title: Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.
abstract: Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.
authors: Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware, USA. kgripp@nemours.org
authors: Karen W
authors: KW
authors: Gripp
authors: Elizabeth
authors: E
authors: Hopkins
authors: Katia
authors: K
authors: Sol-Church
authors: Deborah L
authors: DL
authors: Stabley
authors: Marni E
authors: ME
authors: Axelrad
authors: Daniel
authors: D
authors: Doyle
authors: William B
authors: WB
authors: Dobyns
authors: Cindy
authors: C
authors: Hudson
authors: John
authors: J
authors: Johnson
authors: Romano
authors: R
authors: Tenconi
authors: Gail E
authors: GE
authors: Graham
authors: Ana Berta
authors: AB
authors: Sousa
authors: Raoul
authors: R
authors: Heller
authors: Maria
authors: M
authors: Piccione
authors: Giovanni
authors: G
authors: Corsello
authors: Gail E
authors: GE
authors: Herman
authors: Marco
authors: M
authors: Tartaglia
authors: Angela E
authors: AE
authors: Lin
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D056685:Costello Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D005145:Face / Q000002:abnormalities; D005260:Female; D006330:Heart Defects, Congenital / Q000209:etiology; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009139:Musculoskeletal Abnormalities / Q000209:etiology; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000209:etiology; D010641:Phenotype; D011247:Pregnancy; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D055815:Young Adult
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras)