eMedicine Specialties > Pediatrics: General Medicine > Hematology

Osler-Weber-Rendu Syndrome

Author: Lawrence C Wolfe, MD, Professor, Department of Pediatrics, Tufts University School of Medicine; Chief of Transfusion Service, Chief, Division of Pediatric Hematology/Oncology, New England Medical Center, Floating Hospital for Infants and Children
Coauthor(s): Arun Panigrahi, MD, Resident Physician, Department of Pediatrics, Tufts University School of Medicine; Norman A Silver, MD, Assistant Professor, Department of Emergency Medicine, University of Manitoba, Canada
Contributor Information and Disclosures

Updated: Dec 5, 2008

Introduction

Background

Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disorder typically identified 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 consists of management of bleeding via both medical and surgical options, as well as surgical management of arteriovenous malformations and further sequelae. The prognosis of the disease varies based on the severity of symptoms.

Pathophysiology

The clinical manifestations of Osler-Weber-Rendu disease are caused by the development of abnormal vasculature, including telangiectasias, AVMs, and aneurysms. The genetic defect largely involves either one of two genes: ENG or ALK-1. Both of these genes transcribe proteins that are highly expressed on endothelial cells and play important roles in tissue repair and angiogenesis through their common function as receptors for transforming growth factor beta. 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 telangiectasias. Most commonly, telangiectasias involve the mucous membranes, as well as the skin, the conjunctiva, the retina, and the GI tract.

AVMs are abnormal tortuous vessels with both arterial and venous components. The larger AVMs can cause left-to-right shunting and, if sufficiently large, may contribute to high-output heart failure. Loss of the muscularis layer and disturbance of the elastic lamina of vessel walls may also give rise to aneurysms in multiple organ systems. AVMs are found in the lungs, brain, and liver.

Frequency

United States

Reported incidence is 1-2 cases per 100,000 population per year, with a prevalence of 1-2 cases per 10,000 population. The disease has a clinical penetrance of 97%.

International

The worldwide prevalence is 1 case per 5,000-10,000 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 both mucosal and visceral sites, as well as high-output cardiac failure, cerebral abscess, ischemic stroke, migraines and further sequelae. Studies show that life expectancy appears to be significantly lower in patients with Osler-Weber-Rendu syndrome compared with the general population.¹  The mortality of these patients revealed an early peak at age 50 years and a later peak at 60-79 years due to acute complications.

• Hemorrhage: Recurrent epistaxis is observed in as many as 90% 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.
• CNS complications: Cerebral abscess due to impaired function of pulmonary vasculature is the most common neurologic manifestation of Osler-Weber-Rendu syndrome. Also, patients with this disease suffer from strokes, which may be either hemorrhagic or ischemic. Ischemic strokes likely due to pulmonary AVMs are common, whereas hemorrhagic strokes due to cerebral AVMs are far less common. 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: Rarely, 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 also be clinically silent. The most common presentation is recurrent epistaxis, which often develops prior to the second decade of life. AVMs may be congenital in nature, therefore they may present as early as the first year of life.

Clinical

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 nasal mucosa, skin, the GI tract, pulmonary vasculature, and the brain.

• Diagnostic criteria are based on 4 components. The diagnosis is considered definite if 3 criteria are present and is considered 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 sites including the lips, oral cavity, fingers, and nose
  • Presence of internal lesions - GI telangiectasia, pulmonary arteriovenous malformations (AVMs), hepatic AVMs, cerebral AVMs, spinal AVMs
  • Family history - A first-degree relative with Osler-Weber Rendu syndrome according to these criteria

Other symptoms that may be reported include the following:

• Nasal mucosa: Epistaxis is the most common manifestation of the disease and occurs in as many as 90% of affected patients. Bleeding may occur as often as every day or as infrequently as once a month. Patients with epistaxis usually present before the second decade of life. Blood transfusions are required in 10-30% of patients, and as many as 50% of patients require surgical treatment.
• GI tract: Recurrent painless GI bleeding occurs in 10-40% of patients and generally occurs later in life than epistaxis. Patients may report abdominal pain that may be due to thrombosis of GI AVMs.
• Pulmonary vasculature
  • Pulmonary AVMs are present in 15-33% of patients with the disease. Dyspnea and exercise intolerance are often presenting symptoms. Pulmonary AVMs may cause enough right-to-left shunting to cause cyanosis, hypoxemia, and secondary polycythemia. Pulmonary AVMs also increase the incidence of infection due to septic emboli formation in the pulmonary vasculature.
  • 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 presenting symptoms.
  • Stroke and brain abscess are more common in patients with Osler-Weber-Rendu syndrome compared with 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 (often asymptomatic) is reported in as many as 40% of patients. Symptoms may include right upper quadrant pain, jaundice, symptoms of high-output cardiac failure, and bleeding from esophageal varices. The complication of 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 telangiectasias. These lesions may be found on the oral mucosa, nasal mucosa, skin, and conjunctiva.
  • Cyanosis and clubbing may be present in patients with pulmonary AVMs. These signs develop due to right-to-left shunting.
  • Liver involvement may 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 telangiectasias in 58-79% of patients. Rectal examination may reveal frank blood.
  • Signs of liver involvement include jaundice, hepatomegaly, and a right upper quadrant bruit or thrill.
• Eyes: Funduscopic examination may reveal retinal telangiectasias and hemorrhages. Bloody tears may be present because of conjunctival telangiectasias.

Causes

The disease is caused by genetic defects with an autosomal dominant inheritance. So far, two primary loci have been identified associated with Osler-Weber-Rendu syndrome: one on chromosome arm 9q33-34 (HHT1) and a second on chromosome arm 12q11-14 (HHT2). Two more genes have recently been implicated; MADH4 gene mutation in patients with a combined syndrome of Osler-Weber-Rendu syndrome and juvenile polyposis and an unidentified HHT3 gene linked to chromosome 5.²

• Chromosome arm 9q33-34 (HHT1) harbors the endoglin gene, which encodes for a homodimeric integral membrane glycoprotein expressed at high levels on human vascular endothelial cells. Over 150 mutations of the endoglin gene have been reported in family members with Osler-Weber-Rendu syndrome. The vast majority of these mutations create premature stop codons and subsequently reduce levels of functional endoglin protein, the likely cause of Osler-Weber-Rendu syndrome type 1.
• Chromosome arm 12q11-14 (HHT2) contains the activin receptorlike kinase 1 (ALK1), which encodes for a surface receptor for the transforming growth factor (TGF)-beta superfamily of ligands. The TGF-beta multifunctional protein plays an important role in angiogenesis and vascular remodeling. Over 120 mutations have been reported in the ALK1 gene, yet unlike Osler-Weber-Rendu type 1, more than 50% of the mutations contributing to type 2 are missense substitutions.
• 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. The prevalence of hepatic AVMs is higher in patients with HHT2 than in patients with HHT1.

• Search for CME/CE on This Topic »

• Osler-Weber-Rendu Syndrome (Dermatology)
• Colorectal Tumors (Pediatrics: General Medicine)
• Dermatologic Manifestations of Gastrointestinal Disease (Dermatology)
• Epistaxis (Pediatrics: Surgery)