2026 Epidermal Differentiation Disorders Symposium

The skin barrier is traditionally viewed as a static structure; however, it is in fact a highly dynamic system that emerges through a continuous transition from living to dead cells. In the epidermis, tight junctions (TJs) formed by living keratinocytes in the stratum granulosum establish a liquid–liquid interface barrier that tightly regulates paracellular permeability. As keratinocytes undergo terminal differentiation, they transition through a unique programmed cell death process, corneoptosis, giving rise to corneocytes that constitute the stratum corneum (SC). Remarkably, these dead cells acquire highly specialized structures—including lipid lamellae, cornified envelopes, and keratin–filaggrin networks—that enable them to function as a robust air–liquid interface barrier. Recent advances have revealed that this transition is not merely degenerative but rather a tightly orchestrated biological process that enhances barrier function. The SC further exhibits spatial heterogeneity, such as three distinct pH zones, which contribute to hydration, antimicrobial defense, and controlled desquamation. Together, TJs and the SC form an integrated, multilayered barrier system that bridges life and death to maintain homeostasis. In this lecture, I will discuss how this continuous transformation—from living junctional networks to functionally evolved dead structures—represents a fundamental design principle of the skin barrier and provides new insights into disease mechanisms and therapeutic strategies.

Our improved understanding of the underlying genetic basis for ichthyoses and palmoplantar keratodermas during the past almost 20 years led a group of 17 global experts and advocates to establish a new gene- and function-based classification that pulls together these groups of epidermal differentiation disorders or EDDs, now subdivided into nonsyndromic, syndromic and palmoplantar groups (nEDDs, sEDDs, and pEDDs, respectively). The new classification will facilitate the addition of new entities as genes are discovered and eliminates eponyms and names that are derogatory to affected individuals. Concurrently, a US-based Consortium of Hereditary EDDs (or CHEDD) has been proposed to study the natural history of EDDs, optimize clinical trial designs and tools, discover new therapeutic targets, and test repurposed and new therapies for EDDs.

The characteristic acantholysis and differentiation defects associated with Darier Disease (ATP2A2-nEDD) typically appear later in childhood and ebb and flare in response to an array of stressors. Phenotypic heterogeneity and a degree of anatomic site specificity suggest that the genetic origin of the disease, haploinsufficiency of the SERCA2 calcium pump encoded by ATP2A2, synergizes with additional factors to elicit cell adhesion defects. Using patient-derived keratinocytes we found that DD cells fail to control stress-induced reactive oxygen species, are depleted in the antioxidant glutathione and demonstrate metabolic abnormalities in the stress-adaptive pentose phosphate pathway. We will discuss how failure to control oxidative stress in DD cells impinges, particularly, on the localization and biochemical attributes of the desmosome-keratin network responsible for imparting mechanical strength to the epidermis. Data addressing potential interventions including activation of the residual, unaffected pool of SERCA2 and antioxidant treatment will be presented, as well as, findings that suggest that this stress sensitivity could elicit DNA damage in DD keratinocytes.

Darier’s disease is a rare genetic skin disorder that often leaves patients facing long diagnostic journeys, limited treatment options, and a sense of isolation. In this presentation, Genevieve Lee, founder of Decoding Darier’s, will explore how patient-led organizations play an essential role in bridging the gap between the medical community and those living with rare skin conditions. Drawing on her own lived experience and the global community she has built, Genevieve will highlight how advocacy networks foster peer support, amplify the patient voice in research, and improve access to reliable information. She will also reflect on the broader lessons the Darier’s disease community offers for rare disease advocacy and the power of collaboration between patients, clinicians, and researchers.

FIRST creates, supports, and cultivates a community of patients, families, and healthcare professionals living with and caring for Epidermal Differentiation Disorders.

