Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis not suspected until adolescence or later. Small AVMs (or telangiectases) close to the surface of the skin and mucous membranes often rupture and bleed after slight trauma. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years. Large AVMs often cause symptoms when they occur in the brain, liver, or lungs; complications from bleeding or shunting may be sudden and catastrophic.
The diagnosis of HHT is based on the presence of epistaxis, cutaneous or mucosal telangiectases, visceral AVMs, family history, and presence of a pathogenic mutation. HHT is caused by mutations in a number of genes involved in the TGF-beta/BMP signaling cascade: ENG, the gene encoding the cell surface co-receptor endoglin; ACVRL1 (ALK1), also a gene encoding a cell surface receptor; SMAD4, a gene encoding an intracellular signaling molecule; and at least two other as-yet unidentified genes. Molecular genetic testing of ENG, ALK1, and SMAD4 detects mutations in approximately 80%-87% of individuals who meet unequivocal clinical diagnostic criteria for HHT; testing is available on a clinical basis.
HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability. Most individuals have an affected parent. Each child of a proband and the sibs of most probands have a 50% risk of inheriting the mutation. Prenatal testing is possible for pregnancies at increased risk if the disease-causing mutation in the family is known.