Costello Syndrome

Costello syndrome (MIM 218040) is a multiple congenital anomaly syndrome originally reported by J.M. Costello. Individuals with Costello syndrome have distinctive facial features, loose skin, hypermobility of small joints, heart defects, cardiomyopathy, and a predisposition to tumors. In 2005, we identified germline mutations in HRAS (Harvey rat sarcoma viral oncogene homolog) in individuals with Costello syndrome. The affected individuals had heterozygous HRAS mutations, indicating an autosomal-dominant inheritance pattern. Costello syndrome is the first disorder reported to be associated with germline mutations in the RAS subfamily of small guanosine triphosphatase. This discovery provides a clue for the identification of germline mutations in genes related to the RAS/mitogen-activated protein kinase pathway in individuals with clinically related disorders, such as Noonan, Costello, and cardio-facio-cutaneous syndromes. These disorders are now referred to as RASopathies. Germline p.Gly12Ser mutations have been identified in 80% of individuals with Costello syndrome with HRAS mutations. Other germline mutations include p.Gly12Ala, p.Gly12Cys, p.Gly12Glu, p.Gly12Asp, p.Gly12Val, p.Gly13Asp, p.Gly13Cys, p.Thr58Ile, p.Lys117Arg, p.Ala146Thr/Val/Pro, and p.Phe156Leu. Recent studies identified intragenic duplications and splicing variants of HRAS in affected individuals. A milder phenotype was noted in individuals with p.Thr58Ile, p.Lys117Arg, and p.Ala146Thr/Val/Pro mutations. Knock-in mouse lines expressing the most frequent p.Gly12Ser or p.Gly12Val mutations partially recapitulate the Costello syndrome phenotypes, including facial dysmorphia, cardiomyopathy with cardiomyocyte hypertrophy, and kidney fibrosis. Heterozygous p.Gly12Ser mice exhibit impaired hepatic energy homeostasis and resistance to high-fat diet-induced obesity. These model animals could aid in elucidating the detailed pathogenetic mechanisms and establishing therapeutic approaches.