Pachyonychia congenita (PC) is a rare genetic disorder in which the most debilitating manifestation is palmoplantar keratoderma (PPK), characterized by painful and hyperkeratotic calluses on the palms and soles. PC is caused by dominantly acting variants in KRT6A–C, KRT16, and KRT17. Previous work from our laboratory showed that Krt16-null mice develop PC-like PPK in footpad skin at the histological and molecular levels. Here, we report the generation of a new mouse model expressing a PC-causing pathogenic missense allele, Krt16 R123C. Mice homozygous for this allele develop PC-like PPK in footpad skin with complete penetrance by 5 months of age. Studies in these mice, as well as in N/TERT human keratinocytes engineered to express the orthologous missense KRT16 variant, revealed that pronounced defects in epidermal differentiation arise early in disease pathogenesis. In parallel, analyses of mouse models, PC biopsies, and molecular screening (with validation) uncovered dysregulation of type I interferon signaling in PPK lesions. Topical treatment of lesional paw skin in Krt16-null mice with ruxolitinib (a JAK inhibitor cream) normalizes interferon signaling and markedly attenuates PPK-like lesions. Together, these advances in modeling PC in mice and in human keratinocytes in culture refine our understanding of this enigmatic disorder and provide a foundation for testing new therapeutic approaches.

Darier disease (DD) and Hailey-Hailey disease (HHD) are rare genetic disorders that cause painful skin breakdown and frequent cutaneous infections due to weakening of adhesion among epidermal keratinocytes. Though these blistering disorders were linked to pathogenic variants in calcium pumps more than two decades ago, neither DD nor HHD has an FDA-approved therapy. We deployed gene editing in human keratinocytes and organotypic epidermis to replicate the key pathologic features of DD and HHD in vitro. These tractable models offered a simplified pre-clinical platform for mapping the primary drivers of their pathogenesis. Transcriptomic analyses nominated druggable pathways, including regulators of desmosomal adhesion and keratinocyte differentiation, which we validated in lesional skin biopsies of DD and HHD. Importantly, targeting these pathways in our disease models robustly restored intercellular adhesion, pointing to potential opportunities for drug repurposing, which we hope will inform future clinical trials to finally move the needle for patients.

A key life-altering symptom of many forms of hereditary palmoplantar keratodermas (PPKs) is pain at the lesion sites. Current therapies for this pain are unfortunately inadequate, necessitating a better understanding of its underlying mechanisms. One curious feature of PPK-associated pain is that it is not equally prevalent among all forms of PPK. This suggests that there may be a combination of conserved changes broadly associated with the presence of PPK and changes that are more idiosynchratic for painful PPK. We have been taking advantage of mouse models of PPK to address this hypothesis. Through the characterization of pain behaviors in these mice, we have identified three lines (SLURP1 KO, SLURP2 KO, K16 KO) that exhibit augmented pain-related behaviors and a fourth (K9 KO) that does not. By focusing on gene expression analysis in the sensory neurons that innervate affected skin in these animals, we have identified candidate genes whose differential expression is specifically correlated with PPK-associated pain. Through pharmacological and genetic approaches, we are interrogating the necessity of these gene expression changes for the pain phenotype, in the hopes of identifying targets for tailored therapy for PPK-associated pain. We are also employing more sophisticated single-cell transcriptomics to identify additional genes elevated in specific pain-associated neuronal subtypes, to broaden our list of candidate therapeutic targets.

Patients living with rare dermatologic conditions, including microcystic lymphatic malformations, cutaneous venous malformations, and other genodermatoses, face a profound unmet need, as these diseases lack FDA-approved therapies and validated clinical endpoints. For sponsors, this absence of precedent creates both significant development challenges and a unique opportunity to establish the first regulatory path forward and deliver meaningful therapies to patients.

At Palvella Therapeutics, our mission is centered on serving patients with rare dermatologic diseases and vascular anomalies by developing therapies that address both the biological drivers of disease and the outcomes that matter most to patients. Achieving this requires that clinical endpoint development begin with, and remain anchored in, the patient experience.

In the absence of established regulatory precedent, the development of optimal clinical endpoints depends on deliberate alignment across three critical stakeholders: patients, clinicians, and regulatory agencies. Endpoints must be scientifically rigorous, acceptable to regulators, and reflective of outcomes that are meaningful to patients.

This presentation outlines a collaborative framework in which patient insights, captured through structured interviews and patient-reported outcome instruments, inform the assessment of visible changes in disease and quality-of-life impact; clinician experts define objective measures of lesion morphology, severity, and progression; and early, iterative engagement with regulatory bodies to align on evidentiary expectations to support demonstration of safety and efficacy.

By integrating these perspectives, sponsors can develop fit-for-purpose clinical outcome assessments, including novel Investigator Global Assessment (IGA) scales and multi-component severity indices. These tools combine objective clinical evaluation with patient-reported measures of change, enabling robust and regulatory-aligned demonstrations of treatment benefit and ultimately accelerating the development of first-in-disease therapies for patients with no existing options.

