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.
- CFC, cardio-facio-cutaneous
- CS, Costello’s syndrome
- GTP, guanosine triphosphate
- MAPK, mitogen-activated protein kinase
- NF1, neurofibromatosis type 1
- NS, Noonan’s syndrome
- SNP, single nucleotide polymorphism
- Costello syndrome
- cardio-facio-cutaneous syndrome
- Noonan syndrome
- MAPK signalling pathway
- Ras genes
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Funding: This work was supported by grants from the Research Council of Norway and the Meltzer Foundation to O Søvik, from Helse Vest and the University of Bergen to A Molven and P R Njølstad, and by NIH grants R01 CA72614 and R01 CA104282 to K Shannon.
Competing interests: None declared.
↵* The second and third authors contributed equally to this work.
Parental informed consent was obtained for publication of figure 1.