Clinical Information

Hereditary vascular malformation syndromes include a group of genetic conditions characterized by abnormal blood vessel development. These syndromes can be of germline or somatic origin. This gene panel is restricted to analysis of genes associated with vascular malformation syndromes of germline origin.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia characterized by the presence of arteriovenous malformations (AVM) of the skin, mucosa, and viscera. Small AVM, or telangiectasias, develop predominantly on the face, oral cavity, and hands, and spontaneous, recurrent epistaxis (nose bleeding) is a common presenting sign.(1) HHT has an estimated prevalence of 1:5000 and is primarily caused by heterozygous, disease-causing variants in the ACVRL1 and ENG genes. Rarely, HHT can be caused by disease-causing variants in the GDF2 gene (also known as BMP9). Additionally, SMAD4 disease-causing variants cause autosomal dominant juvenile polyposis/HHT syndrome, which includes features of juvenile polyposis syndrome and HHT.(2) An overlapping pulmonary arterial hypertension and HHT phenotype have also been reported in association with the BMPR2 gene.(3,4)

Familial cerebral cavernous malformation (CCM) is an autosomal dominant condition characterized by structurally abnormal capillaries in the central nervous system leading to an increased risk of cerebral hemorrhage.(5) The estimated prevalence of familial CCM ranges from 1:3300 to 1:10,000,(5) and the condition displays age-related penetrance with up to 50% of individuals remaining symptom free throughout their life.(5,6) Disease-causing variants in three genes have been associated with familial CCM: KRIT1, CCM2, and PDCD10.

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant condition primarily characterized by capillary malformations localized to the dermis of the face and limbs, AVM or arteriovenous fistulas of the skin, muscle, bone, spine, and brain, and Parkes Weber syndrome.(6) The prevalence of CM-AVM has been estimated in Northern European cohorts at approximately 1:100,000, with penetrance estimated at 90% to 99%.(6) Approximately 60% of cases of CM-AVM can be attributed to disease-causing variants in the EPHB4 and RASA1 genes. The genetic etiology remains unknown in approximately 40% of cases.(6)

Hereditary glomuvenous malformation is a rare autosomal dominant condition characterized by multiple venous malformations within the glomerulus of the kidney. The condition is associated with germline disease-causing variants in the GLMN gene. However, it is thought that a second, somatic (acquired) variant on the second allele, or acquired uniparental disomy, is required for the development of venous malformations.(7,8)

Multiple cutaneous and mucosal venous malformations (also known as cutaneomucosal venous malformation: VMCM) is an autosomal dominant condition characterized by small multifocal cutaneous and mucosal vascular malformations that typically present at birth.(9) These lesions are usually asymptomatic but may become painful if they are large enough to impact the underlying muscle tissue. The prevalence of this condition is unknown but thought to be rare. VMCM is associated with disease-causing variants in the TEK gene, and penetrance is estimated at 90% in individuals with a known genetic etiology.(9)