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Pachyonychia Congenita in Pediatric Patients Natural History, Features, and Impact
Journal of the American Medical Association Dermatology. 16 Oct 2013.

Pachyonychia Congenita Project: A Partnership of Patient and Medical Professional
Journal of the Dermatology Nurses' Association. Jan/Feb 2013
includes an excellent overview of Pachyonychia Congenita

Best treatment practices for pachyonychia congenita 
Journal of the European Academy of Dermatology and Venereology.30 Jan 2013

A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita 
Journal of the American Academy of Dermatology.19 Jan 2012

 The Phenotypic and Molecular Genetic Features of Pachyonychia Congenita  
Journal of  Investigative Dermatology.2011
includes current classification for PC

A Large Mutational Study in Pachyonychia Congenita 
Journal of  Investigative Dermatology.17 Feb 2011

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Title: Pachyonychia Congenita in Pediatric Patients Natural History, Features, and Impact
Journal: JAMA Dermatol 2013 October 16, 201
Authors: Sonal Shah, MD; Monica Boen, MD; Brandi Kenner-Bell, MD; Mary Schwartz, PhD; Alfred Rademaker, PhD; Amy S. Paller,MD


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: Comparative Study of High-Resolution Multifrequency Ultrasound of the Plantar Skin in Patients with Various Types of Hereditary Palmoplantar Keratoderma
Journal: Dermatology 2013 July 9, 2013
Authors: I. Goldberg E. Sprecher M.E. Schwartz D. Gaitini
Pages: 365


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: Pachyonychia Congenita Project: A Partnership of Patient and Medical Professional
Journal: Journal of the Dermatology Nurses' Association 2013 Jan/Feb
Authors: M. E. Schwartz;G. M. Zimmerman;F. J. D. Smith;E. Sprecher
Volume: 5, 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 2013 Jan 30
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: Pachyonychia congenita: A rare genodermatosis
Journal: Indian Dermatology Online Journal 2013 July-September
Authors: Puneet Agarwal, Mahendra K. Chhaperwal, Apurva Singh, Arvind Verma, Manisha Nijhawan, Kishore Singh, Dinesh Mathur
Volume: 4 - Issue 3, Pages: 225-227


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: A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita
Journal: Journal of the American Academy of Dermatology 2012 19 January
Authors: M. J. Eliason;S. A. Leachman;B. Feng;M. E. Schwartz;C. D. Hansen
Volume: ISSN 0190-9622,

Abstract: Background Pachyonychia 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.

Notes: (

Title: Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders
Journal: J Invest Dermatol 2012 May
Authors: J. C. Lessard;P. A. Coulombe
Volume: 132, 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: Building models for keratin disorders
Journal: J Invest Dermatol 2012 May
Authors: M. I. Koster
Volume: 132, 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: Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16
Journal: Br J Dermatol 2012 Apr
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, 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: Homozygous Dominant Missense Mutation in Keratin 17 Leads to Alopecia in Addition to Severe Pachyonychia Congenita
Journal: J Invest Dermatol 2012
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 (; 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: Significance of Patient Registries for Dermatological Disorders
Journal: Journal of Investigative Dermatology 2012 Jul
Authors: M.P. de Souza;V.R. Miller
Volume: 132, 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: Double trouble: homozygous dominant mutations and hair loss in pachyonychia congenita
Journal: J Invest Dermatol 2012 Jul
Authors: A. D. Irvine
Volume: 132, 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: Statins Downregulate K6a Promoter Activity: A Possible Therapeutic Avenue for Pachyonychia Congenita
Journal: J Invest Dermatol 2011 Mar 10
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: A Large Mutational Study in Pachyonychia Congenita
Journal: J Invest Dermatol 2011 Feb 17
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: Use of Self-Delivery siRNAs to Inhibit Gene Expression in an Organotypic Pachyonychia Congenita Model
Journal: J Invest Dermatol 2011 Jan 20
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: The Phenotypic and Molecular Genetic Features of Pachyonychia Congenita
Journal: J Invest Dermatol 2011
Authors: W.H.I. McLean;C.D. Hansen;M.J. Eliason;F.J.D. Smith
Volume: 131, 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: Tackling the Challenge of Nucleic Acid Delivery: Progress & New Approaches
Journal: Drug Development & Delivery 2011 March
Authors: J.J. Cunningham; L.S. Crocker; A. Leone
Volume: 11, 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: Paternal Germ Cell Mosaicism in Autosomal Dominant Pachyonychia Congenita
Journal: Arch Dermatol 2011 16 May
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: Keratin gene mutations in disorders of human skin and its appendages
Journal: Archives of Biochemistry and Biophysics 2011
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: An appraisal of oral retinoids in the treatment of pachyonychia congenita
Journal: J Am Acad Derm 2011 May 21
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 by mutations 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: Josef Jadassohn (1863-1936), Felix Lewandowsky (1979-1921), and their syndrome
Journal: Dove Press Clinical, Cosmetic and Investigational Dermatology 2011
Authors: A. Al Abound; K. Al Abound
Volume: 4, Pages: 179-182

Abstract: Josef Jadassohn (1863

Title: Pachyonychia Congenita with Laryngeal Obstruction
Journal: Pediatric Dermatology 2011
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: Transgrediens pachyonychia congenita (PC): case series of a nonclassical PC presentation
Journal: British Journal of Dermatology 2011
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 typically presents 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: Toward a Treatment for Pachyonychia Congenita: Report on the 7th Annual International Pachyonychia Congenita Consortium Meeting
Journal: Journal of Investigative Dermatology 2011
Authors: R. L. Kaspar;S. A Leachman;W. H. I. McLean;M. E. Schwartz
Volume: 131, Pages: 1011-1014

Title: Pachyonychia Congenita: Cast in Translation
Journal: Journal of Investigative Dermatology 2011
Authors: J. A. McGrath
Volume: 131, Pages: 995

Title: Keratin disorders: from gene to therapy
Journal: Human Molecular Genetics 2011
Authors: W. H. I. McLean;C. B. T. Moore
Volume: 20, Pages: R189-R197

Abstract: The term

Title: Mutations in Frizzled 6 Cause Isolated Autosomal-Recessive Nail Dysplasia
Journal: The American Journal of Human Genetics 2011 10 June
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: Pachyonychia congenita patients with mutations in K6a have more extensive disease compared to patients with mutations in K16.
Journal: British Journal of Dermatology 2011
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: Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation
Journal: Br J Dermatol 2011 Dec
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, 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: A novel frameshift mutation in keratin 16 underlies pachyonychia congenita with focal palmoplantar keratoderma
Journal: Br J Dermatol 2011 Nov
Authors: L. H. Cao;Y. Luo;W. Wen;W. L. Liu;L. Jiang;C. Chen;C. Y. Ji;X. Zhang
Volume: 165, Pages: 1145-1147

Title: Visualization of plasmid delivery to keratinocytes in mouse and human epidermis
Journal: Sci Rep 2011 Nov
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, 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: Pachyonychia congenita type 2
Journal: J Dtsch Dermatol Ges 2011 Feb
Authors: I. M. Scholz;P. Helmbold
Volume: 9, Pages: 144-145

Title: A novel mutation (p.Arg94Gly) of keratin 17 in a Chinese family with steatocystoma multiplex
Journal: Eur J Dermatol 2011 Jan-Feb
Authors: D.Zang;C. Zhou;M. He;X. Ma;J. Zhang
Volume: 21, Pages: 142-144

Title: Pachyonychia congenita: report of two cases and mutation analysis
Journal: Dermatologica Sinica 2011 Sep
Authors: J. Yeh;C. Huang;S. Chao
Volume: 1, Pages: 1-7

Abstract: Pachyonychia congenita (PC) comprises a group of rare autosomal dominant genetic disorders that involve 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: 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 2010 Sep 2010
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, 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: Shoestring Gene Therapy
Journal: The Scientist 2010 01 Aug 2010
Authors: A. Rowe
Volume: 24, Pages: 20

Title: Expediting RNA Delivery with small parcels
Journal: Genetic Engineering & Biotechnology News 2010 October 1
Authors: C. Potera
Pages: 18-19

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

Title: RXi Pharmaceuticals Continues String of Sensible RNAi Delivery Collaborations
Journal: 2010 September 23
Authors: D. Haussecker


Title: Genotype-Phenotype Correlations among Pachyonychia Congenita Patients with K16 Mutations
Journal: J Invest Dermatol 2010 Dec 16
Authors: T. Fu;S.A. Leachman;N.J. Wilson;F.J.D. Smith;M.E. Schwartz;J.Y. Tang

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: Development of Skin-Humanized Mouse Models of Pachyonychia Congenita
Journal: J Invest Dermatol 2010 Dec 9
Authors: M. Garcia;F. Larcher;R.P. Hickerson;E. Baselga;S.A. Leachman;R.L. Kaspar;M. Del Rio

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: In Vivo Imaging of Human and Mouse Skin with a Handheld Dual-Axis Confocal Fluorescence Microscope
Journal: J Invest Dermatol 2010 Dec 30
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: Development of Quantitative Molecular Clinical End Points for siRNA Clinical Trials
Journal: J Invest Dermatol 2010 Dec 30
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: The Allergy Gene - How a mutation in a skin protein revealed a link between eczema and asthma
Journal: The Scientist 2010 Dec 1
Authors: W.H.I. McLean
Volume: 24, Pages: 34

Title: Drug giants turn their backs on RNA interference - A once much-touted technique faces a difficult transition to the clinic.
Journal: Nature 2010 Nov 25
Authors: H. Ledford
Volume: 468, Pages: 487

Title: Mutations in a keratin 6 isomer (K6c) cause a type of focal palmoplantar keratoderma
Journal: J Invest Dermatol 2010 Feb
Authors: P.E. Bowden
Volume: 130, 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: A Modified Surgical Technique for Steatocystoma Multiplex
Journal: J Cutan Aestehet Surg 2010 Jan-Apr
Authors: S. Choudhary; S. Koley; A. Salodkar
Volume: 3, 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: Marathon of eponyms: 10 Jadassohn-Lewandowsky syndrome (Pachyonychia congenita)
Journal: Oral Dis 2010 Apr
Authors: C. Scully;J. Langdon;J. Evans
Volume: 16, 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: Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita
Journal: Br J Dermatol 2010 Nov
Authors: C. Swartling;M. Karlqvist;K. Hymnelius;J. Weis;A. Vahlquist
Volume: 163, 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: Disadhesion of epidermal keratinocytes: a histologic clue to palmoplantar keratodermas caused by DSG1 mutations
Journal: J Am Acad Dermatol 2010 Jan.
Authors: R. Bergman;D. Hershkovitz;D. Fuchs;M. Indelman;Y. Gadot;E. Sprecher
Volume: 62, 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 (MIM:167200, 167210)
Journal: Genetic Skin Disorders 2010 Jun
Authors: V. P. Sybert
Pages: 248 - 253

Title: Oral manifestations of pachyonychia congenita
Journal: Dermatol Online J. 2010 Oct
Authors: P. S. da Silva Santos;F. Mannarino;R. F. Lellis;L. H. Osorio
Volume: 16, 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: First-in-human Mutation-targeted siRNA Phase 1b Trial of an Inherited Skin Disorder
Journal: Mol Ther 2009 Nov 24
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.

Notes: [Epub ahead of print]

Title: Keratin K6c Mutations Cause Focal Palmoplantar Keratoderma
Journal: J Invest Dermatol 2009 Jul 16
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 three unrelated 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: Increased pachyonychia Congenita severity in patients with current keratin and filaggrin mutations
Journal: Br J Dermatol 2009 Dec
Authors: R. Gruber;N.J. Wilson;F.J.D. Smith;D. Grabher;L. Steinwender;P.O. Fritsch;M. Schmuth
Volume: 161, 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 2009 Nov
Authors: R.P. Hickerson;D. Leake;L.N. Pho;S.A. Leachman;R.L. Kaspar
Volume: 56, 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: Pachyonychia Congenita Type 1 Presenting with Subtle Nail Changes
Journal: Pediatr Dermatol 2009 492-3
Authors: M. Iorizzo;C. Vincenzi;F.J.D. Smith;N.J. Wilson;A. Tosti
Volume: 26, 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 2009 Sep
Authors: R.L. Kaspar; W.H. Irwin; M.E. Schwartz
Volume: 129, 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 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: Pachyonychia congenita with unusual features
Journal: Indian Pediatrics 2009 Oct
Authors: S. Balasubramanian; K. Kaarthigeyan; B. Ramnath
Volume: 46, 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 2009 May-Jun
Authors: J.K. Das; S. Sengupta; A. Gangopadhyay
Volume: 75, 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
Journal: GeneReviews: 2009 Jun 25 updated
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 2009 Jun
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, 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: 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 2009 Feb
Authors: M. Kanda; K. Natsuga; W. Nishie; M. Akiyama; A. Nagasaki; T. Shimizu; H. Shimizu
Volume: 160, 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: Pachyonychia congenita type 2, N92S mutation of keratin 17 gene: clinical features, mutation analysis and pathological view
Journal: Eur J Pediatr 2009 Oct
Authors: O. Cogulu; H. Onay; A. Aykut; N.J. Wilson; F.J. Smith; T. Dereli; F. Ozkinay
Volume: 168, 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: Identification of two recurrent mutations in keratin genes in three cases with pachyonychia congenita
Journal: J Eur Acad Dermatol Venereol 2009 Feb
Authors: J.W. Wu; S.X. Xiao; Y. Liu; B. Yu; Z.L. Bai; S.N. Zhou; X.L. Li
Volume: 23, 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: A Case Report
Journal: Cutis 2009 Nov
Authors: N. Kohli
Volume: 84, 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: Persistent hoarseness in a patient with pachyonychia congenita: an early sign of laryngeal involvement.
Journal: Int J Dermatology 2009 Dec
Authors: A.M. Ceyhan; M. Yildirim; V.B. Akkaya; H. Yasan
Volume: 48, Pages: 1346-8

Title: Steatocystoma multiplex, oligodontia and partial persistent primary dentition associated with a novel keratin 17 mutation
Journal: Br J Dermatol 2009 Jul
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, Pages: 1396-1398

Title: Pachyonychia congenita type 1 with skeletal abnormalities
Journal: Eur J Dermatol 2009 Feb
Authors: J. J., Van der Velden;M. A. Van Steensel
Volume: 19, Pages: 274-275

Title: Pachyonychia congenita with woolly hair in a ten month old infant
Journal: Indian J Dermatol Venereol Leprol. 2008 Sep-Oct
Authors: A. Ehsani; F. Moeineddin; A. Rajaee
Volume: 74, 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: 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 2008 Jul 1
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, Pages: 238-40

Title: Recurrent mutation in keratin 17 in a large family with pachyonychia congenita type 2
Journal: Arch Dermatol Res. 2008 Mar 18
Authors: C. Oh Adib;B. Jones;H. Liao;F.J. Smith;R. Solomon;C.A. Egan;S. Leachman
Volume: 300, 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] 2008 2008 Jun 11
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 2008 2008 Jun 208
Authors: M. Zamiri;W.H. McLean;M.B. Hodgins;C.S. Munro
Volume: 159, Pages: 500-1

Title: The chemical chaperone trimethylamine N-oxide ameliorates the effects of mutant keratins in cultured cells
Journal: Br J Dermatol 2008 2008 Jul 1
Authors: D. Lee;D. Santos;H. Al-Rawi;A.M. McNeill;E. Rugg
Volume: 159, Pages: 252-5

Title: Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita.
Journal: J Dermatol Sci. 2008 Sep
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, 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: Stability Study of Unmodified siRNA and Relevance to Clinical Use
Journal: Oligonucleotides 2008 Oct 10
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

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: Pachyonychia congenita tarda: very late onset
Journal: Int J Dermatol. 2008 Nov
Authors: R. Bahhady; O. Abbas; M. Dahdah
Volume: 47, Pages: 1172-1173

Title: Milia: a review and classification
Journal: J Am Acad Dermatol. 2008 Dec
Authors: D.R. Berk; S.J. Bayliss
Volume: 59, 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: Mice Expressing a Mutant Krt75 (K6hf ) Allele Develop Hair and Nail Defects Resembling Pachyonychia Congenita
Journal: J Invest Dermatol. 2008 Feb
Authors: J. Chen; K. Jaeger; Z. Den; P.J. Koch; J.P. Sundberg; D.R. Roop
Volume: 128, 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: Therapeutic interference: a step closer for pachyonychia congenita?
Journal: J Invest Dermatol. 2008 Jan
Authors: E.L. Rugg
Volume: 128, 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: Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco
Journal: Am J Med Genet A. 2008 Nov 1
Authors: R. Mostefai; F. Morice-Picard; F. Boralevi; M. Sautarel; D. Lacombe; M.J. Stasia; J. McGrath; A. Ta
Volume: 146A, 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: Pachyonychia congenita and hidradenitis suppurativa: no response to infliximab therapy
Journal: J Eur Acad Dermatol Venereol. 2008 Dec
Authors: J. Pedraz; P.F. Pe
Volume: 22, Pages: 1500-1501

Title: Hedgehog Signaling, Keratin 6 Induction, and Sebaceous Gland Morphogenesis
Journal: Am J Pathol. 2008 Sep
Authors: L.H. Gu; P.A. Coulombe
Volume: 173, 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: Broken bricks and cracked mortar- epidermal diseases resulting from genetic abnormalities
Journal: Drug Discov Today:Dis Mech 2008
Authors: E.B. Lane; W.H.I. McLean
Volume: doi:10.1016/j, Pages: e1-e9

Abstract: The epidermis is an attractive organ system for therapy development 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
Journal: J Paediatr Child Health 2008
Authors: B. S. Menon;S. B. Ibrahim;E. Juraida;M. Mohamed;H. Ibrahim;
Pages: 386

Title: Single-Nucleotide-Specific siRNA Targeting in a Dominant-Negative Skin Model
Journal: J Invest Dermatol 2007 Oct 4
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.

Notes: [Epub ahead of print]

Title: Development of Therapeutic siRNAs for Pachyonychia Congenita.
Journal: J Invest Dermatol. 2007 Aug 30
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.

Notes: [Epub ahead of print]

Title: A spectrum of mutations in keratins K6a, K16 and K17 causing pachyonychia congenita.
Journal: J Dermatol Sci. 2007 Aug 23
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]

Notes: [Epub ahead of print]

Title: A novel missense mutation L468Q of keratin 6a in pachyonychia congenita type 1
Journal: J Eur Acad Dermatol Venereol 2007 Mar
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, 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 2007 Apr 2007
Authors: V.M. Sharma; S.L. Stein
Volume: 127, Pages: 2060-2062

Title: Acro-osteolysis: A complication of Jadassohn
Journal: International Journal of Dermatology 2007 Feb
Authors: S.B. Murugesh; S. Reddy; S. Ragunatha; M.M.Mohammed Faizal; P. Shashikala
Volume: 46, 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: Supernumerary digits associated with pachyonychia congenita type I
Journal: Indian J Dermatol Venereol Leprol 2007 Nov-Dec
Authors: S. Agarwal; K. Gopal
Volume: 73, Pages: 431-432

Title: Pachyonychia congenita with unusual dental findings: a case report
Journal: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Jul
Authors: A.R. Pradeep; C. Nagaraja
Volume: 104, Pages: 89-93

Title: Pachyonychia congenita associated with median rhomboid glossitis
Journal: Dermatol Online J. 2007 Jan 27
Authors: J.K. Karen; J.V. Schaffer
Volume: 13, 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: The Vein Hook Successfully Used for Eradication of Steatocystoma Multiplex
Journal: Dermatol Surg 2007 Jan
Authors: S.J. Lee; Y.S. Choe; B.C. Park; W.J. Lee; D.W. Kim
Volume: 33, 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: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis
Journal: Nat Genet. 2006 Apr
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, Pages: 441-6

Title: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris
Journal: Nat Genet. 2006 Mar
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, 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: Keratin 17 modulates hair follicle cycling in a TNF{alpha}-dependent fashion
Journal: Genes Dev. 2006 2006 May 15
Authors: Tong X; Coulombe PA
Volume: 20, Pages: 1353-64

Title: A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth
Journal: Nature 2006 2006 May 18
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 2006
Authors: Arika BANSAL; Gomathy SETHURAMAN; Vinod K SHARMA;
Volume: 33, Pages: 437-8

Title: Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion.
Journal: Genes Dev. 2006 May 15
Authors: X. Tong;P.A. Coulombe
Volume: 20, Pages: 1353-64.

Title: SiRNA-mediated selective inhibition of mutant keratin mRNAs responsible for the skin disorder pachyonychia congenita.
Journal: Ann N Y Acad Sci. 2006 Oct
Authors: R. P. Hickerson;F. J. Smith;W. H. McLean;M. Landthaler;R. E. Leube;R. L. Kaspar
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: Treatment of pachyonychia congenita with plantar injections of botulinum toxin.
Journal: Br J Dermatol 2006 Apr
Authors: C. Swartling;A. Vahlquist
Volume: 154, 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: Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity.
Journal: J Dermatol 2006 Mar
Authors: S. W. Oh; M. Y. Kim; J. S. Lee; S. C. Kim
Volume: 33, 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: Pachyonychia congenita: treatment of the thickened nails and palmoplantar circumscribed callosities with urea 40% paste
Journal: J Eur Acad Dermatol Venereol. 2006 May
Authors: M.A. El-Darouti; S.A. Marzouk; N. Nabil; M.R. Abdel-Halim; M.H. El-Komy; M. Abdel-Latif
Volume: 20, Pages: 615-617

Title: A severe case of pachyonychia congenita type 1 due to a novel proline mutations in keritin 6a
Journal: British Journal of Dermatology 2005
Authors: I. Garcia-Rio;P. F. Penas;A. Garcia-Diez;W. H. I. McLean;F. J. D. Smith
Volume: 152, Pages: 800-802

Abstract: SIR, Pachyonychia congenita (PC) is an autosomal dominantly inherited ectodermal dysplasia with variable expression and high penetrance1. The four major features of the syndrome are hypertrophic nail dystrophy, palmoplantar keratoderma, and oral leukokeratosis, accompanied by other ectodermal defects, according to subtype2. Keratin defects have been found to underlie the two major variants of PC3,4. Specifically, keratin K6a or K16 mutations cause type I/Jadassohn-Lewandowsky syndrome (PC-1); and K6b or K17 abnormalities result in type II/Jackson-Lawler syndrome (PC-2). Here we report a new mutation in the K6a gene in a sporadic case of PC-1 with a severe clinical presentation.

Title: Clinical and Pathological Features of Pachyonychia Congenita.
Journal: J Investig Dermatol Symp Proc 2005 Oct
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, 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 2005 Oct
Authors: Milstone LM, Fleckman P, Leachman SA, Leigh IM, Paller AS, van Steensel MA, Swartling C.
Volume: 10, 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 (

Title: The Genetic Basis of Pachyonychia Congenita.
Journal: J Investig Dermatol Symp Proc 2005 Oct
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, 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: Insights into Genotype-Phenotype Correlation in Pachyonychia Congenita from the Human Intermediate Filament Mutation Database.
Journal: J Investig Dermatol Symp Proc 2005 Oct
Authors: McLean WH, Smith FJ, Cassidy AJ.
Volume: 10, 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 (, 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 2005 Oct
Authors: Chen J, Roop DR.
Volume: 10, 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 2005 Oct
Authors: Lewin AS, Glazer PM, Milstone LM.
Volume: 10, 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: Challenges in Developing Therapies for Rare Diseases Including Pachyonychia Congenita
Journal: J Investig Dermatol Symp Proc 2005 Oct
Authors: Kaspar RL.
Volume: 10, 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: What is Pachyonychia Congenita?
Journal: The Institute of Chiropodists and Podiatrists Chiropody Review 2005 Nov / Dec
Volume: 62, Pages: 4-7

Title: Case study: pachyonychia congenita: a mixed type II-type IV presentation
Journal: Skinmed 2004 Jul-Aug
Authors: C. Cardinali;D. Torchia;M. Caproni;N. Petrini;P. Fabbri
Volume: 3, Pages: 233-235

Abstract: A 52-year-old woman in good health with a family history negative for dermatologic diseases presented to our department with thickening and dystrophy of all her fingernails and toenails that started when she was born. She also had hyperkeratosis on the palms of her hands and soles of her feet that was confined to sites of pressure and recurrent plantar blisters that began appearing at puberty. The patient reported marked pain while walking from such plantar involvement. Her medical history revealed a persistent hoarseness; palmoplantar hyperhidrosis; and the appearance of numerous cysts on her back, neck, and scalp since she was 20 years old. These latter lesions had been diagnosed as multiple steatocystoma on the basis of the histologic features. Upon examination, all of her fingernails and toenails appeared shortened, thickened,and dystrophic (Figures 1-3). In addition, they presented subungual keratosis and a yellowish-gray color. Hyperkeratosis and small ulcerations were present on the perionychium. Palmoplantar keratoderma was evident, especially on the soles,in association with superficial erosions (Figure 4). Keratosis pilaris was evident on the extensor surfaces of the forearms as well as on the anterior surfaces of the legs. Multiple nodules were detected on the patient's neck, trunk, and axillary regions(Figure 5). They consisted of multiplex steatocystoma and were characterized by a hemispheric shape, a normal-appearing skin color, and by an elastic consistency on palpation. Oral and dental changes were not detected, although hair anomalies were evident. Laboratory parameters disclosed eosinophilia and increased total IgE levels. The results of serum protein electrophoresis was normal, as were those concerning hepatic and renal functions. The ophthalmology examination showed neither corneal dyskeratosis nor cataracts. The neurologic-psychiatric visit revealed slight mental retardation.

Notes: 1540-9740 Case Reports Journal Article

Title: A role for thyroid hormone in wound healing through keratin gene expression
Journal: Endocrinology 2004
Authors: J. D. Safer, T. M. Crawford, M. F. Holick
Volume: 145, Pages: 2357-2361

Title: Nail that mutation - keratin defect in late-onset pachyonichia
Journal: Soc Inv Derm 2004
Authors: F.J. D. Smith
Volume: 122, Pages: X-XI

Title: A novel mouse type I intermediate filament gene, keratin 17n (K17n), exhibits preferred expression in nail tissue
Journal: J Invest Dermatol 2004 Apr
Authors: X. Tong;P. A. Coulombe
Volume: 122, 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.

Notes: 0022-202x Journal Article

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 2004 Apr
Authors: S. X. Xiao;Y. G. Feng;X. R. Ren;S. S. Tan;L. Li;J. M. Wang;Y. Z. Shi
Volume: 122, 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.

Notes: 0022-202x Case Reports Journal Article

Title: Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity
Journal: Human Molecular Genetics 2004 Aug
Authors: G.M. Essenfelder; R. Bruzzone; J. Lamartine; A. Charollais; C. Blanchet-Bardon; M.T. Barbe; P. Meda; G. Waksman
Volume: 13, 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: Ichthyosis: etiology, diagnosis, and management
Journal: Am J Clin Dermatol 2003
Authors: J. J. DiGiovanna;L. Robinson-Bostom
Volume: 4, Pages: 81-95

Abstract: The ichthyoses are a heterogeneous group of disorders with both inherited and acquired forms. Clinical presentation, pattern of inheritance, and laboratory evaluation may establish a precise diagnosis, which can assist in prognosis and genetic counseling. Congenital autosomal recessive ichthyosis (CARI) usually presents at birth, often as a collodion baby. CARI can progress into any one of a spectrum of disorders. Lamellar ichthyosis is characterized by dark, plate (armor)-like scale. This disease is often caused by mutations in the gene encoding the enzyme transglutaminase 1. Congenital ichthyosiform erythroderma is another phenotype within CARI, marked by generalized redness and fine white scale. Epidermolytic hyperkeratosis is an autosomal dominant disorder characterized by hyperkeratosis and blistering, and at least six clinical phenotypes have been described. It may be due to mutations in the gene encoding the intermediate filament proteins keratin 1 and 10. Ichthyosis vulgaris is the most common ichthyosis, and is inherited in an autosomal dominant pattern. Involvement is generally mild and may vary greatly with climate and humidity. X-linked ichthyosis, due to a defect in the enzyme steroid sulfatase, affects males with generalized scaling that usually begins soon after birth. There may be associated corneal opacities that do not affect vision. Sjogren-Larsson syndrome is an autosomal recessive ichthyosis associated with progressive spastic paralysis and mental retardation. This condition is caused by mutations in the gene for fatty aldehyde dehydrogenase. Refsum's disease, due to accumulation of phytanic acid, results in ichthyosis and progressive neurologic dysfunction. The erythrokeratodermas are characterized by hyperkeratosis and localized erythema. Erythrokeratodermia variabilis is autosomal dominant and characterized by generalized or localized hyperkeratosis and migratory red patches. Mutations in the genes encoding the gap junction proteins, connexins, underlie this disorder. Netherton's syndrome is an autosomal recessive disorder characterized by ichthyosis, a hair shaft abnormality and atopy. The ichthyosis may present at birth with erythroderma or in some cases a collodion presentation. However, a frequent characteristic skin manifestation is ichthyosis linearis circumflexa. Netherton's syndrome has been found to be due to an abnormality in a serum protease inhibitor. Acquired ichthyosis can have a variety of underlying causes including neoplastic, infectious, drugs, endocrine, metabolic, autoimmune, malabsorptive states, and hereditary. Topical, and in more severe cases, systemic, therapy are useful in managing this array of disorders of cornification.

Notes: 1175-0561 Journal Article Review Review, Tutorial

Title: What is your diagnosis? Pachyonychia congenita
Journal: Cutis 2003 Aug
Authors: D. M. Elston
Volume: 72, Pages: 104, 143-104

Notes: 0011-4162 Journal Article

Title: Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts
Journal: Br J Dermatol 2003 Mar
Authors: Y. G. Feng;S. X. Xiao;X. R. Ren;W. Q. Wang;A. Liu;M. Pan
Volume: 148, Pages: 452-455

Abstract: BACKGROUND: Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias caused by mutations in four differentiation-specific keratin genes. Two major clinical subtypes of PC have been generally recognized. Symmetrically thickened fingernails and toenails are the defining characteristic of PC type 2 (PC-2) with onset at infancy. Pilosebaceous cysts are the best hallmark of PC-2, but they usually occur at puberty. OBJECTIVES: To report a Chinese pedigree of PC-2 with unusually early onset sebaceous cysts and to explore the genetic mutation and its phenotype. METHODS: Exon 1 of keratin 17 was amplified by polymerase chain reaction (PCR) from genomic DNA from the three patients in the pedigree, the proband, his half-sister and his younger son, two unaffected members in the pedigree and 50 unrelated and unaffected people. PCR products were directly sequenced to detect the mutation. RESULTS: Direct sequencing of the PCR products revealed a heterozygous 275A-->G mutation in all three affected members. This mutation predicts the substitution of asparagine by serine in codon 92 (N92S) located in the 1A domain of keratin 17. CONCLUSIONS: Mutation in the 1A domain of keratin 17 underlies the affected members' phenotype, PC-2 with early onset sebaceous cysts and late-onset thickened fingernails and toenails. The onset of the cysts is very early in some people within this family and the age at onset of thickened fingernails and toenails is variable within the family, implying the existence of modifying factors.

Notes: 0007-0963 Journal Article

Title: Transcription affects formation and processing of intermediates in oligonucleotide-mediated gene alteration
Journal: Nucleic Acids Res 2003 May 15
Authors: O. Igoucheva;V. Alexeev;M. Pryce;K. Yoon
Volume: 31, Pages: 2659-2670

Abstract: The role of transcription in oligonucleotide (ODN)-directed gene modification has been investigated in mammalian cells. The importance of transcription is demonstrated using mammalian cell lines with varying degrees of transcription of the mutant LacZ reporter gene, residing in both episome and chromosome. Gene correction occurs more efficiently when the target gene is actively transcribed and antisense ODN is more active than sense ODN. Using an approach that combines biochemical studies with a cell-based assay to measure the functional activity of intermediates it is shown that a joint molecule, consisting of supercoiled DNA and homologous ODN targeted to correct the mutated base, is a functional intermediate in the gene repair process. Furthermore, this approach showed that a resected joint molecule is a downstream intermediate of the D-loop. These results indicate that the primary reason for efficient gene repair exhibited by the antisense ODN is its increased accessibility to the non-transcribed strand, and as a consequence an increased formation of intermediate during active transcription. Moreover, the processing of intermediates was also affected by transcription, suggesting that ODN-directed gene repair may be linked to transcription-coupled repair. Thus, transcription plays an important role in ODN-directed gene repair by affecting the formation and processing of key intermediates.

Notes: 1362-4962 Journal Article

Title: Up-regulated gene expression in the conjugated epithelium of patients with Sjogren's syndrome
Journal: Exp Eye Res 2003
Authors: S. Kawasaki, S. Kawamoto, N. Yokoi, C. Connon, Y. Minesaki, S. Kinoshita, K. Okubo
Volume: 77, Pages: 17-26

Title: Pachyonichia congenita-like nail changes treated successfully with a combination of vitamins A and E: A case report
Journal: Ind J Dermatol Venereal Leprol 2003
Authors: B. B. Mahajan, J. W. Van der Valk
Volume: 69, Pages: 338-339

Title: Role for keratins 6 and 17 during wound closure in embryonic mouse skin
Journal: Dev Dyn 2003 Feb
Authors: S. Mazzalupo;P. Wong;P. Martin;P. A. Coulombe
Volume: 226, Pages: 356-365

Abstract: Injury to adult skin triggers a response designed to restore its vital barrier function. A conserved aspect of this response is a rapid switch in gene expression whereby the type II keratin 6 (K6) and type I keratins 16 and 17 (K16, K17) are induced in epithelial cells at the wound edge. This induction occurs at the expense of the keratins normally expressed during terminal differentiation and correlates with the activation of epithelial cells at the wound edge, ahead of their migration into the wound site. Here, we show that the capacity to enact this switch is already acquired in E11.5 stage mouse embryos. Such early timing is well ahead of the onset of differentiation-specific gene expression (approximately E13.5) and the acquisition of barrier formation by developing epidermis (approximately E16.5). Induction of K6, K16, and K17 correlates with changes in the morphology of epithelial cells at the wound edge. The closure of embryonic wounds is significantly delayed in K17 null embryos, but not embryos null for K6. These observations significantly extend the correlation between K6, K16, and K17 expression and epithelial wound closure, and provide direct evidence that expression of these keratins, K17 in particular, is important for the timeliness of this process.

Notes: 1058-8388 Journal Article

Title: Genetic disorders of palm skin and nail
Journal: J Anat 2003 Jan
Authors: W. H. McLean
Volume: 202, Pages: 133-141

Abstract: The outer part of the skin, the epidermis, is specialized to protect the human body from its environment. Because of the high levels of physical stress experienced by the human hand in everyday use, the epidermis of the hand is especially toughened. In particular, the epidermis of the palm is highly specialized to resist mechanical trauma. Like the epidermis, the nails are composed of specialized epithelial cells and are especially strong. In recent years it has become apparent that the physical strength of epithelial cells comes from the keratin cytoskeleton--a dense meshwork of filaments extending throughout the cytoplasm. Keratins are a large family of intermediate filament proteins encoded by more than 50 distinct genes in humans. These different keratin genes are expressed in well-defined combinations in specific epithelial tissues. Several keratin genes are expressed in palmoplantar epidermis and in the stratified epithelia of the nail bed. Genetic mutations in these genes lead to fragility of these tissues and result in a range of genetic disorders characterized by blistering and thickening of palm and sole skin and or nails. Study of these diseases has shed new light on the vital structural role of keratins in maintaining the integrity of epithelial cells.

Notes: 0021-8782 Journal Article Review Review, Tutorial

Title: Histopathological and immunohistochemical assessment of acquired ichthyosis in patients with human T-cell lymphotropic virus type I-associated myelopathy
Journal: Br J Dermatol 2003 Oct
Authors: S. P. Milagres;J. A. Sanches, Jr.;A. C. Milagres;N. Y. Valente
Volume: 149, Pages: 776-781

Abstract: BACKGROUND: Patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy frequently display cutaneous alterations such as acquired ichthyosis. OBJECTIVES: Elucidation of the pattern of acquired ichthyosis in HTLV-I-associated myelopathy. METHODS: Skin fragments from 10 patients with HTLV-I-associated myelopathy presenting with acquired ichthyosis were assessed by histopathological and immunohistochemical tests. We used anticytokeratin antibodies related to normal keratinization (K1 K10), and others related to cutaneous conditions such as activation, migration and hyperproliferation of keratinocytes (K6 K16), and involucrin, a precursor protein in the formation of the protein envelope in keratinocytes. For quantification of the proliferating basal and parabasal cells the anti-Ki-67 antibody was employed. RESULTS: On light microscopy, all skin specimens displayed orthokeratotic hyperkeratosis and hypogranulosis. Three of them presented focal parakeratosis. A slight to moderate perivascular infiltrate of mononuclear lymphocytes was observed in seven cases, three of which showed discrete spongiosis with epidermotropism of lymphocytes. All fragments displayed coexpression of K1, K10 and K16 in the suprabasal layers. Expression of involucrin was also observed in all cases, in the upper spinous and granular layers. Focal expression of K6 was observed in three cases, under a parakeratotic area. The mean number of Ki-67+ basal and parabasal cells was 3.5 cells per mm, similar to that in control skin. CONCLUSIONS: In acquired ichthyosis related to HTLV-I-associated myelopathy, histopathology revealed orthokeratotic hyperkeratosis and a perivascular inflammatory infiltrate of mononuclear lymphocytes, with areas of parakeratosis and foci of epidermotropism in rare cases. The expression profiles of K1, K10 and involucrin were similar to those in normal skin. The diffuse coexpression of K16 with K1 and K10 throughout the analysed epidermis, as well as the occurrence of restricted areas of parakeratosis expressing K6, indicate the presence of keratinocyte activation with induction of the alternative keratinization pathway, probably dependent on the cytokines liberated by the mononuclear cells of the dermal inflammatory infiltrate infected with HTLV-I. The absence of acanthosis and of increased cellular kinetics, as shown by the low rate of Ki-67 antigen expression, allow the inference that the pattern of acquired ichthyosis related to HTLV-I-associated myelopathy may be retentional. The observation of foci of parakeratosis expressing K6 in three specimens suggests that, at least in certain areas and in some cases, interference with epidermal differentiation and maturation occurs.

Notes: 0007-0963 Journal Article

Title: Generation and characterization of epeidermolysis bullosa simple cell lines: scratch assays show faster migration with disruptive keratin mutations
Journal: Brit J Dermatol 2003
Authors: S. M. Morley, M. D. Alessandro, C. Sexton, E. L. Rugg, H. Navsaria, C. S. Shemanko, M. Huber, D. Hohl, A. I. Heagerty, I. M. Leigh, E. B. Lane
Volume: 149, Pages: 46-58

Title: The potential for gene repair via triple helix formation
Journal: J Clin Inv 2003
Authors: M. M. Seidman, P. M. Glazer
Volume: 112, Pages: 487-494

Title: The molecular genetics of keratin disorders
Journal: Am J Clin Dermatol 2003
Authors: F. Smith
Volume: 4, Pages: 347-364

Abstract: Keratins are the type I and II intermediate filament proteins which form a cytoskeletal network within all epithelial cells. They are expressed in pairs in a tissue- and differentiation-specific fashion. Epidermolysis bullosa simplex (EBS) was the first human disorder to be associated with keratin mutations. The abnormal keratin filament aggregates observed in basal cell keratinocytes of some EBS patients are composed of keratins K5 and K14. Dominant mutations in the genes encoding these proteins were shown to disrupt the keratin filament cytoskeleton resulting in cells that are less resilient and blister with mild physical trauma.Identification of mutations in other keratin genes soon followed with attention focussed on disorders showing abnormal clumping of keratin filaments in specific cells. For example, in bullous congenital ichthyosiform erythroderma, clumping of filaments in the suprabasal cells led to the identification of mutations in the suprabasal keratins, K1 and K10. Mutations have now been identified in 18 keratins, all of which produce a fragile cell phenotype. These include ichthyosis bullosa of Siemens (K2e), epidermolytic palmoplantar keratoderma (K1, K9), pachyonychia congenita (K6a, K6b, K16, K17), white sponge nevus (K4, K13), Meesmann's corneal dystrophy (K3, K12), cryptogenic cirrhosis (K8, K18) and monilethrix (hHb6, hHb1).In general, these disorders are inherited as autosomal dominant traits and the mutations act in a dominant-negative manner. Therefore, treatment in the form of gene therapy is difficult, as the mutant gene needs to be inactivated. Ways of achieving this are actively being studied. Reliable mutation detection methods from genomic DNA are now available. This enables rapid screening of patients for keratin mutations. For some of the more severe phenotypes, prenatal diagnosis may be requested and this can now be performed from chorionic villus samples at an early stage of the pregnancy.This review article describes the discovery of, to date, mutations in 18 keratin genes associated with inherited human diseases.

Notes: 1175-0561 Journal Article Review Review, Tutorial

Title: Light-induced resistance of the keratin network to the filament-disrupting tyrosine phosphatase inhibitor orthovanadate
Journal: J Invest Dermatol 2003 Feb
Authors: P. Strnad;R. Windoffer;R. E. Leube
Volume: 120, 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.

Notes: 0022-202x Journal Article

Title: Pachyonychia congenita, type II
Journal: Dermatol Online J 2003 Oct
Authors: B. E. Strober
Volume: 9, 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.

Notes: 1087-2108 Journal Article

Title: Clouston Syndrome can mimic Pachyonychia congenita
Journal: Society for Investigative Dermatology 2003
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, 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: 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 2003 Jul
Authors: K. M. Ward;F. E. Cook-Bolden;A. M. Christiano;J. T. Celebi
Volume: 28, 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.

Notes: 0307-6938 Journal Article

Title: Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair
Journal: J Cell Biol 2003 Oct 27
Authors: P. Wong;P. A. Coulombe
Volume: 163, 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.

Notes: 0021-9525 Journal Article

Title: A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia
Journal: J Dermatol Sci 2003 Jun
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, 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.

Notes: 0923-1811 Journal Article

Title: Keratin 16 expression defines a subset of epithelial cells during skin morphogenesis and the hair cycle
Journal: J Invest Dermatol 2002 Nov
Authors: K. M. Bernot;P. A. Coulombe;K. M. McGowan
Volume: 119, Pages: 1137-1149

Abstract: The morphogenesis of skin epithelia and adult hair follicle cycling both require integrated signaling between the epithelium and underlying mesenchyme. Because of their unique regulation, keratin intermediate filaments represent useful markers for the analysis of determination and differentiation processes in complex epithelia, such as the skin. In this study, we analyzed the distribution of mouse type I keratin 16 during skin morphogenesis, in the adult hair cycle, and in challenged epidermis. In mature hair follicles, we find keratin 16 along with its type II keratin partner keratin 6 in the companion layer of the outer root sheath during anagen and in the club hair sheath during catagen and telogen. During embryonic development, the distribution of keratin 16 is uncoupled from its presumed polymerization partner, keratin 6. Keratin 16 initially localizes within early hair germs, but rapidly shifts to a subset of cells at the interface of basal and suprabasal cells above and around the hair germ. The presence of keratin 16 at the transition between mitotically active and differentiating cells is recapitulated in primary keratinocytes cultured in vitro and in phorbol 12-myristate 13-acetate-treated back skin in vivo. We propose that keratin 16 marks cells in an intermediate state of cellular properties in which keratinocytes retain the flexibility required for activities such as cell migration and even mitosis but are resilient enough to provide the structural integrity required of the early suprabasal layers in the context of development, adult hair cycling, and wound repair.

Notes: 0022-202x Journal Article

Title: 'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments
Journal: Curr Opin Cell Biol 2002 Feb
Authors: P. A. Coulombe;M. B. Omary
Volume: 14, Pages: 110-122

Abstract: Keratins make up the largest subgroup of intermediate filament proteins and represent the most abundant proteins in epithelial cells. They exist as highly dynamic networks of cytoplasmic 10-12 nm filaments that are obligate heteropolymers involving type I and type II keratins. The primary function of keratins is to protect epithelial cells from mechanical and nonmechanical stresses that result in cell death. Other emerging functions include roles in cell signaling, the stress response and apoptosis, as well as unique roles that are keratin specific and tissue specific. The role of keratins in a number of human skin, hair, ocular, oral and liver diseases is now established and meshes well with the evidence gathered from transgenic mouse models. The phenotypes associated with defects in keratin proteins are subject to significant modulation by functional redundancy within the family and modifier genes as well. Keratin filaments undergo complex regulation involving post-translational modifications and interactions with self and with various classes of associated proteins.

Notes: 0955-0674 Journal Article Review Review, Tutorial

Title: Pachyonychia congenita affecting only the nails
Journal: Pediatr Dermatol 2002 Jan-Feb
Authors: S. Dogra;S. Handa;R. Jain
Volume: 19, Pages: 91-92

Notes: 0736-8046 Letter

Title: Durable and stratum-specific gene expression in epidermis
Journal: Gene Ther 2002 Oct
Authors: S. Ghazizadeh;C. Doumeng;L. B. Taichman
Volume: 9, Pages: 1278-1285

Abstract: A number of genetic disorders are manifested in cutaneous epithelium and gene therapy approaches for treatment of such diseases are being considered. A successful gene therapy protocol requires durable and correctly targeted gene expression within the tissue. The continuous renewal and high levels of compartmentalization in epidermis are two challenges for a successful gene therapy of skin disorders. For those disorders which affect the upper layers of epidermis, vectors must be available that target stem cells, but remain silent until the progeny of these cells undergo differentiation. To explore the potential of long-term and targeted vector expression in epidermis, a hybrid retroviral vector encoding the reporter enhanced green fluorescent protein (EGFP) was constructed. The viral enhancer in the long terminal repeat of the vector was replaced with a 510-bp enhancer element of the human involucrin promoter. Keratinocyte-specific expression directed by the hybrid vector was demonstrated in culture and suprabasal-specific expression was observed in organotypic human epidermal cultures. In vivo transduction of mouse skin with this hybrid vector indicated long-term and stratum-specific expression of the transgene in mouse epidermis. The design of similar vectors for various gene therapy applications constitutes an important step toward clinically effective gene therapy.

Notes: 0969-7128 Journal Article

Title: A novel point mutation in the keratin 17 gene in a Japanese case of pachyonychia congenita type 2
Journal: J Invest Dermatol 2002 Mar
Authors: T. Hashiguchi;K. Kobayashi;T. Saheki;T. Kanzaki
Volume: 118, Pages: 545-547

Notes: 0022-202x Letter

Title: Lessons from disorders of epidermal differentiation-associated keratins
Journal: Histol Histopathol 2002 Jan
Authors: A. Ishida-Yamamoto;H. Takahashi;H. Iizuka
Volume: 17, Pages: 331-338

Abstract: A number of diseases have been associated with mutations in genes encoding keratin intermediate filaments. Several of these disorders have skin manifestations, in which histological changes highlight the role of various different keratins in epidermal differentiation. For example, mutations in either K1 or K10 (the major keratin pair expressed in differentiated keratinocytes) usually lead to clumped keratin filaments and cytolysis. Furthermore, the precise nature of the mutation has direct implications for disease phenotype. Specifically, mutations in the H1 and alpha-helical rod domains of K1 K10 result in bullous congenital ichthyosiform erythroderma, underscoring the critical role for this keratin filament domain in maintaining cellular integrity. However, a lysine to isoleucine substitution in the V1 domain of K1 underlies a form of palmoplantar keratoderma, which has different cell biological implications. Keratins are cross-linked into the cornified cell envelopes through this particular lysine residue and the consequences of the mutation lead to changes in keratin-desmosome association and cornified cell morphology, suggesting a role for this keratin subdomain in cornified cell envelope formation. Recently, to extend genotype-phenotype correlation, a frameshift mutation in the V2 region of the K1 tail domain was identified in ichthyosis hystrix (Curth-Macklin type), in which keratin filaments show a characteristic shell-like structure and fail to form proper bundles. In this case, the association of desmosomes with loricrin was also altered, implicating this keratin domain in organizing the intracellular distribution of loricrin during cornification. Collectively, these mutations in K1 K10 provide a fascinating insight into both normal and abnormal processes of epidermal differentiation.

Notes: 0213-3911 Journal Article Review Review, Tutorial

Title: Pachyonychia congenita
Journal: 2002 2002
Authors: A. Kansky
Volume: 2002,

Notes: Topic 812

Title: Cutaneous gene transfer for skin and systemic diseases
Journal: J Int Med 2002
Authors: P. A. Khavari, O. Rollman, A. Vahlquist
Volume: 252, Pages: 1-10

Title: [Pachyonychia congenita: Molecular genetic analysis simplifies clinical classification in subtypes]
Journal: Hautarzt 2002
Authors: J. Krutmann
Volume: 53, Pages: 153

Title: Improved detection of lacZ reporter gene expression in transgenic epithelia by immunofluorescence microscopy
Journal: Exp Dermatol 2002 Apr
Authors: D. Mahony;S. Karunaratne;J. A. Rothnagel
Volume: 11, Pages: 153-158

Abstract: The bacterial lacZ gene is commonly used as a reporter for the in vivo analysis of gene regulation in transgenic mice. However, several laboratories have reported poor detection of beta-galactosidase (the lacZ gene product) using histochemical techniques, particularly in skin. Here we report the difficulties we encountered in assessing lacZ expression in transgenic keratinocytes using classic X-gal histochemical protocols in tissues shown to express the transgene by mRNA in situ hybridization. We found that lacZ reporter gene expression could be reliably detected in frozen tissue sections by immunofluorescence analysis using a beta-galactosidase-specific antibody. Moreover, we were able to localize both transgene and endogenous gene products simultaneously using double-label immunofluorescence. Our results suggest that antibody detection of beta-galactosidase should be used to verify other assays of lacZ expression, particularly where low expression levels are suspected or patchy expression is observed.

Notes: 0906-6705 Journal Article

Title: Keratin 17 null mice exhibit age- and strain-dependent alopecia
Journal: Genes Dev 2002 Jun 1
Authors: K. M. McGowan;X. Tong;E. Colucci-Guyon;F. Langa;C. Babinet;P. A. Coulombe
Volume: 16, Pages: 1412-1422

Abstract: Onset of type I keratin 17 (K17) synthesis marks the adoption of an appendageal fate within embryonic ectoderm, and its expression persists in specific cell types within mature hair, glands, and nail. We report that K17 null mice develop severe alopecia during the first week postbirth, correlating with hair fragility, alterations in follicular histology, and apoptosis in matrix cells. These alterations are incompletely penetrant and normalize starting with the first postnatal cycle. Absence of a hair phenotype correlates with a genetic strain-dependent compensation by related keratins, including K16. These findings reveal a crucial role for K17 in the structural integrity of the first hair produced and the survival of hair-producing cells. Given that identical inherited mutations in this gene can cause either pachyonychia congenita or steatocystoma multiplex, the features of this mouse model suggest that this clinical heterogeneity arises from a cell type-specific, genetically determined compensation by related keratins.

Notes: 0890-9369 Journal Article

Title: A novel connexin 30 mutation in Clouston syndrome
Journal: J Invest Dermatol 2002 Mar
Authors: F. J. Smith;S. M. Morley;W. H. McLean
Volume: 118, 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.

Notes: 0022-202x Journal Article

Title: Extrachromosomal plasmid vectors for gene therapy
Journal: Curr Opin Mol Therapeut 2002
Authors: S. M. Stoll, M. P. Calos
Volume: 4, Pages: 299-305

Title: Two cases of primarily palmoplantar keratoderma associated with novel mutations in keratin 1
Journal: J Invest Dermatol 2002 Oct
Authors: A. Terron-Kwiatkowski;A. S. Paller;J. Compton;D. J. Atherton;W. H. McLean;A. D. Irvine
Volume: 119, 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.

Notes: 0022-202x Case Reports Journal Article

Title: Pairwise assembly determines the intrinsic potential for self-organization and mechanical properties of keratin filaments
Journal: Mol Biol Cell 2002 Jan
Authors: S. Yamada;D. Wirtz;P. A. Coulombe
Volume: 13, 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.

Notes: 1059-1524 Journal Article

Title: Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders
Journal: J Cell Biol 2001 Feb 5
Authors: M. J. Arin;M. A. Longley;X. J. Wang;D. R. Roop
Volume: 152, Pages: 645-649

Abstract: Stem cells are crucial for the formation and maintenance of tissues and organs. The role of stem cells in the pathogenesis of mosaic skin disorders remains unclear. To study the molecular and cellular basis of mosaicism, we established a mouse model for the autosomal-dominant skin blistering disorder, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10. This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase. Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes. This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

Notes: 0021-9525 Journal Article

Title: An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy
Journal: J Cell Biol 2001 Feb 5
Authors: T. Cao;M. A. Longley;X. J. Wang;D. R. Roop
Volume: 152, Pages: 651-656

Abstract: The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomal-dominant fashion. Here we report the generation of a mouse model that allows focal activation of a mutant keratin 14 allele in epidermal stem cells upon topical administration of an inducer, resulting in EBS phenotypes in treated areas. Using laser capture microdissection, we show that induced blisters healed by migration of surrounding nonphenotypic stem cells into the wound bed. This observation provides an explanation for the lack of mosaic forms of EBS-DM. In addition, we show that decreased mutant keratin 14 expression resulted in normal morphology and functions of the skin. Our results have important implications for gene therapy of EBS and other dominantly inherited diseases.

Notes: 0021-9525 Journal Article

Title: Gene targeting via triple-helix formation
Journal: Prog Nucleic Acid Res Mol Biol 2001
Authors: B. P. Casey;P. M. Glazer
Volume: 67, Pages: 163-192

Abstract: A report on a recent workshop entitled "Gene-Targeted Drugs: Function and Delivery" conveys a justified optimism for the eventual feasibility and therapeutic benefit of gene-targeting strategies. Although multiple approaches are being explored, this chapter focuses primarily on the uses of triplex-forming oligonucleotides (TFOs). TFOs are molecules that bind in the major groove of duplex DNA and by so doing can produce triplex structures. They bind to the purine-rich strand of the duplex through Hoogsteen or reverse Hoogsteen hydrogen bonding. They exist in two sequence motifs, either pyrimidine or purine. Improvements in delivery of these TFOs are reducing the quantities required for an effective intracellular concentration. New TFO chemistries are increasing the half-life of these oligos and expanding the range of sequences that can be targeted. Alone or conjugated to active molecules, TFOs have proven to be versatile agents both in vitro and in vivo. Foremost, TFOs have been employed in antigene strategies as an alternative to antisense technology. Conversely, they are also being investigated as possible upregulators of transcription. TFOs have also been shown to produce mutagenic events, even in the absence of tethered mutagens. TFOs can increase rates of recombination between homologous sequences in close proximity. Directed sequence changes leading to gene correction have been achieved through the use of TFOs. Because it is theorized that these modifications are due to the instigation of DNA repair mechanisms, an important area of TFO research is the study of triple-helix recognition and repair.

Notes: 0079-6603 Journal Article Review

Title: Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16
Journal: Br J Dermatol 2001 May
Authors: J. B. Connors;A. K. Rahil;F. J. Smith;W. H. McLean;L. M. Milstone
Volume: 144, Pages: 1058-1062

Abstract: A young girl with clinical features of pachyonychia congenita type 1 was unusual in that the typical skin and nail changes were not noted until the age of 6 years. Direct sequencing of the KRT16A gene, encoding keratin K16, revealed a novel mutation K354N in the central 2B domain of the K16 polypeptide. The mutation created a new BsmI restriction site and therefore, the mutation was confirmed in the patient and excluded from both parents and 50 normal, unrelated individuals by BsmI digestion of KRT16A polymerase chain reaction products. This is the first time a mutation has been described in this location in a keratin other than K14, where similar mutations cause the milder Weber-Cockayne and or Kobner types of epidermolysis bullosa simplex.

Notes: 0007-0963 Journal Article

Title: Intermediate filaments at a glance
Journal: J Cell Sci 2001 Dec
Authors: P. A. Coulombe;L. Ma;S. Yamada;M. Wawersik
Volume: 114, Pages: 4345-4347

Notes: 0021-9533 Journal Article Review Review, Tutorial

Title: A man, a syndrome, a gene: Clouston's hidrotic ectodermal dysplasia (HED)
Journal: Am J Med Genet 2001 Apr 22
Authors: F. C. Fraser;V. M. Der Kaloustian
Volume: 100, Pages: 164-168

Abstract: This paper presents a biographical sketch of Dr. H. R. Clouston, whose eponym is attached to a type of hidrotic ectodermal dystrophy, and a brief account of the mapping of the gene and its identification as the connexin gene, GJB6.

Notes: 0148-7299 Biography Historical Article Journal Article

Title: Keratins and the keratinocyte activation cycle
Journal: J Invest Dermatol 2001
Authors: I. M. Freedburg, M. Tomic-Canic, M. Komine, M. Blumenberg
Volume: 116, Pages: 633-640

Title: Interleukin-1 induces transcription of keratin K6 in human epidermal keratinocytes
Journal: J Invest Dermatol 2001 Feb
Authors: M. Komine;L. S. Rao;I. M. Freedberg;M. Simon;V. Milisavljevic;M. Blumenberg
Volume: 116, Pages: 330-338

Abstract: Keratinocytes respond to injury by releasing the proinflammatory cytokine interleukin-1, which serves as the initial "alarm signal" to surrounding cells. Among the consequences of interleukin-1 release is the production of additional cytokines and their receptors by keratinocytes and other cells in the skin. Here we describe an additional effect of interleukin-1 on keratinocytes, namely the alteration in the keratinocyte cytoskeleton in the form of the induction of keratin 6 expression. Keratin 6 is a marker of hyperproliferative, activated keratinocytes, found in wound healing, psoriasis, and other inflammatory disorders. Skin biopsies in organ culture treated with interleukin-1 express keratin 6 in all suprabasal layers of the epidermis, throughout the tissue. In cultured epidermal keratinocytes, the induction of keratin 6 is time and concentration dependent. Importantly, only confluent keratinocytes respond to interleukin-1, subconfluent cultures do not. In the cells starved of growth factors, epidermal growth factor or tumor necrosis factor-alpha, if added simultaneously with interleukin-1, they synergistically augment the effects of interleukin-1. Using DNA-mediated cell transfection, we analyzed the molecular mechanisms regulating the keratin 6 induction by interleukin-1, and found that the induction occurs at the transcriptional level. We used a series of deletions and point mutations to identify the interleukin-1 responsive DNA element in the keratin 6 promoter, and determined that it contains a complex of C EBP binding sites. The transcription factor C EBPbeta binds this element in vitro, and the binding is augmented by pretreatment of the cells with interleukin-1. The interleukin-1 responsive element is clearly distinct from the epidermal growth factor responsive one, which means that the proinflammatory and proliferative signals independently regulate the expression of keratin 6. Thus, interleukin-1 initiates keratinocyte activation not only by triggering additional signaling events, but also by inducing directly the synthesis of keratin 6 in epidermal keratinocytes, and thus changing the composition of their cytoskeleton.

Notes: 0022-202x Journal Article

Title: [Pachyonychia congenita-steatocystoma multiplex]
Journal: Ryoikibetsu Shokogun Shirizu 2001
Authors: T. Kubota
Pages: 459-460

Notes: Journal Article Review Review, Tutorial

English Language Version

Title: A novel keratin 5 mutation (K5V186L) in a family with EBS-K: a conservative substitution can lead to development of different disease phenotypes
Journal: J Invest Dermatol 2001 Jun
Authors: M. Liovic;J. Stojan;P. E. Bowden;D. Gibbs;A. Vahlquist;E. B. Lane;R. Komel
Volume: 116, Pages: 964-969

Abstract: Epidermolysis bullosa simplex is a hereditary skin blistering disorder caused by mutations in the KRT5 or KRT14 genes. More than 50 different mutations have been described so far. These, and reports of other keratin gene mutations, have highlighted the existence of mutation "hotspots" in keratin proteins at which sequence changes are most likely to be detrimental to protein function. Pathogenic mutations that occur outside these hotspots are usually associated with less severe disease phenotypes. We describe a novel K5 mutation (V186L) that produces a conservative amino acid change (valine to leucine) at position 18 of the 1A helix. The phenotype of this case is unexpectedly severe for the location of the mutation, which lies outside the consensus helix initiation motif mutation hotspot, and other mutations at this position have been associated in Weber--Cockayne (mild) epidermolysis bullosa simplex only. The mutation was confirmed by mismatch-allele-specific polymerase chain reaction and the entire KRT5 coding region was sequenced, but no other changes were identified. De novo K5 K14 (mutant and wild-type) filament assembly in cultured cells was studied to determine the effect of this mutation on filament polymerization and stability. A computer model of the 1A region of the K5 K14 coiled-coil was generated to visualize the structural impact of this mutation and to compare it with an analogous mutation causing mild disease. The results show a high level of concordance between genetic, cell culture and molecular modeling data, suggesting that even a conservative substitution can cause severe dysfunction in a structural protein, depending on the size and structure of the amino acid involved.

Notes: 0022-202x Journal Article

Title: Expression of a truncated keratin 5 may contribute to severe palmar-plantar hyperkeratosis in epidermolysis bullosa simplex patients
Journal: J Invest Dermatol 2001
Authors: R. J. Livingston, V. P. Sybert, L. T. Smith, B. A. Dale, R. B. Presland, K. Stephens
Volume: 116, Pages: 970-974

Abstract: Epidermolysis bullosa simplex are dominant disorders of skin fragility characterized by intraepidermal blistering upon mild mechanical trauma. Skin fragility is caused by expression of either an abnormal keratin 5 or an abnormal keratin 14 protein, which compromises the structure and function of the keratin cytoskeleton of basal cells. We report an epidermolysis bullosa simplex patient with a novel single base substitution (A-->T1414) that changes the lysine residue at amino acid 472 to a non-sense codon (K472X). This change predicts the synthesis of a truncated keratin 5, missing 119 amino acids, including the entire tail domain and the highly conserved KLLEGE motif at the carboxy terminus of the 2B domain of the central rod. Expression of an altered keratin 5, of predicted mass and pI for the product of the K472X allele, was documented by one- and two-dimensional western blots of protein extracts from patient skin. Ultrastructural analysis of the patient's nonhyperkeratotic skin was remarkable for basal keratinocytes with dense and irregular keratin filaments proximal to the basement membrane. Keratinocytes, transfected with a cDNA carrying the A-->T1414 non-sense mutation, overexpressed a truncated keratin 5, and showed a disorganized and collapsed keratin filament cytoskeleton. This is the second epidermolysis bullosa simplex patient reported with a premature termination mutation in the KLLEGE motif. The remarkable occurrence of severe palmar--plantar hyperkeratosis in both patients suggests that the keratin 5 tail domain may have unrecognized, but important, normal functions in palmar-plantar tissues. PMID: 11407989 [PubMed - indexed for MEDLINE]

Title: A 'hot-spot' mutation alters the mechanical properties of keratin filament networks
Journal: Nat Cell Biol 2001 May
Authors: L. Ma;S. Yamada;D. Wirtz;P. A. Coulombe
Volume: 3, Pages: 503-506

Abstract: Keratins 5 and 14 polymerize to form the intermediate filament network in the progenitor basal cells of many stratified epithelia including epidermis, where it provides crucial mechanical support. Inherited mutations in K5 or K14 result in epidermolysis bullosa simplex (EBS), a skin-fragility disorder. The impact that such mutations exert on the intrinsic mechanical properties of K5 K14 filaments is unknown. Here we show, by using differential interference contrast microscopy, that a 'hot-spot' mutation in K14 greatly reduces the ability of reconstituted mutant filaments to bundle under crosslinking conditions. Rheological assays measure similar small-deformation mechanical responses for crosslinked solutions of wild-type and mutant keratins. The mutation, however, markedly reduces the resilience of crosslinked networks against large deformations. Single-particle tracking, which probes the local organization of filament networks, shows that the mutant polymer exhibits highly heterogeneous structures compared to those of wild-type filaments. Our results indicate that the fragility of epithelial cells expressing mutant keratin may result from an impaired ability of keratin polymers to be crosslinked into a functional network.

Notes: 1465-7392 Journal Article

Title: Pachyonychia congenita: mutations and clinical presentations
Journal: Br J Dermatol 2001 May
Authors: C. S. Munro
Volume: 144, Pages: 929-930

Notes: 0007-0963 Comment Editorial

Title: Keratin K6irs is specific to the inner root sheath of hair follicles in mice and humans
Journal: Br J Dermatol 2001 Oct
Authors: R. M. Porter;L. D. Corden;D. P. Lunny;F. J. Smith;E. B. Lane;W. H. McLean
Volume: 145, Pages: 558-568

Abstract: BACKGROUND: Keratins are a multigene family of intermediate filament proteins that are differentially expressed in specific epithelial tissues. To date, no type II keratins specific for the inner root sheath of the human hair follicle have been identified. OBJECTIVES: To characterize a novel type II keratin in mice and humans. METHODS: Gene sequences were aligned and compared by BLAST analysis. Genomic DNA and mRNA sequences were amplified by polymerase chain reaction (PCR) and confirmed by direct sequencing. Gene expression was analysed by reverse transcription (RT)-PCR in mouse and human tissues. A rabbit polyclonal antiserum was raised against a C-terminal peptide derived from the mouse K6irs protein. Protein expression in murine tissues was examined by immunoblotting and immunofluorescence. RESULTS: Analysis of human expressed sequence tag (EST) data generated by the Human Genome Project revealed a fragment of a novel cytokeratin mRNA with characteristic amino acid substitutions in the 2B domain. No further human ESTs were found in the database; however, the complete human gene was identified in the draft genome sequence and several mouse ESTs were identified, allowing assembly of the murine mRNA. Both species' mRNA sequences and the human gene were confirmed experimentally by PCR and direct sequencing. The human gene spans more than 16 kb of genomic DNA and is located in the type II keratin cluster on chromosome 12q. A comprehensive immunohistochemical survey of expression in the adult mouse by immunofluorescence revealed that this novel keratin is expressed only in the inner root sheath of the hair follicle. Immunoblotting of murine epidermal keratin extracts revealed that this protein is specific to the anagen phase of the hair cycle, as one would expect of an inner root sheath marker. In humans, expression of this keratin was confirmed by RT-PCR using mRNA derived from plucked anagen hairs and epidermal biopsy material. By this means, strong expression was detected in human hair follicles from scalp and eyebrow. Expression was also readily detected in human palmoplantar epidermis; however, no expression was detected in face skin despite the presence of fine hairs histologically. CONCLUSIONS: This new keratin, designated K6irs, is a valuable histological marker for the inner root sheath of hair follicles in mice and humans. In addition, this keratin represents a new candidate gene for inherited structural hair defects such as loose anagen syndrome.

Notes: 0007-0963 Journal Article

Title: Novel keratin 17 mutations in pachyonychia congenita type 2
Journal: J Invest Dermatol 2001 May
Authors: F. J. Smith;C. M. Coleman;N. M. Bayoumy;R. Tenconi;J. Nelson;A. David;W. H. McLean
Volume: 116, Pages: 806-808

Abstract: Pachyonychia congenita type 2 is an inherited ectodermal dysplasia characterized by hypertrophic nail dystrophy and multiple pilosebaceous cysts. Focal nonepidermolytic palmoplantar keratoderma, natal teeth, and pili torti may also be present. Epithelial tissues affected in pachyonychia congenita type 2 express the keratin pair K6b K17. Here, we report three novel heterozygous mutations in the K17 gene (KRT17A) in patients presenting with pachyonychia congenita type 2. These mutations, R94-98del (deletion of the peptide sequence RLASY) and missense mutations R94P and L95Q, are all within the 1A domain hotspot for pathogenic keratin mutations.

Notes: 0022-202x Journal Article

Title: Unraveling the molecular mechanisms of hair and nail genodermatoses
Journal: Arch Dermatol 2001
Authors: A. J. Stratigos, H. P. Baden
Volume: 137, Pages: 1463-1471

Title: Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita
Journal: J Invest Dermatol 2001 Dec
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, 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.

Notes: 0022-202x Journal Article

Title: A new type of pachyonychia congenita
Journal: Eur J Dermatol 2001 May-Jun
Authors: M. A. van Steensel;F. J. Smith;P. M. Steijlen
Volume: 11, 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.

Notes: 1167-1122 Journal Article

Title: Pachyonychia congenita: a case report
Journal: Pediatr Dermatol 2001 Nov-Dec
Authors: M. Vijaikumar;D. M. Thappa;C. Laxmisha
Volume: 18, Pages: 541-543

Notes: 0736-8046 Letter

Title: [Keratin 17 gene mutation in patients with steatocystoma multiplex]
Journal: Zhonghua Yi Xue Za Zhi 2001 May 10
Authors: X. Wang;Y. Shi;Y. Ye;F. Liu;W. Jin;W. Chen;M. Wang;L. Hu;G. Zhao;X. Kong
Volume: 81, 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.

Notes: 0376-2491 Journal Article

Title: Increased levels of keratin 16 alter epithelialization potential of mouse skin keratinocytes in vivo and ex vivo
Journal: Mol Biol Cell 2001 Nov
Authors: M. J. Wawersik;S. Mazzalupo;D. Nguyen;P. A. Coulombe
Volume: 12, 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.

Notes: 1059-1524 Journal Article

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 2001 Aug 6
Authors: S. M. Wojcik;M. A. Longley;D. R. Roop
Volume: 154, 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.

Notes: 0021-9525 Journal Article

Title: Repair of triplex-directed DNA alkylation by nucleotide excision repair
Journal: Nucleic Acids Res 2001 Nov 1
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, 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.

Notes: 1362-4962 Journal Article

Title: Surgical Pearl: Mini-incisions for the extraction of steatocystoma multiplex
Journal: J Am Acad Dermatol 2001 June
Authors: T. Schmook;G. Burg;J. Hafner
Volume: 44, Pages: 1041-2

Title: Prenatal diagnosis for inherited skin diseases
Journal: Clin Dermatol 2000 Nov-Dec
Authors: G. H. Ashton;R. A. Eady;J. A. McGrath
Volume: 18, Pages: 643-648

Notes: 0738-081x Journal Article Review Review, Tutorial

Title: Characterization of an inducible, epidermal-specific knockout system: differential expression of lacZ in different Cre reporter mouse strains
Journal: Genesis 2000 Feb
Authors: T. R. Berton;X. J. Wang;Z. Zhou;C. Kellendonk;G. Schutz;S. Tsai;D. R. Roop
Volume: 26, Pages: 160-161

Notes: 1526-954x Journal Article

Title: [Nail pathology in children]
Journal: Rev Prat 2000 Dec 15
Authors: S. Goettmann
Volume: 50, Pages: 2256-2261

Abstract: In children the nail has physiologic characteristics that imply specific abnormalities. The most common dermatological localisation in psoriasis in the child; it is seen as trachyonychia, pitting, and occasionally pachyonychia. Ingrowth of the large toenail is a common problem, whether due to congenital hypertrophy of the lateral nail folds of the hallux in the newborn, to congenital malalignment of the nail of the big toe, or to a juvenile ingrown nail. Many other nail disorders are observed in the child: parakeratosis pustulosa, nail lichen, lichen striatus, melanonychia, dermatophyte onychomycosis, candida infection, herpes. Aside from warts, tumours are rare.

