Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused byRASA1 mutations

Abstract

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.

Parkes Weber Syndrome and Spinal Arteriovenous Malformations

“…3,4 Therefore, although we do not have solid evidence, we hypothesize and propose an association between Parkes Weber syndrome and spinal AVM. …”

Combined surgical and endovascular treatment of complex high-flow conus medullaris arteriovenous fistula associated with Parkes Weber syndrome: case report

“…This mutation helps distinguish PWS from other overgrowth disorders such as hereditary hemorrhagic telangiectasia with highflow AVFs, PTEN hamartomatous tumor syndrome, and KTS. 6,9,10 This gene mutation similarly has been associated with spinal AV anomalies in patients with multifocal capillary malformations. 13 Thus, genetic testing may be helpful to ensure the correct diagnosis in certain patients if it remains unclear clinically and can thereby help direct management and prompt further investigation for spinal vascular malformations.…”

“…This variant is seen primarily in patients with multiple capillary malformations. 10 Spinal vascular malformations in the setting of PWS are typically complex, exhibiting multiple AV shunts that demand a multidisciplinary approach because of the unique angioarchitectural characteristics (including the dural and pial feeders in the same lesion). Successful treatment hinges on surgical and/or endovascular interventions to disconnect all fistulous points.…”

Central Nervous System Vascular Malformations

“…Only 1 case of familial VOGM has been reported [186]. However, mutations in the RASA1 gene have been investigated in association with cutaneous capillary malformation-arteriovenous malformation syndrome, including two patients who also harboured VOGMs [187], raising the possibility that genetic influences may play a role in the development of these malformations.…”

“…Although several genetic loci have been implicated in the development of cutaneous capillary malformations (including mutations of the RASA1 gene, located on chromosome 5q13-22, and implicated in Parkes-Weber Syndrome, a condition associated with cutaneous capillary malformations and brain AVMs) [187], very little is known about the role of genetic abnormalities in capillary telangiectasias of the brain.…”