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

Revencu, Nicole;Boon, Laurence;Mendola, Antonella;Cordisco, Maria Rosa;Vikkula, Miikka;et.al.
(2013) Human Mutation — Vol. 34, n° 12, p. 1632-1641 (2013)

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Abstract
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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Revencu, N., Boon, L., Mendola, A., Cordisco, M. R., Dubois, J., Clapuyt, P., Hammer, F., Amor, D. J., Irvine, A. D., Baselga, E., Dompmartin, A., Syed, S., Martin-Santiago, A., Ades, L., Collins, F., Smith, J., Sandaradura, S., Barrio, V. R., Burrows, P. E., et al. (2013). RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Human Mutation, 34(12), 1632-1641. https://doi.org/10.1002/humu.22431 (Original work published 2013)