eMedicine Specialties > Pediatrics: General Medicine > Hematology

Osler-Weber-Rendu Syndrome

Lawrence C Wolfe, MD, Senior Associate in Pediatric Hematology/Oncology, Schneider Children's Hospital
Arun Panigrahi, MD, Resident Physician, Department of Pediatrics, Tufts University School of Medicine

Updated: Nov 20, 2009

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.

Typical symptoms in a patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the cheeks.

Close-up view of typical symptoms of patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the lips.

Close-up view of typical symptoms in a patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the cheeks.

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: Due to the presence of large AVMS and blood loss, high-output cardiac failure may occur. This known complication of HHT has recently been linked with the onset of severe and recurrent epistaxis in a small sample of patients.²

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; however, recent studies reveal that most patients with pulmonary AVM have no significant respiratory symptoms.³ 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.
• CNS involvement
  • Neurologic involvement occurs in 8-12% of patients with Osler-Weber-Rendu syndrome. A history of headache, seizures, and focal neurologic symptoms (eg, paraplegia, paralysis) 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. A recent study also described the detection of vascular abnormalities deep in the digits in patients with hereditary hemorrhagic telangiectasia (HHT) using a handheld illuminator.⁴
  • 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 5.⁵

• 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. Also, oral and nasal mucosal telangiectasias present earlier in life in patients with the HHT1 genotype. The prevalence of hepatic AVMs is higher in patients with HHT2 than in patients with HHT1. Patients with the HHT2 genotype also present earlier in life with dermal lesions.⁶

Differential Diagnoses

Cockayne Syndrome

Other Problems to Be Considered

Crest syndrome
Louis-Bar syndrome
Ataxia-telangiectasia
Essential telangiectasia
Acne rosacea
Actinically damaged skin
Dermatomyositis
Rothmund-Thomson syndrome
Scleroderma

Workup

Laboratory Studies

At specific centers, genetic tests are available for various mutations in the endoglin gene found on chromosome 9 and the activin receptorlike kinase gene found on chromosome 12. Currently, no laboratory studies are widely available to confirm the diagnosis of Osler-Weber-Rendu syndrome. However, certain laboratory tests may be helpful in identifying specific complications.

• CBC count
  • Hemoglobin may be decreased because of chronic bleeding and iron deficiency anemia, or the patient may be polycythemic because of chronic hypoxemia from a right-to-left shunt.
  • Platelets may be normal or slightly increased.
  • The WBC count should be within the reference range unless an infectious complication, such as a brain abscess, is present.
• Prothrombin time and activated partial thromboplastin time: These values should be normal, unless severe liver involvement is present. A preliminary study also points to the usefulness of factor VIII antigen levels; elevated levels may influence thrombotic risk in Osler-Weber-Rendu syndrome.⁷
• ABG
  • If a right-to-left shunt is present, the pO₂ is low.
  • Performing a hyperoxic test with the arterial blood gas confirms the diagnosis of a right-to-left shunt. A minor increase in the arterial partial pressure of oxygen while the patient is on 100% oxygen indicates the presence of a shunt. In the absence of a shunt, the arterial partial pressure of oxygen should increase to a much larger extent.
  • Screening with a hyperoxic test is shown to have 100% sensitivity and 40% specificity for the detection of pulmonary arteriovenous malformations (AVMs) in patients with Osler-Weber-Rendu syndrome who are suspected of having an AVM.