Notes: 0035-2640 Journal Article Review Review, Tutorial

English Language Version

Title: Pachyonychia congenita tarda
Journal: Australas J Dermatol 2000 Aug
Authors: R. S. Hannaford;K. Stapleton
Volume: 41, Pages: 175-177

Abstract: A 42-year-old man presented with painful toenails which were overcurved transversely and onycholytic. Examination revealed that all toenails, the thumbs and index fingers were similarly affected. In addition, he had a small area of leukokeratosis in the mouth, epidermal cysts of the scrotal skin and a small area of hyperkeratosis on the ulnar borders of his hands. His characteristic nail changes began in the great toenails at the age of 20 years. After renal transplantation at age 39, the other nails changed and he developed the features described above. His sister has overcurvature of the fifth toenails. A diagnosis of pachyonychia congenita tarda was made. His case is compared with 14 other reported cases of this rare syndrome.

Notes: 0004-8380 Journal Article Review Review of Reported Cases

Title: Ribozyme gene therapy for autosomal dominant retinal disease
Journal: Clin Chem Lab Med 2000
Authors: V.W. Hauswirth, M. M. LaVail, J. G. Flannery, A. S. Lewin
Volume: 38, Pages: 147-153

Abstract: Gene delivery to cells of the retina, particularly to photoreceptor cells, has broad potential both for answering basic questions of retinal biology and for more applied therapeutic purposes. The use of ribozymes as therapy for autosomal dominant retinal diseases is a promising technique, and the theoretical and practical basis for their use is discussed. The process involves designing and testing ribozymes first in vitro and then in animal models of retinal disease. Viral vectors based on the nonpathogenic human adeno-associated virus, when coupled with the strong, rod photoreceptor specific opsin promoter, offer an efficient and nontoxic way to deliver and express ribozymes in photoreceptor cells for long time periods of time. Effective ribozyme-mediated therapy also demands careful in vitro analysis of a ribozyme's ability to efficiently and specifically distinguish between mutant and wild type RNAs. Finally, effective demonstration of therapy in an animal model requires careful analysis of any rescue effect in the retina using multiple criteria, including biochemical, structural and physiological assays. For this purpose, ribozyme therapy in a transgenic rat model of retinitis pigmentosa containing a dominant rod opsin mutation (proline-to-histidine change at position 23) is discussed in detail.

Title: Inflammatory versus proliferative processes in epidermis. Tumor necrosis factor alpha induces K6b keratin synthesis through a transcriptional complex containing NFkappa B and C EBPbeta
Journal: J Biol Chem 2000 Oct 13
Authors: M. Komine;L. S. Rao;T. Kaneko;M. Tomic-Canic;K. Tamaki;I. M. Freedberg;M. Blumenberg
Volume: 275, Pages: 32077-32088

Abstract: Epidermal keratinocytes respond to injury by becoming activated, i.e. hyperproliferative, migratory, and proinflammatory. These processes are regulated by growth factors and cytokines. One of the markers of activated keratinocytes is keratin K6. We used a novel organ culture system to show that tumor necrosis factor alpha (TNFalpha) induces the expression of K6 protein and mRNA in human skin. Multiple isoforms of K6 are encoded by distinct genes and have distinct patterns of expression. By having shown previously that proliferative signals, such as epidermal growth factor (EGF), induce expression of the cytoskeletal protein keratin K6b, we here demonstrate that the same isoform, K6b, is also induced by TNFalpha, a proinflammatory cytokine. Specifically, TNFalpha induces the transcription of the K6b gene promoter. By using co-transfection, specific inhibitors, and antisense oligonucleotides, we have identified NFkappaB and C EBPbeta as the transcription factors that convey the TNFalpha signal. Both transcription factors are necessary for the induction of K6b by TNFalpha and act as a complex, although only C EBPbeta binds the K6b promoter DNA. By using transfection, site-directed mutagenesis, and footprinting, we have mapped the site that responds to TNFalpha, NFkappaB, and C EBPbeta. This site is separate from the one responsive to EGF and AP1. Our results show that the proinflammatory (TNFalpha) and the proliferative (EGF) signals in epidermis separately and independently regulate the expression of the same K6b keratin isoform. Thus, the cytoskeletal responses in epidermal cells can be precisely tuned by separate proliferative and inflammatory signals to fit the nature of the injuries that caused them.

Notes: 0021-9258 Journal Article

Title: Keratinocyte differentiation in hyperproliferative epidermis: topical application of PPA Ralpha activators restores tissue homeostasis
Journal: J Invest Dermatol 2000
Authors: L. G. Komuves, K. Hanley, M. Man, P. M. Elias, M. L. Williams, K. R. Feingold
Volume: 115, Pages: 361-367

Title: [Congenital pachyonychia type II (Jackson-Lawler syndrome)]
Journal: Hautarzt 2000 Mar
Authors: J. Lochner;B. Mohr;I. Garcia-Gutierrez;H. P. Schoppelrey;M. Gummer;R. Breit
Volume: 51, Pages: 192-195

Abstract: Pachyonychia congenita (PC) is a rare ectodermal dysplasia with variable expression. The condition is usually inherited as an autosomal dominant trait. Several classifications of PC have been proposed. Feinstein and colleagues suggested four clinical types of PC. Type II, the Jackson-Lawler-Syndrome, is characterized by multiple epidermal cysts, palmoplantar bullae and hyperhidrosis as well as natal teeth in addition to the main findings of pachyonychia, palmoplantar hyperkeratosis and follicular keratosis. We report two patients (father and son) with Jackson-Lawler-Syndrome and describe in detail pathogenesis, diagnostic criteria and treatment approaches as well as the different classifications of pachyonychia congenita.

Notes: 0017-8470 Journal Article

English Language Version

Title: Supplementation of a mutant keratin by stable expression of desmin in cultured human EBS keratinocytes
Journal: J Cell Sci 2000 Dec
Authors: T. M. Magin;H. W. Kaiser;S. Leitgeb;C. Grund;I. M. Leigh;S. M. Morley;E. B. Lane
Volume: 113 Pt 23, Pages: 4231-4239

Abstract: Mutations in keratin genes give rise to a number of inherited skin fragility disorders, demonstrating that the intermediate filament cytoskeleton has an essential function in maintaining the structural integrity of epidermis and its appendages. Epidermolysis bullosa simplex (EBS) is an autosomal dominant disorder caused by mutations in keratins K5 or K14, which are expressed in the basal layer of stratified epithelia. Using a keratinocyte cell line established from an EBS patient, we investigated whether the muscle-specific intermediate filament protein desmin would be able to functionally complement a mutant keratin 14 in cultured keratinocytes. We show that in stably transfected EBS cells, desmin forms an extended keratin-independent cytoskeleton. Immunogold-EM analysis demonstrated that in the presence of numerous keratin filaments attached to desmosomes, desmin could nevertheless interact with desmosomes in the same cell, indicating the dynamic nature of the filament-desmosome association. When desmin-transfected cells were subjected to heat shock, the mutant keratin filaments showed a transient collapse while desmin filaments were maintained. Thus the defective keratin filaments and the wild-type desmin filaments appear to coexist in cells without interference. Expression of a type III intermediate filament protein like desmin may offer a strategy for the treatment of patients suffering from epidermal keratin mutations.

Notes: 0021-9533 Journal Article

Title: Analysis of mouse keratin 6a regulatory sequences in transgenic mice reveals constitutive, tissue-specific expression by a keratin 6a minigene
Journal: J Invest Dermatol 2000 Nov
Authors: D. Mahony;S. Karunaratne;G. Cam;J. A. Rothnagel
Volume: 115, Pages: 795-804

Abstract: The analysis of keratin 6 expression is complicated by the presence of multiple isoforms that are expressed constitutively in a number of internal stratified epithelia, in palmoplantar epidermis, and in the companion cell layer of the hair follicle. In addition, keratin 6 expression is inducible in interfollicular epidermis and the outer root sheath of the follicle, in response to wounding stimuli, phorbol esters, or retinoic acid. In order to establish the critical regions involved in the regulation of keratin 6a (the dominant isoform in mice), we generated transgenic mice with two different-sized mouse keratin 6a constructs containing either 1.3 kb or 0.12 kb of 5' flanking sequence linked to the lacZ reporter gene. Both constructs also contained the first intron and the 3' flanking sequence of mouse keratin 6a. Ectopic expression of either transgene was not observed. Double-label immunofluorescence analyses demonstrated expression of the reporter gene in keratin 6 expressing tissues, including the hair follicle, tongue, footpad, and nail bed, showing that both transgenes retained keratinocyte-specific expression. Quantitative analysis of beta-galactosidase activity verified that both the 1.3 and 0.12 kb keratin 6a promoter constructs produced similar levels of the reporter. Notably, both constructs were constitutively expressed in the outer root sheath and interfollicular epidermis in the absence of any activating stimulus, suggesting that they lack the regulatory elements that normally silence transcription in these cells. This study has revealed that a keratin 6a minigene contains critical cis elements that mediate tissue-specific expression and that the elements regulating keratin 6 induction lie distal to the 1.3 kb promoter region.

Notes: 0022-202x Journal Article

Title: Keratin 17 expression in the hard epithelial context of the hair and nail, and its relevance for the pachyonychia congenita phenotype
Journal: J Invest Dermatol 2000 Jun
Authors: K. M. McGowan;P. A. Coulombe
Volume: 114, Pages: 1101-1107

Abstract: The hard-keratin-containing portion of the murine hair shaft displays a positive immunoreactivity with an antibody against the soft epithelial keratin, K17. The K17-expressing cell population is located in the medulla compartment of the hair. Consistent with this observation, K17-containing cells also occur in the presumptive medulla precursor cells located in the hair follicle matrix. Western blot analysis of hair extracts prepared from a number of mouse strains confirms this observation and suggests that K17 expression in the hair shaft is a general trait in this species. The expression of K17 in human hair extracts is restricted to eyebrow and facial hair samples. These are the major sites for the occurrence of the pili torti (twisted hair) phenotype in the type 2 (Jackson-Lawler) form of pachyonychia congenita, previously shown to arise from inherited K17 mutations. Given that all forms of pachyonychia congenita show an involvement of the nail, we compared the expression of the two other genes mutated in pachyonychia congenita diseases, K6 and K16, with that of K17 in human nail. All three keratins are abundantly expressed within the nail bed epithelium, whereas K17 protein is expressed in the nail matrix, which contains the epithelial cell precursors for the nail plate. Our data suggest a role for K17 in the formation and maintenance of various skin appendages and directly support the concept that pachyonychia congenita is a disease of the nail bed.

Notes: 0022-202x Journal Article

Title: Characterization of a 300 kbp region of human DNA containing the type II hair keratin gene domain
Journal: J Invest Dermatol 2000 Mar
Authors: M. A. Rogers;H. Winter;L. Langbein;C. Wolf;J. Schweizer
Volume: 114, Pages: 464-472

Abstract: Screening of an arrayed human genomic P1 artificial chromosome DNA library by means of the polymerase chain reaction with a specific primer pair from the human type II hair keratin hHb5 yielded two P1 artificial chromosome clones covering approximately 300 kb of genomic DNA. The contig contained six type II hair keratin genes, hHb1-hHb6, and four keratin pseudogenes psihHbA-psihHbD. This hair keratin gene domain was flanked by type II epithelial keratins K6b K6hf and K7, respectively. The keratin genes pseudogene are 5-14 kbp in size with intergenic distances of 5-19 kbp of DNA and do not exhibit a single direction of transcription. With one exception, type II hair keratin genes are organized into nine exons and eight introns, with strictly conserved exon-intron boundaries. The functional hair keratin genes are grouped into two distinct subclusters near the extremities of the hair keratin gene domain. One subcluster encodes the highly related hair keratins hHb1, hHb3, and hHb6; The second cluster encodes the structurally less related hair keratins hHb2, hHb4, and hHb5. Reverse transcription-polymerase chain reaction shows that all hair keratin genes are expressed in the hair follicle. Pseudogene psihHbD is also transcriptionally expressed, albeit with alterations in splicing and frameshift mutations, leading to premature stop codons in the splice forms analyzed. Evolutionary tree analysis revealed a divergence of the type II hair keratin genes from the epithelial keratins, followed by their segregation into the members of the two subclusters over time. We assume that the approximately 200 kbp DNA domain contains the entire complement of human type II hair keratin genes.

Notes: 0022-202x Journal Article

Title: DNA based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex
Journal: Prenat Diagn 2000 May
Authors: E. L. Rugg;D. Baty;C. S. Shemanko;G. Magee;S. Polak;R. Bergman;T. Kadar;M. Boxer;T. Falik-Zaccai;Z. Borochowitz;E. B. Lane
Volume: 20, Pages: 371-377

Abstract: Epidermolysis bullosa simplex (EBS) is a skin fragility disorder in which mild physical trauma leads to blistering. The phenotype of the disorder is variable, from relatively mild affecting only the hands and or feet, to very severe with widespread blistering. For the severest forms of EBS there is a demand for prenatal diagnosis which until now has involved a fetal skin biopsy in the second trimester. The identification of mutations in the genes encoding keratins K5 and K14 as the cause of EBS opens up the possibility of much earlier diagnosis of the disease. We report here four cases in which prenatal testing was performed. In three of the cases the genetic lesions were unknown at the start of the pregnancy, requiring the identification of the causative mutation prior to testing fetal DNA. In two of the four cases novel mutations were identified in K14 and in the two remaining families, a previously identified type of mutation was found. Fetal DNA, obtained by chorionic villus sampling or amniocentesis, was analysed for the identified mutations. Three of the DNA samples were found to be normal; a mutant K14 allele was identified in the fourth case and the pregnancy was terminated. These results demonstrate the feasibility of DNA-based prenatal testing for EBS in families where causative mutations can be found.

Notes: 0197-3851 Case Reports Journal Article

Title: Structural hair shaft abnormalities in hypomelanosis of ito and other ectodermal dysplasias
Journal: Acta Paediatr 2000 May
Authors: E. Selvaag;A. M. Aas;S. Heide
Volume: 89, Pages: 610-612

Abstract: Hair samples from patients with different ectodermal dysplasias; hypohidrotic ectodermal dysplasia, pachyonychia congenita, tricho-dento-osseous syndrome, tricho-rhino-phalangeal syndrome, and hypomelanosis of Ito were investigated using a scanning electron microscope. The hairs of the patients showed different structural abnormalities; twisted hairs, longitudinal grooves, trichorrhexis nodosa as well as variations in the hair caliber. Hair shaft abnormalities, as in our patients with tricho-dento-osseous syndrome, and hypomelanosis of Ito have so far not been described.

Notes: 0803-5253 Journal Article

Title: Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma
Journal: Exp Dermatol 2000 Jun
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, 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.

Notes: 0906-6705 Journal Article

Title: Eruptive vellus hair cyst and epidermoid cyst in a patient with pachyonychia congenita
Journal: J Dermatol 2000 Oct
Authors: T. Takeshita;H. Takeshita;K. Irie
Volume: 27, 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.

Notes: 0385-2407 Journal Article

Title: A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus
Journal: J Invest Dermatol 2000 Jun
Authors: A. Terrinoni;P. Puddu;B. Didona;V. De Laurenzi;E. Candi;F. J. Smith;W. H. McLean;G. Melino
Volume: 114, 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.

Notes: 0022-202x Journal Article

Title: [Pachyonychia congenita type 2 due to mutation in the keratin 6b gene]
Journal: Ned Tijdschr Geneeskd 2000 Aug 5
Authors: G. G. Toth;H. Van Goor;W. H. McLean;M. F. Jonkman
Volume: 144, Pages: 1563-1564

Notes: 0028-2162 Journal Article

English Language Version

Title: Nonviral skin gene therapy
Journal: Hum Gene Ther 2000 Nov 1
Authors: J. C. Vogel
Volume: 11, 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.

Notes: 1043-0342 Journal Article Review Review, Tutorial

Title: Forced expression of keratin 16 alters the adhesion, differentiation, and migration of mouse skin keratinocytes
Journal: Mol Biol Cell 2000 Oct
Authors: M. Wawersik;P. A. Coulombe
Volume: 11, 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.

Notes: 1059-1524 Journal Article

Title: Delayed wound healing in keratin 6a knockout mice
Journal: Mol Cell Biol 2000 Jul
Authors: S. M. Wojcik;D. S. Bundman;D. R. Roop
Volume: 20, 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.

Notes: 0270-7306 Journal Article

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 2000 Aug 21
Authors: P. Wong;E. Colucci-Guyon;K. Takahashi;C. Gu;C. Babinet;P. A. Coulombe
Volume: 150, 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.

Notes: 0021-9525 Journal Article

Title: Transduction of a preselected population of human epidermal stem cells: consequences for gene therapy
Journal: Proc Assoc Am Physicians 1999 May-Jun
Authors: J. R. Bickenbach;D. R. Roop
Volume: 111, Pages: 184-189

Abstract: Continuously renewing tissues, such as the epidermis, are populated by a hierarchy of dividing transient amplifying cells, which are maintained by stem cells. Transient amplifying cells divide to maintain the tissue, but they are limited to a finite number of cell divisions before they differentiate and are sloughed. Only the stem cells remain for the life of the tissue. Thus, it is critical to target stem cells when designing gene therapy regimes for genetically inherited diseases, such as epidermolysis bullosa simplex (EBS). Unfortunately, isolating pure epithelial stem cells has been problematic. In this study, we used rapid adherence to collagen type IV to successfully enrich for epidermal stem cells from adult human skin. These preselected stem cells were slow to proliferate, but they ultimately formed large colonies. When recombined with the dermal substrate AlloDerm, the stem cells re-formed a stratified squamous epidermis within 1 week after raising the AlloDerm to the air-liquid interface. These organotypic cultures grew continuously and, even after 6 weeks in culture, they maintained a proliferative basal layer. When transduced with a retroviral LacZ vector, preselected stem cells formed beta-galactosidase-positive clones in submerged and organotypic cultures. Transduced cells showed persistent expression through 12 weeks in organotypic culture, demonstrating the feasibility of using preselected stem cells for gene therapy. Currently, we are developing two models of EBS to test a gene therapy approach, which is based on the premise that EBS stem cells with a mutant keratin (K)14 gene corrected to wild type will have a growth advantage over noncorrected EBS stem cells.

Notes: 1081-650x Journal Article Review Review, Tutorial

Title: Mutation report: identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2
Journal: J Invest Dermatol 1999 Nov
Authors: J. T. Celebi;E. L. Tanzi;Y. J. Yao;E. J. Michael;M. Peacocke
Volume: 113, Pages: 848-850

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. It has been demonstrated that PC-2 is associated with germline mutations in the keratin 17 (K17) gene and in its expression partner keratin 6b. In this report, we describe a novel germline mutation in K17, M88T, in a family with PC-2.

Notes: 0022-202x Journal Article

Title: Targeted correction of an episomal gene in mammalian cells by a short DNA fragment tethered to a triplex-forming oligonucleotide
Journal: J Biol Chem 1999 Apr 23
Authors: P. P. Chan;M. Lin;A. F. Faruqi;J. Powell;M. M. Seidman;P. M. Glazer
Volume: 274, Pages: 11541-11548

Abstract: Triplex-forming oligonucleotides (TFOs) can bind to polypurine polypyrimidine regions in DNA in a sequence-specific manner and provoke DNA repair. We have coupled a TFO to a short donor fragment of DNA that shares homology to a selected gene as a strategy to mediate gene targeting and correction. In this bifunctional oligonucleotide, the TFO domain is designed to bind the target gene and stimulate repair and recombination, with the donor domain positioned for recombination and information transfer. A series of these tethered donor-TFO (TD-TFO) molecules with donor domains of 40-44 nucleotides and TFO domains in both the purine and pyrimidine triplex motifs were tested for their ability to mediate either gene correction or mutation of a supF reporter gene contained in a SV40 shuttle vector in mammalian cells. In vitro binding assays revealed that the attachment of the donor domain via a flexible linker did not significantly alter the binding affinity of the TFO domain for the polypurine site in the supF target DNA, with equilibrium dissociation constants in the 10(-8) M range. Experiments in which the target vector and the linked TD-TFOs were pre-incubated in vitro and co-transfected into cells led to conversion frequencies approaching 1%, 4-fold greater than with the two domains unlinked. When cells that had been previously transfected with the SV40 vector were electroporated with the TD-TFOs, frequencies of base pair-specific gene correction were seen in the range of 0.04%, up to 50-fold over background and at least 3-fold over either domain alone or in unlinked combinations. Sequence conversion by the TD-TFOs was achieved using either single- or double-stranded donor domains and either triplex motif. Substitution of either domain in the TD-TFO with control sequences yielded reagents with diminished activity, as did mixtures of unlinked TFO and donor DNA segments. The boost in activity provided by the attached TFO domain was reduced in cells deficient in the nucleotide excision repair factor XPA but was restored in a subclone of these cells expressing XPA cDNA, suggesting a role for nucleotide excision repair in the pathway of triple helix-stimulated gene conversion. The ability to correct or mutate a specific target site in mammalian cells using the TD-TFO strategy may provide a useful tool for research and possibly for therapeutic applications.

Notes: 0021-9258 Journal Article

Title: Avoiding Pachyonychia congenita using oocyte donation
Journal: Dermatology 1999
Authors: M. A. Cohen;S. R. Lindheim;M. V. Sauer
Volume: 198, Pages: 107-108

Notes: 1018-8665 Letter

Title: Current and future nail research - areas ripe for study
Journal: Skin Pharmacol Appl Skin Physiol 1999 May-Jun
Authors: P. Fleckman
Volume: 12, Pages: 146-153

Abstract: This discussion examines five common topics that affect nails adversely, onychomycosis, brittle nails, developmental nail disorders, chronic paronychia and onycholysis. What is known about these processes, what areas of research, old and new, might lead to improved understanding of the underlying basis of the problems and what prospects the future might hold are considered.

Notes: 1422-2868 Journal Article

Title: Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation
Journal: Br J Dermatol 1999 May
Authors: A. D. Irvine;W. H. McLean
Volume: 140, Pages: 815-828

Abstract: Keratins are obligate heterodimer proteins that form the intermediate filament cytoskeleton of all epithelial cells. Keratins are tissue and differentiation specific and are expressed in pairs of types I and II proteins. The spectrum of inherited human keratin diseases has steadily increased since the causative role of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa simplex (EBS) was first reported in 1991. At the time of writing, mutations in 15 epithelial keratins and two trichocyte keratins have been associated with human diseases which include EBS, bullous congenital ichthyosiform erythroderma, epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, diffuse and focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita and monilethrix. Mutations in extracutaneous keratins have been reported in oral white sponge naevus and Meesmann's corneal dystrophy. New subtleties of phenotype-genotype correlation are emerging within the keratin diseases with widely varying clinical presentations attributable to similar mutations within the same keratin. Mutations in keratin-associated proteins have recently been reported for the first time. This article reviews clinical, ultrastructural and molecular aspects of all the keratin diseases described to date and delineates potential future areas of research in this field.

Notes: 0007-0963 Journal Article Review Review, Academic

Title: Eruptive vellus hair cyst in a patient with pachyonychia congenita
Journal: J Dermatol 1999 Jun
Authors: H. T. Lee;S. H. Chang;T. Y. Yoon
Volume: 26, Pages: 402-404

Abstract: Pachyonychia congenita is characterized by symmetrical nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and follicular hyperkeratosis. In addition to these features, multiple cutaneous cysts of various kinds have been described. We report a case of pachyonychia congenita associated with eruptive vellus hair cyst.

Notes: 0385-2407 Journal Article

Title: A case of pachyonychia congenita with oral leukoplakia and steatocystoma multiplex
Journal: J Dermatol 1999 Oct
Authors: T. W. Lim;J. H. Paik;N. I. Kim
Volume: 26, Pages: 677-681

Abstract: Pachyonchia congenita (PC) is an uncommon autosomal dominant genodermatosis affecting the nails and other ectodermal tissues. The most striking features are symmetrically thickened dysmorphic nails and hyperkeratotic skin lesions. We report a case of pachyonychia congenita in a 30-year-old male patient who had thickening and gray-brown discoloration of all nails and many nodules on his back and neck. He also had hyperkeratotic skin lesions on both feet. His tongue had irregularly-shaped, whitish plaques. Histology of these nodules revealed the characteristic features of steatocystoma multiplex. After treatment with oral retinoic acid, his hyperkeratotic skin lesions improved.

Notes: 0385-2407 Journal Article

Title: Identification of sporadic mutations in the helix initiation motif of keratin 6 in two pachyonychia congenita patients: further evidence for a mutational hot spot
Journal: Exp Dermatol 1999 Apr
Authors: M. T. Lin;M. L. Levy;P. E. Bowden;C. Magro;L. Baden;H. P. Baden;D. R. Roop
Volume: 8, Pages: 115-119

Abstract: Pachyonychia congenita (PC) is a rare, autosomal dominant, ectodermal dysplasia characterized most distinctly by the presence of symmetric nail hypertrophy. In the Jadassohn-Lewandowsky form, or PC-1, additional cutaneous manifestations may include palmoplantar hyperkeratosis, hyperhidrosis, follicular keratoses, and oral leukokeratosis. Mutations have previously been identified in the 1A helix initiation motif of either keratin 6 or keratin 16 in patients with PC-1. In the current study, we have identified 2 sporadic, heterozygous mutations in the 1A helix region of the K6 isoform (K6a). The first mutation identified was a 3 base pair deletion (K6adelta N171). The second mutation was a C-to-A transversion resulting in an amino acid substitution (K6a N171K). These data, in combination with previous reports, provide further evidence that this location is a mutational hot spot.

Notes: 0906-6705 Journal Article

Title: Keratin filament suspensions show unique micromechanical properties
Journal: J Biol Chem 1999 Jul 2
Authors: L. Ma;J. Xu;P. A. Coulombe;D. Wirtz
Volume: 274, Pages: 19145-19151

Abstract: All epithelial cells feature a prominent keratin intermediate filament (IF) network in their cytoplasm. Studies in transgenic mice and in patients with inherited epithelial fragility syndromes showed that a major function of keratin IFs is to provide mechanical support to epithelial cell sheets. Yet the micromechanical properties of keratin IFs themselves remain unknown. We used rheological methods to assess the properties of suspensions of epidermal type I and type II keratin IFs and of vimentin, a type III IF polymer. We find that both types of IFs form gels with properties akin to visco-elastic solids. With increasing deformation they display strain hardening and yield relatively rapidly. Remarkably, both types of gels recover their preshear properties upon cessation of the deformation. Repeated imposition of small deformations gives rise to a progressively stiffer gel for keratin but not vimentin IFs. The visco-elastic moduli of both gels show a weak dependence upon the frequency of the input shear stress and the concentration of the polymer, suggesting that both steric and nonsteric interactions between individual polymers contribute to the observed mechanical properties. In support of this, the length of individual polymers contributes only modestly to the properties of IF gels. Collectively these properties render IFs unique among cytoskeletal polymers and have strong implications for their function in vivo.

Notes: 0021-9258 Journal Article

Title: The functional diversity of epidermal keratins revealed by the partial rescue of the keratin 14 null phenotype by keratin 16
Journal: J Cell Biol 1999 Sep 6
Authors: R. D. Paladini;P. A. Coulombe
Volume: 146, Pages: 1185-1201

Abstract: The type I epidermal keratins K14 and K16 are remarkably similar at the primary sequence level. While a structural function has been clearly defined for K14, we have proposed that a function of K16 may be to play a role in the process of keratinocyte activation that occurs after acute injury to stratified epithelia. To compare directly the functions of the two keratins we have targeted the expression of the human K16 cDNA to the progenitor basal layer of the epidermis of K14 null mice. Mice null for K14 blister extensively and die approximately 2 d after birth (Lloyd, C., Q.C. Yu, J. Cheng, K. Turksen, L. Degenstein, E. Hutton, and E. Fuchs. 1995. J. Cell Biol. 129:1329-1344). The skin of mice expressing K16 in the absence of K14 developed normally without evidence of blistering. However, as the mice aged they featured extensive alopecia, chronic epidermal ulcers in areas of frequent physical contact, and alterations in other stratified epithelia. Mice expressing a control K16-C14 cDNA also rescue the blistering phenotype of the K14 null mice with only a small percentage exhibiting minor alopecia. While K16 is capable of rescuing the blistering, phenotypic complementation in the resulting skin is incomplete due to the multiple age dependent anomalies. Despite their high sequence similarity, K16 and K14 are not functionally equivalent in the epidermis and other stratified epithelia and it is primarily the carboxy-terminal approximately 105 amino acids of K16 that define these differences.

Notes: 0021-9525 Journal Article

Title: The mouse keratin 6 isoforms are differentially expressed in the hair follicle, footpad, tongue and activated epidermis
Journal: Differentiation 1999 Oct
Authors: J. A. Rothnagel;T. Seki;M. Ogo;M. A. Longley;S. M. Wojcik;D. S. Bundman;J. R. Bickenbach;D. R. Roop
Volume: 65, Pages: 119-130

Abstract: Keratin 6 (K6) is expressed constitutively in a variety of internal stratified epithelia as well as in palmoplantar epidermis and in specialized cells of the hair follicle. K6 expression can also be induced by hyperproliferative conditions as in wound healing or by conditions that perturb normal keratinocyte function. The functional significance of the expression of K6 on keratinocyte biology under these disparate conditions is not known. Here we report on the characterization of two isoforms of mouse K6 that are encoded by separate genes. The two genes (denoted K6a and K6b) are linked, have the same orientation and are actively transcribed. Sequence analysis revealed, that although they encode almost identical products, they have distinctly different regulatory regions, suggesting that the two K6 genes would be differentially expressed. In an attempt to define the expression characteristics of the K6 isoforms, we produced transgenic mice with each gene after modifying the C-terminal sequences to enable detection of the transgenic proteins with specific antibodies. The constitutive expression of the K6a transgene paralleled that of the endogenous genes in all K6 expressing tissues, except in the tongue. The K6b transgene was also expressed in these tissues but, in contrast to K6a, was only expressed in suprabasal cells. Both K6 transgenes were also induced in the interfollicular epidermis in response to phorbol esters, with K6a induced in all layers of the treated epidermis, while K6b was expressed only in suprabasal cells. These studies suggest that the K6 isoforms have overlapping yet distinct expression profiles.

Notes: 0301-4681 Journal Article

Title: Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1
Journal: Br J Dermatol 1999 Dec
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, 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.

Notes: 0007-0963 Journal Article

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 1999 Apr
Authors: F. J. Smith;K. E. McKenna;A. D. Irvine;E. A. Bingham;C. M. Coleman;J. Uitto;W. H. McLean
Volume: 8, 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.

Notes: 0906-6705 Journal Article

Title: Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1
Journal: Prenat Diagn 1999 Oct
Authors: F. J. Smith;V. A. McKusick;K. Nielsen;E. Pfendner;J. Uitto;W. H. McLean
Volume: 19, 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.

Notes: 0197-3851 Journal Article

Title: [Pachyonychia congenita. Keratin gene mutations with pleiotropic effect]
Journal: Hautarzt 1999 Jul
Authors: O. Swensson
Volume: 50, 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.

Notes: 0017-8470 Journal Article Review Review, Tutorial

Title: Using transgenic models to study the pathogenesis of keratin-based inherited skin diseases
Journal: J Dermatol Sci 1999 Sep
Authors: K. Takahashi;P. A. Coulombe;Y. Miyachi
Volume: 21, 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.

Notes: 0923-1811 Journal Article Review Review, Tutorial

Title: A direct in vivo approach for skin gene therapy
Journal: Proc Assoc Am Physicians 1999 May-Jun
Authors: J. C. Vogel
Volume: 111, 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.

Notes: 1081-650x Journal Article Review Review, Tutorial

Title: [Type I pachyonychia congenita (Jadarssohn-Lewandowsky)]
Journal: Klin Padiatr 1999 May-Jun
Authors: M. B. Wimmershoff;W. Stolz;R. Schiffner;M. Landthaler
Volume: 211, Pages: 179-183

Abstract: BACKGROUND: Pachyonychia congenita is considered to be a genodermatosis of autosomal inheritance. It is characterized by nail hypertrophy, shortly present after birth. Later on follicular keratosis of the extremities and hyperkeratosis of palms and soles can be found. HISTORY AND CLINICAL FINDINGS: We report a child with pachyonychia congenita type-I (Jadassohn-Lewandowsky). Shortly after birth nail hypertrophy of all finger- and toenails and leukoplakia of the palate and tongue were found. At the age of 3 years follicular keratosis of the extremities and plantar bullae could be found additionally. CONCLUSION: The underlying disturbance is a mutation within genes for keratin 6, 16 and 17 which leads to formation of abnormal tonofilaments. In adult patients retinoids can be used for symptomatic treatment especially of the palmoplantar keratosis.

Notes: 0300-8630 Journal Article

English Language Version

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 1999 Oct
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, 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.

Notes: 0301-4681 Journal Article

Title: Type I keratin 16 forms relatively unstable tetrameric assembly subunits with various type II keratin partners: biochemical basis and functional implications
Journal: Biol Bull 1998 Jun
Authors: P. A. Coulombe;M. Wawersik;R. D. Paladini;E. Noensie
Volume: 194, Pages: 364-365; discus

Notes: 0006-3185 Journal Article

Title: Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2
Journal: Br J Dermatol 1998 Sep
Authors: S. P. Covello;F. J. Smith;J. H. Sillevis Smitt;A. S. Paller;C. S. Munro;M. F. Jonkman;J. Uitto;W. H. McLean
Volume: 139, Pages: 475-480

Abstract: Pachyonychia congenita type 2 (PC-2; Jackson-Lawler syndrome) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, mild focal keratoderma, multiple pilosebaceous cysts and other features of ectodermal dysplasia. Keratin 17 (K17) is a differentiation-specific keratin expressed in the nail bed, hair follicle, sebaceous gland and other epidermal appendages. Previously, we have demonstrated that PC-2 is caused by mutations in K17 and that similar mutations in this gene can present as steatocystoma multiplex with little or no nail dystrophy. Here, we describe three unrelated kindreds carrying K17 mutations. Two of these families have identical missense mutations (R94C) in the 1A domain of K17. However, while affected members of one kindred have the classical features of PC-2, affected persons in the other family have the steatocystoma multiplex phenotype. In a third family with PC-2, mutation N92S was detected, bringing the total number of distinct mutations reported in K17 thus far to 11. These results demonstrate that K17 mutations commonly underlie both PC-2 and steatocystoma multiplex and that the alternate phenotypes which arise from these genetic lesions in K17 are independent of the specific mutation involved.

Notes: 0007-0963 Journal Article

Title: The molecular basis of inherited disorders of keratinization
Journal: Hosp Med 1998 Jan
Authors: M. G. Dunnill
Volume: 59, Pages: 17-22

Abstract: Inherited disorders of keratinization can result in a wide variety of clinical features. The skin is usually affected with blistering or ichthyosis, but other body systems may be involved. The severity of these disorders varies greatly. This article reviews the advances in the molecular pathology of these disorders, and shows how this has benefited our understanding of cell biology.

Notes: 1462-3935 Journal Article

Title: Pachyonychia congenita type 2: keratin 17 mutation in a Japanese case
Journal: J Am Acad Dermatol 1998 Jun
Authors: W. Fujimoto;G. Nakanishi;S. Hirakawa;T. Nakanishi;T. Shimo;M. Takigawa;J. Arata
Volume: 38, Pages: 1007-1009

Notes: 0190-9622 Journal Article

Title: Pachyonychia congenita with steatocystoma multiplex. A report of two cases and a discussion of the classification
Journal: Eur J Dermatol 1998 Apr-May
Authors: S. Giustini;B. Amorosi;C. Canci;G. Camplone;U. Bottoni;R. Porciello;S. Calvieri
Volume: 8, Pages: 158-160

Abstract: Pachyonychia congenita is a rare syndrome in which the main and most common clinical sign is onychodystrophy of all finger and toe nails. The most frequent type of transmission seems to be autosomal dominant, but recessive forms have also been described. Typical onychodystrophy can be associated with other clinical manifestations. The most recent literature refers to descriptions of about 250 cases up until 1993. Numerous classifications of pachyonychia congenita have been suggested by several authors over the years. We report two cases of pachyonychia congenita in association with steatocystoma multiplex in a mother and son.

Notes: 1167-1122 Journal Article

Title: Disorders of keratinyation
Journal: Textbook of Dermatol 6th ed 1998
Authors: W. A. D. Griffiths
Pages: 1483, 1557-1481

Title: Functional differences between keratins of stratified and simple epithelia
Journal: J Cell Biol 1998 Oct 19
Authors: E. Hutton;R. D. Paladini;Q. C. Yu;M. Yen;P. A. Coulombe;E. Fuchs
Volume: 143, Pages: 487-499

Abstract: Dividing populations of stratified and simple epithelial tissues express keratins 5 and 14, and keratins 8 and 18, respectively. It has been suggested that these keratins form a mechanical framework important to cellular integrity, since their absence gives rise to a blistering skin disorder in neonatal epidermis, and hemorrhaging within the embryonic liver. An unresolved fundamental issue is whether different keratins perform unique functions in epithelia. We now address this question using transgenic technology to express a K16-14 hybrid epidermal keratin transgene and a K18 simple epithelial keratin transgene in the epidermis of mice null for K14. Under conditions where the hybrid epidermal keratin restored a wild-type phenotype to newborn epidermis, K18 partially but not fully rescued. The explanation does not appear to reside in an inability of K18 to form 10-nm filaments with K5, which it does in vitro and in vivo. Rather, it appears that the keratin network formed between K5 and K18 is deficient in withstanding mechanical stress, leading to perturbations in the keratin network in regions of the skin that are subjected either to natural or to mechanically induced trauma. Taken together, these findings suggest that the loss of a type I epidermal keratin cannot be fully compensated by its counterpart of simple epithelial cells, and that in vivo, all keratins are not equivalent.

Notes: 0021-9525 Journal Article

Title: Pachyonychia congenita associated with steatocystoma multiplex
Journal: J Dermatol 1998 Jul
Authors: J. U. Kim;T. Nogita;S. Terajima;M. Kawashima
Volume: 25, Pages: 479-481

Abstract: We present an unique case of pachyonychia congenita associated with steatocystoma multiplex. A 33-year-old Japanese man had thickening and gray-brown dicoloration of all nails and a large number of nodules or tumors over his entire skin. No palmar and plantar hyperkeratosis, leukokeratosis of the mucous membranes, or follicular keratosis were observed. Histology of these tumors revealed the typical features of steatocystoma multiplex.

Notes: 0385-2407 Journal Article

Title: Palmoplantar keratoderma and leukokeratosis anogenitalis: the second case of a new disease
Journal: Dermatology 1998
Authors: S. Lautenschlager;M. R. Pittelkow
Volume: 197, Pages: 300-302

Abstract: An increasing number of syndromes with palmoplantar keratoderma (PPK) with associated diseases are being identified, representing a wide spectrum of distinct entities. At present only one case report has described the combination of marked anogenital leukokeratosis with diffuse PPK evolving in a collodion baby. We report a patient with a diffuse, nonprogressive PPK in combination with an intermittently pruritic, slowly progressive anogenital leukokeratosis. Hyperkeratosis of the perineal area was most pronounced and extended to the distal portion of the anal mucosa. The opalescent lesion was also visualized at the margin of the major labia. Vulvar structures were not otherwise involved or dystrophic. There were no signs or symptoms of ectodermal dysplasia. Specifically, the nails were normal and showed no signs of pachyonychia congenita. Other differential diagnoses included dyskeratosis congenita and white sponge nevus, which may be associated with anogenital leukokeratosis, but a keratoderma is not associated with these entities. Keratin immunocytochemistry showed marked expression of suprabasal K17 and absence of K6 and K16. Further examination of the initial case described by Itin and Rufli demonstrated the same expression pattern and supports the contention that these two cases represent the same entity.

Notes: 1018-8665 Case Reports Journal Article

Title: The wound repair-associated keratins 6, 16, and 17. Insights into the role of intermediate filaments in specifying keratinocyte cytoarchitecture
Journal: Subcell Biochem 1998
Authors: K. McGowan;P. A. Coulombe
Volume: 31, Pages: 173-204

Notes: 0306-0225 Journal Article Review Review, Academic

Title: Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development
Journal: J Cell Biol 1998 Oct 19
Authors: K. M. McGowan;P. A. Coulombe
Volume: 143, Pages: 469-486

Abstract: The type I keratin 17 (K17) shows a peculiar localization in human epithelial appendages including hair follicles, which undergo a growth cycle throughout adult life. Additionally K17 is induced, along with K6 and K16, early after acute injury to human skin. To gain further insights into its potential function(s), we cloned the mouse K17 gene and investigated its expression during skin development. Synthesis of K17 protein first occurs in a subset of epithelial cells within the single-layered, undifferentiated ectoderm of embryonic day 10.5 mouse fetuses. In the ensuing 48 h, K17-expressing cells give rise to placodes, the precursors of ectoderm-derived appendages (hair, glands, and tooth), and to periderm. During early development, there is a spatial correspondence in the distribution of K17 and that of lymphoid-enhancer factor (lef-1), a DNA-bending protein involved in inductive epithelial-mesenchymal interactions. We demonstrate that ectopic lef-1 expression induces K17 protein in the skin of adult transgenic mice. The pattern of K17 gene expression during development has direct implications for the morphogenesis of skin epithelia, and points to the existence of a molecular relationship between development and wound repair.

Notes: 0021-9525 Journal Article

Title: Directed expression of keratin 16 to the progenitor basal cells of transgenic mouse skin delays skin maturation
Journal: J Cell Biol 1998 Aug 24
Authors: R. D. Paladini;P. A. Coulombe
Volume: 142, Pages: 1035-1051

Abstract: We previously hypothesized that the type I keratin 16 (K16) plays a role in the process of keratinocyte activation that occurs in response to skin injury (Paladini, R.D., K. Takahashi, N.S. Bravo, and P.A. Coulombe. 1996. J. Cell Biol. 132:381-397). To further examine its properties in vivo, the human K16 cDNA was constitutively expressed in the progenitor basal layer of transgenic mouse skin using the K14 gene promoter. Mice that express approximately as much K16 protein as endogenous K14 display a dramatic postnatal phenotype that consists of skin that is hyperkeratotic, scaly, and essentially devoid of fur. Histologically, the epidermis is thickened because of hyperproliferation of transgenic basal cells, whereas the hair follicles are decreased in number, poorly developed, and hypoproliferative. Microscopically, the transgenic keratinocytes are hypertrophic and feature an altered keratin filament network and decreased cell-cell adhesion. The phenotype normalizes at approximately 5 wk after birth. In contrast, control mice expressing a K16-K14 chimeric protein to comparable levels are normal. The character and temporal evolution of the phenotype in the K16 transgenic mice are reminiscent of the activated EGF receptor- mediated signaling pathway in skin. In fact, tyrosine phosphorylation of the EGF receptor is increased in the newborn skin of K16 transgenic mice. We conclude that expression of K16 can significantly alter the response of skin keratinocytes to signaling cues, a distinctive property likely resulting from its unique COOH-terminal tail domain.

Notes: 0021-9525 Journal Article

Title: Human keratin-1.bcl-2 transgenic mice aberrantly express keratin 6, exhibit reduced sensitivity to keratinocyte cell death induction, and are susceptible to skin tumor formation
Journal: Oncogene 1998 Feb 19
Authors: J. Rodriguez-Villanueva;D. Greenhalgh;X. J. Wang;D. Bundman;S. Cho;M. Delehedde;D. Roop;T. J. McDonnell
Volume: 16, Pages: 853-863

Abstract: Nonmelanoma skin cancers (NMSC) are among the most common malignancies in the world. Typically, these neoplasms grow slowly and are comparatively indolent in their clinical behavior. The most frequent molecular alterations implicated in the pathogenesis of these neoplasms involve genes known to be regulators of cell death including p53, Ha-ras and bcl-2. In order to evaluate the significance cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1.bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic HK1.bcl-2 protein was expressed at high levels specifically in the epidermis extending from the stratum basale through the stratum granulosum. The epidermis of HK1.bcl-2 mice exhibited multifocal hyperplasia without associated hyperkeratosis and aberrant expression of keratin 6. The rate of proliferation was similar in HK1.bcl-2 and control epidermis although suprabasal BrdUrd incorporating cells were present only in HK1.bcl-2 skin. Keratinocytes from the HK1.bcl-2 mice were significantly more resistant to cell death induction by U.V.-B, DMBA, and TPA, compared to control keratinocytes. Furthermore, papillomas developed at a significantly greater frequency and shorter latency in the HK1.bcl-2 mice compared to control littermates following initiation with DMBA and promotion with TPA. Together these results support a role for bcl-2 in the pathogenesis of NMSC.

Notes: 0950-9232 Journal Article

Title: A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2
Journal: Hum Mol Genet 1998 Jul
Authors: F. J. Smith;M. F. Jonkman;H. van Goor;C. M. Coleman;S. P. Covello;J. Uitto;W. H. McLean
Volume: 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.

Notes: 0964-6906 Journal Article

Title: Specialized keratin expression pattern in human ridged skin as an adaptation to high physical stress
Journal: Br J Dermatol 1998 Nov
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, 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.

Notes: 0007-0963 Journal Article

Title: The two functional keratin 6 genes of mouse are differentially regulated and evolved independently from their human orthologs
Journal: Genomics 1998 Oct 15
Authors: K. Takahashi;B. Yan;K. Yamanishi;S. Imamura;P. A. Coulombe
Volume: 53, 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.

Notes: 0888-7543 Journal Article

Title: Genetic approaches to understanding the keratinopathies
Journal: Adv Dermatol 1997
Authors: S. J. Bale;J. J. DiGiovanna
Volume: 12, Pages: 99-113; discuss

Abstract: Genetic methods (both statistical and laboratory based), along with close clinical scrutiny, have led to the recent discovery that abnormal keratin genes underlie several disorders of cornification (Table 3). The ability to classify diseases based on the specific underlying gene mutation has now become a reality (e.g., the ability to distinguish IBS from EHK and to correlate palmoplantar hyperkeratosis in EHK with keratin 1 mutations vs. the lack of palmoplantar hyperkeratosis with keratin 10 mutations). Understanding how specific keratin mutations cause their associated clinical phenotypes will lead to better appreciation of the function of KIFs in epidermis in normal and disease states.

Notes: 0882-0880 Journal Article Review Review, Tutorial

Title: What syndrome is this? Pachyonychia congenita
Journal: Pediatr Dermatol 1997 Nov-Dec
Authors: M. A. Carroll;H. J. Kim;R. A. Skidmore
Volume: 14, Pages: 491-493

Notes: 0736-8046 Journal Article

Title: [Transgenic mice: a model for the study of hereditary cutaneous bullous diseases]
Journal: Ann Dermatol Venereol 1997
Authors: A. Coulombe
Volume: 124, Pages: 197-204

Notes: 0151-9638 Journal Article

English Language Version

Title: Towards a molecular definition of keratinocyte activation after acute injury to stratified epithelia
Journal: Biochem Biophys Res Commun 1997 Jul 18
Authors: P. A. Coulombe
Volume: 236, Pages: 231-238

Abstract: While in recent years we have come to increasingly appreciate the multifaceted role of skin, probably none of these novel contributions is as vital as its barrier function, inferred centuries ago. In human skin this function is fulfilled nearly entirely by the epidermis, a thin stratified squamous epithelium made up primarily of keratinocytes and located at the skin surface. Disruption of the integrity of epidermis triggers a homeostatic response involving blood-derived elements and resident skin cell types that is designed to rapidly restore a functional epithelial lining over the wound site. This article is focused on the process of recruitment of keratinocytes from intact skin tissue at the proximal wound edges to participate in re-epithelialization.

Notes: 0006-291x Journal Article Review Review, Academic

Title: Steatocystoma multiplex and oligosymptomatic pachyonychia congenita of the Jackson-Sertoli type
Journal: Dermatology 1997
Authors: D. Hohl
Volume: 195, Pages: 86-88

Abstract: A family with affected members, previously reported to carry an R94H mutation of keratin K17, and characterized by a variable and oligosymptomatic form of pachyonychia congenita of the Jackson-Sertoli type with steatocystoma multiplex, is described in detail.

Notes: 1018-8665 Journal Article

Title: Mutations in cornea-specific keratins K3 or K12 cause Meesmann's corneal dystrophy
Journal: Nature Genet 1997
Authors: A. D. Irvine, L. D. Corden, O. Swensson, B. Swensson, J. Moore, D. G. Fracer, F. J. D. Smith, R. G. Knowlton, E. Christophers, R. Rochels, J. Uitto, W. H. I. McLean
Volume: 16, Pages: 184-187

Abstract: BACKGROUND: The molecular basis of Meesmann's epithelial corneal dystrophy (MECD) has recently been attributed to mutations in the cornea specific keratin genes KRT3 and KRT12. The mechanisms by which these mutations cause the Meesmann's phenotype are not clear. This study presents new data, examines clinical, histological, ultrastructural, and molecular aspects of MECD, and compares the features seen in this condition with those observed in other well studied keratin diseases such as epidermolysis bullosa simplex. METHODS: A two generation family with typical features of Meesmann's epithelial corneal dystrophy (MECD) was studied. All family members were examined under a slit lamp. Biopsy material from elective keratoplasty was studied by histopathological and ultrastructural analysis using standard techniques. Direct automated sequencing of genomic DNA was used for mutation detection, mutations were confirmed by restriction digest analysis. RESULTS: The abnormal corneal epithelium was acanthotic and contained numerous dyskeratotic cells and intraepithelial vesicles. By electron microscopy abnormally aggregated and clumped keratin filament bundles were detected in basal and suprabasal keratinocytes from the centre of the cornea. Direct sequencing of the patients' genomic DNA revealed a novel missense mutation (423T>G) in exon 1 of the cornea specific keratin 12 (KRT12) gene. This mutation predicts the amino acid change N133K within the helix initiation motif of the K12 polypeptide. Comparative studies with well established keratin disorders of other human epithelia underscore the pathogenic relevance of K3 and K12 gene mutations in Meesmann's epithelial corneal dystrophy. The morphological data presented here illustrate the disruptive effects of keratin gene mutations on the integrity of corneal keratinocytes. CONCLUSIONS: A clinical, histopathological, and ultrastructural study of a previously unreported family with MECD is presented. In this family the disease is ascribed to a novel mutation in KRT12. A molecular mechanism is proposed for MECD based on the comparison with other well characterised keratin diseases

Title: Connective tissue disease registries
Journal: Arthritis Rheum 1997 Sep
Authors: M. D. Mayes;E. H. Giannini;L. M. Pachman;J. P. Buyon;P. Fleckman
Volume: 40, Pages: 1556-1559

Notes: 0004-3591 Journal Article Review Review, Tutorial

Title: Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex
Journal: J Invest Dermatol 1997 Feb
Authors: F. J. Smith;L. D. Corden;E. L. Rugg;R. Ratnavel;I. M. Leigh;C. Moss;M. J. Tidman;D. Hohl;M. Huber;L. Kunkeler;C. S. Munro;E. B. Lane;W. H. McLean
Volume: 108, Pages: 220-223

Abstract: Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias in which the main phenotypic characteristic is hypertrophic nail dystrophy. In the Jackson-Lawler form (PC-2), pachyonychia is accompanied by multiple pilosebaceous cysts, natal teeth, and hair abnormalities. By direct sequencing of genomic PCR products, we report heterozygous K17 missense mutations in the same conserved protein motif in a further five PC-2 families (K17 N92S in one familial and three sporadic cases; K17 Y98D in one familial case) confirming that mutations in this gene are a common cause of PC-2. We also show heterozygous missense mutations in K17 (N92H and R94H) in two families diagnosed as steatocystoma multiplex. Mild nail defects were observed in some but not all of these patients on clinical re-evaluation of these families. All the K17 mutations reported here were shown to co-segregate with the disease in the pedigrees analyzed and were excluded from 100 unaffected, unrelated chromosomes by restriction enzyme analysis of K17 genomic PCR products. We conclude that phenotypic variation is observed with K17 mutations, as is the case with other keratin disorders.

Notes: 0022-202x Journal Article

Title: Genetic Skin Disorders
Journal: Oxford Monographs On Medical Genetics 1997
Authors: V.P. Sybert
Volume: 33, Pages: 675

Title: Defining a region of the human keratin 6a gene that confers inducible expression in stratified epithelia of transgenic mice
Journal: J Biol Chem 1997 May 2
Authors: K. Takahashi;P. A. Coulombe
Volume: 272, 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.

Notes: 0021-9258 Journal Article

Title: Pachyonychia congenita-associated alopecia. A microscopic analysis using transverse section technique
Journal: Am J Dermatopathol 1997 Apr
Authors: S. F. Templeton;S. E. Wiegand
Volume: 19, 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.

Notes: 0193-1091 Journal Article

Title: Expression of keratins (K10 and K17) in steatocystoma multiplex, eruptive vellus hair cysts, and epidermoid and trichilemmal cysts
Journal: Am J Dermatopathol 1997 Jun
Authors: H. Tomkova;W. Fujimoto;J. Arata
Volume: 19, 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.

Notes: 0193-1091 Journal Article

Title: A proline residue in the alpha-helical rod domain of type I keratin 16 destabilizes keratin heterotetramers
Journal: J Biol Chem 1997 Dec 19
Authors: M. Wawersik;R. D. Paladini;E. Noensie;P. A. Coulombe
Volume: 272, 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.

Notes: 0021-9258 Journal Article

Title: A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix
Journal: Hum Genet 1997 Dec
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, 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.

Notes: 0340-6717 Journal Article

Title: Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix
Journal: Nat Genet 1997 Aug
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, 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.

Notes: 1061-4036 Journal Article

Title: Otological lesions in pachyonychia congenita syndrome
Journal: J Laryngol Otol 1996 Dec
Authors: R. F. Bento;M. H. Guatimosim;L. Bensadon Rde;T. G. Sanchez;R. L. Voegels
Volume: 110, Pages: 1145-1147

Abstract: The authors report a case of a patient with pachyonychia congenita syndrome, a rare genodermatosis inherited as an autosomal dominant trait, who also had otological lesions beyond the other classic signs and symptoms of the syndrome. Many kinds of treatment have already been proposed, but all failed to show satisfactory results. A new, cheap and easy-to-use treatment was developed in this study, using keratoplastics interpolated with humectant lotion for 90 days. The results after three years of follow-up are still thoroughly satisfactory.

Notes: 0022-2151 Journal Article

Title: Human keratin diseases: hereditary fragility of specific epithelial tissues
Journal: Exp Dermatol 1996 Dec
Authors: L. D. Corden;W. H. McLean
Volume: 5, Pages: 297-307

Abstract: Keratins are heteropolymeric proteins which form the intermediate filament cytoskeleton in epithelial cells. Since 1991, mutations in several keratin genes have been found to cause a variety of human diseases affecting the epidermis and other epithelial structures. Epidermolysis bullosa simplex (EBS) was the first mechanobullous disease for which the underlying genetic lesion was found, with mutations in both the K5 and K14 genes rendering basal epidermal keratinocytes less resilient to trauma, resulting in skin fragility. The site of mutation in the keratin protein correlates with phenotypic severity in this disorder. Since mutations were identified in the basal cell keratins, the total number of keratin genes associated with diseases has risen to eleven. The rod domains of suprabasal keratins K1 and K10 are mutated in bullous congenital ichthyosiform erythroderma (BCIE; also called epidermolytic hyperkeratosis, EH) and mosaicism for K1 K10 mutations results in a nevoid distribution of EH. An unusual mutation in the VI domain of K1 has also been found to cause diffuse non-epidermolytic palmoplantar keratoderma (DNEPPK). Mutations in palmoplantar specific keratin K9 cause epidermolytic palmoplantar keratoderma (EPPK) and mutations in the late differentiation suprabasal keratin K2e cause ichthyosis bullosa of Siemens (IBS). In the last year or so, mutations were discovered in differentiation specific keratins K6a and K16 causing pachyonychia congenita type 1 and K17 mutations occur in pachyonychia congenita type 2. K16 and K17 mutations have also been reported to produce phenotypes with little or no nail changes: K16 mutations can present as focal non-epidermolytic palmoplantar keratoderma (NEPPK) and K17 mutations can result in a phenotype resembling steatocystoma multiplex. Recently, mutation of mucosal keratin pair K4 and K13 has been shown to underlie white sponge nevus (WSN). This year, the first mutations in a keratin-associated protein, plectin, were shown to cause a variant of epidermolysis bullosa associated with late-onset muscular dystrophy (MD-EBS). An unusual mutation has been identified in K5 which is responsible for EBS with mottled pigmentation and genetic linkage analysis suggests that the hair disorder monilethrix is likely to be due to a mutation in a hair keratin. The study of keratin diseases has led to a better understanding of the importance of the intermediate filament cytoskeleton and associated connector molecules in maintaining the structural integrity of the epidermis and other high stress epithelial tissues, as well as allowing diagnosis at the molecular level thus facilitating prenatal testing for this heterogeneous group of genodermatoses.

Notes: 0906-6705 Journal Article Review Review, Tutorial

Title: The cytoskeleton and disease: genetic disorders of intermediate filaments
Journal: Annu Rev Genet 1996
Authors: E. Fuchs
Volume: 30, Pages: 197-231

Abstract: Specialized cytoskeletons play many fascinating roles, including mechanical integrity and wound-healing in epidermal cells, cell polarity in simple epithelia, contraction in muscle cells, hearing and balance in the inner ear cells, axonal transport in neurons, and neuromuscular junction formation between muscle cells and motor neurons. These varied functions are dependent upon cytoplasmic networks of actin microfilaments (6 nm), intermediate filaments (10 nm) and microtubules (23 nm), and their many associated proteins. In this chapter, I review what is known about the cytoskeletons of intermediate filaments and their associated proteins. I focus largely on epidermal cells, which devote most of their protein-synthesizing machinery to producing an extensive intermediate filament network composed of keratin. Recent studies have shown that many of the devastating human disorders that arise from degeneration of this cell type have as their underlying basis either defects in the genes encoding keratins or abnormalities in keratin IF networks. I discuss what we know about the functions of IFs, and how the link to genetic disease has enhanced this understanding.

Notes: 0066-4197 Journal Article Review

Title: JSID Tanioku Memorial Lecture 1996. Genetic disorders of keratins and their associated proteins
Journal: J Dermatol Sci 1996 Dec
Authors: E. Fuchs
Volume: 13, Pages: 181-192

Abstract: It has recently been demonstrated that genetic defects in keratin genes cause a number of different skin disorders, including epidermolysis bullosa simplex (EBS), epidermolytic hyperkeratosis (EH), the EH form of epidermal nevi, epidermolytic and non-epidermolytic forms of palmoplantar keratoderma (EPPK and PPK) and pachyonychia congenita (PC). In this review, I describe the research that led to this discovery.

Notes: 0923-1811 Lectures

Title: Eruptive vellus hair cysts and steatocystoma multiplex. variants of one entity?
Journal: Br J Dermatol 1996 Feb
Authors: P. Kiene;A. Hauschild;E. Christophers
Volume: 134, Pages: 365-367

Abstract: Eruptive vellus hair cysts and steatocystoma multiplex are two clinically similar conditions which show multiple papules and nodules, mainly located over the anterior chest wall. Most cases can be differentiated on histological examination, but in some patients overlapping histological features have been described. We present a patient who showed features of both entities and interpret this as suggesting that eruptive vellus hair cysts and steatocystoma multiplex are variants of one disorder which originates in the pilosebaceous duct.

Notes: 0007-0963 Case Reports Journal Article

Title: Pachyonychia congenita tarda
Journal: J Am Acad Dermatol 1996 Aug
Authors: N. Mouaci-Midoun;S. Cambiaghi;P. Abimelec
Volume: 35, Pages: 334-335

Abstract: Pachyonychia congenita is a rare genetic disorder classified in clinical subtypes. Late onset of the disease has recently been described and designated as pachyonychia congenita tarda. A patient in whom typical manifestations of pachyonychia congenita appeared at the age of 39 years is described. This report substantiates previous observations on the phenomenon of late-onset pachyonychia congenita.

Notes: 0190-9622 Journal Article

Title: Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: defining a potential role for keratin 16
Journal: J Cell Biol 1996 Feb
Authors: R. D. Paladini;K. Takahashi;N. S. Bravo;P. A. Coulombe
Volume: 132, Pages: 381-397

Abstract: Injury to stratified epithelia causes a strong induction of keratins 6 (K6) and 16 (K16) in post-mitotic keratinocytes located at the wound edge. We show that induction of K6 and K16 occurs within 6 h after injury to human epidermis. Their subsequent accumulation in keratinocytes correlates with the profound reorganization of keratin filaments from a pan-cytoplasmic distribution to one in which filaments are aggregated in a juxtanuclear location, opposite to the direction of cell migration. This filament reorganization coincides with additional cytoarchitectural changes and the onset of re-epithelialization after 18 h post-injury. By following the assembly of K6 and K16 in vitro and in cultured cells, we find that relative to K5 and K14, a well-characterized keratin pair that is constitutively expressed in epidermis, K6 and K16 polymerize into short 10-nm filaments that accumulate near the nucleus, a property arising from K16. Forced expression of human K16 in skin keratinocytes of transgenic mice causes a retraction of keratin filaments from the cell periphery, often in a polarized fashion. These results imply that K16 may not have a primary structural function akin to epidermal keratins. Rather, they suggest that in the context of epidermal wound healing, the function of K16 could be to promote a reorganization of the cytoplasmic array of keratin filaments, an event that precedes the onset of keratinocyte migration into the wound site.

Notes: 0021-9525 Journal Article

Title: Linkage of an American pedigree with palmoplantar keratoderma â?¦
Journal: Arch Dermatol 1996
Authors: H. P. Stevens, D. P. Kelsell, S. P. Bryant, T. Bishop, N. K. Spurr, J. Weissenbach, D. Marger, R. S. Marger, I. M. Leigh
Volume: 132, Pages: 640-651

Title: A transgenic mouse model with an inducible skin blistering disease phenotype
Journal: Proc Natl Acad Sci U S A 1996 Dec 10
Authors: K. Takahashi;P. A. Coulombe
Volume: 93, 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.

Notes: 0027-8424 Journal Article

Title: Novel regulation of keratin gene expression by thyroid hormone and retinoid receptors
Journal: J Biol Chem 1996 Jan 19
Authors: M. Tomic-Canic;D. Day;H. H. Samuels;I. M. Freedberg;M. Blumenberg
Volume: 271, 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.

Notes: 0021-9258 Journal Article

Title: Codominant regulation of keratin gene expression by cell surface receptors and nuclear receptors
Journal: Exp Cell Res 1996 Apr 10
Authors: M. Tomic-Canic;I. M. Freedberg;M. Blumenberg
Volume: 224, 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.

Notes: 0014-4827 Journal Article

Title: [Congenital pachyonychia, neurofibromatosis and sensory-motor polyneuropathy]
Journal: Ann Dermatol Venereol 1995
Authors: A. F. Bensa;S. Dalac;F. Beer;A. Nivelon-Chevalier;C. Blanchet-Bardon;D. Lambert
Volume: 122, Pages: 428-431

Abstract: INTRODUCTION. A 71-year-old man consulted because he could not walk due to spots of hyperalgic, invalidating plantar keratodermia. A nearly identical symptomatology was observed in several members of the family suggesting an autosomal dominant hereditary disease due to painful callosities as described by Roth in 1978. CASE REPORT. The patient had pachyonychia on all fingers and toes, only the ring fingers and the fifth toes were not involved. Multiple epidermoid follicular cysts were also found on the trunk suggesting the diagnosis of type II hereditary pachyonychia or Jackson-Lawler disease. Axonal polyneuropathy was also found with cutaneous signs of neurofibromatosis. Cytology studies were performed in order to elucidate the relationship between these different findings. It was not possible to retain the diagnosis of complex axonal polyneuropathy as described by Tolmie where autosomal dominant inheritance of early onset ungueal dystrophy is associated with punctuated palmoplantar keratodermia and hereditary sensoromotor axonal neuropathy. CONCLUSION. This patient presented several types of complex neurocutaneous manifestations which could not be successfully related to each other.

Notes: 0151-9638 Journal Article

English Language Version

Title: Mutation of a type II keratin gene (K6a) in pachyonychia congenita
Journal: Nat Genet 1995 Jul
Authors: P. E. Bowden;J. L. Haley;A. Kansky;J. A. Rothnagel;D. O. Jones;R. J. Turner
Volume: 10, Pages: 363-365

Abstract: Pachyonychia congenita (PC) is a rare autosomal dominant condition characterized by multiple ectodermal abnormalities. Patients with Jadassohn-Lewandowsky Syndrome (MIM #167200; PC-1) have nail defects (onchyogryposis), palmoplantar hyperkeratosis, follicular hyperkeratosis and oral leukokeratosis. Those with the rarer Jackson-Lawler Syndrome (MIM #167210; PC-2) lack oral involvement but have natal teeth and cutaneous cysts. Ultra-structural studies have identified abnormal keratin tonofilaments and linkage to the keratin gene cluster on chromosome 17 has been found in PC families. Keratins are the major structural proteins of the epidermis and associated appendages and the nail, hair follicle, palm, sole and tongue are the main sites of constitutive K6, K16 and K17 expression. Furthermore, mutations in K16 and K17 have recently been identified in some PC patients. Although we did not detect K16 or K17 mutations in PC families from Slovenia, we have found a heterozygous deletion in a K6 isoform (K6a) in the affected members of one family. This 3 bp deletion (AAC) in exon 1 of K6a removes a highly conserved asparagine residue (delta N170) from position 8 of the 1A helical domain (delta N8). This is the first K6a mutation to be described and this heterozygous K6a deletion is sufficient to explain the pathology observed in this PC-1 family.

Notes: 1061-4036 Journal Article

Title: Overexpression of human keratin 16 produces a distinct skin phenotype in transgenic mouse skin
Journal: Biochem Cell Biol 1995 Sep-Oct
Authors: P. A. Coulombe;N. S. Bravo;R. D. Paladini;D. Nguyen;K. Takahashi
Volume: 73, Pages: 611-618

Abstract: Human cytokeratin 16 (K16; 48 kDa) is constitutively expressed in postmitotic keratinocytes in a variety of stratified epithelial tissues, but it is best known for the marked enhancement of its expression in stratified squamous epithelia showing hyperproliferation or abnormal differentiation. Of particular interest to us, K16 is strongly induced at the wound edge after injury to the epidermis, and its accumulation correlates spatially and temporally with the onset of reepithelialization. To examine the properties of K16 in its natural cellular context, we introduced a wild-type human K16 gene into the germ line of transgenic mice. Several transgenic lines were established and characterized. Under most conditions, the human K16 transgene is regulated tissue specifically in the skin of transgenic mice. Animals that feature low levels of transgene expression are indistinguishable from controls during the first 6-8 months of life. In contrast, transgenic animals expressing the transgene at higher levels develop skin lesions at 1 week after birth, coinciding with the emergence of fur. At a cellular level, alterations begin with the reorganization of keratin filaments and are first seen at the level of the hair follicle outer root sheath (ORS), where K16 expression is known to occur constitutively. The lesions then progressively spread to involve the proximal epidermis, with which the ORS is contiguous. Elevated transgene expression is associated with a marked thickening of these two epithelia, along with altered keratinocyte cytoarchitecture and aberrant keratinization but no keratinocyte lysis. The implications of this phenotype for epithelial differentiation, human genodermatoses, and wound healing in skin are discussed.

Notes: 0829-8211 Journal Article Review Review, Tutorial

Title: Jadassohn-Lewandowski syndrome (pachyonychia congenita)
Journal: Semin Dermatol 1995 Jun
Authors: P. R. Dahl;M. S. Daoud;W. P. Su
Volume: 14, Pages: 129-134

Abstract: Pachyonychia congenita is an uncommon autosomal dominant disorder with variable expression. Symmetrical nail hypertrophy, present in nearly all cases, is accompanied by dyskeratosis and dysplasia of other ectodermal tissues. This article reviews the genetics, clinical manifestations, histopathology, and treatment of pachyonychia congenita. Many clinical features have been reported in association with this syndrome. From a review of the literature, we propose criteria for the diagnosis of pachyonychia congenita using the more important of these clinical manifestations.

Notes: 0278-145x Journal Article

Title: Retinoic acid regulates oral epithelial differentiation by two mechanisms
Journal: J Invest Dermatol 1995 Apr
Authors: M. B. Kautsky;P. Fleckman;B. A. Dale
Volume: 104, Pages: 546-553

Abstract: The effect of retinoic acid (RA) concentration on differentiation of oral keratinocytes and the influence of fibroblasts on RA-dependent regulation were investigated in a lifted culture system. Keratinocyte differentiation was assessed by morphology, immunohistochemistry and immunoblotting. Filaggrin profilaggrin and keratin 1 were used as biochemical markers for cornified epithelium and keratins 13 and 19 as markers for noncornified epithelium. Cultured oral keratinocytes in RA-free conditions differentiated in a manner that closely resembled the differentiation pattern of gingival epithelia in vivo. Increasing RA concentrations altered the in vivo-like terminal differentiation of oral keratinocytes by disruption of organized stratification, inhibition of filaggrin profilaggrin and K1 expression, and stimulation of K13 and K19 expression. Differentiation of keratinocytes from both cornified and noncornified regions of the oral cavity varied in a similar manner in response to added RA, with the exception of K19 expression. K19 was consistently expressed at higher levels in keratinocytes originating from noncornified epithelial as compared to those from cornified epithelia. The level of RA regulation was ultimately dependent on the type of fibroblasts underlying the epithelial cells. Homologous fibroblasts rendered the oral keratinocytes less sensitive to the effects of RA than skin fibroblasts. In addition, at a given RA concentration, fibroblasts from cornified oral mucosa potentiated keratinocyte expression of RA sensitive markers of keratinization as compared to the influence exerted by fibroblasts originating from noncornified oral mucosa. These results indicate that the RA regulation of oral epithelial differentiation is mediated by two separate mechanisms: a direct, RA concentration-dependent effect, and an indirect, fibroblast-mediated effect.

Notes: 0022-202x Corrected and Republished Article Journal Article

Title: Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in vivo and in vitro
Journal: Br J Dermatol 1995 Oct
Authors: I. M. Leigh;H. Navsaria;P. E. Purkis;I. A. McKay;P. E. Bowden;P. N. Riddle
Volume: 133, Pages: 501-511

Abstract: Keratinocyte differentiation in psoriasis was examined using a panel of monospecific monoclonal antibodies to keratins (K), including two recently developed monoclonal antibodies raised to carboxy terminal peptides of K6 (LL020) and K16 (LL025). Keratinocytes from normal skin, untreated psoriatic plaques and non-lesional psoriatic skin, were cultured using multiple in vitro systems. Time-lapse cinephotography was used to measure the intermitotic time of normal and psoriatic keratinocytes in both low calcium-defined and serum-containing media. The intermitotic time did not differ significantly between psoriatic and normal keratinocytes. Keratin expression of psoriatic and normal keratinocytes in vitro was examined by both gel electrophoresis and immunocytochemistry. K6, K16 and K17 were detected suprabasally in all culture systems in vitro, but only in interfollicular psoriatic epidermis in vivo, and not in normal skin. Small subpopulations of keratinocytes expressed simple epithelial keratins K7, K8, K18 and K19 in cultures on plastic substrates, but these keratins were absent in skin equivalents of normal or psoriatic skin. No psoriasis-specific pattern of differentiation was found in vitro. As the K6 peptide antibody reacted with basal cells of normal skin, probably due to K5 cross-reactivity, K16 expression determined by LL025 was found to be the most sensitive indicator of the psoriatic state of differentiation, and this antibody is recommended for future work on psoriasis. K17 had a distinct pattern of tissue distribution in normal skin: K17, but not K16, was present in basal myoepithelial cells in sweat glands, and the deep outer root sheath, but K17 distribution paralleled that of K16 in suprabasal psoriatic epidermis. As keratins K6, K16 and K17 are expressed in keratinocyte hyperproliferation, when high levels of certain cytokines are also expressed, the role of growth factors and regulatory nuclear transcription factors in the control of K6, K16 and K17 expression in psoriasis requires further study, in order to provide insight into the relationship between proliferation and differentiation.

