AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
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Background

Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is a rare genetically determined disorder that affects blood vessels throughout the body and results in a tendency for bleeding. HHT is an autosomal dominant disorder characterized by vascular dysplasia and hemorrhage. The prognosis for the disease is good as long as bleeding is promptly recognized and adequately controlled.

Pathophysiology

The pathogenesis regarding the heterogeneity of vascular malformations in patients with HHT is obscure. A partial explanation of the pathogenesis of HHT has become possible with the identification of 2 distinct genes: the endoglin gene and the activin receptorlike kinase type I (ALK-1) gene. Endoglin and ALK-1 are type III and type I transforming growth factor-beta (TGF-B) receptors, and both are exclusively expressed on vascular endothelial cells. The binding of TGF-B to the type II TGF-B receptor on endothelial cells, which is accelerated in the presence of endoglin, results in the phosphorylation of type I TGF-B receptors, activin receptorlike kinase type 5 (ALK-5), and ALK-1. Phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively.

The activated Smad proteins dissociate from the type I TGF-B receptor, bind to Smad4, and enter the nucleus to transmit TGF-B signals by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between the 2 signaling pathways involving ALK-5 and ALK-1 is important in determining the properties of endothelial cells during angiogenesis.

Mutations of endoglin genes and ALK-1 genes are involved in the genetic pathogenesis of HHT type 1 and HHT type 2, respectively. To date, different mutations in endoglin (at least 29) and ALK-1 (at least 17) have been found; these include missense, nonsense, frameshift, and deletion mutations. The precise mechanisms of by which these mutations elicit the vascular abnormalities in patients with HHT remain uncertain. However, the elucidation of the intracellular signal transduction mechanisms and change in targeted gene expressions by using mutant recombinant endoglin or ALK-1 proteins and knockout mice will enable physicians to understand the genetic and molecular pathogenesis of HHT and to effectively treat patients with HHT.

HHT is a disorder that is inherited in an autosomal dominant fashion, although 20% of patients are unaware of a positive family history, partly because the lesions may be minimal and because 10% of patients have no episodes of bleeding. The homozygous condition probably is fatal. Histopathologic studies reveal large, irregular, thinly walled blood vessels, but the pathogenesis has not been fully established. One current theory states that systemic nevus vascular damage may not be equally expressed in all individuals with HHT. Individuals with blood group type O are affected more often, whereas males and females are affected equally. Coagulation abnormalities and increased fibrinolytic activity in the lesions may contribute to the tendency for bleeding.

Frequency

United States

HHT is rare. Prevalence is 1-2 cases per 100,000 population.

International

The onsets, courses of illness, and sex distributions are the same worldwide. The condition is much more common on the Danish island of Fyn, in the Dutch Antilles, and in parts of France.

Mortality/Morbidity

Most patients with HHT have a favorable prognosis.

• Frequent nosebleeds and melena may result from telangiectasia in the nose and GI tract. Patients with the severe form of HHT have heavy bleeding and resultant iron-deficiency anemia. Recurrent epistaxis is observed in 50-80% of patients. In half the patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients.
• Pulmonary and CNS arteriovenous aneurysms may appear later in life. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract.
• Other sites of bleeding may include sites in the GI tract, kidney, spleen, bladder, liver, meninges, and brain. Strokes in patients with Osler-Weber-Rendu syndrome may be either hemorrhagic or ischemic. 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. Retinal arteriovenous aneurysms occur only rarely.

Race

No racial predilection is recognized.

Sex

Males and females are affected equally.

Age

HHT may occur in children, in whom a tendency to bleed may be the first symptom. However, HHT is far more common during puberty or adulthood. The syndrome most often manifests by the second or third decade of life. Pulmonary AVMs may be congenital and, therefore, diagnosed within the first year of life. The risk of GI tract bleeding increases in patients older than 50 years.

CLINICAL

Section 3 of 11  

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• Follow-up
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• Multimedia
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History

• Recurrent epistaxis is the first symptom in 95% of patients. Patients usually have a family history of telangiectasia and recurrent bleeding in other family members. Bleeding may occur as often as every day or as infrequently as once a month. Blood transfusions are required in 10-30% of patients.
• Telangiectases often appear 1 year after the first episode of epistaxis.
• Telangiectases are not usually seen before puberty.
• Commonly, telangiectases are first noticed in those aged 20-40 years.
• Rarely, telangiectases are prominent in childhood.
• The mucous membranes are almost invariably involved.
• The risk of GI tract bleeding increases in patients aged approximately 50 years. Recurrent painless GI bleeding occurs in 10-40% of patients and generally occurs later in life than epistaxis. Patients may report abdominal pain, which may be due to thrombosis of alimentary AVMs.
• Pulmonary AVMs may cause enough right-to-left shunting to cause cyanosis, hypoxemia, and secondary polycythemia. Half the patients with pulmonary AVMs are asymptomatic.
• Neurologic involvement occurs in 8-12% of patients with Osler-Weber-Rendu syndrome. Untreated patients have a 2% risk of stroke and 1% risk of brain abscess.

