The HRAS Variant c.175G>A (p.Ala59Thr) Causes a Predominantly Ectodermal Phenotype Lacking Classic Costello Syndrome Features

Costello syndrome (CS) is a rare dominant HRAS RASopathy characterized by curly hair, cardiac abnormalities, craniofacial anomalies, and developmental delay. HRAS codon 58, 59, and 60 variants are associated with milder phenotypes. We describe a three‐generation family with a previously unreported heterozygous HRAS variant c.175G>A (p.Ala59Thr) causing a predominantly ectodermal phenotype. Exome and Sanger sequencing were used for genetic analysis. Dermatological and cardiac evaluations were performed, including skin biopsy and hair sample microscopy. A 14‐year‐old proband, her twin sister, mother, mother's father, and mother's paternal half‐brother all shared a phenotype of woolly and sparse hair, curly eyelashes, sparse eyebrows, ulerythema ophryogenes, keratosis pilaris, palmoplantar keratoderma, and low‐set posteriorly rotated ears. One patient required a gastrostomy after birth but otherwise classic CS features, including craniofacial anomalies, hypertrophic cardiomyopathy, and intellectual disability, were absent. We conducted a comparison supporting the attenuated CS phenotype associated with HRAS codon 58–60 variants. In conclusion, HRAS c.175G>A (p.Ala59Thr) causes predominantly an ectodermal phenotype, consistent with milder HRAS ‐related RASopathies involving codons 58–60 distinguishable from classic CS. HRAS variants should be considered in patients with ectodermal and CS‐like features for accurate genetic diagnosis and targeted management.