Imaging Studies

• Because of the prevalence of AVMs and associated sequelae, screening tests using multiple imaging modalities have become the standard of care for patients with Osler-Weber-Rendu syndrome. Some centers also use screening for asymptomatic children with a family history of Osler-Weber-Rendu syndrome in an effort to reduce serious complications associated with AVMs.
• Chest radiography followed by agitated saline solution transthoracic contrast echocardiography (TTCE) with grading is now recommended as the screening test of choice for pulmonary AVMs in patients with Osler-Weber-Rendu syndrome. This modality in initial studies may have superior sensitivity compared with CT scanning; however, because long-term follow-up data are not currently available, all patients with even low-grade evidence of pulmonary pathology on TTCE require CT imaging as a confirmatory study.
• If a pulmonary AVM is present, chest radiography may reveal a peripheral noncalcified coin lesion attached by vascular strands to the hilus.
• CT scanning may be used to better delineate AVMs of the lung or head. It may also reveal larger brain abscesses.
• MRI scanning is the primary screening modality for cerebral AVMs as well as telangiectasias in the CNS. 
• Doppler ultrasonography of the liver may be used for screening and first-line imaging in patients with Osler-Weber-Rendu syndrome for hepatic AVM and other associated sequelae.
• Angiography is used to map the exact extent of the vascular lesions, usually when surgery is contemplated.

Other Tests

• Colonoscopy reveals GI telangiectasias as small well-defined lesions surrounded by an anemic halo.
• Videocapsule endoscopy may be used because it often reveals telangiectasias unnoticed in the GI tract in patients with unknown sources of bleeding.⁸

Histologic Findings

• Biopsies of affected areas of the skin reveal focal dilatations of postcapillary venules in the dermal upper-horizontal plexus.
• Abnormal stress fibers are present in the venule pericytes. These findings vary from other forms of hereditary telangiectasia. 
• Liver biopsies in patients with significant liver involvement often reveal pseudocirrhosis due to shunting from the hepatic artery to the hepatic vein or shunting from the hepatic artery to the portal vein. 

Treatment

Medical Care

• Medical and surgical care in patients with Osler-Weber-Rendu syndrome are aimed at decreasing the amount of hemorrhage and minimizing the sequelae of arteriovenous malformations (AVMs), which may develop in multiple organ systems. Historically, estrogen-related hormones and antifibrinolytic agents have been used the management of bleeding; however, recent studies reveal that their use likely increases the risk of thrombotic events in patients with Osler-Weber-Rendu who have pulmonary AVMs. Because of this finding, patients should receive screening studies for the presence of pulmonary AVMs prior to treatment of the disease.
• Novel therapies, such as N-acetylcysteine and tamoxifen (antiestrogenic agent), are also being studied as options for management of recurrent epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT).^9,10 A recent case report also illustrates the use of bevacizumab (Avastin) in the treatment of HHT.¹¹
• Recent recommendations also advocate the use of antibiotic prophylaxis prior to surgical or dental procedures in all patients with known pulmonary AVMs or positive contrast echocardiography findings (agitated saline solution transthoracic contrast echocardiography [TTCE] grade 1 or higher). Recent studies also recommend that women with HHT who conceive should be considered to have high-risk pregnancies because of rare major complications and improved survival outcome following prior recognition.¹²

Surgical Care

• Septal dermoplasty can reduce the severity of epistaxis by 75%. This procedure is performed by replacing the nasal mucosa with autologous skin grafts. Telangiectasias may also develop on the autologous skin grafts.
• Pulsed dye laser treatment may also be used to photocoagulate telangiectasias in the nasal mucosa. As many as 3 subsequent treatments may be necessary before any change in bleeding frequency or severity is observed.
• Endovascular embolization for treatment of severe acute epistaxis is also a treatment modality.¹³ Patients who undergo endovascular embolization often require repeat embolization and surgical procedures.
• Septectomy combined with septal dermoplasty may also be a viable option for patients with severe transfusion-dependent epistaxis.¹⁴
• Embolization of pulmonary AVMs has been shown to be a safe and effective procedure that prevents brain abscess and ischemic stroke if complete occlusion of all pulmonary AVMs is acheived.¹⁵ Embolization is currently recommended for every pulmonary AVM with a feeding artery of 3 mm or more.³ Other treatment modalities for pulmonary AVMs include surgical ligation.
• Life-threatening GI bleeds are often effectively treated by segmental bowel resection.
• Embolization of the hepatic artery in selected patients with liver involvement may be used, as well as liver transplantation.^16,17
• Radiosurgery, microsurgery, or embolization are used to treat cerebral AVMs.

