Date of Award

January 2026

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Keith A. Choate

Abstract

Epidermal differentiation disorders (EDDs) are a heterogeneous group of inherited skin diseases characterized by impaired epidermal barrier function, scaling, and erythema. Although substantial progress has been made in identifying the genetic causes of EDD, long-standing clinical observations—including impaired growth, ectropion, and increased rates of preterm birth—remain poorly characterized across genotypes. The prevalence, severity, and clinical significance of these manifestations have not been systematically evaluated in large, genotype-stratified cohorts, limiting the ability to provide anticipatory guidance and tailored clinical care. This thesis seeks to (1) characterize growth trajectories in children with EDD and determine genotype-specific patterns of growth impairment; (2) assess the prevalence and severity of ectropion across EDD genotypes and validate the Ectropion Severity Score (ESS) for use in this population; and (3) evaluate the incidence of preterm birth across genetic subtypes of EDD. We hypothesized that systemic manifestations of EDD—including growth impairment, ectropion, and prematurity—vary substantially by genotype and are driven by intrinsic disease biology rather than secondary or modifiable factors alone. We further hypothesized that specific genotypes associated with more severe epidermal barrier dysfunction would demonstrate higher rates of these complications. Growth outcomes were evaluated using two complementary data sources: a cross-sectional case–control analysis of the NIH All of Us Research Hub and a longitudinal cohort from the National Registry for Ichthyosis. Longitudinal growth parameters (weight, height, and head circumference) were compared with population norms and unaffected siblings using linear mixed models. Ectropion prevalence and severity were assessed using the ESS applied to standardized clinical photographs, with interrater reliability measured using intraclass correlation coefficients. Preterm birth rates were calculated from registry data across 54 genetically confirmed EDD subtypes and compared with population-level rates. Children with EDD demonstrated significantly increased risk of early-life growth impairment, with substantial heterogeneity by genotype. While many participants exhibited catch-up growth after infancy, individuals with SPINK5 variants showed persistent height deficits extending through adolescence. Nutritional supplementation did not significantly alter growth trajectories, suggesting that excessive metabolic expenditure related to barrier dysfunction is a primary driver of impaired growth. Ectropion prevalence and severity varied widely by genotype, with the highest burden observed in TGM1, ABCA12, SPINK5, and PNPLA1 variants. The ESS demonstrated excellent interrater reliability, supporting its use in EDD. Preterm birth occurred at significantly elevated rates in multiple genotypes, including ABCA12, TGM1, ALOX12B, and SPINK5, while STS variants were associated with reduced prematurity risk. This work provides the most comprehensive genotype-stratified analysis to date of growth impairment, ectropion, and prematurity in EDD. By identifying genotype-specific risks and trajectories, these findings enable more precise anticipatory guidance, improved multidisciplinary care, and earlier intervention for affected individuals. For patients and families, this work offers critical information to inform expectations, surveillance, and decision-making across childhood and pregnancy. For clinicians and researchers, it establishes a framework for genotype-driven risk stratification and highlights key areas for future mechanistic and therapeutic investigation.

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This is an Open Access Thesis.

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