HRAS – Noonan Syndrome-like Disorder with Loose Anagen Hair

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is an ultra-rare RASopathy characterized by dysmorphic facial features resembling Noonan syndrome and distinctive ectodermal findings including sparse, easily pluckable, thin, and slow-growing hair (MONDO:0011899). Germline mutations in RAS/MAPK pathway genes underlie RASopathies; however, NS/LAH has been most commonly associated with activating variants in SHOC2. Recent evidence implicates germline gain-of-function variants in HRAS as a cause of an attenuated RASopathy overlapping NS/LAH.

In a single three-generation pedigree, six affected individuals harbor the heterozygous HRAS variant c.176C>T (p.Ala59Val) and share a mild RASopathy with ectodermal anomalies and characteristic NS/LAH features. The variant segregates in an autosomal dominant fashion with complete penetrance across three generations, with no reports of nonpenetrance or unaffected carriers (6 affected relatives) (PMID:37194190).

The c.176C>T (p.Ala59Val) change affects the highly conserved switch II/G3 region of H-Ras p21. Functional assays previously demonstrated that substitution of alanine at codon 59 impairs intrinsic GTP hydrolysis, resulting in prolonged GTP-bound active HRAS and downstream MAPK pathway activation consistent with other RASopathy-causing gain-of-function alleles (PMID:37194190).

No additional unrelated probands have been reported to date. Despite robust segregation and mechanistic concordance, evidence is currently limited to a single pedigree. Additional cases and independent functional studies would further solidify the gene–disease relationship.

Key Take-home: Germline HRAS c.176C>T (p.Ala59Val) acts via impaired GTP hydrolysis to cause an attenuated, autosomal dominant RASopathy clinically overlapping NS/LAH, warranting inclusion of HRAS in diagnostic RASopathy gene panels for patients with loose anagen hair phenotypes.

References

• American journal of medical genetics. Part A • 2023 • A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C>T p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome PMID:37194190

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