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.