Notes: 0007-0963 Journal Article

Title: Empigen BB: a useful detergent for solubilization and biochemical analysis of keratins
Journal: Biochem Biophys Res Commun 1995 Jan 5
Authors: L. A. Lowthert;N. O. Ku;J. Liao;P. A. Coulombe;M. B. Omary
Volume: 206, Pages: 370-379

Abstract: Intermediate filament (IF) proteins make up some of the most insoluble proteins known, and within the IF protein family, keratins are the least soluble. We compared the efficiency of nonionic, cationic, mixed nonionic and anionic, and zwitterionic detergents in solubilizing keratins from insect cells that express recombinant human keratins and from human colonic cell lines and normal keratinocytes. The cationic detergent cetyltrimethylammonium bromide was similar to the zwitterionic detergent Empigen BB in its ability to efficiently solubilize keratins, but the latter detergent was superior in that it maintained antibody reactivity and allowed for immunoprecipitation of the keratins. Although Nonidet-P40 partially solubilizes keratins, Empigen BB solubilizes a significant amount of keratins not solubilized by Nonidet-P40. In the case of vimentin, differences in solubilization efficiency among the detergents was not as dramatic as with keratins. Our results show that Empigen BB solubilizes a significant amount of epidermal and glandular keratins while preserving antigenicity. This detergent should prove useful for carrying out biochemical and molecular studies on these proteins and may be similarly beneficial for other IF proteins.

Notes: 0006-291x Journal Article

Title: Pachyonychia congenita tarda
Journal: Clin Exp Dermatol 1995 May
Authors: G. P. Lucker;P. M. Steijlen
Volume: 20, Pages: 226-229

Abstract: Pachyonychia congenita is a distinct hereditary disorder of keratinization, in which dystrophy of all nails is associated with palmoplantar keratoderma and other hyperkeratoses. Recently a late-onset type has been reported. We report a second family with late-onset pachyonychia congenita, showing a remarkable clinical heterogeneity. Furthermore, one patient demonstrated a number of associated hyperkeratoses not previously recognized. Acitretin proved useful in the treatment of this late-onset form of pachyonychia congenita.

Notes: 0307-6938 Journal Article

Title: Intermediate filaments in disease
Journal: Curr Opin Cell Biol 1995 Feb
Authors: W. H. McLean;E. B. Lane
Volume: 7, Pages: 118-125

Abstract: Intermediate filaments are major structural proteins encoded by a large multigene family. Their tissue-specific expression makes them important in studies of development, differentiation and pathology. Most intermediate filaments are keratins; recent discoveries of keratin mutations in a range of genetic skin disorders have clarified their role as providing essential structural support for cells in different physical settings.

Notes: 0955-0674 Journal Article Review Review, Tutorial

Title: Keratin 16 and keratin 17 mutations cause pachyonychia congenita
Journal: Nat Genet 1995 Mar
Authors: W. H. McLean;E. L. Rugg;D. P. Lunny;S. M. Morley;E. B. Lane;O. Swensson;P. J. Dopping-Hepenstal;W. A. Griffiths;R. A. Eady;C. Higgins;et al.
Volume: 9, Pages: 273-278

Abstract: Pachyonychia congenita (PC) is a group of autosomal dominant disorders characterized by dystrophic nails and other ectodermal aberrations. A gene for Jackson-Lawler PC was recently mapped to the type I keratin cluster on 17q. Here, we show that a heterozygous missense mutation in the helix initiation motif of K17 (Asn92Asp) co-segregates with the disease in this kindred. We also show that Jadassohn-Lewandowsky PC is caused by a heterozygous missense mutation in the helix initiation peptide of K16 (Leu130Pro). The known expression patterns of these keratins in epidermal structures correlates with the specific abnormalities observed in each form of PC.

Notes: 1061-4036 Journal Article

Title: Elements controlling the expression and induction of the skin hyperproliferation-associated keratin K6
Journal: J Bio Chem 1995
Authors: J. M. Navarro, J. Casatorres, J. L. Jorcanos
Volume: 270, Pages: 21362-21367

Title: cDNA cloning and bacterial expression of the human type I keratin 16
Journal: Biochem Biophys Res Commun 1995 Oct 13
Authors: R. D. Paladini;K. Takahashi;T. M. Gant;P. A. Coulombe
Volume: 215, Pages: 517-523

Abstract: The human type I keratin 16 is constitutively expressed in a number of complex epithelial tissues, including skin, but is better known for its induction under conditions favoring enhanced proliferation or abnormal differentiation, including wound healing, psoriasis, and cancer. We cloned the coding sequence of human K16 by applying a coupled reverse transcription-polymerase chain reaction procedure to mRNAs prepared from cultured human skin keratinocytes. We then expressed the human K16 coding sequence in E. coli and purified the solubilized protein by anion-exchange chromatography. The recombinant protein recovered behaves similarly to human K14 (a related acidic keratin) on the anion-exchanger, co-migrates with native human K16 on SDS-PAGE (M(r) 48 kD), and reacts with antisera directed against human K16. Based on the nucleotide sequence obtained and the properties of the corresponding recombinant protein, we conclude that we have cloned the coding portion of the human K16 cDNA. The sequence data obtained in this study is compared to earlier reports of the human K16 sequence, which are conflicting in many respects. The availability of K16 in a purified recombinant form will allow us to study how its properties may relate to its function during wound healing and in skin diseases.

Notes: 0006-291x Journal Article

Title: Keratin 13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus
Journal: Nat Genet 1995 Dec
Authors: G. Richard;V. De Laurenzi;B. Didona;S. J. Bale;J. G. Compton
Volume: 11, Pages: 453-455

Abstract: Although pathogenic keratin mutations have been well characterized in inherited epidermal disorders, analogous defects in keratins expressed in non-epidermal epithelia have yet to be described. White sponge nevus (WSN) is a rare autosomal dominant disorder of non-cornifying squamous epithelial differentiation that presents clinically as bilateral white, soft, thick plaques of the oral mucosa. Less frequently the mucous membranes of the nose, esophagus, genitalia and rectum are involved. Histopathological features, including epithelial thickening, parakeratosis, extensive vacuolization of the suprabasal keratinocytes and compact aggregates of keratin intermediate filaments (KIF) in the upper spinous layers, resemble those found in epidermal disorders due to keratin defects. We analysed a multigenerational family with WSN and found cosegregation of the disease with the keratin gene cluster on chromosome 17. We identified a missense mutation in one allele of keratin 13 that leads to proline substitution for a conserved leucine. The mutation occurred within the conserved 1A region of the helical rod domain, which is critical for KIF stability and is the site of most pathogenic keratin mutations. This mutation enlarges the spectrum of keratins with disease-causing defects to include mucosally expressed keratin 13, and extends the known keratin diseases to disorders of non-cornifying stratified squamous epithelia.

Notes: 1061-4036 Journal Article

Title: Defects in the barrier
Journal: Science 1995 Jan 27
Authors: D. Roop
Volume: 267, Pages: 474-475

Notes: 0036-8075 Comment Journal Article Review Review, Tutorial

Title: A mutation in the mucosal keratin K4 is associated with oral white sponge nevus
Journal: Nat Genet 1995 Dec
Authors: E. L. Rugg;W. H. McLean;W. E. Allison;D. P. Lunny;R. I. Macleod;D. H. Felix;E. B. Lane;C. S. Munro
Volume: 11, Pages: 450-452

Abstract: White sponge nevus (WSN) is a benign autosomal dominant disorder which affects non-cornifying stratified squamous epithelia (MIM 193900) (ref. 1). Phenotypically it presents as white 'spongy' plaques (oral leukokeratoses), most commonly in the mouth but also reported in the esophagus and anogenital mucosa. Histologically, the plaques show evidence of hyperproliferation, acanthosis and tonofilament aggregation. These types of pathogenic changes are characteristic of many of the epidermal keratin disorders. Keratins are expressed in pairs by epithelial cells in a tissue and cell specific manner. The major differentiation specific keratins of the buccal mucosa, nasal, esophageal and anogenital epithelia are K4 and K13 (ref. 7). The tissue distribution and nature of the lesions in patients affected by WSN suggested that mutations in K4 and or K13 might be responsible for this disorder. We have now confirmed this hypothesis and report here a three base-pair (bp) deletion in the helix initiation peptide of K4 in affected members from two families with this condition.

Notes: 1061-4036 Journal Article

Title: Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families
Journal: Hum Mol Genet 1995 Oct
Authors: M. K. Shamsher;H. A. Navsaria;H. P. Stevens;R. C. Ratnavel;P. E. Purkis;D. P. Kelsell;W. H. McLean;L. J. Cook;W. A. Griffiths;S. Gschmeissner;et al.
Volume: 4, Pages: 1875-1881

Abstract: Keratins K6 and K16 are expressed in suprabasal interfollicular epidermis in wound healing and other pathological conditions associated with hyperproliferation, such as psoriasis and are induced when keratinocytes are cultured in vitro. However, these keratins are also constitutively expressed in normal suprabasal mucosal and palmoplantar keratinocytes. Mutations in keratins have been reported in the basal keratin pair K5 and K14 in epidermolysis bullosa simplex and in suprabasal epidermal keratins K1, K2 and K10 in epidermolytic ichthyoses. Two families with autosomal dominant disorder of focal non epidermolytic palmoplantar keratoderma, have oral mucosal and follicular lesions in addition to the palmoplantar hyperkeratosis. Previous studies have shown linkage in these families to the type I keratin gene cluster at 17q12-q21 and this report shows that the cDNA of affected members of both families have novel heterozygous mutations in the expressed keratin 16 gene. These mutations (R10C and N8S) lie in the helix initiation motif of the 1A domain. These mutations do not appear to cause epidermolysis on light or electron microscopy, which may reflect differences in function, assembly or interaction of the 'hyperproliferative' or 'mucoregenerative' keratins from other major types of keratins. The mutations reported here are the first to describe the molecular pathology of focal non epidermolytic palmoplantar keratoderma.

Notes: 0964-6906 Journal Article

Title: Cloning and characterization of multiple human genes and cDNAs encoding highly related type II keratin 6 isoforms
Journal: J Biol Chem 1995 Aug 4
Authors: K. Takahashi;R. D. Paladini;P. A. Coulombe
Volume: 270, 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.

Notes: 0021-9258 Journal Article

Title: Diagnosis and management of laryngeal obstruction in childhood pachyonychia congenita
Journal: Int J Pediatr Otorhinolaryngol 1995 Jan
Authors: S. A. Wudy;H. Lenders;W. Pirsig;W. Mohr;W. M. Teller
Volume: 31, 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.

Notes: 0165-5876 Journal Article

Title: Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis
Journal: J Invest Dermatol 1994 Nov
Authors: I. Anton-Lamprecht
Volume: 103, Pages: 6S-12S

Abstract: The present article discusses specific, directly gene-dependent ultrastructural markers of dominantly inherited epidermal disorders that serve as clues to their underlying molecular genetic abnormalities. These are epidermolysis bullosa simplex Koebner and Weber-Cockayne with rupture or non-assembly of basal cell keratins and point mutations in keratins 5 and 14. Clumping of basal cell keratins is pathognomonic of EB Dowling-Meara and caused by mutations in hot spots of the rod domain of K5 and K 14. Clumps and aggregates of basal keratins occur side by side in the same cell and thus do not indicate specific different types of mutations. Similar clumping of suprabasal keratins in bullous CIE Brocq and in palmoplantar keratoderma Voerner have been assigned to identical types of mutations in the same critical position of the rod domain in K 1, K 10, and K 9, respectively. Highly unusual tubular keratins are pathognomonic of another dominant palmoplantar keratoderma type the genetic basis of which still awaits elucidation. Shell formation of (low molecular weight?) keratins in ichthyosis hystrix Curth-Macklin is not linked to the keratin gene clusters on chromosomes 12 and 17 and might be related to regulatory genes of keratin expression. Suprabasal shells in congenital reticular ichthyosiform erythroderma do not consist of keratins but resemble glycoprotein networks. Finally, the keratohyalin abnormality in ichthyosis vulgaris was the clue for the identification of a filaggrin deficiency, at the same time giving evidence to the heterogeneity of keratohyalin proteins.

Notes: 0022-202x Journal Article Review Review, Tutorial

Title: Sequence and expression of human hair keratin genes
Journal: J Dermatol Sci 1994 Jul
Authors: P. E. Bowden;S. Hainey;G. Parker;M. B. Hodgins
Volume: 7 Suppl, Pages: S152-163

Abstract: Normal hair growth and differentiation requires co-ordinate expression of many hair specific structural protein genes. It has been established that one of the 4 major groups of hair structural proteins, low-sulphur hair keratins, belongs to the intermediate filament (IF) multigene family. Hair keratin IF proteins differ from those of other epithelia as they contain cysteine-rich terminal domains allowing more extensive disulphide bonding to the high-sulphur hair matrix proteins. Until recently, little information concerning the primary sequence of hair keratins was available but cloning of some mouse hair and sheep wool keratins has now been reported. Using these sequences, we have polymerase chain reaction (PCR) amplified genomic fragments of human hair-specific keratin IF genes and isolated cosmid clones containing full length genes. We have sequenced part of these genes and studied their expression in human hair follicles. Hair specific keratin fragments were amplified from placental gDNA by PCR primed with synthetic oligonucleotides. Fragments were cloned and sequenced after ligation into pGEM-3Z and labelled riboprobes were generated for in situ hybridization on human skin sections. A human cosmid library was screened with PCR fragments and clones encoding human hair keratin genes were characterised by southern hybridization and sequencing. The type I human hair-specific keratin clones obtained (HaKA1-b2, 386 bp; hHaKA1-XH1, 1202 bp) encoded 2B helix, C-terminal and 3'nc regions and were 65% homologous to mouse sequences. The type II hair keratin clone (hHaKB2-1, 829 bp) also encoded 2B helix and C-terminal regions and was 95% homologous to mouse. In situ hybridization on human skin sections showed a specific reaction with precortical cells of the hair follicle. One human cosmid clone, isolated with the hHaKB2-1 probe, contained two type II hair keratin genes about 7 kb apart, each of which had 9 exons spanning approximately 6 kb. The coding sequences were homologous to mouse cDNA (77-88%). These human hair-specific keratin clones are useful molecular tools for studies of hair differentiation.

Notes: 0923-1811 Journal Article

Title: Pachyonychia congenita in the absence of other syndrome abnormalities
Journal: J Am Acad Dermatol 1994 Jun
Authors: A. Chang;G. P. Lucker;P. C. van de Kerkhof;P. M. Steijlen
Volume: 30, Pages: 1017-1018

Notes: 0190-9622 Journal Article

Title: Intermediate filaments: structure, dynamics, function, and disease
Journal: Annu Rev Biochem 1994
Authors: E. Fuchs;K. Weber
Volume: 63, Pages: 345-382

Notes: 0066-4154 Journal Article Review

Title: Pachyonychia congenita
Journal: Acta Dermatovener 1994
Authors: A. Kansky, M. Penko, Z. Milakic-Snoj
Volume: 3, Pages: 153-160

Title: Keratin diseases
Journal: Curr Opin Gen Dev 1994
Authors: E. B. Lane
Volume: 4, Pages: 412-418

Title: The hereditary palmoplantar keratoses: an updated review and classification
Journal: Brit J Dermatol 1994
Authors: G.P. Lucker, P. C. M. Van de Kerkhof, P. M. Steijlen
Volume: 131, Pages: 1-14

Title: Eruptive vellus hair cyst and steatocystoma multiplex in a patient with pachyonychia congenita
Journal: J Am Acad Dermatol 1994
Authors: S. E. Moon
Volume: 30, Pages: 275-276

Title: A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12-q21
Journal: J Med Genet 1994 Sep
Authors: C. S. Munro;S. Carter;S. Bryce;M. Hall;J. L. Rees;L. Kunkeler;A. Stephenson;T. Strachan
Volume: 31, Pages: 675-678

Abstract: Pachyonychia congenita (PC) is a group of hereditary syndromes which have in common a hypertrophic dystrophy of the distal nail, and are associated with a variety of additional features, notably various dyskeratoses of skin and mucous membranes. The pathology is unknown but the array of clinical features suggests the possibility of a keratin abnormality. In the present report we describe linkage analyses in a large PC pedigree of the Jackson-Lawler type, a subtype which is characterised by multiple epidermal cysts, hair abnormalities, and natal teeth. The disease locus in this family was found to be tightly linked to markers mapping within, or very close to, the keratin type I cluster at 17q12-q21; maximum lod scores for linkage of the disease to a KRT10 polymorphism and to D17S800, a marker known to be very tightly linked to KRT10, were respectively +4.51 and +7.73, both at theta = 0.00. Although always likely, our findings provide strong evidence of a keratin gene anomaly underlying an inherited disorder affecting epidermis, nail, hair, and mucosa. These findings permit testing to see if pachyonychia congenita shows any locus heterogeneity and suggest specific candidate keratin genes for mutation searching studies. In addition, they suggest a role for keratins in the phenomenon of natal dentition.

Notes: 0022-2593 Journal Article

Title: A family with pachyonychia congenita affecting the nails only
Journal: Clin Exp Dermatol 1994 Nov
Authors: D. W. Pryce;J. L. Verbov
Volume: 19, Pages: 521-522

Abstract: A family with pachyonychia congenita in which affected individuals showed nail involvement only is described. Pachyonychia congenita is a rare hereditary disorder inherited in an autosomal dominant manner. Various classifications of pachyonychia congenita have been suggested but none indicates nail involvement as a solitary finding.

Notes: 0307-6938 Journal Article

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 1994 Sep
Authors: P. M. Steijlen;H. Kremer;F. Vakilzadeh;R. Happle;A. P. Lavrijsen;H. H. Ropers;E. C. Mariman
Volume: 103, 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.

Notes: 0022-202x Journal Article

Title: Increased expression of keratin 16 causes anomalies in cytoarchitecture and keratinization in transgenic mouse skin
Journal: J Cell Biol 1994 Oct
Authors: K. Takahashi;J. Folmer;P. A. Coulombe
Volume: 127, 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.

Notes: 0021-9525 Journal Article

Title: Pachyonychia congenita. A historical note
Journal: Am J Dermatopathol 1993 Dec
Authors: J. Bondeson
Volume: 15, Pages: 594-599

Abstract: Pachyonychia congenita is an uncommon type of ectodermal dysplasia, characterized by thickened, dystrophic nails and hyperkeratotic skin lesions. In the literature, it has been widely accepted that the first cases of this syndrome were published in the first years of the 20th century. However, a search of the older literature reveals several older cases of definite pachyonychia congenita, some of them from the 17th and 18th centuries. In 1716, the Danish physician Musaeus described a case of the pachyonychia congenita syndrome in some detail, with an excellent plate showing all the major symptoms.

Notes: 0193-1091 Historical Article Journal Article

Title: The cellular and molecular biology of keratins: beginning a new era
Journal: Curr Opin Cell Biol 1993 Feb
Authors: P. A. Coulombe
Volume: 5, Pages: 17-29

Abstract: The past year has been extremely fruitful for research on intermediate filaments in general, and keratins in particular. Unprecedented progress has been made in our understanding of the structural requirements for keratin filament assembly and network formation, the dynamism characterizing keratin filaments, their function, and implication in human genetic disorders primarily affecting the skin. These exciting findings have several implications for future research.

Notes: 0955-0674 Journal Article Review Review, Academic

Title: Pachyonychia congenita with late onset of nail dystrophy--a new clinical entity?
Journal: Clin Exp Dermatol 1993 Sep
Authors: S. Iraci;L. Bianchi;S. Gatti;A. M. Carrozzo;D. Bettini;G. Nini
Volume: 18, Pages: 478-480

Abstract: Pachyonychia congenita syndrome (PCS) is a genetic disease with an autosomal dominant mode of transmission in which the main sign, pachyonychia, usually arises at birth or in childhood together with other disorders of keratinization. A 28-year-old woman developed subungual hyperkeratosis of all toe-nails and thumb-nails associated with pain on pressure and walking. She had a scrotal tongue with leucokeratotic areas, blister formation, plantar hyperkeratosis, palmoplantar hyperhidrosis and dental cavities since childhood. The present case, interpreted as PCS of late onset, could be a clinical variant of the Jadassohn-Lewandowsky syndrome with the late onset of pachyonychia or else an additional form of PCS due to the expression of a new and different allele.

Notes: 0307-6938 Journal Article

Title: Epidermal growth factor and transforming growth factor specifically induce the activation-and hyperproliferation-associated keratins 6 and 16
Journal: Proc Natl Acad Sci 1993
Authors: C. K. Jiang, T. Magnaldo, M. Ohtsuki, I. M. Freedberg, F. Bernerd, M. Blumenberg
Volume: 90, Pages: 6786-6790

Title: Pachyonychia congenita (Jadassohn-Lewandowsky syndrome)--evaluation of symptoms in 36 patients
Journal: Arch Dermatol Res 1993
Authors: A. Kansky;A. Basta-Juzbasic;N. Videnic;D. Ivankovic;A. Stanimirovic
Volume: 285, Pages: 36-37

Notes: 0340-3696 Journal Article

Title: Keratins
Journal: Connective Tissue and its Heritable Disorders. Molecular, Genetic, and Medical Aspects 1993
Authors: E. B. Lane
Pages: 237-247

Title: Mutations in the genes for epidermal keratins in epidermolysis bullosa and epidermolytic hyperkeratosis
Journal: Arch Dermatol 1993 Dec
Authors: I. M. Leigh;E. B. Lane
Volume: 129, Pages: 1571-1577

Abstract: BACKGROUND: Clues from clinicopathologic studies of epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH) have implicated abnormalities in keratin filaments as possibly underlying the pathogenesis of these diseases. Multiple avenues of study have now converged, which confirm this hypothesis. OBSERVATIONS: The clinical spectrum of EBS and EH is reviewed together with classic histologic, electron microscopic, and immuno-electron microscopic studies. Linkage analyses have shown in EBS and EH that the disease traits are linked to the keratin gene clusters on chromosomes 12 and 17. Transgenic mice bearing mutations or deletions in genes coding for basal cell keratin K14 express the phenotype of EBS, and transgenic mice bearing abnormal K1 K10 genes resemble EH. Increasing numbers of point mutations in the human keratin genes have been found in both sporadic and familial cases of EBS in keratins 5 14 and EH in keratins K1 K10 genes, respectively, particularly in highly conserved subdomains of the keratin proteins. CONCLUSIONS: The recent and rapid progress in understanding the molecular biology of EBS and EH will also enhance knowledge about intermediate filament structure and function. Further studies of the effects of these mutations on the control of keratinocyte growth and differentiation are required. They will lead the way to rational pharmacologic or gene therapy.

Notes: 0003-987x Journal Article Review Review, Tutorial

Title: Pachyonychia congenita
Journal: Clinical Dermatol 1993
Authors: J. B. Patterson
Volume: 1, Pages: 1-7

Title: Transgenic models of skin diseases
Journal: Arch Dermatol 1993 Nov
Authors: J. A. Rothnagel;D. A. Greenhalgh;X. J. Wang;K. Sellheyer;J. R. Bickenbach;A. M. Dominey;D. R. Roop
Volume: 129, Pages: 1430-1436

Abstract: BACKGROUND: Transgenic animals have greatly enhanced our understanding of the contribution of various structural and regulatory components to epidermal biology. The expression of mutant versions of these components in the epidermis of transgenic mice has generated animal models of specific human skin diseases. OBSERVATIONS: The expression of mutant keratin genes has produced animal models of epidermolysis bullosa simplex and epidermolytic hyperkeratosis and, in doing so, has focused attention on the genetics of keratins in these and other skin disorders. Similarly, the generation of mice overexpressing growth factors and or oncogenes, exclusively in the epidermis, has identified the role of these factors in normal skin and produced models of disease states where the regulation of these factors is perturbed. CONCLUSIONS: These models of keratin disorders and other diseases not only enable the determination of the cause of these disorders, but also allow evaluation of novel therapeutic techniques for the amelioration of these skin diseases.

Notes: 0003-987x Journal Article Review Review, Tutorial

Title: Keratinocyte gene therapy
Journal: Arch Dermatol 1993 Nov
Authors: J. C. Vogel
Volume: 129, 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.

Notes: 0003-987x Journal Article Review Review, Tutorial

Title: Regulation of keratin gene expression: the role of the nuclear receptors for retinoic acid, thyroid hormone, and vitamin D3
Journal: J Invest Dermatol 1992 Jun
Authors: M. Blumenberg;D. M. Connolly;I. M. Freedberg
Volume: 98, Pages: 42S-49S

Abstract: Keratinization, the orderly process of differentiation of epidermal keratinocytes from stratum basale to stratum corneum, is influenced by hormones and vitamins. We have used expression of epidermal keratins as a paradigm of keratinization processes and analyzed the effects of retinoic acid, thyroid hormone, and vitamin D3 on keratin gene expression. DNA constructs in which keratin gene promoters drive expression of reporter genes were co-transfected with vectors expressing nuclear receptors for the above molecules into various cell types. The keratin promoters studied included K3, K5, K10, K14, and K16. The recipient cell types were HeLa and primary cultures of rabbit corneal and esophageal epithelial cells and of human epidermal keratinocytes. We found that retinoic acid, via its nuclear receptor, suppresses expression of all the above-listed keratin genes. Thyroid hormone and its receptor similarly suppressed those genes. The site of interaction between these two receptors and the promoter sequences of K10 and K14 genes has been identified. Surprisingly, vitamin D3 and its receptor had no direct effect on keratin promoters. Our results suggest that a retinoic acid has a twofold effect on keratin gene expression: by regulating keratinocyte differentiation it determines which keratins are expressed, basal cell specific or differentiation specific; by direct interaction between its receptor and keratin genes, retinoic acid determines the total amount of keratin protein within the cell. Vitamin D3, on the other hand, also regulates keratinocyte differentiation, but does not directly interact with the keratin genes.

Notes: 0022-202x Journal Article

Title: Of mice and men: genetic skin diseases of keratin
Journal: Cell 1992 Jun 12
Authors: E. Fuchs;P. A. Coulombe
Volume: 69, Pages: 899-902

Notes: 0092-8674 Journal Article Review Review, Tutorial

Title: Do the ends justify the mean? Proline mutations at the ends of the keratin coiled-coil rod segment are more disruptive than internal mutations
Journal: J Cell Biol 1992 Mar
Authors: A. Letai;P. A. Coulombe;E. Fuchs
Volume: 116, Pages: 1181-1195

Abstract: Intermediate filament (IF) assembly is remarkable, in that it appears to be self-driven by the primary sequence of IF proteins, a family (40-220 kd) with diverse sequences, but similar secondary structures. Each IF polypeptide has a central 310 amino acid residue alpha-helical rod domain, involved in coiled-coil dinner formation. Two short (approximately 10 amino acid residue) stretches at the ends of this rod are more highly conserved than the rest, although the molecular basis for this is unknown. In addition, the rod is segmented by three short nonhelical linkers of conserved location, but not sequence. To examine the degree to which different conserved helical and nonhelical rod sequences contribute to dimer, tetramer, and higher ordered interactions, we introduced proline mutations in residues throughout the rod of a type I keratin, and we removed existing proline residues from the linker regions. To further probe the role of the rod ends, we introduced more subtle mutations near the COOH-terminus. We examined the consequences of these mutations on (a) IF network formation in vivo, and (b) 10-nm filament assembly in vitro. Surprisingly, all proline mutations located deep in the coiled-coil rod segment showed rather modest effects on filament network formation and 10-nm filament assembly. In addition, removing the existing proline residues was without apparent effect in vivo, and in vitro, these mutants assembled into 10-nm filaments with a tendency to aggregate, but with otherwise normal appearance. The most striking effects on filament network formation and IF assembly were observed with mutations at the very ends of the rod. These data indicate that sequences throughout the rod are not equal with respect to their role in filament network formation and in 10-nm filament assembly. Specifically, while the internal rod segments seem able to tolerate considerable changes in alpha-helical conformation, the conserved ends seem to be essential for creating a very specific structure, in which even small perturbations can lead to loss of IF stability and disruption of normal cellular interactions. These findings have important implications for the disease Epidermolysis Bullosa Simplex, arising from point mutations in keratins K5 or K14.

Notes: 0021-9525 Journal Article

Title: Hair-nail dysplasia--a new pure autosomal dominant ectodermal dysplasia
Journal: Clin Genet 1992 Jun
Authors: M. Pinheiro;N. Freire-Maia
Volume: 41, Pages: 296-298

Abstract: An apparently hitherto undescribed pure ectodermal dysplasia of the tricho-onychic subgroup is described. Its cause is an autosomal dominant gene with complete penetrance and variable expressivity. Differential diagnosis considered 18 conditions belonging to the same subgroup, as well as Clouston syndrome. This report increases the number of conditions of the tricho-onychic subgroup to 19, and the total number of ectodermal dysplasias to 155.

Notes: 0009-9163 Journal Article

Title: Morphology and intermediate filament composition of human mammary epithelial cells treated with stable butyrate derivative
Journal: Anticancer Res 1992 Nov-Dec
Authors: P. Planchon;V. Magnien;G. Ronco;P. Villa;D. Brouty-Boye
Volume: 12, Pages: 2315-2320

Abstract: A new stable butyrate derivative monobut-3 was previously shown to inhibit proliferation and promote differentiation in human mammary established cell lines. The present study on monobut-3's effects on mammary epithelial cells cultured from human non-malignant and malignant breast tissues demonstrated pronounced morphological alterations suggestive of cellular differentiation. In addition, some degree of architectural differentiation was also evident in treated primary cultures. Monobut-3 did not affect the expression of vimentin and cytokeratin 18 when assessed in human breast cell lines expressing one or both types of intermediate filaments. However, it did induce expression of cytokeratin 19, characteristic of fully differentiated mammary cells, in one of the two cell lines devoid of this cytokeratin subtype. Furthermore, the network of intermediate filaments was often more largely extended in cells treated with monobut-3 than in untreated ones. These results indicate that monobut-3 can induce subtle changes in intermediate filaments which may contribute to its ability to promote differentiation in human mammary cells.

Notes: 0250-7005 Journal Article

Title: Acute or chronic topical retinoic acid treatment of human skin in vivo alters the expression of epidermal transglutaminase, loricrin, involucrin, filaggrin, and keratins 6 and 13 but not keratins 1, 10, and 14
Journal: J Invest Dermatol 1992 Mar
Authors: D. S. Rosenthal;C. E. Griffiths;S. H. Yuspa;D. R. Roop;J. J. Voorhees
Volume: 98, Pages: 343-350

Abstract: Histologic and immunocytochemical analyses were performed on cutaneous biopsies from 10 patients treated with retinoic acid under occlusion for 4 d compared to biopsies from 19 patients treated nightly for 16 weeks. Acute application of RA caused epidermal thickening (9 of 10 samples), stratum granulosum thickening (7 of 10), parakeratosis (4 of 10), a marked increase in the number of cell layers expressing epidermal transglutaminase (7 of 10), and focal expression of two non-epidermal keratins, K6 (8 of 10) and K13 (2 of 10), changes also observed with chronic treatment. Involucrin, filaggrin, and loricrin were also altered in samples from both acute and chronic treatment. An increased number of cell layers expressed both involucrin and filaggrin from both the acute (7 of 10) and chronic (14 of 19) treatment groups. In the acute group, loricrin expression was significantly reduced or absent in some regions of the epidermis (5 of 10), whereas most chronic samples showed an increased number of cell layers expressing loricrin (12 of 19). The pattern of expression of three major epidermal differentiation products, keratins K1, K10, and K14, was not significantly altered in any of the acute or chronic samples, although there was a slight reduction in the detection of K10 in two of the acute samples. Thus, acute topical RA treatment under occlusion caused substantial changes in the epidermis, and reproduced most, but not all of the effects of chronic treatment.

Notes: 0022-202x Clinical Trial Journal Article Randomized Controlled Trial

Title: Characterization of the human gene encoding cytokeratin 17 and its expression pattern
Journal: European J Cell Biol 1992
Authors: S. M. Troyanovsky, R. E. Leube, W. W. Franke
Volume: 59, Pages: 127-137

Title: Pachyonychia congenita-like disorder in cotton-top tamarins (Saguinus oedipus oedipus)
Journal: J Med Primatol 1991 Oct
Authors: M. Brack;H. Klensang
Volume: 20, Pages: 394-401

Abstract: A spontaneous genodermatosis in 13 cotton-top tamarins is described as a retrospective study. The disease appeared as alopecia, pigmentary disturbances, and claw dystrophy similar but not identical to human Pachyonychia congenita. The disease in the tamarins seems to be inherited as an autosomal recessive trait, becoming clinically apparent around adolescence. In certain families the neonatal mortality rate was also above average, reaching 100%.

Notes: 0047-2565 Journal Article

Title: Pili torti and onychodysplasia. Report of a previously undescribed hidrotic ectodermal dysplasia
Journal: Dermatologica 1991
Authors: P. Calzavara-Pinton;A. Carlino;A. Benetti;G. De Panfilis
Volume: 182, Pages: 184-187

Abstract: Ectodermal dysplasias are a large and heterogeneous groups of clinically and genetically distinct syndromes. We studied a family suffering from dystrophies of the distal part of the nails and trichodysplasia. Scalp, beard, pubic and axillary hair were broken off leaving a stubble 1-10 mm in length. Eyebrows, eyelashes and body hair were completely absent. Serum levels of copper and plasma levels of amino acids were within the normal range. Inheritance was autosomal recessive. Previous reports of ectodermal dysplasias and other complex syndromes with pili torti are reviewed.

Notes: 0011-9075 Case Reports Journal Article

Title: [Jackson-Lawler syndrome: a study in 2 families]
Journal: Ann Dermatol Venereol 1991
Authors: J. Chevrant-Breton;C. Lezoraine;D. Mazeas;A. M. Bousser;M. Patoux-Pibouin;M. Gosselin;G. Lancien;B. Le Marec
Volume: 118, Pages: 781-784

Notes: 0151-9638 Journal Article

English Language Version

Title: Picture of the month. Pachyonychia congenita
Journal: Am J Dis Child 1991 Nov
Authors: P. R. Cohen;A. A. Hebert;M. Feingold;W. W. Tunnessen, Jr.
Volume: 145, Pages: 1301-1302

Notes: 0002-922x Journal Article

Title: Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry
Journal: J Am Acad Dermatol 1991 Jan
Authors: J. D. Fine;E. A. Bauer;R. A. Briggaman;D. M. Carter;R. A. Eady;N. B. Esterly;K. A. Holbrook;S. Hurwitz;L. Johnson;A. Lin;et al.
Volume: 24, Pages: 119-135

Abstract: Inherited epidermolysis bullosa encompasses a number of diseases, with the common finding of blister formation after minor mechanical trauma to the skin. In some forms significant, if not eventually fatal, extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently, many new phenotypes have been recognized, in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately, this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.

