INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disorder identified typically by the triad of telangiectasia, recurrent epistaxis, and a positive family history for the disorder. The major cause of morbidity and mortality due to this disorder lies in the presence of multiorgan arteriovenous malformations (AVMs) and the associated hemorrhage that may accompany them. The disease has a wide spectrum of presentations; patients may be asymptomatic or have multiple organ involvement, presenting at any age. Treatment mainly is supportive and consists of controlling and treating the bleeding. The prognosis of the disease is good as long as bleeding is promptly recognized and adequately controlled.

Pathophysiology: The clinical manifestations of Osler-Weber-Rendu disease are caused by the development of abnormal vasculature, including telangiectases, AVMs, and aneurysms. The main defect in some families is in the mutation of the protein endoglin, a receptor for transforming growth factor beta, which has a role in tissue repair and angiogenesis. Defects in the endothelial cell junctions, endothelial cell degeneration, and weakness of the perivascular connective tissue are thought to cause dilation of capillaries and postcapillary venules, which manifest as telangiectases.

Clinically, nasal telangiectasia is more likely to bleed than the cutaneous telangiectasia. This may be because of stronger tissue-supporting telangiectases in the skin, as opposed to the relatively weak mucous membranes. AVMs are abnormal tortuous vessels with both arterial and venous components. The larger AVMs can cause some left-to-right shunting and, if sufficiently large, may contribute to high-output cardiac failure. Loss of the muscularis layer and disturbance of the elastic lamina of vessel walls may give rise to aneurysms in multiple organ systems. Most commonly, telangiectases involve the mucous membranes, the skin, the conjunctiva, the retina, and the GI tract. AVMs are found in the lungs, brain, and liver.

Frequency:

• In the US: Prevalence is 1-2 cases per 100,000 population.

• Internationally: The worldwide prevalence is 1-2 cases per 100,000 population, with a much higher incidence in the Danish island of Fyn, the Dutch Antilles, and parts of France.

Mortality/Morbidity: Patients are at risk for hemorrhage from multiple sites (especially the nasal mucosa), pulmonary hemorrhage, high-output cardiac failure, ischemic stroke, migraines, and paradoxical emboli. Fewer than 10% of patients die of complications of the disease.

• Hemorrhage: Recurrent epistaxis is observed in 50-80% of patients. In one half of patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract.

• Stroke: Strokes in patients with Osler-Weber-Rendu disease may be either hemorrhagic or ischemic. Hemorrhagic strokes are due to cerebral AVMs. Ischemic strokes are due to pulmonary AVMs, which, in addition to strokes, contribute to an increased incidence of brain abscesses. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke and 1% per year are estimated to develop a brain abscess.

• High-output cardiac failure: Uncommonly, large AVMs develop in the liver. This can cause a substantial left-to-right shunt and result in cardiac failure.

Race: The disease most commonly occurs in white patients, but it has been described in patients of Asian, African, and Arabic descent.

Sex: The syndrome occurs with equal frequency and severity in both sexes.

Age:

• The syndrome most often presents by the third decade of life but may be clinically silent.

• The most common presentation is recurrent epistaxis, which often develops prior to the second decade of life.

• Pulmonary AVMs may be congenital and, therefore, diagnosed within the first year of life.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: Because Osler-Weber-Rendu syndrome is an autosomal dominant disease, a family history of telangiectasia and recurrent bleeding in other family members is usually present. Symptoms vary depending on the area of involvement. The main areas of involvement are the nasal mucosa, skin, the GI tract, the pulmonary vasculature, and the brain.

• Diagnostic criteria are based on 4 components. The diagnosis is considered definite if 3 criteria are present and possible if 2 criteria are present. The diagnosis is unlikely if fewer than 2 criteria are present. The criteria are as follows:
  • Nosebleeds - Spontaneous and recurrent

  • Telangiectasias - Multiple, at characteristic sites, including the lips, oral cavity, fingers, and nose

  • Presence of internal lesions - GI telangiectasia, pulmonary AVMs, hepatic AVMs, cerebral AVMs, spinal AVMs

  • Family history - A first-degree relative with HHT according to these criteria

• Nasal mucosa: Epistaxis is the most common manifestation of the disease and occurs in up to 90% of affected patients. Bleeding may occur as often as every day or as infrequently as once a month. Patients with epistaxis initially present before the second decade of life. Blood transfusions are required in 10-30% of patients.

• GI tract: Recurrent painless GI bleeding occurs in 10-40% of patients and generally occurs later in life than epistaxis; typically, GI bleeding occurs around the fourth or fifth decades of life. Patients may report abdominal pain that may be due to thrombosis of alimentary AVMs.

