SHOC2 – Costello Syndrome

SHOC2 encodes a scaffold protein in the RAS-MAPK pathway and is implicated in Noonan-like syndrome with loose anagen hair, but its role in classical Costello syndrome (CS) remains unsupported. Comprehensive mutation screens in CS cohorts (n=5) have identified HRAS pathogenic variants exclusively, with no SHOC2 changes detected (PMID:21784453; PMID:23250860). In a Brazilian RASopathy series (26 cases), 2 SHOC2 variants were found among mixed Noonan and CS referrals, yet neither case met strict CS diagnostic criteria (PMID:36304179).

Functional assays of SHOC2 mutants (e.g., p.Ser2Gly, p.Met173Ile) demonstrate gain-of-function effects on ERK1/2 signaling and developmental phenotypes in cell and animal models, but these relate to Mazzanti syndrome/Noonan-like hair syndrome rather than CS. No genotype-phenotype data support SHOC2 pathogenicity in CS, and clinical features such as papillomata, loose anagen hair, and ectodermal abnormalities differ from the classic CS spectrum. Taken together, the evidence disputes a causal link between SHOC2 variants and Costello syndrome.

References

• The Journal of pediatrics • 2011 • Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. PMID:21784453
• International journal of hematology • 2013 • Ras/MAPK syndromes and childhood hemato-oncological diseases. PMID:23250860
• The application of clinical genetics • 2022 • RASopathy Cohort of Patients Enrolled in a Brazilian Reference Center for Rare Diseases: A Novel Familial LZTR1 Variant and Recurrent Mutations. PMID:36304179

Evidence Based Scoring (AI generated)