Costello syndrome

Costello syndrome

Costello syndrome is a genetic disorder due to missense mutations in HRAS gene [1], which is detected in 80 – 90% of those with the clinical diagnosis and can have cardiac involvement. Aoki et al identified four heterozygous de novo mutations of HRAS in twelve of thirteen patients studied by them. These have been previously reported as somatic and oncogenic mutations in various tumours. The authors noted that germline mutations in HRAS alter human development and increase susceptibility to tumours. Patients with Costello syndrome have a 15% lifetime risk of malignant tumors including rhabdomyosarcoma, neuroblastoma and transitional cell carcinoma. Inheritance is in an autosomal dominant pattern.

Cardiac involvement in Costello syndrome occurs in the form of hypertrophic cardiomyopathy, valvular pulmonary stenosis and atrial arrhythmias (chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Children with Costello syndrome have failure to thrive, short stature, developmental delay, intellectual disability, coarse facial features, hypotonia and joint laxity. Polyhydramnios, often severe, is an important prenatal association (90%) as well as severe postnatal feeding difficulties.

Reference

1. Yoko Aoki, Tetsuya Niihori, Hiroshi Kawame, Kenji Kurosawa, Hirofumi Ohashi, Yukichi Tanaka, Mirella Filocamo, Kumi Kato, Yoichi Suzuki, Shigeo Kure, Yoichi Matsubara. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005 Oct;37(10):1038-40.