Hereditary hemorrhagic telangiectasia

Clinical characteristics 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. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are most evident on the lips, tongue, buccal mucosa, face, chest, and fingers. The average age of onset is generally later than epistaxis, but may be during childhood. Large AVMs often cause symptoms when they occur in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years. Diagnosis/testing The diagnosis of HHT is established in a proband with three or more of the following clinical features: epistaxis, mucocutaneous telangiectases, visceral AVMs, and/or a family history of HHT. Identification of a heterozygous pathogenic variant in ACVRL1, ENG, GDF2, or SMAD4 establishes the diagnosis if clinical features are inconclusive. Management Treatment of manifestations: Nosebleeds are treated with humidification, nasal lubricants, hemostatic products, laser ablation, sclerotherapy, nasal closure, and oral or topical medications. GI bleeding is treated with iron replacement therapy and (if needed) endoscopic ablation, surgical resection of bleeding sites, and/or medical therapy. Pulmonary AVMs with a feeding vessel 1 mm or greater in diameter require consideration of occlusion. Cerebral AVMs are treated, when indicated by location or symptoms, by surgery, embolotherapy, and/or stereotactic radiosurgery. Symptomatic hepatic AVMs are managed medically; liver transplantation is recommended for individuals who do not respond to medical therapy and who develop hepatic failure. Women with HHT considering pregnancy are screened and treated for pulmonary and cerebral AVMs; pulmonary AVMs discovered during pregnancy are treated during the second trimester. Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia. Prevention of secondary complications: When pulmonary AVMs are present or suspected, antibiotic prophylaxis for dental and invasive procedures and a filter on intravenous lines to prevent air bubbles from being inadvertently infused is recommended. Surveillance: Annual evaluations for anemia; supine and sitting pulse-oximetry every one to two years during childhood; evaluation for pulmonary AVMs every five years with contrast echocardiography by age ten years; head MRI in infancy and then rescreening for cerebral AVMs by brain MRI after puberty; periodic screening for gastrointestinal polyps and malignant change in persons with juvenile polyps. Agents/circumstances to avoid: Vigorous nose blowing; lifting heavy objects; straining during bowel movements; electric or chemical cautery for nosebleeds; anticoagulant and anti-inflammatory agents (including aspirin) in individuals with significant nose or GI bleeding; scuba diving unless contrast echocardiography within the last five years was negative for evidence of a right to left shunt; liver biopsy. Evaluation of relatives at risk: Molecular genetic testing is offered to at-risk family members if the germline pathogenic variant has been identified in the family. If the pathogenic variant in the family is not known, at-risk family members should be evaluated for signs and symptoms of HHT and screening should be offered to at-risk family members if the diagnosis cannot be ruled out. Genetic counseling 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 are at a 50% risk of inheriting the pathogenic variant. Prenatal testing is possible for a pregnancy at increased risk if the pathogenic variant in the family is known.