Costello syndrome and related disorders.
OBJECTIVE
Costello syndrome is a rare congenital disorder affecting multiple organ systems, encompassing severe failure to thrive, cardiac anomalies including hypertrophic cardiomyopathy and atrial tachycardia, tumor predisposition, and cognitive impairment. Costello syndrome shares findings with cardio-facio-cutaneous syndrome and the diagnosis can be challenging. The discovery of gene mutations underlying these and other closely related disorders allows for molecular confirmation of a clinical diagnosis.


RESULTS
The identification of germline HRAS mutations in Costello syndrome, and mutations in BRAF, MEK1 and MEK2 in cardio-facio-cutaneous syndrome, uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the gene products within the Ras-mitogen-activated protein kinase pathway. Changes in other genes encoding mitogen-activated protein kinase pathway proteins are responsible for Noonan syndrome and the KRAS mutation phenotype.


CONCLUSIONS
Costello syndrome is caused by heterozygous de-novo point mutations in HRAS, resulting in increased activation of the mitogen-activated protein kinase pathway. Despite their overlapping presentation, Costello syndrome and its related disorders are distinct, and the phenotypes become more distinctive with age. Molecular testing is available and a clinical diagnosis should be reconsidered if it is inconsistent with the molecular result.
Quezada
Emilio
E
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Gripp
Karen W
KW
D000015:Abnormalities, Multiple / Q000235:genetics*; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics; D003937:Diagnosis, Differential; D005145:Face / Q000002:abnormalities*; D019066:Facies; D011905:Genes, ras / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D044542:LEOPARD Syndrome / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012208:Rhabdomyosarcoma / Q000235:genetics; D012868:Skin Abnormalities / Q000175:diagnosis / Q000235:genetics; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins