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.Gly13Asp, 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.

Keywords: Costello syndrome; HRAS; cancer; ectodermal; mutation p.Gly13Asp.

Figure 1

Clinical features of patients 1-4. Facial features at different ages observed in patients 1 (A – infancy, B – childhood and C and D – adolescence), 2 (E – infancy and F – adulthood) and 3 (I – infancy and J – childhood). Frontal and lateral view of patient 4 is depicted in K and L. Note the short, sparse hair with abnormal texture, especially in individuals 1 and 3, perinasal papilloma in patient 2(D), and the prominent hyperkeratosis in the hands of patient 2 (G,H).

Figure 2

Clinical features of patient 5 and chromatogram of HRAS sequencing. A- Facial features at age 3 years 11 months, note high forehead and short blond hair, B- Hyperkeratosis on her knees, C-hyperkeratosis on her foot, D- scalp hair with a majority of short blond hairs and very few long brown hairs, E- scalp hair over her occiput showing the majority of blond hair with a patch of darker, longer and typical appearing hair, as well as streaky skin hypopigmentation compared to the relatively hyperpigmented surrounding skin of the neck. F- chromatogram of HRAS sequencing of the probands cheek swab derived DNA (labeled buccal) showing the more prominent wild type and the lesser mutant allele (arrow); the chromatogram for hair root cell derived DNA (labeled blond and brown, respectively) showing 50% mutant allele (blond hair, arrow) or only wild type allele (brown hair, arrow), respectively.