Potential meaningful functional endpoint for clinical trials in pEDD drug development
Braiman Liora¹, Leibman Barak Shelly¹ , Patel Majeeda^2,3, De Brito Marianne^2,3, C David Hansen⁴, Schwartz Janice⁵, Evans Holly⁵, Katz Luba ¹, Brener Ephraim¹, Mashriki Tal¹, Aviezer David^1,6 Michel Dayana¹, O’Toole, Edel^2,3
1Kamari Pharma, Ness Ziona, Israel;² Center for Cell Biology and Cutaneous Research, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; ³Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK; ⁴Department of Dermatology, University of Utah, Salt Lake City, Utah; ⁵Pachyonychia Congenita Project, Salt Lake City, Utah; ⁶Bar Ilan University, Ramat Gan, Israel ⁸Kamari Pharma, Ness Ziona, Israel
Rare palmoplantar Epidermal Differentiation Disorders (pEDDs) are characterized by painful plantar keratoderma and substantial impaired mobility. It is of major importance to establish a clinically meaningful and objective endpoint for the development of novel treatments. This study evaluated the feasibility and relevance of such assessments: “Timed Up and Go” (TUG) and “Timed Free-Standing”(TFS) were employed in combination with a Pain NRS in patients with KRT6,16,17-pEDD and TRPV3-pEDD. Sixteen participants from PC Project’s patient research registry, completed the study under 3 conditions (shoes, socks, barefoot), alongside pain ratings and questionnaires. Mean ±SD TUG completion times increased progressively amid conditions evaluated (shoes 10.9 ±4.6 sec, socks 13.4 ±5.3 sec, barefoot 15.3 ±9.8 sec), and most participants did not achieve normal values (>10sec). Pain intensity increased as a function of conditions tested (3.6 ±2.5, 4.5 ±2.8 and 5.2 ±3.2, respectively). Higher pain correlated with slower TUG performance. For TFS, over 50% of participants completed 5-min standing across all conditions. Questionnaires showed substantial functional limitation and significant pain. These findings provide promising evidence that the TUG test combined with Pain NRS, is a clinically meaningful functional endpoint to assess mobility impairment and associated pain in pEDD’s. Further studies are planned to confirm the use of the TUG as a patient-centric, objective, functional outcome in clinical trials.

The recent years have witnessed dramatic advances in our understanding of the way genetic defects cause disease manifestations. While in the past, a specific genetic defect was expected to always give rise to the same clinical phenotype, it is today clear that environmental factors, epigenetic changes and co-inherited genetic variations can significantly affect the phenotypic expression of pathogenic variants driving disease manifestations. Modifiers of all three types have been identified in a wide range of skin diseases, including blistering disorders, ichthyoses and hair diseases. Phenotypic modification is not only of relevance to the genetic counseling of families at risk for genodermatoses, they may also point at novel therapeutic targets for these as well as more common diseases.

Keratin filaments: Regulating the organization and dynamics of ER-associated compartments

Navaneetha Krishnan Bharathan¹, William Giang¹, Andrew Kowalczyk¹

¹Department of Dermatology, Penn State College of Medicine, Hershey

Keratins are epithelial-specific intermediate filament proteins that provide mechanical resistance in tissues such as the epidermis. Epidermolysis bullosa simplex (EBS), a skin blistering disease, is caused by keratin 5/14 variants that aggregate the filaments. Prior studies have reported activation of endoplasmic reticulum (ER) stress and disruption of junctional desmosomes in EBS cell culture models. We find that peripheral ER tubules are in close proximity to keratin filaments and form paired arrangements at desmosome cell-cell junctions. Focused ion beam scanning electron microscopy (FIB-SEM) and live-cell fluorescence microscopy revealed intricate ER-keratin associations at points of contact we term the keratin-ER contact site. We also observe these associations in zebrafish (Danio rerio) embryonic epidermis. Optical flow analysis further demonstrates that keratin filaments stabilize ER membrane dynamics. Triggering disruption of keratin filaments by an EBS-causing aggregation variant, K14^R125C, leads to changes in ER morphology, converting ER tubules at the cell periphery to ER sheets. Lastly, we determined the effects of keratin aggregation on ER exit sites (ERES) using fluorescently-labelled Sec16A. In K14^WT cells, ERES are dynamic and migrate along filamentous keratin. In K14^R125C cells however, these compartments co-localize with aggregates and remain “stalled” along the ER membrane. Our results demonstrate that keratin filaments regulate the dynamics and organization of the ER and secretory compartments in epithelial cells, potentially leading to perturbation of desmosome assembly observed in EBS.

