Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women.
(See also Overview of Vascular Bleeding Disorders.)
More than 80% of patients have mutations in one of the following genes (1):
- Endoglin (ENG) gene, which encodes a receptor for transforming growth factor beta-1 (TGF-β1) and transforming growth factor beta-3
- ACVRL1 gene, which encodes the activin receptor-like kinase (ALK1)
- MADH4 gene, which encodes SMAD4, a protein active in the TGF beta signalling pathway
- 1. Kritharis A, Al-Samkari H, Kuter D: Hereditary hemorrhagic telangiectasia: Diagnosis and management from the hematologist’s perspective. Haematologica 103:1433–1443, 2018. doi: 10.3324/haematol.2018.193003.
Symptoms and Signs
The most characteristic lesions of hereditary hemorrhagic telangiectasia are small red-to-violet telangiectatic lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. Similar lesions may be present throughout the mucosa of the gastrointestinal (GI) tract, resulting in recurrent GI bleeding. Patients may experience recurrent, profuse nosebleeds. Some patients have pulmonary arteriovenous malformations (AVMs). These AVMs may cause significant right-to-left shunts, which can result in dyspnea, fatigue, cyanosis, or erythrocytosis. However, the first sign of the presence of AVMs may be a brain abscess, transient ischemic attack, or stroke as a result of infected or noninfected emboli. Cerebral or spinal AVMs occur in some families and may cause subarachnoid hemorrhage, seizures, or paraplegia. Hepatic AVMs may lead to liver failure and high output heart failure. Chronic iron deficiency anemia is commonly present.
- Clinical evaluation
- Sometimes endoscopy or angiography
- Sometimes genetic testing
Diagnosis of hereditary hemorrhagic telangiectasia is based on the finding of characteristic arteriovenous malformations on the face, mouth, nose, digits, and/or internal organs in the context of epistaxis and family history. The Curaçao criteria include the following:
- Spontaneous recurrent epistaxis
- Multiple telangiectasias in typical locations
- Documented visceral arteriovenous malformations (eg, in the lung, liver, brain, and spine)
- First-degree family member with hereditary hemorrhagic telangiectasia
Hereditary hemorrhagic telangiectasia is definite if 3 of these criteria are met and possible if 2 are met (1).
Endoscopy or angiography is sometimes needed. Laboratory findings are usually normal except for iron deficiency anemia in many patients.
Testing for the ENG, ACVRL1, and MADH4 mutations may be helpful in some patients with atypical features or for screening asymptomatic family members.
If a family history of pulmonary, hepatic, or cerebral arteriovenous malformations exists, screening at puberty and at the end of adolescence with pulmonary CT, hepatic CT, and cerebral MRI is recommended.
- 1. Shovlin CL, Guttmacher AE, Buscarini E, et al: Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91(1):66–67, 2000. doi: 10.1002/(sici)1096-8628(20000306)91:1<66::aid-ajmg12>3.0.co;2-p.
- Sometimes laser ablation, surgical resection, or embolization of symptomatic arteriovenous malformations
- Supplemental iron therapy
- Possibly blood transfusions
- Sometimes antifibrinolytic drugs (eg, aminocaproic acid, tranexamic acid)
- Sometimes angiogenesis inhibitors (eg, bevacizumab, pomalidomide, thalidomide)
Treatment for most patients is supportive, but accessible telangiectasias (eg, in the nose or gastrointestinal tract via endoscopy) may be treated with laser ablation. Arteriovenous malformations may be treated by surgical resection or coil embolization.
Many patients require continuous iron therapy to replace iron lost in repeated mucosal bleeding (see treatment of Iron Deficiency Anemia); many patients require parenteral iron and sometimes erythropoietin.
Treatment with drugs that inhibit fibrinolysis, such as aminocaproic acid or tranexamic acid, may be beneficial.
Treatment with drugs that inhibit angiogenesis such as bevacizumab, pomalidomide, or thalidomide can reduce the number and density of abnormal vessel growth (1). In addition, bevacizumab has recently been shown to reduce the incidence of nasal and gastrointestinal bleeding.
To avoid paradoxical embolization of particulate matter to the brain through pulmonary arteriovenous malformations, all IV fluids need to given through a filter.
- 1. Al-Samkari H, Kritharis A, Rodriguez-Lopez JM, Kuter D: Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia. J Intern Med 285(2):223–231, 2019. doi: 10.1111/joim.12832. Epub 2018 Oct 9.
- Nasal and gastrointestinal telangiectasias may cause significant external hemorrhage.
- Vascular malformations in the central nervous system, lungs, and liver may bleed; hepatic and pulmonary malformations may cause significant shunting.
- Accessible mucosal telangiectasias and arteriovenous malformations may be treated with laser ablation; coil embolization or surgical resection may be needed for other vascular malformations.
- Antifibrinolytic drugs and angiogenesis inhibitors may reduce the incidence of bleeding.
- Many patients require parenteral iron supplements because of chronic blood loss.
- All IV solutions should be given through a filter to avoid paradoxical embolization of particulate matter to the brain through pulmonary arteriovenous malformations.
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