Capillary Malformation-Arteriovenous Malformation 1

A number sign (#) is used with this entry because of evidence that capillary malformation-arteriovenous malformation-1 (CMAVM1) is caused by heterozygous mutation in the RASA1 gene (139150) on chromosome 5q14.

Description

Capillary malformation-arteriovenous malformation-1 is an autosomal dominant disorder characterized by atypical capillary malformations (CMs), often in association with fast-flow vascular malformations, including arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs), and Parkes Weber syndrome (PKWS). The CMs are usually multifocal and are surrounded by a pale halo with a central red dot; they increase in number with age. The AVMs generally occur in the brain or on the face or extremities. Intracranial AVMs include vein of Galen aneurysmal malformations (VGAMs). Parkes Weber syndrome is a specific type of CMAVM that presents with limb overgrowth, more commonly affecting one of the lower extremities (Eerola et al., 2003; Revencu et al., 2013; Johnson and Navarro, 2017). Parkes Weber syndrome is characterized by a cutaneous blush with underling multiple micro-AVFs in association with soft-tissue and skeletal hypertrophy of the affected limb (Mulliken and Young, 1988).

Genetic Heterogeneity of Capillary Malformation-Arteriovenous Malformation

Also see CMAVM2 (618196), caused by mutation in the EPHB2 gene on chromosome 7q22.

Clinical Features

Capillary malformation, or 'port-wine stain,' (see 163000) is a common cutaneous vascular anomaly that appears as a red macular stain that darkens over years. Six families reported by Eerola et al. (2003) manifested atypical capillary malformations that were multiple, small, round to oval in shape, and pinkish red in color. In these 6 families the capillary malformations were associated with arteriovenous malformation, arteriovenous fistula (AVF), or Parkes Weber syndrome. Eerola et al. (2003) named this phenotype caused by RASA1 mutations 'capillary malformation-arteriovenous malformation' (CMAVM).

Boon et al. (2005) provided a review of CMAVM associated with mutations in the RASA1 gene.

In a study of 100 patients with CMAVM, Revencu et al. (2013) observed that several had cutaneous areas of numerous white pale halos of 1-cm diameter with a red punctate spot in the middle.

Mapping

In a study of 13 families with familial capillary malformation, Eerola et al. (2002) identified a susceptibility locus, which they termed CMC1, on 5q14-q21. In a later study, Eerola et al. (2003) used a new family to narrow the locus to 5 cM.

Molecular Genetics

In the 5-cM interval to which Eerola et al. (2003) mapped the CMC1 locus, 8 characterized genes were found, 3 of which were considered to be candidates of functional interest: RASA1 (139150), EDIL3 (606018), and MEF2C (600662). They screened the RASA1 gene, encoding p120-RasGAP, for mutations in 17 families. Heterozygous inactivating RASA1 mutations were detected in 6 families with CMAVM (see, e.g., 139150.0004-139150.0005). Eerola et al. (2003) suggested that the phenotypic variability could be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.

In affected members of 3 Ashkenazi Jewish families with capillary malformations, Hershkovitz et al. (2008) identified heterozygous mutations in the RASA1 gene (139150.0006-139150.0008). An arteriovenous malformation was only identified in 1 of the families, suggesting that the phenotypic spectrum of RASA1-related CMAVM can include patients with only capillary malformations.

In a combined retrospective and prospective study of 261 individuals with CMAVM and related phenotypes, Revencu et al. (2013) screened for mutations in the RASA1 gene and identified 58 in 68 of the 100 individuals with CMAVM and in none in those with related disorders, including 100 with common CMs, 37 with Sturge-Weber syndrome, and 24 with AVMs.

Revencu et al. (2013) analyzed DNA from a neurofibroma that had developed in a congenital Parkes-Weber lesion in a CMAVM patient with a previously confirmed germline mutation in the RASA1 gene. The DHPLC elution profile was indicative of loss of function of the wildtype allele in the tissue. SNP array showed mosaic loss of chromosome 5q, including the RASA1 gene, and part of chromosome 22, including the NF2 gene (607379). Sequencing of the NF2 gene revealed a nonsense mutation in the tissue, but not in the blood. The authors suggested that the 2 hits in the NF2 gene explain the development of the neurofibroma, and they speculated that the somatic loss of 5q, including the RASA1 gene, is involved in the pathogenesis of the Parkes Weber lesion.

Pathogenesis

Another inherited vascular malformation, cerebral capillary malformation (CCM; 116860), has also been related to misregulated Ras signaling. The mutated protein, KRIT1 (604214) was originally identified as a binding partner of Rap1a (179520), an antagonist of Ras transformation. KRIT1 has also been shown to bind ICAP1 (607153), a protein that links integrins and the actin cytoskeleton, which implies a process of integrin-signaling-mediated cellular adhesion in the pathogenesis of CCM. CMAVM and CCM may be due to similar cellular processes, since p120-RasGAP can bind Rap1a, which has an important role in integrin-mediated cellular adhesion. It is noteworthy that in certain families with CCM and mutations in KRIT1, some members also have cutaneous lesions characterized as hyperkeratotic capillary-venous malformations (Labauge et al., 1999; Eerola et al., 2000).

History

Parkes Weber syndrome was described by the same F. Parkes Weber (1863-1962) whose name is also attached to hereditary hemorrhagic telangiectasia (187300), Sturge-Weber syndrome (185300), Weber-Christian disease, and Klippel-Trenaunay-Weber syndrome (149000).