Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp

Abstract

Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p ly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.

Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results

“…Data in Brief, Table 1 shows the distribution of the affected genes by syndrome. Of note, one patient, carrying a missense mutation in HRAS mutation (p.Gly13Asp) rarely occurring in CS, was diagnosed as affected by NS based on his clinical features, in line with a recent report [16]. This patient was not affected by heart disease.…”

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

“…Consistent with the collected functional data, p.Gln72Leu (analogous to p.Gln61Leu in HRAS, NRAS, and KRAS) is a strong activating mutation and has not been observed to occur as a germline event in HRAS, KRAS, or NRAS. Similar differences in the biological and phenotypic consequences have previously been reported for HRAS, NRAS, and KRAS, [12][13][14]30,31,[46][47][48][49][50][51][52][53] including the positions corresponding to the presently identified RRAS2 mutations. The genotype-phenotype correlations in HRAS are illustrative and correlate well with the present findings: while p.Ala59Thr has been associated with Costello syndrome and p.Gly12Val has been reported with severe expression of Costello syndrome, 46 p.Gln61Leu and other changes at this codon have only been reported as somatic events in cancer (Table S1).…”

A case of woolly hair nevus, multiple linear pigmentation, and epidermal nevi with somatic HRAS p.G12S mutation

“…Ninety percent of Costello syndrome patients showed HRAS p.G12S mutations . According to a report by Bertola et al . woolly hair was found in 88% of cases with HRAS p.G12S mutations and in 33% of cases with other mutation.…”