: 722-723

Title: Defining a region of the human keratin 6a gene that confers inducible expression in stratified epithelia of transgenic mice
Journal: J Biol Chem
Authors: K. Takahashi;P. A. Coulombe
Volume: 272, Issue: 18, Pages: 11979-11985

Abstract:

Injury to the epidermis and other stratified epithelia triggers a repair response involving the rapid induction of several genes, including keratin 6 (K6). The signaling pathways and mechanisms presiding over this induction in keratinocytes at the wound edge remain to be defined. We reported previously that of the multiple genes encoding K6 isoforms in human, K6a is dominant in skin epithelia (Takahashi, K., Paladini, R., Coulombe, P. A. (1995) J. Biol. Chem. 270, 18581-18592). Using bacterial LacZ as a reporter gene in transgenic mice, we show that the proximal 5.2 kilobases of 5'-upstream sequence from the K6a gene fails to direct sustained expression in any adult tissue, including those where K6 is constitutively expressed (e.g. hair follicle, nail, oral mucosa, tongue, esophagus, forestomach). In contrast, the proximal 960 base pairs of 5'-upstream sequence suffice to mediate an induction of beta-galactosidase expression in a near-correct spatial and temporal fashion after injury to epidermis and other stratified epithelia. Transgene expression also occurs following topical application of phorbol esters, all-trans-retinoic acid, or 2-4-dinitro-1-fluorobenzene, all known to induce K6 expression in skin. Our data show that critical regulatory sequences for this inducibility are located between -960 and -550 bp in the 5'-upstream sequence of K6a and that their activity is influenced by enhancer element(s) located between -2500 and -5200 base pairs. These findings have important implications for the control of gene expression after injury to stratified epithelia.

Title: A transgenic mouse model with an inducible skin blistering disease phenotype
Journal: Proc Natl Acad Sci U S A
Authors: K. Takahashi;P. A. Coulombe
Volume: 93, Issue: 25, Pages: 14776-14781

Abstract:

One of the current limitations of gene transfer protocols involving mammalian genomes is the lack of spatial and temporal control over the desired gene manipulation. Starting from a human keratin gene showing a complex regulation as a template, we identified regulatory sequences that confer inducible gene expression in a subpopulation of keratinocytes in stratified epithelia of adult transgenic mice. We used this cassette to produce transgenic mice with an inducible skin blistering phenotype mimicking a form of epidermolytic hyperkeratosis, a keratin gene disorder. Upon induction by topical application of a phorbol ester, the mutant keratin transgene product accumulates in the differentiating layers of epidermis, leading to keratinocyte lysis after application of mechanical trauma. This mouse model will allow for a better understanding of the complex relationship between keratin mutation, keratinocyte cytoarchitecture, and hypersensitivity to trauma. The development of an inducible expression vector showing an exquisite cellular specificity has important implications for manipulating genes in a spatially and temporally controlled fashion in transgenic mice, and for the design of gene therapy strategies using skin as a tissue source for the controlled delivery of foreign substances.

Title: [Pachyonychia congenita. Keratin gene mutations with pleiotropic effect]
Journal: Hautarzt
Authors: O. Swensson
Volume: 50, Issue: 7, Pages: 483-490

Abstract:

Pachyonychia congenita (PC) comprises a heterogeneous group of autosomal dominantly inherited conditions showing characteristic nail thickening and associated signs such as palmoplantar keratoderma, follicular keratoses, and mucosal leukokeratoses. Less frequently epidermal cysts, hairshaft abnormalities, natal teeth and laryngeal involvement may be seen. Phenotypically and genetically two major forms of PC are recognized, pachyonychia congenita Jadassohn-Lewandowsky PC type I (Medelian inheritance in man-MIM-167200) and pachyonychia congenita Jackson-Lawler PC type II (MIM 167210). Both conditions show nail deformities, focal palmoplantar keratoderma, and follicular hyperkeratoses. Diagnostically relevant are leukokeratoses of the oral mucosa in patients with PC type I. In contrast individuals affected with PC type II show premature dentition and multiple pilosebaceous cysts predominantly affecting the upper trunk. The latter closely resemble eruptive vellus hair cysts and steatocystoma multiplex. By mutational analysis keratin K6a and K16 gene mutations have been detected in patients with PC type I, and keratin K6b and K17 gene mutations have been shown to be the underlying genetic defect in patients with PC type II.

