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

Area of Science:

• Genetics
• Dermatology
• Rare Diseases

Background:

• Costello syndrome (CS) is a rare dominant RASopathy caused by HRAS gene mutations.
• Specific HRAS variants in codons 58-60 are linked to milder clinical presentations.
• Ectodermal abnormalities are key features in some RASopathy phenotypes.

Purpose of the Study:

• To characterize a novel heterozygous HRAS variant (c.175G>A, p.Ala59Thr) in a three-generation family.
• To investigate the clinical phenotype associated with this specific HRAS variant.
• To differentiate this phenotype from classic Costello syndrome.

Main Methods:

• Genetic analysis using exome and Sanger sequencing.
• Clinical evaluations including dermatological and cardiac assessments.
• Microscopic examination of skin biopsy and hair samples.

Main Results:

• Identified a previously unreported HRAS variant c.175G>A (p.Ala59Thr) in affected family members.
• Observed a consistent phenotype primarily involving ectodermal features: woolly/sparse hair, curly eyelashes, sparse eyebrows, ulerythema ophryogenes, keratosis pilaris, palmoplantar keratoderma, and ear anomalies.
• Classic Costello syndrome features like craniofacial anomalies, hypertrophic cardiomyopathy, and intellectual disability were notably absent or minimal.

Conclusions:

• The HRAS c.175G>A (p.Ala59Thr) variant results in a predominantly ectodermal phenotype, representing a milder form of HRAS-related RASopathy.
• This phenotype is distinguishable from classic Costello syndrome, particularly due to the lack of severe systemic involvement.
• Considering HRAS variants in patients presenting with ectodermal and Costello syndrome-like features is crucial for accurate diagnosis and management.