Consultations

Consultation with multiple specialists may be useful in the diagnosis and treatment of this disease. Certain specialists may only warrant consultation when certain complications arise.

• Dermatologist
• Pulmonologist
• Hematologist
• Gastroenterologist
• Neurologist and neurosurgeon

Diet

• In most patients, no special diet is required.
• Iron can be depleted if the patient experiences chronic blood loss.
• Folate requirements can be high if the bone marrow is chronically activated.

Activity

• Most patients can continue normal activities.

Medication

Estrogen and progesterone combinations and aminocaproic acid may help safely control mucosal bleeding in patients with Osler-Weber-Rendu syndrome whose screening test findings reveal the absence of pulmonary arteriovenous malformations (AVMs).

Oral contraceptives

These agents may be used to decrease the amount of bleeding. Topical preparations can be used to help strengthen mucosa and decrease the susceptibility of the mucosa to external trauma. Prior to use, screening tests for pulmonary AVMs should be performed because of the risk of complications involving thromboembolism.

Norethindrone acetate and ethinyl estradiol (Yasmin, Loestrin 1.5/30)

Used to decrease mucosal bleeding. Probably works by strengthening mucosal tissues and thereby making them more resistant to trauma.

Dosing

Adult

PO contraceptives that contain ethinyl estradiol 30 mcg and norethindrone 1.5 mg/tab: 1 tab PO qd
Use until bleeding controlled

Pediatric

Not well established; use adult doses for older children

Interactions

May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control

Contraindications

Documented hypersensitivity; thrombophlebitis or thromboembolic disorders; history of stroke; coronary artery disease; active liver disease; carcinoma of the breast; undiagnosed vaginal bleeding; ophthalmic vascular disease; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Women >35 y who smoke are at increased risk of serious adverse effects on the heart and blood vessels; caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease

Antifibrinolytics

These agents are used to enhance hemostasis when fibrinolysis contributes to bleeding. Prior to use, screening for pulmonary AVMs should be performed due to risk of thromboembolic events.

Aminocaproic acid (Amicar)

Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Used to prevent or treat mucosal bleeding caused by bleeding disorders or trauma.

Dosing

Adult

3.5 g IV initially, then 1 g/h until bleeding stops; not to exceed 8 h treatment duration
3.5 g/dose PO tid/qid for 3-4 d
Topical: Insert a gauze soaked in a 10% solution of aminocaproic acid into the nasal cavity

Pediatric

50-100 mg/kg IV infused over 30-60 min, then 30-50 mg/kg/h until bleeding stops; not to exceed 8 h treatment duration
50 mg/kg/dose PO tid/qid for 3-4 d
Topical: Administer as in adults

Interactions

Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; disseminated intravascular coagulation ([DIC] because aminocaproic acid can be fatal in patients with DIC, differentiate between hyperfibrinolysis and DIC)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Reduce dose in cardiac, renal, or hepatic disease

Immunomodulating agent

Two case reports have documented the regression of Osler-Weber-Rendu lesions with the use of interferon alpha in patients who were treated for other indications.^18,19

Interferon alfa-2a (Roferon-A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Dosing

Adult

HHT: Not established
Airway hemangiomas: 3 million IU/m²/d SC

Pediatric

HHT: Not established
Airway hemangiomas: Administer as in adults

Interactions

Theophylline may increase toxicity of interferon alpha by reducing clearance; cimetidine may increase antitumor effects of interferon alpha; zidovudine and vinblastine may increase toxicity of interferon alpha

Contraindications

Documented hypersensitivity; avoid in patients who have anaphylactic sensitivity to mouse IgG, egg protein, or neomycin; autoimmune hepatitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Depression and suicidal ideation may be side effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported in association with interferon alpha therapy
Bone marrow suppression: Prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor patient periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 6 mo, discontinue treatment; if response occurs, continue treatment until no further improvement observed (not known whether continued treatment after that time is beneficial)

Follow-up

Further Inpatient Care

• Admit for control of bleeding and complications associated with Osler-Weber-Rendu syndrome.

