Hypohidrotic ectodermal dysplasia: association between EDA mutations and hypotrichosis - a case series.

Hypohidrotic ectodermal dysplasia (HED) is the most common form of ectodermal dysplasia in the general population. The clinical manifestations of HED include fever due to hypohidrosis, hypotrichosis, dental hypoplasia, and characteristic aged facial features, along with multisystem involvement. Over 20 genes have been implicated in HED, with EDA being the most frequent pathogenic gene. To expand the mutational spectrum of HED and explore the association between EDA mutations and hypotrichosis. Whole-exome sequencing, target gene sequencing, and Sanger sequencing were performed with prediction of protein structure. We identified five novel variants and five structural variants (with large indels and copy number variation). Copy number variation was validated through targeted sequencing and quantitative PCR. Patients harbouring deletion, nonsense, and splice-site mutations exhibited more severe phenotypes. We report a series of HED cases with mutations in EDA, EDAR, and NFKBIA, expanding the mutational spectrum of EDA, with analysis of genotype-phenotype correlations associated with EDA mutations. We propose that focal alopecia may serve as an easily observable clinical marker for disease severity stratification. Mutations disrupting critical structural domains or altering spatial conformation of the EDA protein may underlie these severe clinical manifestations by impairing protein stability or functional interactions.