Palmoplantar (PP) skin is functionally and histologically distinct from non-PP skin. Inflammatory skin diseases may present differently when affecting PP versus other skin, and diseases in PP skin are often more refractory to topical and systemic therapies. These observations suggest PP skin embodies a unique immunological niche that is functionally distinct. We aimed to identify these differences by performing single-cell RNA-sequencing on CD45+ immune cells isolated from matched palm and hip biopsies from 6 healthy donors. No significant differences were seen in immune cell numbers between PP and non-PP skin. Unsupervised clustering of these immune cells revealed the major populations were antigen presenting cells (APC), T cells, and mast cells. While the APC populations between the skin sites were distinct, Langerhans cells (LCs) were the primary cell type in both PP and non-PP skin based on robust expression of CD207 and CD1A. Interestingly, inflammatory LCs (InLC), with gene ontology enrichment of inflammatory response, as well as IFN-γ, TNF and IL-2/STAT5 signaling, were predominantly isolated from the palm. In contrast, conventional LCs (ConvLC) were largely isolated from the hip. While ConvLCs also expressed TNF signature, they mainly upregulated metabolic pathways and environmental response such as MYC, mTORC1, protein folding, and UV response. While T cell subset proportions were similar between the two sites, they also appeared functionally distinct, with palmar CD4 and CD8 T cells exhibiting increased activation compared to those from the hip. Cell-cell interaction analysis between APCs and T cells revealed that palmar-specific interactions were focused on modulation of inflammation. These results define PP skin as a unique immunological site. They further suggest that PP presentations of common inflammatory dermatoses should be studied as disease entities independent from their non-PP counterparts and may require alternative therapeutic management.

Epigenetic regulation is fundamental to skin homeostasis and disease progression; however, the information on cell heterogenicity and the combinational histone modifications at a given cell state remain to be defined. Here we report the development of single-nucleus proteoform mass spectrometry (snPiMS), a technology that integrates nuclei isolation, top-down analysis of proteoforms (intact histone variants and their combinatorial post-translational modifications), and individual ion mass spectrometry (I²MS) coupled to nano-desorption electrospray ionization (nano-DESI). Applying snPiMS to human epidermal keratinocyte differentiation, we profiled ~400 proteoforms across >17,000 individual nuclei. Clustering of single-nucleus PiMS data using Seurat resolved 12 distinct proteoform-defined cell clusters, defining a continuum from an undifferentiated proliferative state to terminal differentiation. The undifferentiated, progenitor-enriched cluster (Cluster 4) exhibited elevated levels of HMGN2, acetylated H2A/H2B variants, and H2A.Z. The differentiated-keratinocyte-enriched cluster (Cluster 3) was defined by high levels of histone H3 bearing H3K4 acetylation together with H3K9 monomethylation. Bulk histone profiling corroborated these state-specific signatures. The enrichment H2A.Z in epidermal progenitors was validated at both the protein and mRNA levels. Functional studies demonstrated that H2A.Z is essential for epidermal progenitor function and tissue regeneration by maintaining nuclear integrity. Mechanistically, H2A.Z’s high expression in progenitors depends on MEK-ERK and mTOR-AKT signaling. H2A.Z’s dysregulation is observed in both psoriasis and atopic dermatitis. Together, these findings built a foundation for future work applying snPiMS to identify and subsequent characterization on epigenetic changes in skin homeostasis and disease progression.