Notes: 0190-9622 Consensus Development Conference Journal Article Review

Title: Sorting out IF networks: consequences of domain swapping on IF recognition and assembly
Journal: J Cell Biol 1991 Jun
Authors: M. B. McCormick;P. A. Coulombe;E. Fuchs
Volume: 113, Pages: 1111-1124

Abstract: Vimentin and keratin are coexpressed in many cells, but they segregate into two distinct intermediate filament (IF) networks. To understand the molecular basis for the sorting out of these IF subunits, we genetically engineered cDNAs encoding hybrid IF proteins composed of part vimentin and part type I keratin. When these cDNAs were transiently expressed in cells containing vimentin, keratin, or both IFs, the hybrid IF proteins all recognized one or the other or both networks. The ability to distinguish networks was dependent upon which segments of IF proteins were present in each construct. Constructs containing sequences encoding either helix 1B or helix 2B seemed to be the most critical in conferring IF recognition. At least for type I keratins, recognition was exerted at the level of dimer formation with wild-type type II keratin, as demonstrated by anion exchange chromatography. Interestingly, despite the fact that swapping of helical domains was not as deleterious to IF structure function as deletion of helical domains, keratin vimentin hybrids still caused structural aberrations in one or more of the cytoplasmic IF network. Thus, sequence diversity among IF proteins seems to influence not only coiled-coil but also higher ordered associations leading to 10-nm filament formation and or IF interactions with other cellular organelles proteins.

Notes: 0021-9525 Journal Article

Title: Callused feet, thick nails, and white tongue. Pachyonychia congenita
Journal: Arch Dermatol 1991 Jan
Authors: H. A. Oriba;J. S. Lo;W. F. Bergfeld
Volume: 127, Pages: 113-114, 116-11

Notes: 0003-987x Journal Article

Title: Pachyonychia congenita tarda. A late-onset form of pachyonychia congenita
Journal: Arch Dermatol 1991 May
Authors: A. S. Paller;J. A. Moore;R. Scher
Volume: 127, Pages: 701-703

Abstract: Pachyonychia congenita is an autosomal dominant disorder that usually develops in early infancy. We have observed five patients with the onset of the typical subungual hyperkeratoses of pachyonychia during the teenage years. Leukokeratosis and keratoderma of the palms and soles were associated. The family history of three of the patients suggests that pachyonychia congenita tarda is also inherited in an autosomal dominant manner.

Notes: 0003-987x Journal Article Review Review of Reported Cases

Title: Follicular hybrid cysts: An expanded spectrum
Journal: Am J Dermatopathol 1991
Authors: L. Requena, E. S. Yus
Volume: 13, Pages: 28-33

Notes: Requera, L.

Title: Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12
Journal: Cytogenet Cell Genet 1991
Authors: M. Rosenberg;E. Fuchs;M. M. Le Beau;R. L. Eddy;T. B. Shows
Volume: 57, Pages: 33-38

Abstract: We have localized the genes which encode the human type II epidermal keratins K5, K6a, and K6b and the simple epithelial keratin K7 (KRT5, KRT6A, KRT6B, and KRT7, respectively) to chromosome 12 using Southern blot analysis of somatic cell hybrids. In addition, we have sublocalized the genes for K6a and K7 to bands 12q12----q14 on the long arm of this chromosome by in situ hybridization of metaphase chromosomes.

Notes: 0301-0171 Journal Article

Title: A human epidermal differentiation-specific keratin gene is regulated by calcium but not negative modulators of differentiation in transgenic mouse keratinocytes
Journal: Cell Growth Differ 1991 Feb
Authors: D. S. Rosenthal;P. M. Steinert;S. Chung;C. A. Huff;J. Johnson;S. H. Yuspa;D. R. Roop
Volume: 2, Pages: 107-113

Abstract: Keratins K1 and K10 represent the major differentiation products of the maturing epidermal keratinocytes. Primary epidermal cell cultures from newborn K1 transgenic mice containing a 12-kilobase human K1 genomic fragment were established in order to examine the expression of both human and mouse K1 in the presence of known modulators of epidermal differentiation. Elevated levels of Ca2+ in the culture medium induced both mouse K1 and human K1. Supplementing the medium with retinoic acid or 12-O-tetradecanoylphorbol-13-acetate or introducing a Harvey viral ras oncogene (v-rasHa) into the cells completely suppressed mouse K1 but not human K1. Our results suggest that: (a) the human 12-kilobase insert contains all the necessary cis-acting elements to respond to the Ca2+ signal, and (b) other cis-acting elements, not present within this insert, may function independently to regulate the response of K1 to retinoids, 12-O-tetradecanoylphorbol-13-acetate, and v-rasHa transformation. This transgenic model provides an approach to identify elements required for the regulation of an epidermal differentiation-specific gene.

Notes: 1044-9523 Journal Article

Title: The nature and significance of the transverse white band of human nails
Journal: Semin Dermatol 1991 Mar
Authors: T. S. Sonnex;W. A. Griffiths;W. J. Nicol
Volume: 10, 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.

Notes: 0278-145x Journal Article

Title: Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease
Journal: Cell 1991 Jan 25
Authors: R. Vassar;P. A. Coulombe;L. Degenstein;K. Albers;E. Fuchs
Volume: 64, 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.

Notes: 0092-8674 Journal Article

Title: Multiple Congenital Anomalies. A Diagnostic Compendium 1st ed
Journal: 1991
Authors: R. M. Winter, M. Baraitser

Notes: p. 1433

Title: Pachyonychia congenita. Immunohistologic findings
Journal: Zentralbl Pathol 1991
Authors: U. Wollina;H. Schaarschmidt;V. Funfstuck;B. Knopf
Volume: 137, 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.

Notes: 0863-4106 Journal Article

Title: [Bone complications from chronic etretinate intoxication in children]
Journal: Ann Pediatr (Paris) 1990 Sep
Authors: M. Cointin;D. Sommelet-Olive;J. F. Cuny;M. C. Bretagne
Volume: 37, Pages: 458-460

Abstract: Clinical, roentgenographic and biologic features of etretinate bone toxicity in a 13-year-old girl with pachyonychia congenita syndrome are reported. Etretinate is a synthetic derivative of vitamin A that infrequently induces bone and joint abnormalities in children. The following manifestations can be observed: cortical hyperostosis, pain, calcification of tendons, thinning of long bones, demineralization, premature closure of epiphyses, or abnormal remodelling. Onset of these anomalies is often delayed since etretinate has a long half-life. Mechanisms are unknown. We advocate use of the minimum effective dosage and regular monitoring of patients.

Notes: 0066-2097 Case Reports Journal Article

English Language Version

Title: Deletions in epidermal keratins leading to alterations in filament organization in vivo and in intermediate filament assembly in vitro
Journal: J Cell Biol 1990 Dec
Authors: P. A. Coulombe;Y. M. Chan;K. Albers;E. Fuchs
Volume: 111, Pages: 3049-3064

Abstract: To investigate the sequences important for assembly of keratins into 10-nm filaments, we used a combined approach of (a) transfection of mutant keratin cDNAs into epithelial cells in vivo, and (b) in vitro assembly of mutant and wild-type keratins. Keratin K14 mutants missing the nonhelical carboxy- and amino-terminal domains not only integrated without perturbation into endogenous keratin filament networks in vivo, but they also formed 10-nm filaments with K5 in vitro. Surprisingly, keratin mutants missing the highly conserved L L E G E sequence, common to all intermediate filament proteins and found at the carboxy end of the alpha-helical rod domain, also assembled into filaments with only a somewhat reduced efficiency. Even a carboxy K14 mutant missing approximately 10% of the rod assembled into filaments, although in this case filaments aggregated significantly. Despite the ability of these mutants to form filaments in vitro, they often perturbed keratin filament organization in vivo. In contrast, small truncations in the amino-terminal end of the rod domain more severely disrupted the filament assembly process in vitro as well as in vivo, and in particular restricted elongation. For both carboxy and amino rod deletions, the more extensive the deletion, the more severe the phenotype. Surprisingly, while elongation could be almost quantitatively blocked with large mutations, tetramer formation and higher ordered lateral interactions still occurred. Collectively, our in vitro data (a) provide a molecular basis for the dominance of our mutants in vivo, (b) offer new insights as to why different mutants may generate different phenotypes in vivo, and (c) delineate the limit sequences necessary for K14 to both incorporate properly into a preexisting keratin filament network in vivo and assemble efficiently into 10-nm keratin filaments in vitro.

Notes: 0021-9525 Journal Article

Title: Elucidating the early stages of keratin filament assembly
Journal: J Cell Biol 1990 Jul
Authors: P. A. Coulombe;E. Fuchs
Volume: 111, Pages: 153-169

Abstract: Because of extraordinarily tight coiled-coil associations of type I and type II keratins, the composition and structure of keratin subunits has been difficult to determine. We report here the use of novel genetic and biochemical methods to explore the early stages of keratin filament assembly. Using bacterially expressed humans K5 and K14, we show that remarkably, these keratins behave as 1:1 complexes even in 9 M urea and in the presence of a reducing agent. Gel filtration chromatography and chemical cross-linking were used to identify heterodimers and heterotetramers as the most stable building blocks of keratin filament assembly. EM suggested that the dimer consists of a coiled-coil of K5 and K14 aligned in register and in parallel fashion, and the tetramer consists of two dimers in antiparallel fashion, without polarity. In 4 M urea, both end-to-end and lateral packing of tetramers occurred, leading to a variety of larger heteromeric complexes. The coexistence of multiple, higher-ordered associations under strongly denaturing conditions suggests that there may not be a serial sequence of events leading to the assembly of keratin intermediate filaments, but rather a number of associations may take place in parallel.

Notes: 0021-9525 Journal Article

Title: Pachyonychia congenita: a four generation pedigree
Journal: Cutis 1990 Nov
Authors: B. J. Fitzgerald;L. J. Sanders
Volume: 46, Pages: 435-439

Abstract: Pachyonychia congenita is a rare genodermatosis characterized by symmetrical thickening and discoloration of the nails with a wedge-shaped, pinched-up, or claw-like appearance. Subungual hyperkeratosis results in a lifting up of the free edge of the nail. Nail changes may be seen alone or in combination with a variety of other cutaneous findings. The authors present a kindred with fifteen cases of pachyonychia congenita in four generations, in Lebanon County, Pennsylvania.

Notes: 0011-4162 Journal Article

Title: Pachyonychia congenita. Manifestations for the otolaryngologist
Journal: Arch Otolaryngol Head Neck Surg 1990 Jun
Authors: S. P. Hersh
Volume: 116, Pages: 732-734

Abstract: When discovered, leukoplakia of the oral cavity is commonly an acquired lesion. Pachyonychia congenita is a member of a rare group of disorders in which congenital white lesions of the oral cavity are present. Additional findings of note to the otolaryngologist are described as well.

Notes: 0886-4470 Journal Article

Title: [Die Klinischen Syndrome: Sequenzen and Symptomkomplexe]
Journal: Urban & Schwarzenberg, Munchen, Wein, Baltimore 1990
Authors: B. Leiber
Volume: 1, Pages: 805

English Language Version

Title: Cornified envelopes in congenital disorders of keratinization
Journal: Br J Dermatol 1990 Jan
Authors: S. Michel;L. Juhlin
Volume: 122, Pages: 15-21

Abstract: A morphological and biochemical analysis was made of cornified envelopes isolated from patients with different congenital disorders. Nomarski contrast microscopy of the envelopes showed that their morphology was not greatly altered in several types of keratoderma and parapsoriasis, but it was grossly modified in ichthyotic disorders. The various types of ichthyoses, keratoderma palmoplantare, KID syndrome and parapsoriasis showed, after cyanogen-bromide cleavage, peptide patterns similar to those obtained from healthy subjects. In contrast, envelopes from patients with Darier's disease, congenital pachyonychia and erythrokeratoderma variabilis showed markedly different peptide patterns.

Notes: 0007-0963 Journal Article

Title: Pachyonychia congenita associated with 46,XYq-karyotype
Journal: Acta Paediatr Jpn 1990 Oct
Authors: K. Ozaki;O. Shinohara;S. Kato;I. Takakura;M. Kimura;K. Ishikawa
Volume: 32, Pages: 579-581

Notes: 0374-5600 Journal Article

Title: Pachyonychia congenita: therapeutic and immunologic aspects
Journal: Pediatr Dermatol 1990 Dec
Authors: A. E. Rohold;F. Brandrup
Volume: 7, Pages: 307-309

Abstract: A 4-year-old girl with pachyonychia congenita was followed from birth. During childhood, slow progression of the nail hypertrophy was seen because she was not willing to have the nails ground or cut. After grinding of her nails under general anesthesia, the child has had acceptable nail thickness, and continued regular grinding without anesthesia. The child had recurrent oral and cutaneous candidiasis. Investigations showed a weakly positive response to Candida albicans in the lymphocyte transformation test, and absence of a delayed hypersensitivity skin test response to Candida. The secondary infection due to Candida seemed to prevail because of an immune defect.

Notes: 0736-8046 Journal Article

Title: Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium
Journal: Cell Growth Differ 1990 Apr
Authors: G. H. Smith;T. Mehrel;D. R. Roop
Volume: 1, 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.

Notes: 1044-9523 Journal Article

Title: Pachyonychia congenita: a clinical study of 12 cases and review of the literature
Journal: Pediatr Dermatol 1990 Mar
Authors: W. P. Su;S. I. Chun;D. E. Hammond;H. Gordon
Volume: 7, 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.

Notes: 0736-8046 Journal Article Review Review, Tutorial

Title: [Early detection lymphedema of the lower extremities combined with pachyonychia]
Journal: Vestn Dermatol Venerol 1990
Authors: G. I. Sukolin, O. A. Pasportnikova
Pages: 60-63

English Language Version

Title: Pachyonychia congenita complicated by hidradenitis suppurativa: a family study
Journal: Br J Dermatol 1990 Nov
Authors: P. Todd;J. Garioch;M. Rademaker;W. Susskind;C. Gemell;J. Thomson
Volume: 123, 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.

Notes: 0007-0963 Journal Article

Title: [Pachyonychia congenita. Presentation of a case and histological-histochemical findings]
Journal: Hautarzt 1990 Oct
Authors: U. Wollina;V. Funfstuck;H. Schaarschmidt;U. Henkel;B. Knopf
Volume: 41, Pages: 557-561

Abstract: We report on two cases of pachyonychia congenita, Jadassohn-Lewandowsky type, in a father and daughter. Histopathological examination revealed thickened, aggregated bundles of tonofilaments and an increased number of atypical keratohyalin granula, which is suggestive of an altered keratinization. Immunohistological staining with antibodies to cytokeratins (A45-B B3, A51-B H4, A53-B A2, RPN 1161) was unchanged. Filaggrin could not be detected. Basal cells immunoreactive for calmodulin were markedly reduced or even absent in the rete ridges. Staining with a monoclonal antibody against Ki67 made epidermal cell hyperproliferation seem unlikely. The epidermal lectin binding was normal. C3 was detectable in vessel walls mainly of the stratum reticulare. The findings are discussed with reference to pachyonychia pathogenesis.

Notes: 0017-8470 Journal Article

English Language Version

Title: Reconstruction of a functional and esthetic nail
Journal: Hand Clin 1990 Feb
Authors: E. G. Zook;R. C. Russell
Volume: 6, 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.

Notes: 0749-0712 Journal Article Review Review, Tutorial

Title: Familial steatocystoma multiplex: HLA, Gm, Km genotyping and chromosomal analysis in two unrelated families
Journal: Clin Genet 1989 Aug
Authors: M. Cuccia-Belvedere;V. Brazzelli;M. Martinetti;E. Berardesca;J. M. Dugoujon;F. De Paoli;G. Borroni;G. Rabbiosi
Volume: 36, Pages: 136-140

Abstract: Steatocystoma Multiplex (S.M.) is an inherited condition characterized by the appearance of cysts during the first or second decade of life. Familial cases have occasionally been reported. We studied 13 patients affected by S.M. from two unrelated families, focusing our attention on HLA, Gm and Km genotypes and on chromosomal analyses. Although we failed to correlate the syndrome with a particular HLA, Gm or Km haplotype, we report some peculiarities and differences between these two families and the healthy Italian population.

Notes: 0009-9163 Case Reports Journal Article

Title: [Rheumatologic effects of etretinate]
Journal: Ann Dermatol Venereol 1989
Authors: J. F. Cuny;J. L. Schmutz;M. N. Terver;R. Aussedat;M. Cointin;M. Weber;J. Beurey
Volume: 116, Pages: 95-102

Abstract: The effects of chronic hypervitaminosis A and long-term isotretinoin treatment on bone include cortical hyperostosis, ligament calcification and premature epiphyseal closure. Similar effects have now been reported in patients under maintenance treatment with etretinate in high doses. Etretinate, an oral, aromatic, synthetic vitamin A derivative, is widely used in Europe for disorders of keratinization. We report the cases of two patients--one with lamellar ichthyosis, the other with pachyonychia congenita--who developed such bone diseases during treatment with etretinate over 2 and 6 years respectively. The doses ranged from 0.5 to 1 mg kg day. Two years after starting treatment (total dose 25 g), the patient with lamellar ichthyosis complained of mechanical pain in the lumbar region and hips. Radiography showed calcification of the extraspinal tendons and ligaments and hyperostosis of the calcaneus bone at the insertion of the plantar ligament. After six years of etretinate treatment (total dose 50 g), the patient with pachyonychia congenita presented with scoliosis and limb length discrepancy. The musculoskeletal abnormalities resembled chronic hypervitaminosis A, with such osseous changes as demineralization, thinning and increased curvature of long bones with osteopenia, and premature closure of the epiphyses. Acroosteolysis was also present. Etretinate has been implicated in the formation of spinal hyperostoses and calcification of extraspinal ligaments in patients who had taken the drug for many years. The occurrence of premature epiphyseal closure in children certainly is a consequence of therapy with relatively high doses of etretinate for six years. But premature epiphyseal closure may also result from trauma to a fragile bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Notes: 0151-9638 Case Reports Journal Article Review Review of Reported Cases

English Language Version

Title: Re-expression of disease-characteristic features of non-bullous congenital ichthyosiform erythroderma (CIE) after grafting of the pathological keratinocyte cultures to athymic mice
Journal: J Cutan Pathol 1989 Feb
Authors: M. Haftek;J. Thivolet;L. Thomas;A. Joubaud;M. Faure
Volume: 16, Pages: 1-6

Abstract: Epidermal keratinocytes separated from skin lesions of non-bullous congenital ichthyosiform erythroderma were investigated in an attempt at experimental reproduction of this keratinization disorder. In vitro studies on growth and differentiation of pathological keratinocytes isolated from the influence of the host's dermal and humoral components were performed using the immersed epidermal cell culture technique. Ten to 25-day-old confluent and stratified cultures were examined by means of photonic and electron microscopy, and stained with various differentiation markers for indirect immunofluorescence studies. The cultured epidermis showed low-grade differentiation and no clear-cut evenly distributed signs of the original disease. Grafting on congenitally athymic nude mice allowed further differentiation of the epidermal sheets and re-expression of the histologic and ultrastructural features of non-bullous congenital ichthyosiform erythroderma. Thus, the purely epidermal origin of this particular form of autosomal recessive ichthyosis could be confirmed. Large amounts of pathological keratinocytes generated from small skin biopsies may be used for experimental purposes after grafting on several athymic animals.

Notes: 0303-6987 Journal Article

Title: Pachyonychia congenita (a case report)
Journal: J Postgrad Med 1989 Jul
Authors: A. Parikh;V. U. Vaidya;B. A. Bharucha;N. B. Kumta
Volume: 35, Pages: 189-190

Notes: 0022-3859 Journal Article

Title: Keratin expression in mouse epidermal tumors
Journal: Carcinog Compr Surv 1989
Authors: D. R. Roop;T. Mehrel;T. M. Krieg;H. Nakazawa;C. K. Cheng;S. H. Yuspa
Volume: 11, Pages: 257-271

Notes: 0147-4006 Journal Article Review Review, Tutorial

Title: Pachyonychia congenita with tuberous sclerosis
Journal: Int J Dermatol 1989 Jun
Authors: V. K. Sharma;R. Sharma;S. Kaur
Volume: 28, Pages: 332-333

Notes: 0011-9059 Journal Article

Title: Patterns of expression of keratin 17 in human epithelia: dependency on cell position
Journal: J Cell Sci 1989
Authors: S. M. Troyanovsky, V. I. Guelstein, T. A. Tchipysheva, V. A. Krutovskikh, G. A. Bannikov
Volume: 93, Pages: 419-426

Title: Etretinate-responsive pachyonychia congenita
Journal: Br J Dermatol 1988 Oct
Authors: F. Carabott;C. B. Archer;W. A. Griffiths
Volume: 119, Pages: 551-553

Notes: 0007-0963 Letter

Title: Modification of keratin by the chemotherapeutic drug mitoxantrone
Journal: Biochem Pharmacol 1988 Aug 1
Authors: A. E. Cress;R. A. Roberts;G. T. Bowden;W. S. Dalton
Volume: 37, Pages: 3043-3046

Notes: 0006-2952 Journal Article

Title: Pachyonychia congenita
Journal: J Am Acad Dermatol 1988 Oct
Authors: A. Feinstein;J. Friedman;M. Schewach-Millet
Volume: 19, Pages: 705-711

Abstract: Pachyonychia congenita is a rare hereditary disorder characterized mainly by nail hypertrophy and dyskeratoses of skin and mucous membranes. A thorough literature survey since its first description in 1904 up to 1985 revealed 168 cases of pachyonychia congenita. There were no indications of any sex or ethnic group predilection. Based on this survey the following classification is suggested: type I (56.2% of cases), hyperkeratosis of nails, palmoplantar keratosis, follicular keratosis, and oral leukokeratosis; type II (24.9% of cases), clinical findings of type I plus bullae of palms and soles, palmar and plantar hyperhidrosis, natal or neonatal teeth, and steatocystoma multiplex; type III (11.7% of cases), clinical findings of types I and II plus angular cheilosis, corneal dyskeratosis, and cataracts; and type IV (7.2% of cases), clinical findings of types I, II, and III plus laryngeal lesions, hoarseness, mental retardation, hair anomalies, and alopecia.

Notes: 0190-9622 Journal Article Review Review, Academic

Title: [Lectin staining of disorders of keratinization. I. Ichthyosis, Darier's disease and acrokeratosis verruciformis]
Journal: Med Cutan Ibero Lat Am 1988
Authors: L. Martinez Ojeda;A. Ramirez Bosca;M. C. Marzo Lopez;P. Soto Ferrando;A. Castells Rodellas
Volume: 16, Pages: 133-136

Abstract: Lectin application is used to study 12 cases of ichthyosis, 8 cases of Darier's disease and two of acrokeratosis verruciformis, establishing comparative patterns with normal skin.

Notes: 0210-5187 Journal Article

English Language Version

Title: Effector functions of epidermal keratinocytes
Journal: Ann N Y Acad Sci 1988
Authors: L. M. Milstone
Volume: 548, Pages: 1-3

Notes: 0077-8923 Journal Article

Title: [The cytoskeleton in hereditary ichthyoses]
Journal: Hautarzt 1988 Feb
Authors: I. Moll;H. Traupe;V. Voigtlander;R. Moll
Volume: 39, Pages: 82-90

Abstract: The hereditary forms of ichthyosis can be considered to be models of impaired terminal epidermal differentiation. Analysis of the cytokeratin polypeptide pattern represents a new attempt at elucidating the mechanisms of keratinization mechanisms which are still unclear. We therefore studied the cytokeratin expression of the following types of ichthyosis: autosomal dominant ichthyosis vulgaris (n = 4), X-linked recessive ichthyosis vulgaris (n = 4), recessive non-bullous congenital ichthyosiform erythroderma (n = 1), recessive classical lamellar ichthyosis (n = 2), autosomal dominant lamellar ichthyosis (n = 1), and Netherton syndrome (n = 1). After dissection of frozen sections of the interfollicular epidermis, two-dimensional gel electrophoresis was performed. For immunofluorescence microscopy a panel of monoclonal cytokeratin antibodies (KG8.13, KK8.60, KA5 and AE1) was used. Cytokeratin polypeptide expression was basically unchanged compared with normal epidermis. In contrast, however, the antibody AE1 did not stain the basal cell layer in most types of ichthyosis, regardless of their genetic type. The cytokeratin polypeptides nos. 6 and 16, which are generally considered markers of hyperproliferation, were not expressed in either type of ichthyosis vulgaris (XRI or ADI), but were detected in trace amounts in various types of congenital ichthyosis.

Notes: 0017-8470 Journal Article

English Language Version

Title: Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis
Journal: Cancer Res 1988 Jun 1
Authors: D. R. Roop;T. M. Krieg;T. Mehrel;C. K. Cheng;S. H. Yuspa
Volume: 48, Pages: 3245-3252

Abstract: Monospecific antikeratin antisera and specific complementary DNA probes were used to analyze expression of keratin genes in newborn mouse skin and skin papillomas and carcinomas by indirect immunofluorescence, immunoblotting, and in situ hybridization. Tumors were induced by initiation with 7,12-dimethylbenz[a]anthracene and promotion with 12-O-tetradecanoylphorbol-13-acetate. Type I epidermal keratin K14 protein (Mr 55,000) is found in all living layers of the newborn skin but is most abundant in the lower strata. K1 (Mr 67,000) and K10 (Mr 59,000) proteins are predominantly suprabasal and K1 is processed in the stratum corneum. Transcripts for K14 were confined largely to the basal cell layer by in situ hybridization. Transcripts for K1 and K10 were highly expressed in suprabasal cells including the granular cell layer. In benign tumors, distribution of K14 protein is similar to that in newborn skin, while the abundance of K1 and K10 appears to be somewhat reduced although the tissue distribution remains suprabasal. Transcription of K14 is aberrant in benign tumors and transcripts persist throughout much of the suprabasal cell layers. Transcripts of K1 and K10 are normally distributed in papillomas but grain density is less intense than in newborn epidermis. Keratin expression in carcinomas is highly disturbed. K14 protein and transcripts are highly expressed in all strata in carcinomas while protein and transcripts for K1 and K10 are essentially absent. These results suggest that papilloma cells fail to respond to or generate signals to regulate K14 expression in the differentiating suprabasal cell layers and may not fully express their suprabasal cell keratins. Carcinomas fail to express suprabasal cell keratins and this is regulated at the transcriptional level. The loss of suprabasal keratin expression may provide a marker for malignant conversion in the mouse skin carcinogenesis model.

Notes: 0008-5472 Journal Article

Title: A group of type I keratin genes on human chromosome 17: characterization and expression
Journal: Mol Cell Biol 1988 Feb
Authors: M. Rosenberg;A. RayChaudhury;T. B. Shows;M. M. Le Beau;E. Fuchs
Volume: 8, Pages: 722-736

Abstract: The human type I keratins K16 and K14 are coexpressed in a number of epithelial tissues, including esophagus, tongue, and hair follicles. We determined that two genes encoding K16 and three genes encoding K14 were clustered in two distinct segments of chromosome 17. The genes within each cluster were tightly linked, and large parts of the genome containing these genes have been recently duplicated. The sequences of the two K16 genes showed striking homology not only within the coding sequences, but also within the intron positions and sequences and extending at least 400 base pairs 5' upstream and 850 base pairs 3' downstream from these genes. Despite the strong homologies between these two genes, only one of the genes encoded a protein which assembled into keratin filaments when introduced into simple epithelial cells. While there were no obvious abnormalities in the sequence of the other gene, its promoter seemed to be significantly weaker, and even a hybrid gene with the other gene's promoter gave rise to a much reduced mRNA level after gene transfection. To demonstrate that the functional K16 gene that we identified was in fact responsible for the K16 expressed in human tissues, we made a polyclonal antiserum which recognized our functional K16 gene product in both denatured and filamentous form and which was specific for bona fide human K16.

Notes: 0270-7306 Journal Article

Title: Cutaneous and immunologic reactions to phenytoin
Journal: J Am Acad Dermatol 1988 Apr
Authors: A. K. Silverman;J. Fairley;R. C. Wong
Volume: 18, Pages: 721-741

Abstract: Phenytoin (diphenylhydantoin; Dilantin) is a highly effective and widely prescribed anticonvulsant and antiarrhythmic agent. Since 1938 it has been invaluable in the treatment of grand mal and psychomotor epilepsy. Hydantoin derivatives have been used medicinally for more than a half-century. In recent years dermatologists have broadened the indications for phenytoin use to include recessive dystrophic epidermolysis bullosa, linear scleroderma, and pachyonychia congenita. In spite of widespread use and popularity, it is interesting that the frequency of complications relating to drug therapy remains low, relatively speaking. Nevertheless, a broad spectrum of cutaneous and immunologic reactions to phenytoin have been reported. These range from tissue proliferative syndromes (side effects), drug hypersensitivity syndromes (allergic effects), and a possible linkage with lymphoma (idiosyncratic effects). Therapeutic and toxic reactions to this commonly prescribed drug are comprehensively reviewed, analyzed, and summarized in this monograph.

Notes: 0190-9622 Journal Article Review Review, Academic

Title: Control of plantar blisters in pachyonychia congenita with topical aluminium chloride
Journal: Br J Dermatol 1988 Mar
Authors: M. J. Tidman;R. S. Wells
Volume: 118, Pages: 451-452

Notes: 0007-0963 Letter

Title: Signal transduction for proliferation and differentiation in keratinocytes
Journal: Ann N Y Acad Sci 1988
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.

Notes: 0077-8923 Journal Article Review Review, Tutorial

Title: Pachyonychia congenita with laryngeal involvement
Journal: Int J Pediatr Otorhinolaryngol 1987 Aug
Authors: B. Benjamin;D. S. Parsons;H. F. Molloy
Volume: 13, Pages: 205-209

Abstract: NOTE: Later genetic testing found this patient does not have a keratin mutation (i.e. does not have Pachyonychia congenita) but does have a connexin 30 mutation.// Pachyonychia congenita (Jadassohn-Lewandowsky Syndrome) is a rare autosomal dominant disorder characterized by nail dystrophy, hyperkeratosis of the palms and soles, leukoplakia of the mucosa of the upper respiratory tract and anus, follicular keratoses especially about the knees and elbows, and palmar and plantar hyperhidrosis. We present a patient with pachyonychia congenita and an exophytic lesion in the larynx at the posterior commissure. He is the youngest of 4 family members with this disorder covering 3 generations. Each of the 4 patients also exhibited both oral leukoplakia compatible with the Jadassohn-Lewandowsky syndrome (Ikonograph Dermatol. Lab., 1 (1906) p. 29), and subcutaneous cysts of the face and scalp as described by Jackson and Lawler (Ann. Eugenics (1951) 142.

Notes: 0165-5876 Journal Article

Title: Expression and modification of keratins during terminal differentiation of mammalian epidermis
Journal: Curr Top Dev Biol 1987
Authors: P. E. Bowden;H. J. Stark;D. Breitkreutz;N. E. Fusenig
Volume: 22, Pages: 35-68

Notes: 0070-2153 Journal Article Review Review, Academic

Title: Keratinocytes cultured from subjects with ichthyosis vulgaris are phenotypically abnormal
Journal: J Invest Dermatol 1987 May
Authors: P. Fleckman;K. A. Holbrook;B. A. Dale;V. P. Sybert
Volume: 88, Pages: 640-645

Abstract: Ichthyosis vulgaris (IV) is an autosomal dominant, scaling disorder in which keratohyaline granules and filaggrin are reduced in or absent from the epidermis of affected individuals. Morphologic and biochemical markers of epidermal differentiation were studied in keratinocytes cultured from clinically unaffected skin of patients with IV, from clinically unaffected skin of an obligate gene carrier, and from normal skin of unaffected family members and an adult volunteer. Cultured keratinocytes from affected subjects formed thickened layers of scaly cells that failed to react with monoclonal antibody to filaggrin. In contrast, normal cells contained many large, immunoreactive granules. Electron microscopy confirmed the absence of keratohyaline granules in affected cells and the presence of large keratohyaline granules in normal cells. Immunoblot analysis of keratinocyte extracts from subjects with ichthyosis showed that profilaggrin was absent, but no differences in keratins were detected between affected and control cells. For all parameters, findings in cells of the clinically unaffected obligate gene carrier were intermediate between those from affected patients and controls. We conclude that keratinocytes cultured from patients with IV maintain structural and biochemical phenotypic characteristics of the disease in vitro.

Notes: 0022-202x Journal Article

Title: Pachyonychia congenita in an 11 year old female
Journal: J Pedod 1987 Summer
Authors: E. J. Kay;A. S. Blinkhorn
Volume: 11, Pages: 391-395

Notes: 0145-5508 Journal Article

Title: Natal teeth and steatocystoma multiplex: a newly recognized syndrome
Journal: J Craniofac Genet Dev Biol 1987
Authors: N. M. King;A. M. Lee
Volume: 7, Pages: 311-317

Abstract: A Chinese family is reported in which five generations have exhibited natal teeth and generalized multiple steatocystomas. This autosomal dominant condition is not similar to the two reported types of pachyonychia congenita, because nail lesions, palmoplantar keratosis and hyperhidrosis, follicular keratosis, and oral leukokeratosis were not observed. Therefore, it is suggested that this family exhibits a newly recognized syndrome.

Notes: 0270-4145 Journal Article

Title: Pachyonichia congenita with laryngeal involvement
Journal: Int J Pediatr Otor 1987
Authors: D. S. Parsons
Volume: 13, Pages: 205-209

Title: Regulation of keratin gene expression during differentiation of epidermal and vaginal epithelial cells
Journal: Curr Top Dev Biol 1987
Authors: D. R. Roop
Volume: 22, Pages: 195-207

Notes: 0070-2153 Journal Article Review Review, Academic

Title: Regulated expression of differentiation-associated keratins in cultured epidermal cells detected by monospecific antibodies to unique peptides of mouse epidermal keratins
Journal: Differentiation 1987
Authors: D. R. Roop;H. Huitfeldt;A. Kilkenny;S. H. Yuspa
Volume: 35, Pages: 143-150

Abstract: Monospecific antibodies to mouse epidermal keratins were generated in rabbits and guinea pigs by injecting synthetic peptides of unique keratin sequences. The sequences were deduced from nucleotide sequences of cDNA clones representing basal (K14) and suprabasal (K1 and K10) cell-specific and hyperproliferative (K6) keratins of both the type-I and type-II subclasses. By applying single-and double-label immunofluorescence analysis, the expression of keratin peptides was analyzed in cultured keratinocytes maintained in the basal or suprabasal cell phenotypes. These cell types were selected by growth in medium containing 0.05 mM Ca2+ (basal cell) or 1.4 mM Ca2+ (suprabasal cell). The cultured basal cells expressed K6 and K14, but less than 1% expressed K1 and K10. Within a few hours after being placed in 1.4 mM Ca2+, K1 expression was observed, and by 24 h, 10%-17% of the cells expressed K1. K10 expression appeared to lag behind K1 expression, with only 5%-10% of cells in 1.4 mM Ca2+ exhibiting K10 immunoreactivity. Double-labeling studies indicated that virtually all K10-positive cells also expressed K1, while only about one-half of the K1-positive cells expressed K10. The treatment of basal cells with retinoic acid at pharmacological concentrations prevented the expression of K1 and K10 when cells were challenged by 1.4 mM Ca2+. Similarly, the introduction of the v-rasH oncogene into basal cells by a defective retroviral vector prevented the expression of suprabasal keratins in 1.4 mM Ca2+ medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Notes: 0301-4681 Journal Article

Title: Failure of etretinate therapy in pachyonychia congenita
Journal: Br J Dermatol 1987 Aug
Authors: U. Soyuer;M. F. Candan
Volume: 117, Pages: 264

Notes: 0007-0963 Letter

Title: Keratins of the human hair follicle: "hyperproliferative" keratins consistently expressed in outer root sheath cells in vivo and in vitro
Journal: Differentiation 1987
Authors: H. J. Stark;D. Breitkreutz;A. Limat;P. Bowden;N. E. Fusenig
Volume: 35, 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.

