Document Detail

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations.
MedLine Citation:
PMID:  22261753     Owner:  NLM     Status:  MEDLINE    
Costello syndrome (OMIM# 218040) is a distinctive rare multisystem disorder comprising a characteristic coarse facial appearance, intellectual disabilities, and tumor predisposition. Although the diagnosis can be suspected clinically, confirmation requires identification of a heterozygous mutation in the proto-oncogene HRAS. In contrast to somatic oncogenic mutations in neoplasia, the Costello syndrome changes are typically introduced in the paternal germline. The predicted amino acid substitutions allow for constitutive or prolonged activation of the HRAS protein, resulting in dysregulation of the Ras/mitogen activated protein kinase pathway. Dysregulation of this signaling pathway is the disease mechanism shared among Costello syndrome and other rasopathies, including neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. The Ras/mitogen activated protein kinase pathway governs cell proliferation and differentiation, and its dysregulation affects cardiac and brain development, accounting for the significant overlap in physical and developmental differences and common medical problems among rasopathies. Unlike the genetically heterogeneous Noonan syndrome and cardio-facio-cutaneous syndrome, Costello syndrome is caused by HRAS mutations only. Patients, clinicians, and researchers may benefit from a multidisciplinary "rasopathy clinic," which serves patients with more common conditions such as Noonan syndrome and neurofibromatosis and those affected by rare conditions such as Costello syndrome.
Karen W Gripp; Angela E Lin
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Publication Detail:
Type:  Case Reports; Journal Article; Review    
Journal Detail:
Title:  Genetics in medicine : official journal of the American College of Medical Genetics     Volume:  14     ISSN:  1530-0366     ISO Abbreviation:  Genet. Med.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-06     Completed Date:  2012-07-09     Revised Date:  2012-08-16    
Medline Journal Info:
Nlm Unique ID:  9815831     Medline TA:  Genet Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  285-92     Citation Subset:  IM    
Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
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MeSH Terms
Costello Syndrome / diagnosis,  epidemiology,  genetics*,  therapy
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease
Germ-Line Mutation*
Protein-Serine-Threonine Kinases / genetics
Proto-Oncogene Proteins p21(ras) / genetics*,  metabolism
Reg. No./Substance:
EC 2.7.1.-/Mnk1 protein, rat; EC Kinases; EC Proteins p21(ras)

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