Mutation and phenotypic spectrum in patients with cardio‐facio‐cutaneous and Costello syndrome

Cardio‐facio‐cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS–RAF–MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF , MAP2K1 , MAP2K2 and KRAS , HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC‐affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty‐four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC‐affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty‐eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1 ‐ and MAP2K2 ‐mutation positive individuals, suggesting possible genotype–phenotype correlations.