title: De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features.
abstract: Mutations in genes involved in Ras signalling cause Noonan syndrome and other disorders characterised by growth disturbances and variable neuro-cardio-facio-cutaneous features. We describe two sisters, 46 and 31 years old, who presented with dysmorphic features, hypotonia, feeding difficulties, retarded growth and psychomotor retardation early in life. The patients were initially diagnosed with Costello syndrome, and autosomal recessive inheritance was assumed. Remarkably, however, we identified a germline HRAS mutation (G12A) in one sister and a germline KRAS mutation (F156L) in her sibling. Both mutations had arisen de novo. The F156L mutant K-Ras protein accumulated in the active, guanosine triphosphate-bound conformation and affected downstream signalling. The patient harbouring this mutation was followed for three decades, and her cardiac hypertrophy gradually normalised. However, she developed severe epilepsy with hippocampal sclerosis and atrophy. The occurrence of distinct de novo mutations adds to variable expressivity and gonadal mosaicism as possible explanations of how an autosomal dominant disease may manifest as an apparently recessive condition.
authors.affiliation: Section for Pediatrics, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Oddmund
authors.initials: O
authors.lastname: Søvik
authors.forename: Suzanne
authors.initials: S
authors.lastname: Schubbert
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.forename: Solrun J
authors.initials: SJ
authors.lastname: Steine
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norgård
authors.forename: Bernt
authors.initials: B
authors.lastname: Engelsen
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics; D006624:Hippocampus / Q000002:abnormalities / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D012868:Skin Abnormalities / Q000235:genetics; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins