TY - JOUR T1 - De novo <em>HRAS</em> and <em>KRAS</em> mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features JF - Journal of Medical Genetics JO - J Med Genet SP - e84 LP - e84 DO - 10.1136/jmg.2007.049361 VL - 44 IS - 7 AU - Oddmund Søvik AU - Suzanne Schubbert AU - Gunnar Houge AU - Solrun J Steine AU - Gunnar Norgård AU - Bernt Engelsen AU - Pål R Njølstad AU - Kevin Shannon AU - Anders Molven Y1 - 2007/07/01 UR - http://jmg.bmj.com/content/44/7/e84.abstract N2 - 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. ER -