Parkes Weber syndrome (PKWS)

RASA1 related disorders

Capillary malformation-arteriovenous malformation (CMAVM; MIM 608354) and some cases of Parkes Weber syndrome (PKWS; MIM 608355) are caused by mutations in the RASA1 gene. Capillary malformation-arteriovenous malformation (CMAVM) is an autosomal dominant disorder characterized by multiple capillary malformations or port-wine stains, in addition to fast-flow vascular lesions.  The capillary malformations are small flat cutaneous lesions that vary in number from a single malformation to multiple randomly distributed malformations. The associated fast-flow vascular lesions include arteriovenous malformations (AVM) and arteriovenous fistulas (AVF) which have been described in the skin, bone, internal organs and brain. The fast-flow lesions described in patients with CMAVM can be life-threatening and cause epilepsy, seizures, hydrocephalus, heart failure and death. There is evidence of phenotypic variation in CMAVM families as fast-flow lesions have been described in only one third of patients and some families have no individuals with fast-flow lesions. Mutations in the RASA1 gene have also been associated with Parkes Weber syndrome (PKWS), an autosomal dominant disorder previously considered to be a sporadic overgrowth syndrome with unknown etiology.  PKWS is characterized by a large vascular stain with multiple underlying micro-arteriovenous fistulas and soft tissue and skeletal hypertrophy of the affected limb.  PKWS is clinically and etiologically heterogeneous as some individuals with PKWS who lack cutaneous capillary malformations do not have an identifiable RASA1 mutation.

RASA1 encodes RAS p21 protein activator 1 (GAP), a member of the GAP1 family of GTPase-activating proteins. It is an inhibitor of RAS p21, which controls cellular growth, proliferation and differentiation.  The GAP protein has also been implicated in the remodeling of the actin cytoskeleton and integrin-mediated cellular adhesion.