JOURNAL ARTICLE

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

Nicole Revencu, Laurence M Boon, Antonella Mendola, Maria Rosa Cordisco, Josée Dubois, Philippe Clapuyt, Frank Hammer, David J Amor, Alan D Irvine, Eulalia Baselga, Anne Dompmartin, Samira Syed, Ana Martin-Santiago, Lesley Ades, Felicity Collins, Janine Smith, Sarah Sandaradura, Victoria R Barrio, Patricia E Burrows, Francine Blei, Mariarosaria Cozzolino, Nicola Brunetti-Pierri, Asuncion Vicente, Marc Abramowicz, Julie Désir, Catheline Vilain, Wendy K Chung, Ashley Wilson, Carol A Gardiner, Yim Dwight, David J E Lord, Leona Fishman, Cheryl Cytrynbaum, Sarah Chamlin, Fred Ghali, Yolanda Gilaberte, Shelagh Joss, Maria Del C Boente, Christine Léauté-Labrèze, Marie-Ange Delrue, Susan Bayliss, Loreto Martorell, Maria-Antonia González-Enseñat, Juliette Mazereeuw-Hautier, Brid O'Donnell, Didier Bessis, Reed E Pyeritz, Aicha Salhi, Oon T Tan, Orli Wargon, John B Mulliken, Miikka Vikkula
Human Mutation 2013, 34 (12): 1632-41
24038909
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.

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