Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations.
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.
Revencu
Nicole
N
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Boon
Laurence M
LM
Mulliken
John B
JB
Enjolras
Odile
O
Cordisco
Maria Rosa
MR
Burrows
Patricia E
PE
Clapuyt
Philippe
P
Hammer
Frank
F
Dubois
Josée
J
Baselga
Eulalia
E
Brancati
Francesco
F
Carder
Robin
R
Quintal
José Miguel Ceballos
JM
Dallapiccola
Bruno
B
Fischer
Gayle
G
Frieden
Ilona J
IJ
Garzon
Maria
M
Harper
John
J
Johnson-Patel
Jennifer
J
Labrèze
Christine
C
Martorell
Loreto
L
Paltiel
Harriet J
HJ
Pohl
Annette
A
Prendiville
Julie
J
Quere
Isabelle
I
Siegel
Dawn H
DH
Valente
Enza Maria
EM
Van Hagen
Annet
A
Van Hest
Liselot
L
Vaux
Keith K
KK
Vicente
Asuncion
A
Weibel
Lisa
L
Chitayat
David
D
Vikkula
Miikka
M
D001165:Arteriovenous Malformations; D005190:Family; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics*; D057127:Single-Chain Antibodies; D013577:Syndrome; D054079:Vascular Malformations / Q000235:genetics*; D054080:Vein of Galen Malformations / Q000235:genetics*; D020729:p120 GTPase Activating Protein
D007135:Immunoglobulin Variable Region; C557248:RASA1 protein, human; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D020729:p120 GTPase Activating Protein