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- Presentation
New Insights into Ectodermal Dysplasia Pathogenesis from the Registry of Ectodermosis and Related Skin Types
Description
This talk described the Registry of Ectodermosis and Related Skin Types at Yale, which collects detailed clinical data, photographs, genetic results, and consent from patients with ectodermal dysplasias and related disorders. More than 1,582 kindreds have been enrolled and over 90% solved using a stepwise approach: phenotyping, targeted gene panels, and whole-exome sequencing for unsolved cases. Several recent discoveries were highlighted. In one non-syndromic case, progressive symmetric erythrokeratoderma was linked to a novel EMP2L4P mutation; spatial transcriptomics and protein studies showed aberrant EGFR and FAK/Src/ERK signaling, and treatment with an EGFR inhibitor led to near-complete resolution. In a syndromic EGFR-mutant disorder with skin, lung, and neurodevelopmental findings, the same pathway was activated, and third-generation EGFR inhibition improved both skin lesions and lung nodules. A diagnostically challenging mosaic acantholytic disorder was ultimately attributed to a GJB2 L28H variant found only in affected keratinocytes; functional assays showed desmosomal fragility and increased MAPK signaling, which was corrected by trametinib, producing clinical remission. The speaker emphasized that unresolved cases may involve structural variants, repeat expansions, or unknown genes, and that multi-omic methods such as transcriptomics, long-read sequencing, and immune profiling are helping uncover them. The registry aims to expand participation, improve diagnosis, and identify targeted therapies for rare but treatable disease.
View moreConclusions
- A large registry-based, phenotype-first approach can solve most EDD cases and provides a powerful resource for gene discovery and translational research.
- Novel de novo EMP2 mutations can cause PSEK, and the disease appears to involve aberrant EGFR and FAK-Src-ERK signaling in patient skin and keratinocytes.
- Targeting the activated EGFR pathway with EGFR inhibitors can produce marked clinical improvement or complete resolution in EMP2-associated PSEK.
- De novo germline EGFR L858R can cause a syndromic EDD phenotype with skin disease plus lung and neurodevelopmental involvement.
- EGFR inhibition with osimertinib can improve both cutaneous lesions and pulmonary nodules in EGFR-SEDD, suggesting a disease-modifying therapy.
- Some acantholytic eruptions that resemble classic disorders may instead be mosaic diseases, so repeat evaluation and somatic testing are essential when germline testing is negative.
- Somatic GJB2 L28H can cause acantholytic dyskeratosis by impairing intercellular adhesion and destabilizing keratinocyte sheets.
- MEK inhibition can restore adhesion in GJB2-associated acantholytic disease and lead to durable clinical improvement.
- The unresolved EDD cases likely fall into categories including missed structural variants, unknown genes, and complex mosaic mechanisms.
- Multi-omic strategies, especially transcriptomics plus long-read genome sequencing, are needed to uncover hidden variants such as exon skipping and tandem repeat expansions.
- Immune profiling suggests that EDD is not one uniform inflammatory state, because some patients show Th17-like patterns while others show Th2-like patterns.
- Immune endotyping may help guide personalized treatment choices in EDDs.
- The remaining unsolved cases and their candidate mechanisms indicate that further registry participation is needed to complete the genetic and therapeutic map of EDDs.
- Jiang et al. Proc Natl Acad Sci U S A. 2025 Aug.
- Jiang et al. JAMA Dermatol. 2026 Mar.
- Wang et al. 2021. PMID: 34909719.
- Wang & Murphy et al. 2025, medRxiv.
- De Novo Germline L858R EGFR Variants and Generalized Acanthosis Nigricans.