title: Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype?
abstract: Costello syndrome is a rare congenital disorder typically characterized by severe failure-to-thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, distinctive facial features, a predisposition to papillomata and malignant tumors, neurologic abnormalities, developmental delay, and mental retardation. Its underlying cause is de novo germline mutations in the oncogene HRAS. Almost all Costello syndrome mutations affect one of the glycine residues in position 12 or 13 of the protein product. More than 80% of patients with Costello syndrome share the same underlying mutation, resulting in a G12S amino acid change. We report on two patients with novel HRAS mutations affecting amino acids 58 (T58I) and 146 (A146V), respectively. Despite facial features that appear less coarse than those typically seen in Costello patients, both patients show many of the physical and developmental problems characteristic for Costello syndrome. These novel HRAS mutations may be less common than the frequently reported G12S change, or patients with these changes may be undiagnosed due to their less coarse facial features. In addition to the findings previously known to occur in Costello syndrome, one of our patients had hypertrophic pyloric stenosis. This led us to review the medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients, and we found a statistically significantly (P < 0.001) increased frequency of pyloric stenosis in Costello syndrome (5/58) compared to the general population frequency of 2-3/1,000. Thus we add hypertrophic pyloric stenosis to the abnormalities seen with increased frequency in Costello syndrome.
authors.affiliation: Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware 19899, USA. kgripp@nemours.org
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Marni E
authors.initials: ME
authors.lastname: Axelrad
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Gillan
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.forename: Christine
authors.initials: C
authors.lastname: Davies
authors.forename: Norma J
authors.initials: NJ
authors.lastname: Leonard
authors.forename: Monique
authors.initials: M
authors.lastname: Lapointe
authors.forename: Daniel
authors.initials: D
authors.lastname: Doyle
authors.forename: Sarah
authors.initials: S
authors.lastname: Catalano
authors.forename: Linda
authors.initials: L
authors.lastname: Nicholson
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Stabley
authors.forename: Katia
authors.initials: K
authors.lastname: Sol-Church
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003071:Cognition / Q000502:physiology; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D005146:Facial Asymmetry / Q000150:complications / Q000151:congenital* / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011581:Psychological Tests; D011707:Pyloric Stenosis / Q000150:complications / Q000175:diagnosis; D013577:Syndrome
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)