Further Outpatient Care

• Monitor for symptoms and signs of blood loss and anemia with yearly stool guaiac testing and CBC count with differential.
• Screen patients for pulmonary, hepatic and CNS arteriovenous malformations (AVMs) at the time of diagnosis and at the onset of any suggestive symptoms and signs.

Inpatient & Outpatient Medications

• Medications include oral contraceptives and aminocaproic acid, which are used to decrease the amount of mucosal bleeding yet should only be used if the patient has received screening for the presence of pulmonary AVMs.
• Humidification of the ambient air helps decrease the amount of mucosal bleeding.
• Iron and folate supplementation may be needed because of chronic blood loss and a chronically activated bone marrow.

Transfer

• Transfer may be necessary for further diagnostic evaluation and surgical interventions.

Complications

• Hemorrhagic or ischemic stroke
• Brain abscess
• High-output congestive heart failure
• Chronic GI bleeding and anemia
• Portal hypertension with esophageal varices
• Pulmonary hemorrhage
• Liver cirrhosis

Prognosis

• Prognosis greatly depends on the severity of the disease; with appropriate screening and aggressive management, life expectancy may approach that of the normal population.

Patient Education

• Educate patients on the complications of the disease.
• Explain the autosomal dominant inheritance of the disease to patients.

Miscellaneous

Medicolegal Pitfalls

• Failure to screen for complications such as pulmonary, hepatic, and CNS arteriovenous malformations (AVMs)
• Failure to inform patients of the autosomal dominant nature of the condition and to counsel accordingly

Special Concerns

• Currently, prenatal diagnosis is rarely used in families affected by Osler-Weber-Rendu syndrome. These families are encouraged to have DNA diagnosis of affected individuals where available. 
• If the specific mutation within the family is revealed, cord blood from neonates may be analyzed for presence of the disease, and multiple screening modalities for AVMs may be used.

Multimedia

Media file 1: Typical symptoms in a patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the cheeks.

Media file 2: Close-up view of typical symptoms of patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the lips.

Media file 3: Close-up view of typical symptoms in a patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the cheeks.

References

1. Sabba C, Pasculli G, Suppressa P, et al. Life expectancy in patients with hereditary haemorrhagic telangiectasia. Quarterly Journal of Medicine. May 2006;99(5):327-334. [Medline].

2. Khalid SK, Pershbacher J, Makan M, Barzilai B, Goodenberger D. Worsening of nose bleeding heralds high cardiac output state in hereditary hemorrhagic telangiectasia. Am J Med. Aug 2009;122(8):779.e1-9. [Medline].

3. Lacombe P, Lagrange C, Beauchet A, et al. Diffuse pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: long-term results of embolization according to the extent of lung involvement. Chest. Apr 2009;135(4):1031-7. [Medline].

4. Mohler ER, Doraiswamy V, Sibley A et al. Transillumination of the fingers for vascular anomalies: a novel method for evaluating hereditary hemorrhagic telangiectasia. Genetics in Medicine. May 2009;11(5):356-8.

5. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. Journal of Medical Genetics. Feb 2006;43(2):97-110. [Medline].

6. Letteboer TG, Mager HJ, Snijder RJ, et al. Genotype - phenotype relationship in Hereditary Hemorrhagic Telangiectasia. J Med Genet. 2005;Sep 9 (Epub ahead of print):[Medline].

7. Shovlin CL, Sulaiman NL, Govani FS, Jackson JE, Begbie ME. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost. Nov 2007;98(5):1031-9. [Medline].