Title: Specialized keratin expression pattern in human ridged skin as an adaptation to high physical stress
Journal: Br J Dermatol
Authors: O. Swensson;L. Langbein;J. R. McMillan;H. P. Stevens;I. M. Leigh;W. H. McLean;E. B. Lane;R. A. Eady
Volume: 139, Issue: 5, Pages: 767-775

Abstract:

We have analysed the expression of keratins in the epidermis of normal human palm and sole skin (ridged skin) using immunohistochemistry and in situ hybridization. The epidermis of human ridged skin expresses a more complex pattern of keratins than thin skin, which is probably due to the greater stress that ridged skin has to withstand. In addition to keratin K9, we document specific expression patterns of keratins K6, K16 and K17 which are suggestive of regional adaptations of this epidermis to a high cell turnover rate. In particular, the sequestered location of nests of K17-positive cells at the bottom of the deep primary epidermal ridges supports the notion of functional heterogeneity of basal cells and suggests that the K17-positive sites may include stem cells. Expression of K6 and K16 in some basal and most suprabasal keratinocytes is compatible with a constitutively high proliferative activity of normal ridged epidermis, but may also reflect different physical properties of the suprabasal cells, in contrast with regions expressing K9. The distinct labelling patterns observed in primary and secondary epidermal ridges as well as epidermal layers above dermal papillae suggest the existence of local microenvironmental niches leading to differences in keratinocyte differentiation.

Title: Genetic Skin Disorders
Journal: Oxford Monographs On Medical Genetics
Authors: V.P. Sybert
Volume: 33, Pages: 675

Title: Pachyonychia congenita: A clinical study of eleven cases
Journal: Brit J Dermatol
Authors: W. P. Su-Daniel
Volume: 105, Issue: 19, Pages: 21-22

Title: Studies on blisters produced by friction
Journal: J. Invest Dermatol
Authors: M. B. Sulzberger, T. A. Cortese, L. Fishman, H. S. Wiley
Volume: 47, Pages: 456-465

Title: Oral vitamin A acid in treatment of dermatoses with pathologic keratinization
Journal: Int J Dermatol
Authors: G. Stuttgen;H. Ippen;G. Mahrle
Volume: 16, Issue: 6, Pages: 500-502

Title: Pachyonychia congenita: a clinical study of 12 cases and review of the literature
Journal: Pediatr Dermatol
Authors: W. P. Su;S. I. Chun;D. E. Hammond;H. Gordon
Volume: 7, Issue: 1, Pages: 33-38

Abstract:

Twelve cases of pachyonychia congenita were reviewed. The mode of inheritance was autosomal dominant. The clinical features of these patients included thickened nails, hyperkeratosis of the palms and soles, thinning of hair or alopecia, painful bullae or ulcerations of the palms and soles, leukokeratosis oris, verrucous lesions of the extremities, hyperhidrosis, premature eruption of teeth, paronychial infections, epidermal cysts with milia, and corneal dyskeratosis at times associated with cataracts. Biopsy from the plantar lesions usually revealed marked hyperkeratosis, acanthosis, moderate hypergranulosis, and minimal dermal inflammatory infiltration. Treatment with keratolytic agents and lubricants is indicated to areas of palmar and plantar hyperkeratosis but usually produces only transient benefit. Squamous cell carcinoma developed in one of the patients over the site of chronic plantar ulcerations. Areas of chronic bullous formation or ulceration should be observed for possible skin malignancy.

Title: Light-induced resistance of the keratin network to the filament-disrupting tyrosine phosphatase inhibitor orthovanadate
Journal: J Invest Dermatol
Authors: P. Strnad;R. Windoffer;R. E. Leube
Volume: 120, Issue: 2, Pages: 198-203

Abstract:

