Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

Genet Med. 2012 Mar;14(3):285-92. doi: 10.1038/gim.0b013e31822dd91f.

Abstract

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.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Alleles
  • Child
  • Costello Syndrome / diagnosis
  • Costello Syndrome / epidemiology
  • Costello Syndrome / genetics*
  • Costello Syndrome / therapy
  • Facies
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Male
  • Phenotype
  • Prevalence
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Mknk1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • OMIM/218040