Sodium is essential for maintaining tissue homeostasis, regulating fluid balance, and supporting immune function. Most of the body’s exchangeable sodium is stored in the skin at the dermatoepidermal junction, and it has been hypothesized that sodium forms an ionic concentration gradient that helps to reduce water loss. Therefore, we evaluated whether sodium magnetic resonance imaging (23Na MRI) can detect changes in skin sodium concentration following mechanical barrier disruption with tape stripping. Ten participants (56–80 years; 6 females, 4 males) underwent 23Na MRI of the calf at 7 Tesla using a dual-tuned 23Na/1H RF coil (RAPID Biomedical GmbH) equipped with a five-compartment NaCl (10–50 mM) phantom for quantitative reference 24 hours after barrier disruption via tape stripping with 20 D-Squame tapes on a standardized area on the right calf. On average, transepidermal water loss (TEWL) increased by 2.98 (SD 1.32) grams per square meter per hour (g/m²/h) after tape stripping. The mean skin sodium concentration was significantly higher in tape-stripped skin compared with non-tape-stripped control regions on the same calf (20.60 ± 8.24 mM vs. 18.96 ± 7.88 mM, p = 0.01). These findings demonstrate that 23Na MRI can noninvasively detect localized increases in skin sodium following mechanical barrier disruption. Skin sodium imaging may provide a novel biomarker of barrier integrity and may be useful for studying treatment response in future clinical studies.

Human pluripotent stem cell-derived tissue engineering offers great promise for cell-based therapeutics, but harnessing such potential requires a deeper understanding of tissue-level interactions. We previously developed a cell replacement manufacturing method for ectoderm-derived skin epithelium. However, it remains challenging to manufacture other iPSC-derived tissues such as the endoderm-derived esophageal epithelium despite possessing a similar stratified epithelial structure. The talk will reveal how we can employ single-cell and spatial technologies to generate a multi-omits digital twin of the developing tissue and then use machine-learning approaches to prioritize candidate developmental signals for iPSC-derived differentiation. Similar approaches could be used to generate a programmable tissue replacement platform. 

This presentation will give an overview of the development of a gene therapy skin graft for Epidermolysis Bullosa (EB) from Stanford to FDA approval and commercialization. Lessons learned will include filing an IND, starting an investigator-initiated Phase 1 trial, interacting with the FDA on rare disease endpoints, and licensing the project to a commercial company.  The Phase 3 randomized, controlled trial of Pz-cel (Zevaskyn) achieved both co-primary endpoints of wound healing and pain improvement compared with control. Pz-cel was approved in 2025.

Genetic skin diseases such as recessive dystrophic epidermolysis bullosa (RDEB) remain challenging to treat due to the need for efficient, safe, and durable gene delivery to the epidermis. We are developing a non-viral platform based on self-amplifying RNA (replicons) to enable high-level, more durable protein expression following topical administration. By combining replicon engineering with biomaterial-assisted delivery, we aim to overcome key barriers in skin penetration, cellular uptake, and sustained expression within keratinocytes. This approach offers a potentially scalable and repeatable strategy for restoring gene function without genomic integration, providing a new therapeutic paradigm for RDEB and other genetic skin disorders.

Rare genetic disorders affect millions worldwide, yet therapeutic development is limited by small patient populations, disease heterogeneity, and lack of validated endpoints. Designing effective clinical trials therefore requires innovative strategies, including natural history studies, patient registries, biomarker development, and adaptive trial designs. Collaboration among investigators, industry, regulators, and patient advocacy groups may help overcome key barriers and accelerate the translation of scientific discoveries into meaningful therapies for patients.

Rare diseases present unique challenges for clinicians and researchers due to small patient populations, limited expertise concentrated in few centers, and fragmented research efforts. International collaboration has therefore become essential to accelerate diagnosis, improve understanding of disease mechanisms, and facilitate the development of new therapies. Multinational networks enable the creation of shared registries, harmonized clinical criteria, and multicenter studies that would otherwise be impossible in rare conditions. This talk will explore the power of networking in the rare disease ecosystem through the example of the Darier Disease International Task Force (DD-ITF), a global collaborative initiative established to advance research and clinical care for Darier disease. The DD-ITF brings together international experts in dermatology to develop consensus definitions, harmonize diagnostic and severity assessment tools, and promote collaborative research efforts worldwide. The presentation will highlight how building structured international networks can catalyze progress in rare dermatologic diseases by connecting clinicians, researchers, patient organizations, and industry partners. Practical insights will be shared on establishing collaborative frameworks, fostering cross-border research, and creating opportunities for young investigators and clinicians to engage in global initiatives. Ultimately, the experience of the Darier Disease International Task Force illustrates how strategic networking can transform a rare disease field—from isolated efforts to a coordinated international community—accelerating scientific discovery and improving outcomes for patients worldwide.