Open AccessDe novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features
Author(s) -
Oddmund Søvik,
Suzanne Schubbert,
Gunnar Houge,
Solrun J. Steine,
Gunnar Norgård,
Bernt A. Engelsen,
Pål R. Njølstad,
Kevin Shan,
Anders Molven
Publication year - 2009
Publication title -
bmj case reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.231
H-Index - 26
ISSN - 1757-790X
DOI - 10.1136/bcr.07.2008.0550
Subject(s) - hras , costello syndrome , short stature , genetics , noonan syndrome , germline mosaicism , medicine , mutation , germline mutation , hypertrichosis , expressivity , germline , kras , hypotonia , biology , gene
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, who presented with dysmorphic features, hypotonia, retarded growth and psychomotor retardation. The patients were initially diagnosed with Costello syndrome, an 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.