Epidermal keratinocytes respond to low-dose light irradiation by inducing signaling cascades that lead to long-term effects on gene transcription thereby protecting cells against damage. In contrast, little is known about immediate light-induced alterations of structural proteins. We have made the intriguing observation that light produces fundamental changes in the properties of the keratin filament system of cultured epidermoid A-431 cells. A short light exposure (1-10 min) causes the keratin cytoskeleton to become immediately resistant to the tyrosine phosphatase inhibitor orthovanadate, which otherwise disrupts the keratin filament network completely in just a few minutes. This protective effect is inducible throughout the entire visible spectrum and is elicited by normal room light (<200 Lux). Exposure of cells to monochromatic light of various wavelengths is therefore equally effective. In addition, the acquisition of orthovanadate resistance has been directly monitored in living cells; a partially disrupted keratin cytoskeleton recovers to a completely filamentous network in half an hour. Finally, the protective light effect is largely reversed in 2 h and can be mimicked by preincubation with the p38 kinase inhibitor SB203580. In contrast, the mitogen-activated protein kinase inhibitor PD98059 and epidermal growth factor inhibit orthovanadate action to a lesser extent. Taken together, these observations suggest a stabilizing function of light on the keratin filament network; this may be of relevance to the treatment of skin diseases with reduced keratin stability.

Title: Pachyonychia congenita, type II
Journal: Dermatol Online J
Authors: B. E. Strober
Volume: 9, Issue: 4, Pages: 12

Abstract:

A 5-year-old girl presented with extensor hyperkeratotic papules and subungual hyperkeratosis with nail-plate discoloration affecting all twenty nails. The mother reported that her daughter had natal teeth. By report, the father has a similar history and constellation of clinical findings. The patient's clinical presentation and history was consistent with pachyonychia congenita, which is a genodermatosis linked to mutations in the genes encoding keratins 6, 16, and 17.

Title: Extrachromosomal plasmid vectors for gene therapy
Journal: Curr Opin Mol Therapeut
Authors: S. M. Stoll, M. P. Calos
Volume: 4, Issue: 4, Pages: 299-305

Title: Steatocystoma multiplex: keratin 17 - the key player?
Journal: Br J Dermatol
Authors: A.S. Antal; D. Kulichova; S. Redler; R.C. Betz; T. Ruzicka
Volume: 167, Section: 6, Pages: 1395-7

Title: Unraveling the molecular mechanisms of hair and nail genodermatoses
Journal: Arch Dermatol
Authors: A. J. Stratigos, H. P. Baden
Volume: 137, Pages: 1463-1471

Title: Hereditary multiple sebaceous cysts
Journal: J Hered
Authors: F. E. Stephens
Volume: 50, Pages: 299-301

Title: Pachyonychia Congenita (Jadassohn-Lewandowsky syndrome): a seventeen-member, four-generation pedigree with unusual respiratory and dental involvement
Journal: Am J Med Genet
Authors: J. B. Stieglitz;W. R. Centerwall
Volume: 14, Issue: 1, Pages: 21-28

Abstract:

Pachyonychia Congenita (PC) is an autosomal dominant syndrome of thick nails and other epithelial defects. A hospitalization for severe respiratory distress in a 3-year-old boy with PC and an affected father led to the discovery of 17 affected persons in a kindred spanning four generations. Nine relatives had varying degrees of upper respiratory tract obstruction, and eleven had dental aberrations. We review PC and discuss other unusual findings in this kindred, ie, arthritis in four affected relatives and a discrepancy between expected and observed ratios of affected to unaffected offspring of mothers with PC.

Title: The molecular biology of intermediate filaments
Journal: Cell
Authors: P. M. Steinert;A. C. Steven;D. R. Roop
Volume: 42, Issue: 2, Pages: 411-420

Title: Structural features of epidermal keratin filaments reassembled in vitro
Journal: J Invest Dermatol
Authors: P. M. Steinert;A. C. Steven;D. R. Roop
Volume: 81, Issue: 1 Suppl, Pages: 86s-90s

Abstract:

We have studied the structure of epidermal keratin filaments polymerized in vitro, addressing two different levels of organization. First, we have determined the amino acid sequence of a mouse epidermal keratin subunit from the nucleotide sequence of a cDNA clone. The subunit contains a large central region, representing about 50 percent, whose sequence strongly suggests that it assumes a coiled-coil alpha-helical conformation. This is flanked on the amino and carboxyl terminals by long glycine-rich sequences. Second, we have used scanning transmission electron microscopy to study the structure of frozen, unstained filaments. Analyses of such images provides information on the mass per unit length and on the distribution of mass within the filament. These data impose rigorous constraints on possible models for the packing of protofilaments within the filament. Epidermal keratin filaments assembled in vitro are polymorphic; however, the majority of bovine filaments weigh about 37 kD nm, but most human filaments have masses of only about 27 kD nm. The filament width is at least 15 nm, substantially more than the generally accepted value of 8 to 10 nm, owing to the existence of low-density mass at the periphery that has not been visualized by conventional microscopic methods. We currently postulate that the alpha-helical regions of the subunits comprise the structural core or backbone of the filament from which at least some of the glycine-rich sequences protrude.

Title: Epidermal cell confluence and implications for a two-step mechanism of wound closure
Journal: J Invest Dermatol
Authors: K. S. Stenn;L. M. Milstone
Volume: 83, Issue: 6, Pages: 445-447

Abstract:

In contrast to freshly isolated cells, some cultured keratinocytes have the ability to adhere and spread in protein-free media. Reported here are experiments testing the hypothesis that the social history of keratinocytes influences their ability to spread in defined media. The experiments indicate that confluent cells lack the ability to spread in defined media while subconfluent cells have this property. The inability of dissociated confluent cells to spread in protein-free media is referred to phenomenologically as a "confluent block." The confluent block is acquired rapidly (1-3 days) and lost slowly (5-7 days). The ability of subconfluent cells to spread in the absence of media protein is sensitive to cycloheximide. Aortic endothelial cells and dermal fibroblasts do not demonstrate a confluent block. These observations are consonant with a two-step mechanism of epidermal wound repair: the first occurs immediately after wounding during which the cells require substratum-active proteins, and the second occurs 5-7 days later when the cells are able to synthesize their own substratum.

Title: Amino acid sequences of mouse and human epidermal type II keratins of Mr 67,000 provide a systematic basis for the structural and functional diversity of the end domains of keratin intermediate filament subunits
Journal: J Biol Chem
Authors: P. M. Steinert;D. A. Parry;W. W. Idler;L. D. Johnson;A. C. Steven;D. R. Roop
Volume: 260, Issue: 11, Pages: 7142-7149

Abstract:

From the nucleotide sequences of specific cDNA clones, we present partial amino acid sequences (75-90% of the total) of 67-kDa type II keratin subunits expressed in terminally differentiating mouse and human epidermis. Analysis of the sequence information reveals that their secondary structures conform to the pattern common for all intermediate filament (IF) subunits. Together with the previously published sequence of the mouse 59-kDa type I keratin (Steinert, P. M., Rice, R. H., Roop, D. R., Trus, B. L., and Steven, A. C. (1983) Nature 302, 794-800) these data allow us to make comparisons between two keratins which are coexpressed in an epithelial cell type and which coassemble into the same IF. Moreover, these comparisons suggest a systematic plan for the general organization of the end domains of other keratin subunits. We postulate that each end domain consists of a set of subdomains which are distributed with bilateral symmetry with respect to the central alpha-helical domain. Type II (but not type I) keratins contain short globular sequences, H1 and H2, immediately adjacent to the central domain, that have been conserved in size and sequence and which account for most of the difference in mass between coexpressed type II and type I keratins. These are flanked by subdomains V1 and V2 that are highly variable in both length and sequence, often contain tandem peptide repeats, and are conspicuously rich in glycines and or serines. At the termini are strongly basic subdomains (N and C, respectively) that are variable in sequence. Among keratins of a given type, their variability in mass appears to reside in the size of their V1 and V2 subdomains. However, coexpressed type I and type II keratins have generally similar V1 and or V2 sequences. By virtue of the ease with which large portions of these subdomain sequences can be removed from intact keratin IF by limited proteolysis, we hypothesize that they lie on the periphery of the IF where they participate in interactions with other constituents of epithelial cells.

Title: The complete cDNA and deduced amino acid sequence of a type II mouse epidermal keratin of 60,000 Da: analysis of sequence differences between type I and type II keratins
Journal: Proc Natl Acad Sci U S A
Authors: P. M. Steinert;D. A. Parry;E. L. Racoosin;W. W. Idler;A. C. Steven;B. L. Trus;D. R. Roop
Volume: 81, Issue: 18, Pages: 5709-5713

Abstract:

We present the complete nucleotide and deduced amino acid sequences of a mouse epidermal keratin subunit of 60,000 Da. The keratin possesses a central alpha-helical domain of four tracts (termed 1A, 1B, 2A, and 2B) that can form coiled-coils, interspersed by short linker sequences, and has non-alpha-helical terminal domains. This pattern of secondary structure is emerging as common to all intermediate filament subunits. The alpha-helical sequences conform to the type II class of keratins. Accordingly, this is the first type II keratin for which complete sequence information is available, and thus it facilitates elucidation of the fundamental distinctions between type I and type II keratins. It has been observed that type I keratins are acidic and type II keratins are neutral--basic in charge. We suggest that the basis for this empirical correlation between type and charge resides in the respective net charges of the 1A and 2B tracts. Calculations on interchain interactions between charged residues in the alpha-helical domains indicate that this keratin prefers to participate in dimers according to an in-register parallel arrangement. The terminal domains of this keratin possess characteristic glycine-rich sequences, and the carboxyl-terminal domain is highly homologous to that of a human epidermal keratin of 56,000 Da. According to the hypothesis that end-domains are located on the periphery of keratin filaments, we conclude that the corresponding mouse and human keratins are closely related, both structurally and functionally.

Title: Complete amino acid sequence of a mouse epidermal keratin subunit and implications for the structure of intermediate filaments
Journal: Nature
Authors: P. M. Steinert;R. H. Rice;D. R. Roop;B. L. Trus;A. C. Steven
Volume: 302, Issue: 5911, Pages: 794-800

Abstract:

We have determined the complete primary structure of an intermediate filament subunit, the 59,000 molecular weight subunit of mouse epidermal keratin, from the nucleotide sequence of cDNA clones. The central portion of the sequence forms extended tracts of a coiled-coil alpha-helical conformation. This is flanked at both termini by similar non-alpha-helical sequences that are extremely rich in glycine residues, frequently configured in tandem peptide repeats. Limited chymotryptic digestion of keratin filaments containing this protein suggests a structural organization whereby the terminal glycine-rich sequences protrude from a conserved core structure into which the coiled-coil alpha-helical segments are packed.

Title: Hyperkeratosis of the large toe-nails and sebaceous cysts
Journal: J Hered
Authors: J. Stauffer, I. Simmons
Volume: 33, Pages: 285

Title: Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa
Journal: J Invest Dermatol
Authors: P. M. Steijlen;H. Kremer;F. Vakilzadeh;R. Happle;A. P. Lavrijsen;H. H. Ropers;E. C. Mariman
Volume: 103, Issue: 3, Pages: 282-285

Abstract:

Ichthyosis bullosa of Siemens is an autosomal dominant disease characterized by mild hyperkeratosis and blistering. Autosomal dominant ichthyosis exfoliativa is a recently described disease with clinical features similar to ichthyosis bullosa of Siemens, but in contrast to ichthyosis bullosa of Siemens no histologic signs typical for epidermolytic hyperkeratosis are observed. We used linkage analysis to test whether keratin gene mutations might underlie both diseases. This analysis showed linkage of both disorders with the region of chromosome 12 in which the keratin type II gene cluster is located. The keratin type I gene cluster on chromosome 17 is excluded. These data, combined with clinical observations, strongly suggest that the genes coding for keratin 1 or keratin 2e, both expressed in the suprabasal compartment of the epidermis and located in the type II gene cluster, are candidate genes for ichthyosis bullosa of Siemens and ichthyosis exfoliativa.

Title: Structural and functional implications of amino acid sequences of keratin intermediate filament subunits
Journal: Ann N Y Acad Sci
Authors: P. M. Steinert;W. W. Idler;X. M. Zhou;L. D. Johnson;D. A. Parry;A. C. Steven;D. R. Roop
Volume: 455, Pages: 451-461

Title: Failure of etretinate therapy in pachyonychia congenita
Journal: Br J Dermatol
Authors: U. Soyuer;M. F. Candan
Volume: 117, Issue: 2, Pages: 264

Title: Erupted teeth in the newborn
Journal: Oral Surg Oral Med Oral Pathol
Authors: J. D. Spouge, W. H. Feasby
Volume: 22, Pages: 198-208

Title: Keratins of the human hair follicle: "hyperproliferative" keratins consistently expressed in outer root sheath cells in vivo and in vitro
Journal: Differentiation
Authors: H. J. Stark;D. Breitkreutz;A. Limat;P. Bowden;N. E. Fusenig
Volume: 35, Issue: 3, Pages: 236-248

Abstract:

Keratins produced by morphologically distinct compartments of the human hair folicle (hHF) were analysed and compared to those produced by cultured hHF and interfollicular keratinocytes. Five of the major keratins, the basic keratins nos. 5 and 6 (apparent mol. mass 60 and 58 kDa) and the acidic keratins nos. 14, 16, and 17 (51, 49 and 48 kDa), could be labelled in intact hHF and were found in all fractions of the outer root sheath (ORS). The other major keratins, which were not labelled under these conditions (basic-neutral hHbI and -II; 60-62 kDa and acidic hHaI and -II; 40-42 kDa) were associated with hair shaft (hHS) both in the follicle and, virtually unchanged, in the distal part of the hair. Another, previously undescribed, group of proteins with keratin-like properties exhibiting a broad pI-spectrum (basic to slightly acidic: hIC-I, -II, -III, 64-67 kDa; distinctly acidic: hIC-IV, about 54 kDa) was detected in isolated inner root sheath (IRS), in the cuticular material shed from denuded hHS, and also in nail plates. In our experiments only ORS cells grew readily in culture irrespective of their origin from peripheral (mesenchyme-adjacent) or more central ORS-cell layers. In contrast to keratinocytes from interfollicular epidermis (IFE) the cultured ORS cells expressed a keratin set virtually identical to that expressed in vivo. This set also closely resembled that expressed by IFE keratinocyte cultures. The identity of the respective keratins (nos. 5, 6, 14, 16, and 17) present in all these cells in vivo and in vitro was confirmed by tryptic peptide mapping. The data indicated that the microenvironment (in situ) directs the differentiation of ORS cells in a manner comparable to the way it is directed by conventional culture conditions, with consistent expression of the "basal" and "hyperproliferative" set of keratins. This, however, does not exclude the possibility that other types of environmentally induced response may occur, as seen for example during the reepithelialization of superficial skin wounds by ORS cells.

Title: Pachyonychia congenita
Journal: Arch Dermatol Syphilol
Authors: A. W. Sohrweide
Volume: 32, Pages: 370-376

Title: [Hereditary pachyonychia]
Journal: Sov Med
Authors: B. A. Somov;A. V. Khamaganova;M. A. Bogomil'skaia
Volume: 36, Issue: 9, Pages: 147-148

Title: The nature and significance of the transverse white band of human nails
Journal: Semin Dermatol
Authors: T. S. Sonnex;W. A. Griffiths;W. J. Nicol
Volume: 10, Issue: 1, Pages: 12-16

Abstract:

The nomenclature relating to structures at the distal part of the nail is confusing. A distal yellow line traversing the nail, described by Pinkus, has been relatively ignored in the literature and remains unnamed. Clinical and histological studies presented in this article show that this band is present in more than 90% of normal adult fingernails and represents the most proximal point of attachment of the fingertip stratum corneum to the nail plate. Therefore, it should be referred to as the onychocorneal band or junction. This region has distinctive histological features and is the first major barrier to material passing proximally beneath the nail plate. It is possible that abnormalities of this structure may result in onycholysis, pachyonychia congenita, and pterygium inversum unguis.

Title: Nail that mutation - keratin defect in late-onset pachyonichia
Journal: Soc Inv Derm
Authors: F.J. D. Smith
Volume: 122, Pages: X-XI

Title: Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium
Journal: Cell Growth Differ
Authors: G. H. Smith;T. Mehrel;D. R. Roop
Volume: 1, Issue: 4, Pages: 161-170

Abstract:

Two keratins whose expression has been associated with proliferation (K14) and hyperproliferation (K6) in mouse epithelia were detected in normal, preneoplastic, and neoplastic mouse mammary tissues. K6 and K14 keratins were independently expressed in distinct epithelial cell populations in developing mammary anlage. K6 was confined to a small number of mammary epithelial cells associated with the growing end buds and among the proximal luminal epithelium, whereas K14 expression appeared in basally located fusiform cells that correspond to the location of mammary myoepithelial cells. This pattern was maintained in mature glands and through full functional differentiation with the exception that K6-positive cells were only rarely detectable. During lobuloalveolar growth in early pregnancy, K6 and K6 K14 coexpressing cells were observed among the luminal and suprabasal cells in the expanding lobular epithelium. This K6 K14 coexpressing epithelial subset persisted throughout pregnancy, lactation, and involution, albeit in much smaller numbers than observed in early pregnancy. Two patterns of K6 and K14 expression in preneoplastic and neoplastic lesions of mouse mammary glands were induced by various carcinogenic stimuli. In one, increased numbers of K6- or K14-positive cells were present in distinct cellular populations; in the other, coexpression of K6 K14 was found in a large subpopulation of both preneoplastic and neoplastic mammary epithelium. These observations suggest that expression of K6 and K14 keratins in the mouse mammary gland is associated with growth and expansion of specific mammary epithelial cell populations, and as such these keratins may be useful probes with which to identify mammary epithelium-specific primordial cells. In agreement with this possibility, K6 K14 expression was demonstrated within a distinct subset of morphologically distinct luminal mammary epithelial cells that have been reported to possess kinetic properties in vitro consistent with those expected of latent mammogenic stem cells.

Title: Pachyonychia congenita with epidermal cysts and other congenital dyskeratoses
Journal: Arch Dermatol
Authors: N. A. Soderquist;W. B. Reed
Volume: 97, Issue: 1, Pages: 31-33

Title: A mutation detection strategy for the human keratin 6A gene and novel missense mutations in two cases of pachyonychia congenita type 1
Journal: Exp Dermatol
Authors: F. J. Smith;K. E. McKenna;A. D. Irvine;E. A. Bingham;C. M. Coleman;J. Uitto;W. H. McLean
Volume: 8, Issue: 2, Pages: 109-114

Abstract:

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy, focal non-epidermolytic palmoplantar keratoderma and variable features of oral leukokeratosis and follicular keratosis. Previously, we have shown that this disease can be caused by mutations in type I keratin K16 and one mutation has been reported in its type II keratin expression partner, K6a. Mutation analysis for K6a has been hampered by the presence of multiple copies of the K6 gene in the human genome, of which some are expressed and others are pseudogenes. Here, we describe a mutation detection strategy where the entire KRT6A gene, approximately 7 kb, is specifically amplified by long-range PCR. Using this technique, we have detected two novel mutations in the 1A domain of the K6a polypeptide, N171K and F174S. Mutations were confirmed in the affected individuals and were excluded from 50 unaffected unrelated individuals by restriction enzyme analysis of KRT6A PCR products. Additionally, mutation N171K was confirmed by RT-PCR in mRNA derived from lesional palmoplantar epidermis of an affected individual, confirming the specificity of the genomic PCR for the functional K6a gene. This, together with a similar strategy which we have developed for the K16 gene, provide a robust system for mutation detection and prenatal diagnosis for patients with PC-1.

Title: Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1
Journal: Prenat Diagn
Authors: F. J. Smith;V. A. McKusick;K. Nielsen;E. Pfendner;J. Uitto;W. H. McLean
Volume: 19, Issue: 10, Pages: 941-946

Abstract:

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by severe nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin K16 cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. These earlier analyses employed an RT-PCR approach to avoid amplification of K16-like pseudogenes. Here, we have cloned the K16 gene (KRT16A) and two homologous pseudogenes (psiKRT16B and psiKRT16C), allowing development of a genomic mutation detection strategy based on a long-range PCR, which is specific for the functional K16 gene. We report a novel heterozygous 3 bp deletion mutation (388del3) in K16 in a sporadic case of PC-1. The mutation was detected in genomic DNA and confirmed at the mRNA level by RT-PCR, showing that our genomic PCR system is reliable for K16 mutation detection. Using this system, we carried out the first prenatal diagnosis for PC-1 using CVS material, correctly predicting a normal fetus. This work will greatly improve K16 mutation analysis and allow predictive testing for PC-1 and the related phenotype of FNEPPK.