• Pulmonary vasculature

• Pulmonary AVMs are present in 15-20% of patients with the disease. Half of the patients with pulmonary AVMs are asymptomatic. Dyspnea and exercise intolerance may be elicited from history. Pulmonary AVMs may cause enough right-to-left shunting to cause cyanosis, hypoxemia, and secondary polycythemia.

• Hemoptysis results from either telangiectasia of the trachea and bronchi or pulmonary arteriovenous (AV) fistulas. Patients usually present around the third or fourth decades of life.

• Migraine headaches are present in 13-50% of patients with Osler-Weber-Rendu syndrome. Although the reason is unclear, the headaches are more prevalent in patients with pulmonary AVMs.

• Brain involvement

• Neurologic involvement occurs in 8-12% of patients with Osler-Weber Rendu syndrome. A history of headache, seizures, and focal neurologic symptoms may be found on questioning. An area of ischemic brain surrounding a cerebral AVM or an intracerebral hematoma may cause these symptoms.

• Stroke and brain abscess are more common in patients with Osler-Weber-Rendu syndrome compared to the healthy population. This is due to loss of the normal filtering function of the pulmonary vasculature in patients with pulmonary AVMs. These AVMs allow thrombotic and septic emboli to travel to the brain. Untreated patients have a 2% risk of stroke and a 1% risk of brain abscess per year.

• Fatigue: Fatigue may be elicited on history and may be due to an iron deficiency anemia caused by recurrent blood loss.

• Visual disturbances: Visual disturbances may be noted, possibly caused by intraocular hemorrhage. Patients may notice bloody tears, which are due to conjunctival telangiectases.

• Liver involvement: Liver involvement may cause right upper quadrant (RUQ) pain, jaundice, symptoms of high-output cardiac failure, and bleeding from esophageal varices. The cardiac failure is caused by a large left-to-right shunt that can occur between the hepatic arteries and veins. Occasionally, patients with Osler-Weber-Rendu syndrome may present with atypical cirrhosis.

Physical: The areas involved dictate the signs that may be found on physical examination.

• Skin

• The most obvious finding on physical examination is telangiectases. These may be found on the oral mucosa, nasal mucosa, skin, and conjunctiva.

• Cyanosis and clubbing may be present in patients with pulmonary AVMs. These develop because of right-to-left shunting.

• Liver involvement can cause jaundice.

• CNS: If a previous stroke, brain abscess, or intracerebral hematoma has occurred, patients may present with focal neurologic signs.

• Respiratory system: In the presence of pulmonary AVMs, the patient may be tachypneic, cyanotic, and have clubbing. A pulmonary bruit may be heard best on inspiration.

• Cardiovascular system: Patients may be cyanotic because of right-to-left pulmonary shunting or pale because of anemia. Patients may have a hyperdynamic circulation if they have hepatic involvement and a large left-to-right shunt. Hyperdynamic circulation may be exacerbated by anemia.

• GI system

• Examination of the oral mucosa reveals telangiectases in 58-79% of patients. Rectal examination may reveal frank blood.

• Signs of liver involvement include jaundice, hepatomegaly, and a RUQ bruit or thrill.

• Eyes: Funduscopic examination may reveal retinal telangiectasis and hemorrhages. Bloody tears may be present because of conjunctival telangiectases.

Causes: The disease is caused by an inherited defect. So far, 2 loci have been identified associated with Osler-Weber-Rendu syndrome: one on chromosome arm 9q33-34 (HHT1) and a second on chromosome arm 12q (HHT2).

• Chromosome arm 9q34 (HHT1) harbors the endoglin gene, which encodes for a homodimeric integral membrane glycoprotein expressed at high levels on human vascular endothelial cells. Several mutations of the endoglin gene have been reported in family members with Osler-Weber- Rendu syndrome.

• Chromosome arm 12q (HHT2) harbors the activin receptorlike kinase 1 (ALK1), which encodes for a surface receptor for the transforming growth factor beta superfamily of ligands. Several families with Osler-Weber-Rendu syndrome harbor mutations of ALK1. Loss-of-function mutations in a single allele of the ALK1 locus have been shown to contribute to defects in maintaining endothelial integrity.

• In patients with the HHT1 genotype, the prevalence of pulmonary AVMs and cerebral AVMs was shown to be higher than that of patients with the HHT2 genotype. Patients with HHT1 also experience more severe GI bleeding than patients with HHT2. The prevalence of hepatic AVMs is higher in patients with HHT2 than in patients with HHT1.