title: Two novel germline KRAS mutations: expanding the molecular and clinical phenotype.
abstract: Noonan and Cardio-facio-cutaneous (CFC) syndromes are characterized by typical dysmorphic features, cardiac defects, short stature, variable ectodermal anomalies, and intellectual disability. Both belong to the Ras/mitogen-activated protein kinase pathway group of disorders and clinical features overlap other related conditions, notably LEOPARD and Costello syndromes. KRAS mutations account for about 2% of reported Noonan and <5% of reported CFC cases. The mutation spectrum includes recurrent missense changes clustering in particular domains of the KRAS protein and conferring gain-of-function. We report three patients from two unrelated families with novel missense KRAS mutations, p.K147E and p.Y71H. Both mutations affect a residue which is highly conserved in KRAS and other RAS isoforms. One of the families includes a mother and son pair who represent the first report of a vertically transmitted KRAS mutation. In addition, the mother and son pair had peripheral neuropathy, complicated by Charcot arthropathy in the mother. An unusual phenotypic effect of the specific KRAS mutation or a coincidence of two independent disorders may be considered. KRAS mutation-associated phenotypes appear to be subject to considerable clinical heterogeneity. All three cases highlight the challenges of clinical assessment in KRAS mutation-positive patients, and the utility of molecular testing as an adjunct to diagnosis.
authors.affiliation: Genetic Health Services Victoria, Murdoch Children's Research Institute, Melbourne, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Stark
authors.forename: G
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: M M
authors.initials: MM
authors.lastname: Ryan
authors.forename: I C
authors.initials: IC
authors.lastname: Cirstea
authors.forename: L
authors.initials: L
authors.lastname: Gremer
authors.forename: M R
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: R
authors.initials: R
authors.lastname: Savarirayan
authors.forename: M
authors.initials: M
authors.lastname: Zenker
mesh_terms: D001177:Arthropathy, Neurogenic / Q000150:complications / Q000235:genetics; D002675:Child, Preschool; D003937:Diagnosis, Differential; D004476:Ectodermal Dysplasia / Q000150:complications / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000150:complications / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000235:genetics; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins