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 characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.
Diagnosis/testing: The diagnosis of HHT is established in a proband with three or more of the following clinical features:
Mucocutaneous telangiectases in characteristic locations
A first-degree relative diagnosed with HHT on the basis of the preceding criteria
Identification of a heterozygous pathogenic variant in ACVRL1, ENG, or SMAD4 establishes the diagnosis if clinical features are inconclusive.
Management: Treatment of manifestations: Nosebleeds are treated with humidification, topical moisturizing therapy, hemostatic products, antifibrinolytic therapy, ablation therapy, systemic antiangiogenic agents, septodermoplasty, and nasal closure as needed. GI bleeding and anemia is treated with iron replacement therapy and (if needed) blood transfusions and antiangiogenic agents. Pulmonary AVMs with a feeding vessel 1-2 mm or greater in diameter typically require occlusion for stroke prevention. When pulmonary shunting is present, use antibiotic prophylaxis for dental and non-sterile invasive procedures, taking care to prevent air bubbles from being introduced in intravenous lines. This may include an air filter when available and compatible with the medication being administered. Treatment of pulmonary artery hypertension as per cardiologist, pulmonologist, and other relevant specialists. Symptomatic hepatic AVMs are managed medically; liver transplantation is recommended for individuals who do not respond to medical therapy and who develop high-output heart failure. Cerebral AVMs are treated as indicated by size, location, or symptoms: by surgery, embolotherapy, and/or stereotactic radiosurgery. Gastrointestinal polyps are treated according to guidelines for juvenile polyposis syndrome.
Surveillance: Annual evaluation by a health care provider familiar with HHT for signs and symptoms of complications; annual hematocrit, hemoglobin, and ferritin; evaluation for pulmonary AVMs every five years with transthoracic contrast echocardiography (TCE) in adults, TCE or chest radiograph with pulse oximetry in children; brain MRI with and without contrast using sequences that detect blood products in infancy and again after puberty for cerebral AVMs; colonoscopy at age 15 years and repeated every three years if no polyps are found, or annually with esophagogastroduodenoscopy if colonic polyps are identified in those with SMAD4-HHT.
Agents/circumstances to avoid: Vigorous nose blowing; lifting heavy objects; straining during bowel movements; finger manipulation in the nose; anticoagulant and anti-inflammatory agents (including aspirin) in individuals with significant nose or GI bleeding; scuba diving unless TCE 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.
Pregnancy management: Women with HHT considering pregnancy are screened and treated for pulmonary and cerebral AVMs; sizable 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 despite aggressive iron replacement therapy.
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.
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