8. [Guideline] Adler DG, Leighton JA, Davila RE, et al. ASGE guideline: The role of endoscopy in acute non-variceal upper-GI hemorrhage. Gastrointest Endosc. Oct 2004;60(4):497-504. [Medline].

9. de Gussem EM, Snijder RJ, Disch FJ, et al. The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study. Rhinology. Mar 2009;47(1):85-8. [Medline].

10. Yaniv E, Preis M, Hadar T, Shvero J, Haddad M. Antiestrogen therapy for hereditary hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial. Laryngoscope. Feb 2009;119(2):284-8. [Medline].

11. Bose P, Holter JL, Selby GB. Bevacizumab in hereditary hemorrhagic telangiectasia. N Engl J Med. May 14 2009;360(20):2143-4. [Medline].

12. Shovlin CL, Sodhi V, McCarthy A, et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG. Aug 2008;115(9):1108-15. [Medline].

13. Layton KH, Kallmes DF, Gray LA, Cloft HJ. Endovascular treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia. American Journal of Neuroradiology. May 2007;28(5):885-8. [Medline].

14. Lesnik GT, Ross DA, Henderson KJ, Joe JK, Leder SB, White RI Jr. Septectomy and septal dermoplasty for the treatment of severe transfusion-dependent epistaxis in patients with hereditary hemorrhagic telangiectasia and septal perforation. American Journal of Rhinology. May 2007;21(3):312-5. [Medline].

15. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax. Mar 2008;63(3):259-66. [Medline].

16. Buscarini E, Plauchu H, Garcia Tsao G, et al. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver International. Nov 2006;26(9):1040-6. [Medline].

17. Lerut J, Orlando G, Adam R, et al. Liver Transplantation for Hereditary Hemorrhagic Telangiectasia: Report of the European Liver Transplant Registry. Annals of Surgery. Dec 2006;244(6):854-864. [Medline]. [Full Text].

18. Massoud OI. Resolution of hereditary hemorrhagic telangiectasia and anemia with prolonged alpha-interferon therapy for chronic hepatitis C. J Clin Gastroenterol. 2004;38(4):377-9. [Medline].

19. Wheatley-Price P, Shovlin C, Chao D. Interferon for metastatic renal cell cancer causing regression of hereditary hemorrhagic telangiectasia. J Clin Gastroenterol. Apr 2005;39(4):344-5. [Medline].

20. Brant AM, Schachat AP, White RI. Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). Am J Ophthalmol. Jun 15 1989;107(6):642-6. [Medline].

21. Cottin V, Chinet T, Lavole A, et al. Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Series of 126 Patients. Medicine. Jan 2007;86(1):1-17. [Medline].

22. Gillis MC. Amicar. In: Compendium of Pharmaceuticals and Specialties. ed. Ottawa, Canada: Canadian Pharmaceutical Association; 1996:56.

23. Gillis MC. Loestrin. In: Compendium of Pharmaceuticals and Specialties. ed. Ottawa, Canada: Canadian Pharmaceutical Association; 1996:784-6.

24. Giordano P, Nigro A, Lenato GM, et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. Journal of Thrombosis & Haemostasis. Jun 2006;4(6):1237-45. [Medline].

25. Gu Y, Jin P, Zhang L, et al. Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood. Mar 1 2006;107(5):1951-4. [Medline].

26. Haitjema T, Westermann CJ, Overtoom TT, et al. Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): new insights in pathogenesis, complications, and treatment. Arch Intern Med. Apr 8 1996;156(7):714-9. [Medline].

27. Harries PG, Brockbank MJ, Shakespeare PG, Carruth JA. Treatment of hereditary haemorrhagic telangiectasia by the pulsed dye laser. J Laryngol Otol. Nov 1997;111(11):1038-41. [Medline].

28. Hereditary Hemorrhagic Telangiectasia Foundation International. 1997 Summary of HHT. Available at http://www.hht.org. Accessed 2000.

