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Hereditary Hemorrhagic Telangiectasia

(Osler-Weber-Rendu Syndrome)

By

David J. Kuter

, MD, DPhil, Harvard Medical School

Last full review/revision May 2020| Content last modified May 2020
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Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women.

  • 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

General reference

  • 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 Transient Ischemic Attack (TIA) A transient ischemic attack (TIA) is focal brain ischemia that causes sudden, transient neurologic deficits and is not accompanied by permanent brain infarction (eg, negative results on diffusion-weighted... read more , or stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more Overview of Stroke as a result of infected or noninfected emboli. Cerebral or spinal AVMs occur in some families and may cause subarachnoid hemorrhage Subarachnoid Hemorrhage (SAH) Subarachnoid hemorrhage is sudden bleeding into the subarachnoid space. The most common cause of spontaneous bleeding is a ruptured aneurysm. Symptoms include sudden, severe headache, usually... read more Subarachnoid Hemorrhage (SAH) , seizures Seizure Disorders A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more , or paraplegia. Hepatic AVMs may lead to liver failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more and high output heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... read more Heart Failure (HF) . Chronic iron deficiency anemia Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more Iron Deficiency Anemia is commonly present.

Manifestations of Hereditary Hemorrhagic Telangiectasia

Diagnosis

  • 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

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

Screening

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.

Diagnosis reference

  • 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.

Treatment

  • 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 Treatment Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more Treatment ); 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 Treatment reference 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... read more Treatment reference ). 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.

Treatment reference

Key Points

  • 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.

Drugs Mentioned In This Article

Drug Name Select Trade
AMICAR
CYKLOKAPRON
POMALYST
AVASTIN
THALOMID
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