Novel EDAR death domain variants in Thai patients with ectodermal dysplasia: clinical, molecular, and scoping review...

Ectodermal dysplasia (ED) is a group of inherited disorders that affect ectodermally derived structures, including teeth, hair, sweat glands, and salivary glands. Variants in the EDAR gene, particularly within its intracellular death domain, disrupt EDA signaling and contribute to ED. Although EDAR-associated ED is well documented globally, clinical and molecular data from Southeast Asia remain limited.

To report two novel Thai cases with heterozygous EDAR variants and to systematically map the phenotypic and genotypic spectrum of previously reported EDAR-related disorders through a scoping review.

Two unrelated Thai patients with dental agenesis underwent detailed clinical, salivary, radiographic, ultrastructural, and genetic evaluations. A systematic scoping review was conducted following PRISMA-ScR guidelines to synthesize clinical phenotypes associated with EDAR variants across diverse populations. Eligibility criteria included original case reports, case series, and cohort studies reporting human subjects with EDAR variants; exclusion criteria were reviews, abstracts, and non-human studies. Sources of evidence included PubMed, Scopus, and Embase searched from January 1995 to April 2025.

Both patients carried heterozygous EDAR variants within the death domain: a de novo frameshift (c.1087_1088insGA; p.Thr363Argfs*10) and a missense variant (c.1271T > G; p.Val424Gly). Both exhibited hypodontia and reduced salivary and sweat gland function, but clinically normal hair and nail morphology. The scoping review included nine studies across Europe, Asia, and the Middle East, highlighting common features like hypohidrosis and dental anomalies, while noting the infrequent assessment of salivary function.

These two EDAR variants broaden the mutational and phenotypic spectrum of EDAR-related ED and, to our knowledge, represent the first cases reported from Thailand, thereby expanding the geographic and ethnic understanding of EDAR-associated disorders. Beyond variant identification, this study emphasizes the diagnostic value of incorporating salivary flow and ultrastructural assessments into phenotyping, features rarely evaluated in prior reports.