HRAS p.Gly12Val mutations in four patients with neonatal lethal Costello syndrome

De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory and muscular complications. Specific HRAS mutations encoding p.Gly12Val, p.Gly12Asp and p.Gly12Cys have been associated with severe, lethal, CS. We report clinical and pathological findings in four further patients with p.Gly12Val mutations. All died within the first 6 postnatal weeks, providing further evidence that these mutations strongly predict a very poor prognosis. High birthweight, polyhydramnios (precipitating delivery at 28 weeks’ and 30 weeks’ gestation in two cases), cardiac hypertrophy, respiratory distress, muscle weakness and postnatal growth failure were present. Dysmorphism was subtle or nonspecific, including oedema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares and low set ears. Talipes and fixed flexion deformities of the wrists were present. Neonatal atrial arrhythmia, highly suggestive of CS, was present in two cases.A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphic signs in neonates requiring intensive care, suggest that this may still be an under-recognised condition. We suggest that severe CS, as described here, should enter the differential diagnosis for very sick infants with a range of clinical problems. Clinical management should be informed by knowledge of the poor prognosis of this condition.