Title: A novel connexin 30 mutation in Clouston syndrome
Journal: J Invest Dermatol
Authors: F. J. Smith;S. M. Morley;W. H. McLean
Volume: 118, Issue: 3, Pages: 530-532

Abstract:

Clouston syndrome (hidrotic ectodermal dysplasia) is an autosomal dominant ectodermal dysplasia characterized by alopecia, palmoplantar hyperkeratosis, and nail dystrophy. Recently, mutations in the GJB6 gene encoding the gap junction protein connexin 30 have been shown to cause this disorder. To date, all mutations have involved two codons: G11R and A88V. Here, we report a novel mutation V37E within the first transmembrane domain of connexin 30 in a spontaneous case of Clouston syndrome. The mutation was detected in genomic DNA, confirmed in reverse transcription polymerase chain reaction products, and was excluded from 100 ethnically matched control individuals by restriction enzyme analysis.

Title: Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1
Journal: Br J Dermatol
Authors: F. J. Smith;M. Del Monaco;P. M. Steijlen;C. S. Munro;M. Morvay;C. M. Coleman;F. J. Rietveld;J. Uitto;W. H. McLean
Volume: 141, Issue: 6, Pages: 1010-1016

Abstract:

Pachyonychia congenita (PC) is a group of inherited ectodermal dysplasias, the characteristic phenotype being hypertrophic nail dystrophy. Two main clinical subtypes, PC-1 and PC-2, are inherited as autosomal dominant disorders, but other less well characterized clinical forms also exist. The PC-1 phenotype may be distinguished by the absence of the epidermal cysts found in PC-2, and it has been shown to be caused by mutations in either keratin K16 or its expression partner, the K6a isoform of K6. Mutations in K16 have also been shown to cause a milder related phenotype, focal non-epidermolytic palmoplantar keratoderma. Recently, we have developed a long-range polymerase chain reaction (PCR) strategy which allows specific amplification of the entire functional K16 gene (KRT16A), without amplification of the two K16 pseudogenes (psiKRT16B and psiKRT16C), enabling mutation analysis based on genomic DNA. Here, using this methodology, we describe novel mutations R127P and Q122P in the helix 1A domain of K16 in two families presenting with PC-1. Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments. In one family, ultrastructural analysis was performed, revealing distinctive tonofilament abnormalities. Specifically, keratin filament bundles were greatly condensed, but did not form the dense amorphous aggregates seen in a number of other keratin disorders. In the second kindred, autosomal dominant cataract was present in some but not all members affected by PC. As the cataract phenotype did not fully cosegregate with the K16 mutation, and given that K16 is not expressed in the lens, these two phenotypes may be coincidental.

Title: Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma
Journal: Exp Dermatol
Authors: F. J. Smith;M. P. Fisher;E. Healy;J. L. Rees;J. M. Bonifas;E. H. Epstein, Jr.;E. M. Tan;J. Uitto;W. H. McLean
Volume: 9, Issue: 3, Pages: 170-177

Abstract:

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244-1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated deltaHTM. Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the deltaHTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.

Title: A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2
Journal: Hum Mol Genet
Authors: F. J. Smith;M. F. Jonkman;H. van Goor;C. M. Coleman;S. P. Covello;J. Uitto;W. H. McLean
Volume: 7, Issue: 7, Pages: 1143-1148

Abstract:

Type I and type II keratins form the heteropolymeric intermediate filament cytoskeleton, which is the main stress-bearing structure within epithelial cells. Pachyonychia congenita (PC) is a group of autosomal dominant disorders whose most prominent phenotype is hypertrophic nail dystrophy accompanied by other features of ectodermal dysplasia. It has been shown previously that mutations in either K16 or K6a, which form a keratin expression pair, produce the PC-1 variant (MIM 184510). Mutations in K17 alone, an unpaired accessory keratin, result in the PC-2 phenotype (MIM 184500). Here, we describe a family with PC-2 in which the K17 locus on 17q was excluded and linkage to the type II keratin locus on 12q was obtained (Z max 3.31 at straight theta = 0). Mutation analysis of candidate keratins revealed the first reported missense mutation in K6b, implying that this keratin is the previously unknown expression partner of K17, analogous to the K6a K16 pair. Co-expression of these genes was confirmed by in situ hybridization and immunohistochemical staining. These results reveal the hitherto unknown role of the K6b isoform in epithelial biology, as well as genetic heterogeneity in PC-2.

Title: The molecular genetics of keratin disorders
Journal: Am J Clin Dermatol
Authors: F. Smith
Volume: 4, Issue: 5, Pages: 347-364