29. Kikuchi K, Kowada M, Sasajima H. Vascular malformations of the brain in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). Surg Neurol. May 1994;41(5):374-80. [Medline].

30. Kjeldsen AD, Oxhoj H, Andersen PE. Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia. Chest. Aug 1999;116(2):432-9. [Medline]. [Full Text].

31. Kjeldson AD, Noller TR, Brusgaard K, et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med. 2005;258(4):349-55. [Medline].

32. Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genetics in Medicine. Jan 2007;9(1):14-22. [Medline].

33. Letteboer TG, Mager HJ, Snijder RJ, et al. Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia. Am J Med Genet A. Nov 1 2008;146A(21):2733-9. [Medline].

34. Longacre AV, Gross CP, Gallitelli M, Henderson KJ, White RI Jr, Proctor DD. Diagnosis and management of gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol. Jan 2003;98(1):59-65. [Medline].

35. Maarouf M, Runge M, Kocher M, et al. Radiosurgery for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia. Neurology. Jul 27 2004;63(2):367-9. [Medline].

36. Mei-Zahav M, Letarte M, Faughnan ME, et al. Symptomatic Children Wtih Hereditary Hemorrhagic Telangiectasia: A Pediatric Center Experience. Archives of Pediatrics & Adolescent Medicine. Jun 2006;160(6):596-601. [Medline].

37. Post MC, Letteboer TGW, Johannes JM, et al. A pulmonary right-to-left shunt in patients with hereditary hemorrhagic telangiectasia is associated with an increased prevalence of migraine. Chest. 2005;128(4):2485-9. [Medline].

38. Sadick H, Bergler WF, Oulmi-Kagermann J, et al. Estriol induced squamous metaplasia on the nasal mucosa in patients with hereditary hemorrhagic telangiectasia. Arch Med Res. 2005;36(5):468-73. [Medline].

39. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66-7. [Medline].

40. Shovlin CL, Hughes JM, Scott J, et al. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet. Jul 1997;61(1):68-79. [Medline]. [Full Text].

41. van Tuyl SA, Letteboer TG, Rogge-Wolf C, et al. Assessment of intestinal vascular malformations in patients with hereditary hemorrhagic teleangiectasia and anemia. European Journal of Gastroenterology & Hepatology. Feb 2007;19(2):153-8. [Medline].

42. White RI et al. Yale HHT Center Accomplishments: 1995-2007. Available at www.hhtavm.org/hhtavm.org-dnn/MS%20WSHA/site/Portals/0/Yale_HHT_Center_Summary_1995-2008.pdf. Accessed January 2008.

43. Zukotynsku K, Chan RP, Chow CM, et al. Contrast Echocardiography Grading Predicts Pulmonary Arteriovenous Malformations on CT. CHEST. Jul 2007;132(1):18-23. [Medline].

Keywords

Osler-Weber-Rendu syndrome, hereditary hemorrhagic telangiectasia, HHT, Rendu-Osler-Weber syndrome, heredofamilial angiomatosis, familial hemorrhagic angiomatosis, Osler's disease, Osler disease, multiorgan arteriovenous malformation, AVM, treatment, diagnosis, symptoms

Contributor Information and Disclosures

Author

Lawrence C Wolfe, MD, Senior Associate in Pediatric Hematology/Oncology, Schneider Children's Hospital
Lawrence C Wolfe, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association of Blood Banks, American Society of Hematology, Children's Oncology Group, and Eastern Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Arun Panigrahi, MD, Resident Physician, Department of Pediatrics, Tufts University School of Medicine
Arun Panigrahi, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MBBS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan
Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

The authors acknowledge valuable personal communication with Dr. Robert I White Jr, medical director of Yale AVM and HHT Center, deemed a HHT Center of Excellence by the HHT Foundation International.

The authors and editors of eMedicine also gratefully acknowledge the contributions of previous author Kent Stobart, MD, and Norman A Silver, MD, to the development and writing of this article.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)