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RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.

Pubmed ID: 24038909

Authors

  • Revencu N
  • Boon LM
  • Mendola A
  • Cordisco MR
  • Dubois J
  • Clapuyt P
  • Hammer F
  • Amor DJ
  • Irvine AD
  • Baselga E
  • Dompmartin A
  • Syed S
  • Martin-Santiago A
  • Ades L
  • Collins F
  • Smith J
  • Sandaradura S
  • Barrio VR
  • Burrows PE
  • Blei F
  • Cozzolino M
  • Brunetti-Pierri N
  • Vicente A
  • Abramowicz M
  • Désir J
  • Vilain C
  • Chung WK
  • Wilson A
  • Gardiner CA
  • Dwight Y
  • Lord DJ
  • Fishman L
  • Cytrynbaum C
  • Chamlin S
  • Ghali F
  • Gilaberte Y
  • Joss S
  • Boente Mdel C
  • Léauté-Labrèze C
  • Delrue MA
  • Bayliss S
  • Martorell L
  • González-Enseñat MA
  • Mazereeuw-Hautier J
  • O'Donnell B
  • Bessis D
  • Pyeritz RE
  • Salhi A
  • Tan OT
  • Wargon O
  • Mulliken JB
  • Vikkula M

Journal

Human mutation

Publication Data

December 14, 2013

Associated Grants

None

Mesh Terms

  • Amino Acid Substitution
  • Arteriovenous Malformations
  • Capillaries
  • DNA Mutational Analysis
  • Female
  • Gene Order
  • Genetic Association Studies
  • Humans
  • Male
  • Mutation
  • Phenotype
  • Port-Wine Stain
  • Prospective Studies
  • Retrospective Studies
  • p120 GTPase Activating Protein