Ectodermal dysplasias and isolated ectodermal anomalies: expanding the clinical and molecular spectrum in a cohort of...

Ectodermal dysplasias are clinically and genetically heterogeneous congenital disorders characterized by abnormal development of at least two of the four ectodermal tissues: teeth, hair, nails, and sweat glands. In this study, we summarized the clinical and molecular characteristics of the patients and contributed to the genotype-phenotype correlation. For genetic diagnosis, single-gene testing, clinical exome sequencing, whole-exome sequencing, and variant confirmation analyses were performed. In this study, 30 ectodermal dysplasia patients from 18 families and six patients with isolated ectodermal anomalies from three families were analyzed. A total of 21 unique variants were identified, five of which were novel. Of these, seven were classified as pathogenic, 11 as likely pathogenic, and three as variants of uncertain significance (LIPH, TSPEAR, HR). Hypohidrotic ectodermal dysplasia was the most frequently identified subtype, with variants in the EDAR gene found in 10 patients and in the EDA gene in seven patients. Two patients harbored WNT10A variants. Variants in the CDH3 gene were identified in six patients with macular degeneration. Additionally, variants in the LIPH and LPAR6 genes were detected in three patients presenting with woolly hair. In the remaining eight patients, variants were identified in the HR, TSPEAR, TP63, DSG1, and CST6 genes. Microcephaly was observed in 47% (8/17) of patients in the hypohidrotic ectodermal dysplasia group (EDA, EDAR) and in 66% (4/6) of patients carrying CDH3 variants. The patient with a TSPEAR variant also had Beckwith-Wiedemann syndrome.

Our clinical findings, together with the identification of novel variants in EDAR, LIPH, LPAR6, HR, and TP63, expand the clinical and molecular spectrum of ectodermal dysplasias. A potential association between microcephaly and ectodermal dysplasia is discussed. This study highlights the genetic heterogeneity of ectodermal dysplasias and emphasizes the importance of combining detailed clinical evaluation with molecular diagnostics.

• Ectodermal dysplasias (EDs) are congenital disorders characterized by abnormal development of at least two of four ectodermal structures, such as hair, nails, teeth, and sweat glands. EDs represent a clinically and genetically heterogeneous group of disorders with over 200 distinct types described.

• In the current study, we report the clinical and molecular genetic analysis of 36 patients and contribute to the genotype-phenotype correlation. Five novel variants were identified. Microcephaly was observed in 47% of patients in the hypohidrotic ectodermal dysplasia group and in 66% of patients carrying CDH3 variants. The patient with a TSPEAR variant also had Beckwith-Wiedemann syndrome.