Hereditary Hemorrhagic Telangiectasia

(Osler-Weber-Rendu Syndrome)

ByDavid J. Kuter, MD, DPhil, Harvard Medical School
Reviewed/Revised May 2023
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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

  • Activin A receptor-like type 1 (ACVRL1) gene, which encodes the activin receptor-like kinase (ALK1)

  • SMADH4 (MADH4) gene, which encodes SMAD4, a protein active in the TGF beta signalling pathway

General reference

  1. 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 of Hereditary Hemorrhagic Telangiectasia

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.

Manifestations of Hereditary Hemorrhagic Telangiectasia
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

This photo shows a close-up of the face of a patient with multiple telangiectasias secondary to hereditary hemorrhagic telangiectasia.

... read more

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Hereditary Hemorrhagic Telangiectasia
Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is an autosomal dominant disorder that manifests with widespread cutaneous, mucosal, and visceral telangiectases and arteriovenous malformations. Papular, punctate, and linear telangiectases occur predominantly on the tongue, lips, digit tips, perioral region, and trunk.

... read more

By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.

Telangiectasias on the Hand
Telangiectasias on the Hand

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Diagnosis of Hereditary Hemorrhagic Telangiectasia

  • 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, palms, 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, 2).

Sometimes endoscopy or angiography or both are needed. Laboratory findings are usually normal except for iron deficiency anemia in many patients.

Testing for the ENG,ACVRL1, and SMADH4 (MADH4) mutations may be helpful in some patients with atypical features or for screening asymptomatic family members.

Diagnosis references

  1. 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

  2. 2. Faughnan ME, Mager JJ, Hetts SW, et al: Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med 173(12):989–1001, 2020. doi: 10.7326/M20-1443

Screening for Hereditary Hemorrhagic Telangiectasia

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. Screening also involves checking for iron deficiency anemia due to the chronic blood loss. Screening may also include blood tests for the gene mutations mentioned above.

Treatment of Hereditary Hemorrhagic Telangiectasia

  • Sometimes laser ablation, surgical resection, or embolization of symptomatic arteriovenous malformations

  • Supplemental oral or intravenous iron therapy

  • Possibly blood transfusions

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 in the lungs can be treated by surgical resection or coil embolization.

Liver lesions may not be amenable to surgical or endovascular treatment. Measurement of serum ammonia level may help assess the degree of hepatic shunting of blood (1).

Repeated blood transfusions may be needed.

Many patients require continuous oral iron therapy to replace iron lost due to repeated mucosal bleeding (see treatment of Iron Deficiency Anemia). Many patients also require parenteral (IV) iron, and sometimes recombinant erythropoietin is necessary.

23, 4, 5).

To avoid paradoxical embolization of particulate matter to the brain through pulmonary arteriovenous malformations, all IV fluids need to given through a filter.

Treatment references

  1. 1. Bloom PP, Rodriguez-Lopez J, Witkin AS, et al: Ammonia predicts hepatic involvement and pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. Clin Transl Gastroenterol 11(1):e00118, 2020. doi:10.14309/ctg.0000000000000118

  2. 2. Al-Samkari H: Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood 137 (7): 888–895, 2021.

  3. 3. Al-Samkari H, Kasthuri RS, Parambil JG, et al: An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica 106(8):2161–2169, 2021. doi: 10.3324/haematol.2020.261859

  4. 4. 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

  5. 5. Faughnan ME, Mager JJ, Hetts SW, et al: Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med 173(12):989–1001, 2020. doi: 10.7326/M20-1443

Key Points

  • Nasal and gastrointestinal telangiectasias may cause significant external hemorrhage in patients with hereditary hemorrhagic telangiectasia.

  • 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 pulmonary 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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