Notes: 0301-4681 Journal Article

Title: Pachyonychia congenita with cutaneous amyloidosis and hyperpigmentation--a distinct variant
Journal: J Am Acad Dermatol 1987 May
Authors: M. J. Tidman;R. S. Wells;D. M. MacDonald
Volume: 16, 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.

Notes: 0190-9622 Journal Article

Title: Environmental induction of differentiation-specific keratins in malignant mouse keratinocyte lines
Journal: Eur J Cell Biol 1986 Dec
Authors: D. Breitkreutz;J. Hornung;J. Pohlmann;L. Brown-Bierman;A. Bohnert;P. E. Bowden;N. E. Fusenig
Volume: 42, Pages: 255-267

Abstract: Four spontaneously transformed keratinocyte lines (HELP I-IV) were raised from primary cultures of mouse epidermal cells grown on gas-permeable (Petriperm) dishes. Although tumorigenic, these cell lines still expressed the differentiated phenotype under mesenchymal influence in vivo in a fashion similar to normal cells and in contrast to previous observations on other transformed cell lines. Initially, after transplantation onto adult mice, HELP cells generally formed well organized ortho-keratinizing epithelia closely resembling those of normal epidermal cells. Later, dysplastic epithelia and papilloma-like structures developed and cells invaded subcutaneous host tissue. When injected subcutaneously into newborn syngeneic mice, all four cell lines gave rise to differentiated carcinomas at high frequency. Keratinized metastases were detected in the lung with HELP I, albeit at low frequency. Although the four HELP cell lines differed morphologically and biochemically in their degree of ortho-keratinization, no inverse relationship to their malignant potential was evident. In contrast to cell cultures, HELP transplants and tumors expressed epidermis-type "suprabasal" keratins. Metabolic labeling and electrophoresis on one and two-dimensional gels revealed both the basic 67 kilodaltons (kDa) and acidic 58 kDa components, including presumptive derivatives analogous to those observed in epidermal stratum corneum. However, associated with alterations in tissue architecture, the spatial control of keratin expression was gradually lost in papilloma-like and invading transplants and tumors, as demonstrated by indirect immunofluorescence microscopy (IIF). Thus, while cell differentiation appeared virtually normal, the progressive disturbances in tissue differentiation indicate important changes in the responsiveness of these malignant keratinocytes to environmental conditions.

Notes: 0171-9335 Journal Article

Title: [Jadassohn-Lewandowski syndrome]
Journal: Vestn Dermatol Venerol 1986
Authors: I. A. Chistiakova
Pages: 62-64

Notes: 0042-4609 Case Reports Journal Article

English Language Version

Title: Pachyonychia congenita Jackson-Lawler type: a distinct malformation syndrome
Journal: Br J Dermatol 1986 Mar
Authors: M. Clementi;E. Cardin de Stefani;C. Dei Rossi;V. Avventi;R. Tenconi
Volume: 114, Pages: 367-370

Abstract: A family with three members in two generations affected by pachyonychia congenita, hyperkeratosis and hyperhidrosis of the palms and soles, follicular keratosis, neonatal teeth and epidermoid cysts (Jackson-Lawler syndrome) is described. The nosological autonomy of this condition is proposed and a further heterogeneity is suggested on the basis of histopathological changes in the subcutaneous cysts.

Notes: 0007-0963 Journal Article

Title: Autosomal recessive pachyonychia congenita
Journal: Arch Dermatol 1986 Aug
Authors: R. M. Haber;T. H. Rose
Volume: 122, Pages: 919-923

Abstract: We report the second and third cases of pachyonychia congenita inherited as an autosomal recessive disorder. Our cases were unusual, with the fingernails showing a striking leukonychia and appearing clinically as Terry's nails. These patients were originally diagnosed as having epidermolysis bullosa simplex because of a history of a life-long blistering disorder. The clinical features and inheritance of pachyonychia congenita, as well as the reasons for the long delay in diagnosis of our cases, are discussed.

Notes: 0003-987x Journal Article

Title: Pachyonychia congenita
Journal: J Indian Med Assoc 1986 Jan
Authors: S. K. Panja;P. K. Datta;A. K. Jaiswal
Volume: 84, Pages: 22-23

Notes: 0019-5847 Journal Article

Title: [Hereditare Onycholysis partialis mit Skleronychie]
Journal: Derm Wschr 1986
Authors: H. D. Schulze
Volume: 152, Pages: 766-775

English Language Version

Title: Evidence for posttranscriptional regulation of the keratins expressed during hyperproliferation and malignant transformation in human epidermis
Journal: J Cell Biol 1986 Nov
Authors: A. L. Tyner;E. Fuchs
Volume: 103, 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.

Notes: 0021-9525 Journal Article

Title: [Jadassohn-Lewandowsky syndrome--dental aspects]
Journal: Zahnarztl Prax 1986 Sep 12
Authors: D. Uthoff
Volume: 37, Pages: 333-335

Notes: 0044-1651 Case Reports Journal Article

English Language Version

Title: [Congenital pachyonychia syndrome]
Journal: Orv Hetil 1985 Jul 14
Authors: M. Csato;I. Toth-Kasa;A. Dobozy;H. Hammer
Volume: 126, Pages: 1727-1728

Notes: 0030-6002 Journal Article

English Language Version

Title: Vitamin A: a key nutrient for the maintenance of epithelial differentiation
Journal: Acta Vitaminol Enzymol 1985
Authors: L. M. De Luca, D. Roop, F. L. Huang
Volume: 7 Suppl, Pages: 13-20

Abstract: Vitamin A deficiency or benzo(a)pyrene instillation into tracheas of Syrian golden hamsters causes squamous metaplasia of tracheobronchial epithelium, normally a mucous secretory tissue. In the present studies, we have employed a tracheal organ culture system and have reproduced the in vivo phenomenon of squamous metaplasia during culturing under vitamin A free conditions as well as after carcinogen treatment. The squamous metaplasia induced by vitamin A deficiency, both in vivo and in vitro, was accompanied by an overall increase in keratin synthesis. Vitamin A deficient tracheas were shown to contain keratins of 50, 48, 46.5 Kd detected with the antibody AE1, and 58, 56 and 52 Kd detected with AE3. These proteins were either absent or present in much less quantity in control tracheas. In deficient tracheas 60 kd keratin was found to be located specifically in squamous suprabasal cells, and 55 and 50 Kd keratin proteins were found in a greatly expanded basal cell compartment. Following carcinogen exposure, the appearance of 60 kd keratin and the enhanced expression of 50 and 55 Kd keratins preceded the squamoid metaplastic response as detected morphologically. Both the keratin changes and the morphological changes were prevented by retinoid treatment.

Notes: 0300-8924 Journal Article Review

Title: [Pachyonychia congenita]
Journal: Arch Stomatol (Napoli) 1985 Oct-Dec
Authors: F. Gombos;V. Pilato;R. Serpico
Volume: 26, Pages: 471-475

Notes: 0004-0320 Journal Article

English Language Version

Title: [Systemic retinoid therapy with etretinate in pachyonychia congenita]
Journal: Hautarzt 1985 Sep
Authors: E. Hoting;S. W. Wassilew
Volume: 36, Pages: 526-528

Abstract: On the basis of two case-reports it is concluded that the aromatic derivative of retinoic acid, etretinate, is a promising drug in the treatment of pachyonychia congenita.

Notes: 0017-8470 Journal Article

English Language Version

Title: Structure of a gene for the human epidermal 67-kDa keratin
Journal: Proc Natl Acad Sci U S A 1985 Apr
Authors: L. D. Johnson;W. W. Idler;X. M. Zhou;D. R. Roop;P. M. Steinert
Volume: 82, Pages: 1896-1900

Abstract: We present the structure and nucleotide sequence of a gene encoding the human epidermal 67-kDa keratin. Three genomic clones were isolated from a lambda Charon 4A human genomic library by hybridization to a specific cDNA probe. One clone of 12.3 kilobase pairs was shown by R-loop, DNA sequence, and primer-extension analyses to encode an entire gene of about 6.25 kilobase pairs. Of eight identified introns, seven are located within the region that encodes the central coiled-coil alpha-helical domain of the protein. Except for one intron located at the end of the region encoding this domain, these do not delineate apparent structural subdomains. The positions of five of the introns exactly coincide with the positions of introns previously reported in the hamster gene for the intermediate filament protein vimentin [Quax, W., Egberts, W.V., Hendricks, W., Quax-Jeuken, Y. & Bloemandal, H. (1983) Cell 35, 215-233]. These findings suggest that the human 67-kDa keratin and vimentin genes arose from a common ancestral gene.

Notes: 0027-8424 Journal Article

Title: [Congenital pachyonychia]
Journal: Vestn Dermatol Venerol 1985 Jun
Authors: A. Khamidov Sh;I. K. Karimova
Pages: 54-56

Notes: 0042-4609 Journal Article

English Language Version

Title: Organization of a type I keratin gene. Evidence for evolution of intermediate filaments from a common ancestral gene
Journal: J Biol Chem 1985 May 25
Authors: T. M. Krieg;M. P. Schafer;C. K. Cheng;D. Filpula;P. Flaherty;P. M. Steinert;D. R. Roop
Volume: 260, Pages: 5867-5870

Abstract: The genomic structure of the mouse 59-kDa keratin gene, a Type I intermediate filament (IF) gene is presented. A comparison of the organization of this gene with that of the human 67-kDa keratin, a Type II IF gene, and hamster vimentin, a Type III IF gene, suggests a common evolutionary origin for Type I, II, and III IF genes. Most introns in these three types of IF genes occur at similar positions within the region encoding sequences predicted to form coiled-coils, but do not delineate structural subdomains. Interestingly though, most of the introns interrupt at or near the beginning of the characteristic 7-residue (heptad) repeat of sequences which form the coiled-coil. These data suggest that the three types of IF genes arose from a common ancestor which may have been assembled from smaller units containing multiple heptad repeats. Subsequent duplication events may then have formed the three known alpha-helical types and each of their various members.

Notes: 0021-9258 Journal Article

Title: The use of cDNA clones and monospecific antibodies as probes to monitor keratin gene expression
Journal: Ann N Y Acad Sci 1985
Authors: D. R. Roop;C. K. Cheng;R. Toftgard;J. R. Stanley;P. M. Steinert;S. H. Yuspa
Volume: 455, Pages: 426-435

Notes: 0077-8923 Journal Article

Title: Pachyonychia congenita
Journal: Int J Dermatol 1985 Apr
Authors: A. Sivasundram;K. Rajagopalan;T. Sarojini
Volume: 24, Pages: 179-180

Notes: 0011-9059 Journal Article

Title: Structural and functional implications of amino acid sequences of keratin intermediate filament subunits
Journal: Ann N Y Acad Sci 1985
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

Notes: 0077-8923 Journal Article Review

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 1985 Jun 10
Authors: P. M. Steinert;D. A. Parry;W. W. Idler;L. D. Johnson;A. C. Steven;D. R. Roop
Volume: 260, 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.

Notes: 0021-9258 Journal Article

Title: The molecular biology of intermediate filaments
Journal: Cell 1985 Sep
Authors: P. M. Steinert;A. C. Steven;D. R. Roop
Volume: 42, Pages: 411-420

Notes: 0092-8674 Journal Article Review

Title: Keratin gene expression in mouse skin tumors and in mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate
Journal: Cancer Res 1985 Nov
Authors: R. Toftgard;S. H. Yuspa;D. R. Roop
Volume: 45, 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)

Notes: 0008-5472 Journal Article

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 1985 Jul
Authors: A. L. Tyner;M. J. Eichman;E. Fuchs
Volume: 82, 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.

Notes: 0027-8424 Journal Article

Title: Hereditary callosities with blisters. Report of a family and review
Journal: J Am Acad Dermatol 1984 Sep
Authors: H. P. Baden;B. R. Bronstein;R. E. Rand
Volume: 11, Pages: 409-415

Abstract: A family with calluses of the soles associated with blistering is described. Electron microscopic study of a bulla showed an intraepidermal blister with cytolysis of keratinocytes and clumping of tonofilaments. Review of the literature and our own experience with keratoderma palmaris et plantaris revealed no similar patients with this combination of findings. The appearance of the soles is similar to pachyonychia congenita, but the lack of nail and mucous membrane changes is not consistent with that disorder. Treatment with isotretinoin caused reduction in the size of the calluses but exacerbated the blistering.

Notes: 0190-9622 Journal Article Review

Title: Pachyonychia congenita
Journal: Ind J Dermatol Venereal Leprol 1984
Authors: A. K. Bajaj, S. C. Gupta
Volume: 50, Pages: 23-26

Notes: Bajaj, A. J.

Title: Concanavalin A distinguishes among diseases of altered epidermal differentiation
Journal: J Invest Dermatol 1984 Jan
Authors: M. M. Brysk;J. Miller;A. A. Hebert
Volume: 82, Pages: 18-20

Abstract: Mannose-containing of glycoproteins from lesional tissue of several diseases of aberrant epidermal differentiation (palmar-plantar keratoderma, pachyonychia congenita, psoriasis, and epidermolytic hyperkeratosis) were analyzed by overlaying iodinated concanavalin A onto molecules separated by polyacrylamide gel electrophoresis. Gel autoradiograms showed that biopsy samples from patients with the same disease were very similar. The radioactivity profiles were different for each disease and were distinguishable from each other and from normal epidermis and callus. The resolution and sensitivity of this technique may be of diagnostic significance.

Notes: 0022-202x Journal Article

Title: [Familial case of Jadssohn-Lewandowski syndrome]
Journal: Vestn Dermatol Venereol 1984
Authors: R.S. Divanyan, A. G. Muradyan
Volume: 11, Pages: 47-49

English Language Version

Title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces hyperplasia in confluent cultures of human keratinocytes
Journal: J Invest Dermatol 1984 May
Authors: L. M. Milstone;J. F. LaVigne
Volume: 82, Pages: 532-534

Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototype for a group of halogenated aromatic hydrocarbons which can be potent modulators of growth and differentiation of epithelial tissues. TCDD causes chloracne and can act as a skin tumor promoter, but these actions have been demonstrated only in animals in which TCDD causes epidermal hyperplasia. Study of the hyperplastic response to TCDD has been hampered by lack of an in vitro model; all previous investigations indicated that TCDD had no in vitro effect on cell growth. We show here that nanomolar concentrations of TCDD cause hyperplasia in confluent cultures of human keratinocytes and suggest that this model system will be useful for analyzing mechanisms of TCDD-induced epithelial hyperplasia and genetic differences in responsiveness to TCDD.

Notes: 0022-202x Journal Article

Title: Pachyonychia congenita with patent ductus arteriosus
Journal: J Dermatol 1984 Jun
Authors: P. Nigam;R. D. Mukhija;K. K. Kapoor
Volume: 11, Pages: 305-307

Notes: 0385-2407 Letter

Title: Synthetic peptides corresponding to keratin subunits elicit highly specific antibodies
Journal: J Biol Chem 1984 Jul 10
Authors: D. R. Roop;C. K. Cheng;L. Titterington;C. A. Meyers;J. R. Stanley;P. M. Steinert;S. H. Yuspa
Volume: 259, Pages: 8037-8040

Abstract: The presence of common antigenic determinants within all keratin proteins has made difficult the production of antisera which are monospecific for individual keratin subunits. Synthetic peptides corresponding to the carboxyl-terminal amino acid sequences of the mouse 59- and 67-kilodalton keratins were used to produce antibodies which were highly specific for these keratin subunits. This method of antibody production was chosen after examination of amino acid sequence data (which were deduced from the nucleotide sequence of cDNA clones for these and other mouse keratins) revealed that the carboxyl-terminal amino acid sequences of various keratins were unique. Indirect immunofluorescence staining of newborn-mouse skin with these antisera demonstrated that the 59- and 67-kilodalton keratins were only present within the differentiated cells of the epidermis (the suprabasal layers) and not in the undifferentiated cells (the basal layer). These results are consistent with our previous work concerning the expression of these keratin genes at the messenger RNA level (Roop, D. R., Hawley-Nelson, P., Cheng, C. K., and Yuspa, S. H. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 716-720). Data obtained with the antisera directed against the 67-kilodalton keratin also indicated that the carboxyl-terminal sequences of this subunit were not present in the nonliving layer (the stratum corneum) of the epidermis. This approach should be useful for the production of antisera specific for other keratin subunits as additional sequence information becomes available.

Notes: 0021-9258 Journal Article

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 1984 Sep
Authors: P. M. Steinert;D. A. Parry;E. L. Racoosin;W. W. Idler;A. C. Steven;B. L. Trus;D. R. Roop
Volume: 81, 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.

Notes: 0027-8424 Journal Article

Title: Epidermal cell confluence and implications for a two-step mechanism of wound closure
Journal: J Invest Dermatol 1984 Dec
Authors: K. S. Stenn;L. M. Milstone
Volume: 83, 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.

Notes: 0022-202x Journal Article

Title: Pachyonychia congenita. Electron microscopic and epidermal glycoprotein assessment before and during isotretinoin treatment
Journal: Arch Dermatol 1984 Nov
Authors: D. R. Thomas;J. L. Jorizzo;M. M. Brysk;J. A. Tschen;J. Miller;E. H. Tschen
Volume: 120, 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.

Notes: 0003-987x Journal Article

Title: [Gottron's erythrokeratodermia congenitalis progressiva symmetrica with atypical involvement of nails in the sense of pachyonychia]
Journal: Z Hautkr 1983 May 1
Authors: B. Kuchmeister;G. Schaeg;A. Kuhlwein
Volume: 58, Pages: 621-632

Abstract: Erythrokeratodermia congenitalis progressiva symmetrica Gottron (ECPSG) is a rare hereditary disorder characterized by plaques of hyperkeratosis on an erythematous basis. The onset of the disease occurs predominantly in early childhood. Morphological and histological findings give hint for the diagnosis. Ultrastructural findings as well as HLA type (A2, A9, B18) are reported. ECPSG connected with pachyonychia has been observed for the first time.

Notes: 0301-0481 Case Reports Journal Article

English Language Version

Title: Expression of keratin genes in mouse epidermis and normal and malignantly transformed epidermal cells in culture
Journal: J Invest Dermatol 1983 Jul
Authors: D. R. Roop;P. Hawley-Nelson;C. K. Cheng;S. H. Yuspa
Volume: 81, Pages: 144s-149s

Abstract: Complementary DNA (cDNA) clones constructed to the 55, 59 and 67 kilodalton (K) keratins, the major keratins synthesized in newborn mouse epidermis, were used as molecular hybridization probes to examine the expression of these genes in newborn epidermis and normal and malignantly transformed epidermal cells in culture. Transcripts of these three keratin genes are abundant in newborn epidermis. However, primary cultures of epidermal cells contain very low levels of these RNAs. The decreased expression of these keratin genes in primary cells appears to be due to factors within the culture system. Unlike primary-cell cultures, the malignantly transformed cell line Pam 212 synthesizes keratin proteins and mRNAs similar to newborn epidermis, including the 67 K keratin. However, synthesis of the 67 K keratin in Pam 212 cells is modulated by culture factors. Keratin gene expression in another Pam line, 321, differs from that of Pam 212 cells in that decreased expression of these three keratin genes occurs. These results indicate that keratin genes that are normally expressed in vivo in epidermis may be expressed in malignant epidermal cells under conditions that do not permit expression of these genes in nonmalignant primary epidermal cells.

Notes: 0022-202x Journal Article

Title: Keratin gene expression in mouse epidermis and cultured epidermal cells
Journal: Proc Natl Acad Sci U S A 1983 Feb
Authors: D. R. Roop;P. Hawley-Nelson;C. K. Cheng;S. H. Yuspa
Volume: 80, Pages: 716-720

Abstract: The major differentiation products of mouse epidermis are keratins of 40-70 kilodaltons (kDal). We have prepared a library of cDNA clones from total poly(A)+ RNA from newborn mouse epidermis. Clones corresponding to the major in vivo keratins of 55, 59, and 67 kDal have been isolated and characterized. By RNA blot analysis of poly(A)+ RNA from newborn mouse epidermis, we have identified RNA species that are approximately 1,600, 2,000, and 2,400 nucleotides in length and are complementary to the cDNAs for the 55-, 59-, and 67-kDal keratins, respectively. Analysis of RNA from primary cultures of newborn mouse epidermis by this same technique shows greatly reduced levels of these RNAs. Transcripts complementary to all three cloned cDNAs are abundant in 14- to 16-day embryonic and adult mouse skin. Thus, altered expression in culture does not appear to be due to induction of a developmentally programmed switch by placing the cells in culture but instead is due to factors modulating expression within the culture system. Because the 55-, 59-, and 67-kDal keratins are the major proteins in epidermis they probably represent keratin associated with terminal differentiation. The expression data suggest that cultured cells are blocked in expression of differentiation keratins but instead synthesize other keratin family members probably related to cytoskeletal functions.

Notes: 0027-8424 Journal Article

Title: Complete amino acid sequence of a mouse epidermal keratin subunit and implications for the structure of intermediate filaments
Journal: Nature 1983 Apr 28
Authors: P. M. Steinert;R. H. Rice;D. R. Roop;B. L. Trus;A. C. Steven
Volume: 302, 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.

Notes: 0028-0836 Journal Article

Title: Structural features of epidermal keratin filaments reassembled in vitro
Journal: J Invest Dermatol 1983 Jul
Authors: P. M. Steinert;A. C. Steven;D. R. Roop
Volume: 81, 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.

Notes: 0022-202x Journal Article

Title: Pachyonychia Congenita (Jadassohn-Lewandowsky syndrome): a seventeen-member, four-generation pedigree with unusual respiratory and dental involvement
Journal: Am J Med Genet 1983 Jan
Authors: J. B. Stieglitz;W. R. Centerwall
Volume: 14, 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.

Notes: 0148-7299 Journal Article

Title: Treatment of pachyonychia congenita with phenytoin
Journal: Br J Dermatol 1982 Jan
Authors: H. Blank
Volume: 106, Pages: 123

Notes: 0007-0963 Letter

Title: The influence of retinoids on cultivated human keratinocytes
Journal: J Am Acad Dermatol 1982 Apr
Authors: J. McGuire;N. Fedarko;E. Johanssen;J. La Vigne;G. Lyons;L. Milstone;M. Osber
Volume: 6, Pages: 630-639

Abstract: Cultured keratinocytes afford an excellent opportunity to study the influence of retinoids on the behavior of a stratified squamous epithelium and the interaction of keratinocytes with substrate. We have found that all-trans-retinoic acid retards the formation of colonies, dose not influence attachment, and causes increased shedding of cells from the cultures. Retinoids do not influence the relative abundance of the keratin polypeptides. Our observations are on human neonatal foreskin-derived keratinocytes grown in Dulbecco's modified Eagle medium containing 20% fetal bovine serum. Because fetal bovine serum contains vitamin A, our findings represent differences between low and high levels of vitamin A.

Notes: 0190-9622 Journal Article

Title: The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells
Journal: Cell 1982 Nov
Authors: R. Moll;W. W. Franke;D. L. Schiller;B. Geiger;R. Krepler
Volume: 31, Pages: 11-24

Notes: 0092-8674 Journal Article Review

Title: [Congenital pachyonychia treated by oral retinoid]
Journal: Med Cutan Ibero Lat Am 1982
Authors: A. J. Rondon Lugo
Volume: 10, Pages: 395-398

Abstract: One female patient 18 years old who suffers from Congenital Uaquioniquis since infancy, with serious alterations of nails, was treated with oral retinoid (Ro 10-9359-Tigason) during 20 months, with clinical improvement of her lesions. Clinical and laboratory controls were carried out periodically and they did not show any alterations. The only side-effects were itching, discrete hair loss headache, chelitis, all which were moderate in degree and transient.

Notes: 0210-5187 Journal Article

English Language Version

Title: Pachyonychia congenita syndrome
Journal: The recognizable patterns of human malformations 1982
Authors: D. W. Smith
Pages: 406

Title: Pachyonychia congenita: surgical management of the nail changes
Journal: J Dermatol Surg Oncol 1982 Jan
Authors: R. J. Thomsen;R. L. Zuehlke;B. I. Beckman
Volume: 8, 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.

Notes: 0148-0812 Journal Article

Title: [Pachyonychia congenita]
Journal: Med Cutan Ibero Lat Am 1981
Authors: B. A. Alperovich;E. H. de los Rios;M. Conejos
Volume: 9, Pages: 121-124

Abstract: The authors describe a new case of this unusual disease, which correspond to a three years old girl, derived from a family without others observations nor consaguinity between her parents. The clinic-neurological examen was normal. The typical dermatological lesions were quite clear to the diagnostic. The pathological anatomy showed the typical structure.

Notes: 0210-5187 Journal Article

English Language Version

Title: Modification of human prekeratin during epidermal differentiation
Journal: Biochem J 1981 Oct 1
Authors: P. E. Bowden;W. J. Cunliffe
Volume: 199, Pages: 145-154

Abstract: The polypeptide-chain components of human epidermal prekeratin and keratin were analysed by high-resolution SDS (sodium dodecyl sulphate) polyacrylamide-gradient-gel electrophoresis. Size heterogeneity existed amongst prekeratin components and at least ten polypeptides, in the molecular-weight range 46,000-70,000, were observed in 0.1 M-citric acid sodium citrate buffer (pH 2.65) extracts of scale epidermis. Prekeratin from scalp pilosebaceous ducts was identical with that from the contiguous epidermis, and no prekeratin was found in extracts of scale dermis. Prekeratin from plantar epidermis contained additional polypeptide chains, but only slight anatomical variation existed between the non-callus sites examined. Keratin differed from prekeratin in at least two major respects: (a) many major components did not co-electrophorese on high-resolution SDS polyacrylamide slab gels, and (b) keratin, but not prekeratin, required denaturing and reducing conditions for extraction. Keratin extracted from scale epidermis after complete removal of prekeratin was identical with forearm stratum-corneum keratin. Palmar and plantar keratin contained additional polypeptide chains and had a different size distribution compared with forearm and scalp keratin components. Modification of prekeratin components to produce the keratin polypeptide profile occurred during epidermal differentiation, and these changes appeared to take place in the granular-layer region of the epidermis.

Notes: 0264-6021 Journal Article

Title: Structural and biochemical parameters of congenital ichthyosis
Journal: Birth Defects Orig Artic Ser 1981
Authors: M. M. Buxman
Volume: 17, Pages: 205-225

Notes: 0547-6844 Journal Article Review

Title: [Pachyonychia congenita. Three familial cases. Effects of the treatment by aromatic retinoid (RO 10.9359) (author's transl)]
Journal: Ann Dermatol Venereol 1981
Authors: A. Dupre;B. Christol;J. L. Bonafe;P. Touron
Volume: 108, Pages: 145-149

Abstract: The authors present three familial cases of Schonfeld's type I pachyonychia. This syndrome represents the association of pachyonychia with palmoplantar keratodermia, frictionnal keratosis and bullae, hyperidrosis, oral leucokeratosis. This genotype is present in the remaining family. Traumatisms produce or increase several symptoms as: a) palmoplantar keratodermia: voluminous callus confined to site of pressure; b) hyperkeratosis of the nails, with hyperplasia and papillomatosis of the nail bed and the hyponychium due to the frequents microtraumatisms of the finger-pulps; c) oral leucokeratosis. The authors describe the painful character of the palmoplantar lesions: walking and working with the hands are very difficult. They assert the outstanding action of aromatic retinoid (RO 10.9359) which entertains a dramatic improvement of the palmoplantar and pachyonychia lesions, the decrease of the pain. Now, the patient life is normal. In these three cases, an hyperuricemia is associated: this feature is probably a fortuitous association. One of these patients has a Lesch-Nyhan's syndrome.

Notes: 0151-9638 Journal Article

English Language Version

Title: Pachyonychia congenita (Jadassohn-Lewandowsky syndrome). A review of 14 cases in Slovenia
Journal: Dermatologica 1981
Authors: J. Franzot;A. Kansky;S. Kavcic
Volume: 162, Pages: 462-472

Notes: 0011-9075 Journal Article

Title: White spong nevus
Journal: Arch Dermatol 1981
Authors: R. J. Jorgenson, L. S. Levin
Volume: 117, Pages: 73-76

Title: Pachyonychia congenita with candidiasis
Journal: Clin Exp Dermatol 1981 Mar
Authors: H. Mawhinney;S. Creswell;J. M. Beare
Volume: 6, Pages: 145-149

Notes: 0307-6938 Journal Article

Title: [Familial case of Jadassohn-Lewandowski syndrome]
Journal: Vestn Dermatol Venerol 1981
Authors: V. I. Siano, A. K. Menshikova, Y. M. Bochkarev, V. T. Kuklin
Pages: 41-42

English Language Version

Title: [Pichyonychia congenita]
Journal: Med Cutan Ibero Lat Am 1981
Authors: B. Somoza de Fernandez;A. J. Rondon Lugo;G. Cortez de Castro
Volume: 9, Pages: 129-133

Abstract: The Authors have followed three cases of congenital pachyonychia. Genetical studies were done to them and their families. The patients had a thorough physical examination, Histopathological studies of the nails and Aminoaciduria was investigated. Different treatments were considered.

Notes: 0210-5187 Journal Article

English Language Version

Title: [Congenital pachyonychia. Jadassohn-Lewandowsky syndrome. 3 cases]
Journal: Actas Dermosifiliogr 1981 Nov-Dec
Authors: Gago Sotillo;Panduro De la Rosa;Sotillo Yebra
Volume: 72, Pages: 527-532

Notes: 0001-7310 Journal Article

English Language Version

Title: Pachyonychia congenita: A clinical study of eleven cases
Journal: Brit J Dermatol 1981
Authors: W. P. Su-Daniel
Volume: 105, Pages: 21-22

Title: [Jadassohn-Lewandowski syndrome]
Journal: Stomatologiia (Mosk) 1980 Jan-Feb
Authors: A. F. Anikin;V. B. Nedoseko;V. G. Suntsov;A. I. Novikov
Volume: 59, Pages: 60-61

Notes: 0039-1735 Case Reports Journal Article

English Language Version

Title: Leukoedema of the oral mucosa. Possibly an acquired white sponge nevus
Journal: Arch Dermatol 1980 Aug
Authors: S. C. Duncan;W. P. Su
Volume: 116, Pages: 906-908

Abstract: Leukoedema is a white or whitish-gray edematous lesion of the buccal and labial oral mucosa. The lesions may be diffuse or patchy, and are usually asymptomatic. Leukoedema may be confused with leukoplakia, Darier's disease, white sponge nevus, pachyonychia congenita, or candidal infection. The condition is seen most frequently among black men. The histologic appearance simulates that of white sponge nevus. Symptomatic leukoedema seems to respond to topical application of tretinoin.

Notes: 0003-987x Journal Article

Title: [Lesion of the eyes in congenital pachyonychia]
Journal: Vestn Oftalmol 1980 Jul-Aug
Authors: N. A. Egorov;V. N. Golychev
Pages: 66-67

Notes: 0042-465x Case Reports Journal Article

English Language Version

Title: [Jadassohn-Lewendowsky Syndrome mit Veranderinger am asophagus]
Journal: ROEFO 1980
Authors: J. Hagemann
Volume: 132, Pages: 181-182

English Language Version

Title: Keratins in cultivated human keratinocytes are stable
Journal: Curr Probl Dermatol 1980
Authors: J. McGuire;L. Milstone;M. Osber;L. Ingalls
Volume: 10, Pages: 327-342

Abstract: Cultures of human keratinocytes were established according to the technique of Rheinwald and Green. When cultures were exposed to [14C] leucine, the uptake of leucine and increase in the specific activity of 6 urea-extractable polypeptides was prompt-each keratin achieved 50% of its peak specific activity in 3-6 hours. Cultures were exposed to [14C] leucine for 6 hours and then permitted to grow in unlabeled medium for 10 days. These confluent cultures shed cells into the medium; the amount or protein shed daily was 22.2 microgram or roughly 0.9% of the protein of the attached cells. Thus, protein shed into the medium over a 10-day period of the pulse-chase experiment was 9% of the total extractable protein. The specific activity of individual polypeptides extracted by urea fell an average of 25% during the 10-day chase. Polypeptides extracted by buffer A showed a fall in specific activity of 55% over this period. The relative amounts of individual urea-extractable polypeptides and individual buffer A-extractable polypeptides remained constant over a 10-day period. The rapid labelling of all urea-extractable polypeptides and the relative stability in the specific activity of these polypeptides is evidence that one keratin is not modified to form another keratin and that, once synthesized, the molecules are stable.

Notes: 0070-2064 Journal Article

Title: Changing concepts of keratin
Journal: Am J Dermatopathol 1980 Summer
Authors: L. M. Milstone
Volume: 2, Pages: 161-163

Notes: 0193-1091 Journal Article

Title: The pachyonychia congenita syndrome
Journal: Acta Derm Venereol 1980
Authors: P. H. Schonfeld
Volume: 60, Pages: 45-49

Abstract: This study presents two patients showing different clinical types of the Pachyonychia congenita Syndrome (PcS). For the first time there is a description of the histopathology of the blister and vesicle formation, as well as of the plantar keratosis. The essential resemblance in the histopathological changes of the different symptoms of the syndrome is discussed.

Notes: 0001-5555 Journal Article

Title: [Congenital Jadassohn-Lewandowski syndrome]
Journal: Vestn Dermatol Venerol 1978 Feb
Authors: N. A. Egorov;G. N. Grigor'eva;V. V. Bobrik
Pages: 61-63

Notes: 0042-4609 Case Reports Journal Article

English Language Version

Title: [Jadassohn-Lewandowsky syndrome (pachyonychia congenita)]
Journal: Actas Dermosifiliogr 1978 Jan-Feb
Authors: D. Garcia Almagro;F. Corripio;C. Peteiro;G. Jaqueti del Pozo
Volume: 69, Pages: 19-26

Notes: 0001-7310 Journal Article

English Language Version

Title: [Hereditary pachyonychia]
Journal: Vestn Dermatol Venerol 1978 Jul
Authors: V. A. Grebennikov;R. A. Chalimova
Pages: 71-75

Notes: 0042-4609 Journal Article

English Language Version

Title: Pachyonychia congenita
Journal: J Am Podiatry Assoc 1978 Aug
Authors: J. H. Langford
Volume: 68, Pages: 587-591

Notes: 0003-0538 Journal Article

Title: Cornoid lamella in pachyonychia congenita
Journal: Arch Dermatol 1978 Dec
Authors: J. K. Wilkin;E. W. Rosenberg;T. Kanzaki
Volume: 114, 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.

Notes: 0003-987x Journal Article

Title: Pachyonychia congenita with recessive inheritance
Journal: Arch Dermatol 1977 May
Authors: T. Chong-Hai;K. Rajagopalan
Volume: 113, Pages: 685-686

Notes: 0003-987x Letter

Title: Pachyonychia congenita and steatocystoma multiplex
Journal: Clin Genet 1977 May
Authors: M. E. Hodes;A. L. Norins
Volume: 11, Pages: 359-364

Notes: 0009-9163 Journal Article

Title: Oral manifestations of pachyonychia congenita. Report of a case
Journal: Oral Surg Oral Med Oral Pathol 1977 Mar
Authors: E. D. Maser
Volume: 43, Pages: 373-378

Abstract: Few cases of pachyonychia congenita are reported in the dental and medical literature because of the rarity of the disease. This article presents a review of the literature and adds a new case history. Examination of a 4-year-old boy revealed the presence of the disease, which was also present in the mother and a newborn sibling.

