title: Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D.
abstract: Costello syndrome (CS) is a rare congenital disorder characterized by severe failure to thrive, coarse facial appearance, cardiac and skin abnormalities, developmental delay, intellectual disability, and predisposition to malignancies. Heterozygous de novo germline mutations in the proto-oncogene HRAS cause CS. About 80% of patients share the same mutation resulting in the amino acid change p.G12S and present a relatively homogeneous phenotype. Other less common lesions in HRAS can induce a milder phenotype on the one hand and a more severe phenotype on the other broadening the spectrum of clinical manifestations in CS-affected individuals. We report two new patients with the HRAS p.G12C and p.G12D substitutions and a severe neonatal manifestation causing death at the age of three months and 13 days, respectively. Both patients had particularly severe heart involvement with hypertrophic cardiomyopathy and tachyarrhythmia, generalized edema, and respiratory distress. In one case, hypertrophic cardiomyopathy was already noted prenatally. These cases together with other individuals harboring the rare HRAS mutations p.G12C, p.G12V, p.G12D, and p.G12E provide further evidence for a genotype-phenotype correlation that could be of importance for counseling and medical management.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Lorenz
authors.forename: Christine
authors.initials: C
authors.lastname: Petersen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kordaß
authors.forename: Heide
authors.initials: H
authors.lastname: Seidel
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D056685:Costello Syndrome / Q000175:diagnosis / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)