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Hereditary Hemorrhagic Telangiectasia Genotypes

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs), that lack 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 not suspected until adolescence or later. The most common clinical manifestation is spontaneous and recurrent nosebleeds that become evident around age 12 years. Approximately 25% of individuals with HHT develop GI bleeding, usually after age 50 years. Large AVMs may occur in brain, spine, liver, pancreas and lungs. Ruptured AVMs in these locations can have catastrophic consequences.

The diagnosis of HHT is based on the presence of nosebleeds, cutaneous or mucosal telangiectases, visceral AVMs, positive family history, and detection of a pathogenic mutation. HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability. Most individuals know of an affected parent. Each child of a proband and the sibs of most probands have a 50% risk of inheriting the mutation.

At least 3 different genes in the TGF-?/BMP signaling cascade have been detected in individuals with a clinical diagnosis of HHT:  ENG, ACVRL1 (ALK1), and SMAD4. Mutations in ENG and ALK1 are associated with classical HHT, whereas mutations in SMAD4 are variably associated with juvenile polyposis.

Simultaneous testing by gene sequence analysis and duplication/deletion analysis of these 3 genes detects mutations in approximately 85% of individuals with unequivocal clinical features of HHT. Mutations in ENG and ALK1 are equally common and detected much more frequently than SMAD4. Approximately 1 to 2% of persons clinically diagnosed with HHT have a mutation detected in SMAD4, or approximately 10% of those who test negative for a mutation in ENG and ACVRL1. Family studies indicate that at least two as-yet-unknown genes are associated with HHT.

To confirm the diagnosis in a proband of an affected individual, simultaneous testing of ENG and ACVRL1 is recommended initially. SMAD4 testing should be reserved for symptomatic individuals in whom no mutation is identified in ENG or ACVRL1 and in any person with HHT and intestinal polyps. It is important to differentiate those with SMAD4-related HHT from those with ENG- or ACVRL1-related HHT because medical management differs significantly.

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