Notes: 0030-4220 Journal Article

Title: Pachyonychia congenita with cardiac involvement
Journal: Arch Dermatol 1977 May
Authors: S. Premalatha;A. S. Thambiah
Volume: 113, Pages: 687

Notes: 0003-987x Letter

Title: Pachyonychia congenita (Jadassohn-Lewandowsky) and Kyrle's disease in the same patient
Journal: Int J Dermatol 1977 Oct
Authors: R. Ruiz-Maldonado;L. Tamayo
Volume: 16, Pages: 675-678

Abstract: An 11-year-old boy with typical lesions of pachyonychia congenita (Jadassohn-Lewandowsky) type II and with keratotic lesions histologically characteristic of Kyrle's Disease is described.

Notes: 0011-9059 Journal Article

Title: Oral vitamin A acid in treatment of dermatoses with pathologic keratinization
Journal: Int J Dermatol 1977 Jul-Aug
Authors: G. Stuttgen;H. Ippen;G. Mahrle
Volume: 16, Pages: 500-502

Notes: 0011-9059 Journal Article

Title: Pachyonychia congenita Jadassohn-Lewandowsky: a disorder of keratinization
Journal: Acta Derm Venereol 1977
Authors: J. Thormann;T. Kobayasi
Volume: 57, 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.

Notes: 0001-5555 Journal Article

Title: Pachyonychia congenita (Jadassohn-Lewandowski syndrome: case report
Journal: Plast Reconstr Surg 1977 Jun
Authors: R. R. th White;R. B. Noone
Volume: 59, 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.

Notes: 0032-1052 Journal Article

Title: Pachyonychia congenita with Steatocystoma multiplex: a report of 12 cases in one family [author's transl]
Journal: Nippon Hifuka Gakkai Zasshi 1976 Sep 20
Authors: T. Aoyagi;O. Ohnishi
Volume: 86, Pages: 767-775

Notes: 0021-499x Journal Article

English Language Version

Title: Pachyonychia congenita with involvement of the larynx
Journal: Arch Otolaryngol 1976 Apr
Authors: A. M. Cohn;J. R. McFarlane;J. Knox
Volume: 102, Pages: 233-235

Abstract: Pachyonychia congenita is a genetic syndrome of epithelial dysplasia that is inherited as an autosomal dominant trait. Its unique involvement within the larynx of a 3-year-old boy prompted this brief report of its clinical behavior and management.

Notes: 0003-9977 Journal Article

Title: Pachyonychia congenita
Journal: Syndr Head Neck 1976
Authors: R. J. Gorlin
Pages: 349, 600-343

Title: Pachyonychia congenita (a case report)
Journal: Indian Pediatr 1976 Sep
Authors: M. A. Khan;J. D. Dulhani;P. S. Mathur;V. Singh;N. C. Sethi
Volume: 13, Pages: 727-728

Notes: 0019-6061 Journal Article

Title: Natal teeth and steatocystoma multiplex complicated by hidradenitis suppurativa. A new syndrome
Journal: Arch Dermatol 1976 Aug
Authors: R. M. McDonald;W. B. Reed
Volume: 112, Pages: 1132-1134

Abstract: A new syndrome, consisting of natal or defective teeth, or both, steatocystomas of the skin, and epidermal cysts of the scalp, is described in several generations. One member of the family had eruptive molars. Male-to-male transmission suggests autosomal dominant inheritance. This syndrome should be separated from pachyonychia congenita I and II.

Notes: 0003-987x Journal Article

Title: Pachyonychia congenita
Journal: Gen malformation syndr clinical med 1976
Authors: W. L. Nyhan
Pages: 255-257

Title: Pachyonychia congenita. A clinical, histological and microradiographic study with special reference to oral manifestations
Journal: Acta Derm Venereol 1975
Authors: G. Anneroth;G. Isacsson;B. Lagerholm;A. M. Lindvall;N. Thyresson
Volume: 55, Pages: 387-394

Abstract: This paper rresents a clinical, histological and microradiographic study of three patients with pachyonychia congenita with special reference to oral manifestations. The patients, who are relatives, exhibited thickening of finger- and toe-nails, follicular keratosis, palmoplantar keratosis and hyperhidrosis, oral leukokeratosis, and natal teeth. It is stated in the discussion that natal teeth and oral leukokeratosis may constitute the earliest clinical manifestations of pachyonychia congenita and that they appear to accur earlier than nail lesions. When there is a hereditary disposition for pachyonychia congenita, it is important to inspect the oral cavity at an early stage.

Notes: 0001-5555 Journal Article

Title: Leukonychia totalis, multiple sebaceous cysts, and renal calculi. A syndrome
Journal: Arch Dermatol 1975 Jul
Authors: L. L. Bushkell;R. J. Gorlin
Volume: 111, Pages: 899-901

Abstract: A 27-year-old man had leukonychia totals, multiple sebaceous cysts, and renal calculi. Pedigree analysis showed a total of four generations involved, with koilonychia additionally present in three of the affected individuals. Autosomal dominant inheritance is a postulation.

Notes: 0003-987x Journal Article

Title: [Proceedings: Pachyonychia congenita]
Journal: Pediatrie 1975 Jul-Aug
Authors: M. Pierson;M. Saborio;G. Grignon;G. Fortier;L. Wuilbercq
Volume: 30, Pages: 535

Notes: 0031-4021 Journal Article

English Language Version

Title: [Familial pachyonychia]
Journal: Bull Soc Franc Dermatol Syphilol 1974
Authors: D. Colomb, F. Vittori, A. Gho
Volume: 81, Pages: 320

English Language Version

Title: Pachyonychia Congenita: Consultations in Dermatology
Journal: 1974
Authors: W. B. Shelley

Notes: pp. 136-41

Title: [Jadassohn - Levandovskii syndrome]
Journal: Vest Derm Mookva 1974
Authors: K. N. Suvorova, M. F. Roytburd, N. I. Levitina
Pages: 62-66

English Language Version

Title: [The Jadassohn-Lewandowsky syndrome]
Journal: Hautarzt 1973 Oct
Authors: S. Bauscher
Volume: 24, Pages: 439-441

Notes: 0017-8470 Journal Article

English Language Version

Title: Synopsis of Oral Pathology
Journal: 1973
Authors: S.N. Bhaskar

Notes: p. 349

Title: Premature eruption in the primary dentition--a clinical and radiological study
Journal: Sven Tandlak Tidskr 1973 Jul
Authors: G. Bjuggren
Volume: 66, Pages: 343-355

Notes: 0039-6745 Journal Article

Title: Pachyonychia congenita. A histologic and microradiographic study
Journal: Acta Derm Venereol 1973
Authors: B. Forslind;B. Nylen;G. Swanbeck;M. Thyresson;N. Thyresson
Volume: 53, Pages: 211-216

Notes: 0001-5555 Journal Article

Title: [Is sebocystomatosis a symptom of the Jadassohn-Lewandowski syndrome?]
Journal: Dermatol Montasschr 1973
Authors: V. E. Moldenhauer, R. Seidel, Y. S. Lee, J. I. Youn
Volume: 159, Pages: 540-543

English Language Version

Title: [Ultrastructural study of cutaneous lesions in Jadassohn Lewandowsky syndrome]
Journal: Arch Dermatol Forsch 1973 Mar 19
Authors: H. Perrot;D. Schmitt;J. Thivolet
Volume: 246, Pages: 114-124

Notes: 0003-9187 Journal Article

English Language Version

Title: [Hereditary pachyonychia]
Journal: Sov Med 1973 Sep
Authors: B. A. Somov;A. V. Khamaganova;M. A. Bogomil'skaia
Volume: 36, Pages: 147-148

Notes: 0038-5077 Journal Article

Title: Pachyonychia congenita. A long-term evaluation of associated oral and dermal lesions
Journal: Oral Surg Oral Med Oral Pathol 1973 Nov
Authors: L. L. Young;J. A. Lenox
Volume: 36, Pages: 663-666

Notes: 0030-4220 Journal Article

Title: [Congenital pachyonichia. Jadassohn-Levandowski syndrome]
Journal: Actas Dermosifiliogr 1972 Mar-Apr
Authors: J. Cabre;J. M. Gomez Armario;J. Vidal
Volume: 63, Pages: 131-138

Notes: 0001-7310 Journal Article

English Language Version

Title: Sebocystomatosis with congenital pachyonychia
Journal: Int J Dermatol 1972 Apr-Jun
Authors: J. P. Velasquez;J. Bustamante
Volume: 11, Pages: 77-81

Notes: 0011-9059 Journal Article

Title: Pachyonychia congenita with epidermal cysts and teeth at birth: 4th generation
Journal: Br J Dermatol 1971 Jan
Authors: F. S. Besser
Volume: 84, Pages: 95-96

Notes: 0007-0963 Journal Article

Title: Pachyonychia and multiple epidermal hamartomata
Journal: Br J Dermatol 1971 Sep
Authors: J. D. Boxley;D. S. Wilkinson
Volume: 85, Pages: 298-299

Notes: 0007-0963 Journal Article

Title: Biophysical studies on keratinized tissues
Journal: Biochem Biol Exp 1971
Authors: B. Forslind
Volume: 9, Pages: 295

Notes: Biochim Biol Speriment

Title: Quantitative microradiography of normal human nail
Journal: Acta Derm Venereol 1971
Authors: B. Forslind;B. Lindstrom;B. Philipson
Volume: 51, Pages: 89-92

Notes: 0001-5555 Journal Article

Title: Steatocystoma multiplex (multiple sebaceous cysts) with familial incidence in the first case
Journal: Birth Defects Orig Art Ser 1971
Authors: P.S. Harper
Volume: 7, Pages: 342

Title: Pachyonychia congenita in father and son
Journal: Birth Defects Orig Artic Ser 1971 Jun
Authors: V. A. McKusick
Volume: 7, Pages: 274-275

Notes: 0547-6844 Journal Article

Title: [Jadassohn-Lewandowski syndrome with microphthalmos]
Journal: Hautarzt 1971
Authors: H. J. Vogt, J. Calap
Volume: 22, Pages: 294-299

English Language Version

Title: Pachyonychia
Journal: Br J Dermatol 1970
Authors: G. Achten;J. Wanet-Rouard
Volume: 83, Pages: Suppl:56-62

Notes: 0007-0963 Journal Article

Title: [On a case of circumscribed disseminated keratosis of the Jadassohn-Lewandowsky (J.L. type)]
Journal: G Ital Dermatol Minerva Dermatol 1970 Aug
Authors: B. Consentino;M. Pippione;G. F. Strani
Volume: 45, Pages: 473-476

Notes: 0300-1318 Journal Article

English Language Version

Title: Biophysical studies of the normal nail
Journal: Acta Derm Venereol 1970
Authors: B. Forslind
Volume: 50, Pages: 161-168

Notes: 0001-5555 Journal Article

Title: Pachyonychia congenita with metacarpal-phalangeal agenesis in a dog
Journal: Vet Med Small Anim Clin 1970 May
Authors: F. L. Frye
Volume: 65, Pages: 446-447

Notes: 0042-4889 Journal Article

Title: [Combinations of sebocystomatosis Gunther with other diseases]
Journal: Dermatol Monatsschr 1969
Authors: S. Engel;Pinzer Barbara
Volume: 155, Pages: 687-699

Notes: 0011-9083 Journal Article

English Language Version

Title: Genetic disorders affecting mucous membranes
Journal: Oral Pathol 1969
Authors: R. J. Gorlin
Volume: 28, Pages: 512-525

Title: [Humoral marginal symptoms in pachyonychia congenita]
Journal: Hautarzt 1969 Jan
Authors: G. W. Korting;H. Holzmann
Volume: 20, Pages: 37-39

Notes: 0017-8470 Journal Article

English Language Version

Title: Pachyonychia congenita
Journal: Arch Dermatol 1969
Authors: H. Pinkus
Volume: 100, Pages: 245-246

Title: Sodium laevothyroxine in pachyonychia congenita
Journal: J Indian Med Assoc 1968 Sep 1
Authors: D. S. Chowdhuri;A. K. Banerjee
Volume: 51, Pages: 246-248

Notes: 0019-5847 Journal Article

Title: Pachyonychia congenita: a case report
Journal: J Am Podiatry Assoc 1968 Apr
Authors: L. S. Horwitz
Volume: 58, Pages: 184

Notes: 0003-0538 Journal Article

Title: [The Jadassohn-Lewandowsky syndrome]
Journal: Hautarzt 1968 Oct
Authors: E. Moldenhauer;K. Ernst
Volume: 19, Pages: 441-447

Notes: 0017-8470 Journal Article Review

English Language Version

Title: [Pachyonychia congenita-Syndrom mit klinischen Erscheinungen der Dystrophia bullosa hered]
Journal: Zbl Haut-u Geschl Kr 1968
Authors: G Niebauer
Volume: 43, Pages: 35-37

English Language Version

Title: Pachyonychia congenita with epidermal cysts and other congenital dyskeratoses
Journal: Arch Dermatol 1968 Jan
Authors: N. A. Soderquist;W. B. Reed
Volume: 97, Pages: 31-33

Notes: 0003-987x Journal Article

Title: Pachyonychia congenita in six generations
Journal: Hereditas 1967
Authors: H. O. Akesson
Volume: 58, Pages: 103-110

Notes: 0018-0661 Journal Article

Title: Pachyonychia congenita--favourable response to sodium laevothyroxine
Journal: Br J Dermatol 1967 Dec
Authors: D. S. Chowdhury;A. K. Banerjee
Volume: 79, Pages: 722

Notes: 0007-0963 Journal Article

Title: Polykeratosis de Louraine
Journal: Arch Dermatol 1967
Authors: C. Nelson
Volume: 96, Pages: 349-351

Title: Studies on blisters produced by friction
Journal: J. Invest Dermatol 1967
Authors: M. B. Sulzberger, T. A. Cortese, L. Fishman, H. S. Wiley
Volume: 47, Pages: 456-465

Title: The longitudinal nail biopsy
Journal: J Invest Dermatol 1967
Authors: N. J. Zaias
Volume: 49, Pages: 406-408

Title: [Congenital pachyonychia]
Journal: Vestn Dermatol Venerol 1966 Oct
Authors: E. I. Danil'iants
Volume: 40, Pages: 96

Notes: 0042-4609 Journal Article

English Language Version

Title: Pachyonychia congenita with sebocystomatosis (sertoli)
Journal: Dermatologica 1966
Authors: W. P. De Groot
Volume: 133, Pages: 344

Journal: Derm Wschr 1966
Authors: G. W. Korting
Volume: 152, Pages: 641-650

English Language Version

Title: Pachyonychia congenita
Journal: Am J Dis Child 1966
Authors: C. R. Laing, J. R. Hayes, G. Scharf
Volume: 111, Pages: 649-652

Title: Pachyonychia congenita
Journal: Proc R Soc Med 1966 Oct
Authors: E. J. Moynahan;A. B. Shrank
Volume: 59, Pages: 975-976

Notes: 0035-9157 Journal Article

Title: Pachyonychia congenita
Journal: Proc Roy Soc Med 1966
Authors: A. B. Shrank
Volume: 59, Pages: 975-976

Title: Erupted teeth in the newborn
Journal: Oral Surg Oral Med Oral Pathol 1966
Authors: J. D. Spouge, W. H. Feasby
Volume: 22, Pages: 198-208

Title: Pachyonychia Congenita
Journal: Indian J Dermatol 1965 Apr
Authors: H. S. El-Nasr;H. El-Hefnawi
Volume: 10, Pages: 77-84

Notes: 0019-5154 Journal Article

Title: [Neurological and genetic aspects of a keratosis follicularis group (Jadassohn-Lewandowsky syndrome)]
Journal: Arch Belg Dermatol Syphiligr 1965 Dec
Authors: J. Hariga;L. Martin;S. Lapiere
Volume: 21, Pages: 341-362

Notes: 0003-956x Journal Article

English Language Version

Title: Plastic Surgery in Pachyonychia Congenita and Other Dyskeratoses. Case Report and Review of the Literature
Journal: Plast Reconstr Surg 1964 Mar
Authors: B. Cosman;F. C. Symonds, Jr.;G. F. Crikelair
Volume: 33, Pages: 226-236

Notes: 0032-1052 Journal Article

Title: Pachonychia Congenita
Journal: Arch Dermatol 1964 Dec
Authors: H. L. Joseph
Volume: 90, Pages: 594-603

Notes: 0003-987x Journal Article

Title: Pachyonychia congenita
Journal: Arch Dermatol 1962 Mar
Authors: W. R. Buckley;J. Cassuto
Volume: 85, Pages: 397-402

Notes: 0003-987x Journal Article

Title: Strean LP
Journal: Clinical Genodermatol 1962
Authors: T. Butterworth
Pages: 64-67

Title: Nail bed ablation: histological grounds for radical operation
Journal: Brit J Surg 1962
Authors: R. W. Lloyd-Davies
Volume: 40, Pages: 44-46

Title: Epidermolysis bullosa with pachyonychia in three generations
Journal: Arch Dermatol 1962
Authors: S.B May
Volume: 85, Pages: 662-663

Title: [Siemens' keratosis multiformis idiopathica (Jadassohn-Lewandowsky's pachyonychia congenita)]
Journal: Arch Klin Exp Dermatol 1961
Authors: G. Jannasch;A. Wiskemann
Volume: 212, Pages: 275-281

Notes: 0300-8614 Journal Article

English Language Version

Title: Why do nails grow out instead of up?
Journal: Arch Dermatol 1961 Aug
Authors: A. M. Kligman
Volume: 84, Pages: 313-315

Notes: 0003-987x Journal Article

Title: Steatocystoma multiplex with pachyonychia congenita. Eight cases in four generations
Journal: Arch Dermatol 1961 Nov
Authors: W. R. Vineyard;R. A. Scott
Volume: 84, Pages: 824-827

Notes: 0003-987x Journal Article

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 1961
Authors: C. J. Witkop, R. J. Gorlin
Volume: 84, Pages: 762-771

Title: [On the clinical aspects and histology of congenital pachyonychia]
Journal: Arch Klin Exp Dermatol 1960
Authors: J. Alkiewicz;J. Lebioda
Volume: 212, Pages: 140-147

Notes: 0300-8614 Journal Article

English Language Version

Title: Unusual stomadromes--pachyonchia congenita, lipoid proteinosis, Reiter's syndrome, epidermolysis bullosa, Bonnevie-Ullrich-Turner's syndrome, and multiple hereditary telangiectasia
Journal: Oral Surg Oral Med Oral Pathol 1960 Mar
Authors: R. J. Gorlin;A. P. Chaudhry
Volume: 13, Pages: 257-268

Notes: 0030-4220 Journal Article

Journal: Vestn Dermatol 1959
Authors: R.S. Babayants
Volume: 6, Pages: 13-16

English Language Version

Title: [Congenital pachyonychia.]
Journal: Klin Med (Mosk) 1959 May
Authors: A. S. Raben;L. D. Krymskii
Volume: 37, Pages: 149-151

Notes: 0023-2149 Journal Article

English Language Version

Title: Hereditary multiple sebaceous cysts
Journal: J Hered 1959
Authors: F. E. Stephens
Volume: 50, Pages: 299-301

Title: [Touraine's Polykeratosis (palmoplantar keratoderma with hypotrichosis and subungual keratosis)]
Journal: Dermatologica 1958
Authors: Fischer
Volume: 116, Pages: 364-365

English Language Version

Title: [Jadassohn-Lewandowski syndrome with polydactylia and alopecia of the eyebrows.]
Journal: Arch Belg Dermatol Syphiligr 1958 Jun
Authors: A. Fontaine;W. Wellens
Volume: 14, Pages: 178-184

Notes: 0003-956x Journal Article

English Language Version

Title: Oral lesions accompanying pachyonychia congenita
Journal: J Oral Surg (Chic) 1958 May
Authors: R. J. Gorlin;A. P. Chaudhry
Volume: 11, Pages: 541-544

Notes: 0146-1575 Journal Article

Title: Report of a case of pachyonychia congenita
Journal: AMA Arch Derm 1958 Jun
Authors: E. W. Kelly, Jr.;H. Pinkus
Volume: 77, Pages: 724-726

Notes: 0096-5359 Journal Article

Title: Dyskeratosis congenita
Journal: AMA Arch Derm 1956 Feb
Authors: M. J. Costello;C. M. Buncke
Volume: 73, Pages: 123-132

Notes: 0096-5359 Journal Article

Title: Pachyonychia congenita
Journal: Nederlands tijdschrift voor geneeskunde 1956
Authors: A. J. Swaak
Volume: 100, Pages: 486-488

English Language Version

Title: The developmental nature of pachyonychia congenita; a twenty year study of a case
Journal: Int Rec Med Gen Pract Clin 1956 Jun
Authors: C. S. Wright
Volume: 169, Pages: 368-370

Notes: 0097-1650 Journal Article

Title: Pachyonychia congenita Jadassohn-Lewandowsky
Journal: Helv Paediatr Acta 1955 Jun
Authors: P. Krepler
Volume: 10, Pages: 369-376

Notes: 0018-022x Journal Article

English Language Version

Title: Pachyonychia congenita; a review and new approach to treatment
Journal: AMA Arch Derm 1955 Feb
Authors: J. F. Mullins;N. Murray;E. M. Shapiro
Volume: 71, Pages: 264-268

Notes: 0096-5359 Journal Article

Title: Experimental fiction blisters
Journal: Brit J Dermatol 1955
Authors: P. F. D. Naylor
Volume: 67, Pages: 327-342

Title: The Skin: A Clinicopathalagic Treatise
Journal: 1954
Authors: A. C. Allen

Notes: pp. 35-8

Title: Microscopic studies of fetal and mature nail and surrounding soft tissue
Journal: Arch Dermatol Syphilol 1954
Authors: B. L. Lewis
Volume: 70, Pages: 732-747

Title: [Congenital pachyonychia with keratosis palmaris et plantaris.]
Journal: Bull Soc Fr Dermatol Syphiligr 1953 Mar-Apr
Authors: Duperrat;Poncelet
Volume: 60, Pages: 126

Notes: Journal Article

English Language Version

Title: Pachyonychia congenita with ectodermal defect
Journal: 10th Int Congr Dermatol Lond 1952
Authors: R. T. Brain
Pages: 507-508

Notes: Barin, R. T.

Title: [Jadassohn-Lewandowsky syndrome]
Journal: Arch Agent Dermatol 1952
Authors: O. G. Costa
Volume: 2, Pages: 154-156

English Language Version

Title: [Congenital pachyonychia with keratoderma and disseminated keratoses of the skin and mucosa (Jadassohn and Lewandowski disease)]
Journal: Bull Soc Fr Dermatol Syphiligr 1952 May-Jun
Authors: E. Hadida;F. G. Marill;E. Timsit;R. Streit
Volume: 59, Pages: 236-240

Notes: Journal Article

English Language Version

Title: Pachyonichia congenita; a report of six cases in one family, with a Nte on linkage data
Journal: Ann Eugen 1951
Authors: A. D. M. Jackson, S. D. Lawler
Volume: 16, Pages: 142-146

Title: [Pachyonychia with hyperkeratosis follicularis.]
Journal: Bull Soc Fr Dermatol Syphiligr 1951 Nov-Dec
Authors: P. Vermenouze
Volume: 58, Pages: 542-543

Notes: Journal Article

English Language Version

Title: [Jadassohn-Lewandowsky sydrome]
Journal: Revista Argentina de Dermatosifilologia 1950
Authors: L. A. Cordiviola, F. E. Ambrosetti, H. J. S. Caballero
Volume: 34, Pages: 54-61

English Language Version

Title: Pachyonychia congenita
Journal: Arch Dermatol 1950
Authors: C. R. Denton
Volume: 184,

Title: Pachyonychia congenita; regression of plantar lesions on patients wearing specially made rubber base foot molds and shoes
Journal: Arch Derm Syphilol 1950 Jul
Authors: J. Garb
Volume: 62, Pages: 117-124

Notes: 0096-6029 Journal Article

Title: Natal and neonatal teeth; a review of 24 cases reported in the literature
Journal: J Pediatr 1950 Mar
Authors: M. Massler;B. S. Savara
Volume: 36, Pages: 349-359

Notes: 0022-3476 Journal Article

Title: Vitamin A in a cae of acquired localized keratosis palmaris et plantaris and one of acquired pachyonychia
Journal: Brit J Dermatol 1950
Authors: A. D. Porter, H. Haber
Volume: 62, Pages: 355-358

Title: Keratosis follicularis with changes in the skin
Journal: Arch Dermatol 1949
Authors: R. H. Harris, C. J. White
Volume: 59, Pages: 346-347

Title: Pachyonychia Congenita Keratosis Palmaris et Plantaris: Diptrophia Inquirium and Leukoplakia Oris
Journal: Arch Dermatol Syphilol 1949
Authors: F. Wise
Volume: 60, Pages: 846-847

Title: [Pachyonychia Congenita with keratoderma disseminated keratosis of the skin and mucosa (Jadassoh-Lewandowski syndrome) (Second presentation)]
Journal: Bull Soc Franc Dermatol 1948
Authors: E. Hadida, J. Sayag, F.G. Marill, E. Timsit
Volume: 55, Pages: 29-30

English Language Version

Title: Familial steatocystoma multiplex â?¦
Journal: Arch Dermatol Syphilol 1948
Authors: R. O. Noojin, J. P. Reynolds
Volume: 57, Pages: 1013-1018

Title: Hereditary onychogryphosis
Journal: Ann Eugen Lond 1948
Authors: A. Videback
Volume: 14, Pages: 139-141

Title: Pachyonychia congenita with keratoderma of palms & soles and leukoplakia oris
Journal: Arch Dermatol Syphilol 1948
Authors: F. Wise
Volume: 58, Pages: 608-609

Title: Pachyonychia congenita: Report of two cases, with studies on therapy
Journal: Arch Dermatol Syphilol 1947
Authors: C. S. Wright, J. P. Guequierre
Volume: 55, Pages: 819-830

Title: Pachyonychia congenita
Journal: Urol Cutan R 1946
Authors: H. Goodman
Volume: 50, Pages: 465-467

Title: Congenital ectodermal dysplasia: Pachyonychia congenita?
Journal: Arch Dermatol Syphilol 1943
Authors: C. S. Wright
Volume: 47, Pages: 435

Title: Hyperkeratosis of the large toe-nails and sebaceous cysts
Journal: J Hered 1942
Authors: J. Stauffer, I. Simmons
Volume: 33, Pages: 285

Title: Pachyonychia congenita
Journal: Arch Dermatol Syphilol 1941
Authors: A. C. Cipollaro
Volume: 43, Pages: 198

Title: Pachyonychia congenita (Jadassohn)
Journal: Arch Dermatol Syphilol 1941
Authors: H. E. Michelson
Volume: 44, Pages: 979-980

Title: Pachyonychia congenita in mother and daughter
Journal: Arch Dermatol 1940
Authors: N. P. Anderson
Volume: 42, Pages: 365

Title: Pachyonychia congenita
Journal: Arch Dermatol 1940
Authors: A. C. Cipollaro
Volume: 42, Pages: 703-704

Title: Pachyonychia congenita (Jadassohn and Lewandowski)
Journal: Proc Roy Soc Med 1939
Authors: J. Franklin
Volume: 32, Pages: 263-265

Journal: Arch Dermatol Syphilol 1937
Authors: H. L. Chung
Volume: 36, Pages: 303-309

Title: Pachyonychia congenita
Journal: Arch Dermatol Syphilol 1937
Authors: B. F. W. Felden
Volume: 37, Pages: 1078

Title: Resistant erosive lesions in pachyonychia congenita of Jadassohn. Treatment with buffered cysteine hydrocholoride
Journal: Arch Dermatol 1937
Authors: L. C. Goldberg
Volume: 36, Pages: 331-334

Title: Pachyonychia congenita
Journal: Arch Dermatol 1937
Authors: A. W. Grace
Volume: 36, Pages: 1255-1256

Title: [Congenital generalized onychogryphosis of the toes]
Journal: Presse Med 1937
Authors: A. Touraine, Soulignac
Volume: 45, Pages: 395

English Language Version

Title: [Hyperectodermose congenitale et familiale (Pachyonychie du type Jadassohn-Riehl avec Keratomes, Keratoses folliculaires et leucoplasie)]
Journal: Bull Soc Franc Dermatol Syphilol 1937
Authors: A. Touraine, Granjon
Volume: 44, Pages: 649-655

English Language Version

Title: Pachyonychia congenita
Journal: Arch Derm Syphilol 1936
Authors: G.C. Andrews
Volume: 33, Pages: 183-184

Title: [Hyperkeratosis subungualis congenitaâ?¦]
Journal: Derm Ztschr 1936
Authors: A. Jordan, R. Rydnick
Volume: 73,

English Language Version

Title: Clinical notes, suggestions, and new instruments
Journal: JAMA 1936
Authors: E. B. Tauber, L. Goldman, H. Claassen
Volume: 107, Pages: 29-30

Title: [Uber Packyonychia congenita (Typus Riehl)].
Journal: Wochenschr 1935
Authors: L. Kumer
Volume: 48, Pages: 174-179

English Language Version

Title: [Pachyonuxis Familial]
Journal: R Franc Dermatol Veneral 1935
Authors: G. Milian
Volume: 11, Pages: 533-537

English Language Version

Title: Pachyonychia congenita
Journal: Arch Dermatol Syphilol 1935
Authors: A. W. Sohrweide
Volume: 32, Pages: 370-376

Title: Pachyonychia congenita Jadassohn
Journal: Arch Dermatol Syphilol 1934
Authors: F. A. Diasio
Volume: 30, Pages: 218-226

Notes: Diazo, F. A.

Title: Inherited Abnormalities of the Skin & Appendages
Journal: 1933
Authors: E.A. Cockayne

Notes: p. 206

Title: Onychogryphosis (congenital)
Journal: Arch Dermatol 1932
Authors: P.E. Bechet
Volume: 25, Pages: 408-409

Title: Dyskeratosis congenita with pigmentation, dystrophia unguis and leukokeratosis oris
Journal: Arch Dermatol Syphilol 1930
Authors: H. N. Cole, J. E. Rauschkolb, J. Toomey
Volume: 21, Pages: 71-95

Title: Cole et al - Dyskeratosis and leukokeratosis
Journal: Arch Dermatol Syphilol 1930
Authors: J. Jadassohn
Volume: 21, Pages: 93-95

Title: Pachyonychia congenita
Journal: NY State Med J 1929
Authors: G.C Andrews, S. Strumwasser
Volume: 29, Pages: 747-749

Title: Pachyonychia congenita (Jadassohn and Lewandowsky)
Journal: Arch Dermatol 1928
Authors: Fox. H
Volume: 18, Pages: 794-795

Title: [Die Krankheiten der Naegel]
Journal: 1927
Authors: J. Heller
Volume: 13, Pages: 86-87

English Language Version

Title: [Zur syptomatologie und histologie der kongenitalen dyskeratosen]
Journal: Dermatol Zschr 1925
Authors: S.R. Brunauer
Volume: 42, Pages: 6-26

English Language Version

Title: [Zur lehre von den congenitalen dyskeratosen]
Journal: Arch Dermatol Syphilol (Berlin) 1925
Authors: E. Schafer
Volume: 148, Pages: 425-432

English Language Version

Title: Hereditary Familial Dystrophy of the Nails
Journal: JAMA 1925 May 23, 1925
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: [Uber keratosis follicularis]
Journal: Arch Dermatol Syphilol (Berlin) 1922
Authors: H. W. Siemens
Volume: 139, Pages: 62-72

English Language Version

Title: Congenital anomalies of the nails. Four cases of hereditary hypertrophy of the nail bed associated with a history of erupted teeth at birth
Journal: Brit J Dermatol 1921
Authors: F. A. Murray
Volume: 33, Pages: 409

Title: Two cases of onychia Congenitals out of Plural Pregnancy
Journal: Urol Cutan R 1919
Authors: S. Mendes da Costa
Volume: 23, Pages: 159

Title: [Angelborne familiare Erkrankungen an den Naegeln]
Journal: Dermatol Wischr 1919
Authors: E. Ebstein
Volume: 68, Pages: 113-124

English Language Version

Title: Die Morphologie der Missbildungen des Menschen und der Tiere
Journal: 1912
Authors: E. Schwarlbe Bettmann

Notes: p. S735; 1909

English Language Version

Title: Ein Beitrag zur Onychogryphos. Symmetrica congenita et hereditaria
Journal: Muench Med Wschr 1909
Authors: G. Koehler
Volume: 56, Pages: 661

English Language Version

Title: The inheritance of certain human abnormalities
Journal: Q J Med 1908
Authors: A. M. Gossage
Volume: 1, Pages: 331-346

Title: [Pachyonychia congenita: Keratosis disseminata circumscripta (follicularis). Tylomata. Leukokeratosis linguae]
Journal: 1906
Authors: J. Jadassohn; P. Lewandowski

Notes: pp. 29-31

English Language Version

Title: Three cases of hereditary hyperkeratosis of the nailbed
Journal: Arch Dermatol Syphilol 1905
Authors: A. G. Wilson
Volume: 17, Pages: 13-14

Title: [On the causes of congenital onychogryphosis]
Journal: Munchen Med Wochenschr 1904
Authors: C. Muller
Volume: 19, Pages: 2180-2182

English Language Version

Title: [Congenital Dyskeratosis and Their Morbid Associations]
Journal: Ann Dermatol Syphilol 1903
Authors: E. Lenglet
Volume: 4, Pages: 369

English Language Version

Title: Congenital deformity of the nails (onychogryphosis)
Journal: Lancet 1888
Authors: Sympson
Volume: 1, Pages: 722-723

Title: Onychogryphosis
Journal: Arch Klin Chri 1869
Authors: T. H. Billroth
Volume: 10, Pages: 619

English Language Version

Title: Ungual affections
Journal: On the diseases of the skin: A system of cutaneous medicine 1867
Authors: Erasmus Wilson
Pages: 708-714

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 1704-1705
Authors: R. Wroe
Volume: 24, Pages: 1899-1900

Title: An account of one who had horny excrescences or extraordinary large nails on his fingers and toes
Journal: Phil Trans R Soc Lond 1695-1697
Authors: J. Locke
Volume: 19, Pages: 694-696

Title: A letter from Mr. St. George Ashe, Sec. Of the Dublinc Society, to one of the Secretaries of the Royal Society: concerning a girl in Ireland, who has several horns growing on her body
Journal: Phil Trans R Soc Lond 1685
Authors: St. G. Ashe
Volume: 15, Pages: 1202-1204

Abstract: Early Letters of the Royal Society From St George Ashe to William Musgrave, 10-10-1685 An account sent by St George Ashe to William Musgrave, as promised the previous month of Anne Jackson, a child suffering from a disorder that caused her to grow 'horns' on her body, who had been brought to the Society to be examined. The description is full, because Anne's 'owner' would not allow drawings to be made of the child, who was presumably earning him money through exhibiting her. Anne was born in Waterford to English parents and had developed normally until the age of 3, some ten years before the Society examined her. Following the death of her mother, her father had been unable to support her and she had become a charge on the parish - a charge that was apparently relieved by her exploitation as a freak show. Ashe regrets the lack of family or friends who could give an account of the early development of Anne's condition, but shows no sympathy for the child, treating her as an interesting scientific curiosity and at one point referring to her as 'it'.

Title: [Ungues monstrosis]
Journal: Acta Med Philosophica Hafnensis 1673
Authors: T. Bartholin
Volume: 1, Pages: 43

Notes: Bartholini, T.

English Language Version

Title: Keratins and Skin Disorders
Journal: J Path 0 2004
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.

Journal: Nucleic Acids Res 0 2003
Authors: F. Nagatsugi; S. Sasaki; P. S. Miller; M. M. Seidman
Volume: 31, 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.