Physical

Obvious physical findings are limited to those in the skin and mucous membranes; however, physical finding may also be present in many other organs.

• Skin lesions begin as dark red lines or punctate, pulsating vascular papules the size of match heads. These may be found on the skin, oral mucosa, nasal mucosa, and conjunctiva.
• More rarely, skin lesions are star shaped and 1-3 mm in diameter; alternatively, they are nonpulsating telangiectases similar to those of araneus nevi.
• Characteristically, dark red lesions appear on the face, lips, ears, conjunctiva, trunk, forearms, hands, and fingers. They often are conspicuous in the nail beds.
• Almost invariably, all of the mucous membranes are involved, including membranes throughout the GI, respiratory, and urinary tracts and those in the nasal septum, oral cavity, and nasopharynx.
• Recurrent epistaxis is usually the presenting symptom. Recurrent epistaxis results in fatigue and anemia.
• Bleeding from the GI, respiratory, and urinary tracts may occur. It usually occurs by the third or fourth decade of life.
• Pulmonary arteriovenous anastomoses lead to fistulae; dyspnea, cyanosis, and clubbing of the fingers during adolescence reveal their presence.
• • Hepatic arteriovenous anastomoses lead to hepatic enlargement, and cirrhosis may cause pain and cardiac failure.
  • CNS arteriovenous anastomoses and aneurysms may lead to paresthesia, stoke, brain abscess, or intracerebral hematoma with focal neurologic signs.
• In pregnant women with HHT, pulmonary arteriovenous malformations may cause life-threatening fetomaternal complications. Pulmonary hemorrhage can occur, compromising maternal and fetal health.
• The spleen may be enlarged in some patients.

Causes

HHT is a defect that is inherited in an autosomal dominant fashion (see Pathophysiology). The homozygous condition is probably lethal. Currently, 2 loci have been identified that are associated with Osler-Weber-Rendu syndrome, one on 9q33-q34 and a second on 12q. Band 9q34 harbors the endoglin gene. Band 12q harbors activin receptorlike kinase 1 (ALK 1), which encodes for a surface receptor for the TGF-B superfamily of ligands.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) syndrome
Rothmund-Thomson syndrome
Dermatomyositis
Louis-Bar syndrome
Ataxia-telangiectasia
Essential telangiectasia
Rosacea

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Blood: Often, iron-deficiency anemia and thrombocytopenia are present. The patient may be polycythemic because of chronic hypoxemia.
• Urine: Evaluate hematuria.
• Stool: Evaluate the presence of blood in the stool.

Imaging Studies

• Chest radiography, angiography, CT, and/or MRI may be required for the evaluation of internal arteriovenous malformations.
• • Chest radiography may show a peripheral noncalcified coin lesion attached by vascular strands to the hilus.
  • CT scanning may be used to delineate AVMs of the lung or head.
  • MRI helps to delineate the extent of pulmonary and CNS AVMs.
  • Angiography is used when surgery is contemplated.

Other Tests

• Liver function tests may reveal elevated enzyme levels.
• Colonoscopy shows GI telangiectasias surrounded by an anemic halo.
• Barium enema is useful if an ulcer or neoplasm is suspected.

Histologic Findings

The diagnosis can be made on the basis of clinical findings; however, skin biopsy findings are often helpful in confirming the diagnosis. Punch biopsy is usually adequate. Findings are localized in the dermal upper-horizontal plexus. The classic features are dilated capillaries and new vessel formation. In the dermis, the walls of dilated vessels may be thickened.

TREATMENT

Section 6 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

One third of the cases of HHT are mild, one third are moderate, and one third are severe.

• In mild cases of HHT, no treatment is necessary.
• Individual skin lesions may be obliterated with cautery or dye laser surgery.
• In severe cases of HHT, recurrent epistaxis is treated surgically with nasal septum skin transplants by using skin taken from the lower trunk.
• Severe cases of HHT may respond to estrogen therapy.
• Pulmonary hemorrhage may be stopped with surgery by using silicone balloon tamponade or other means.
• Antibiotic prophylaxis should be considered during treatment procedures because transient bacteremia may seed arteriovenous malformations.

Surgical Care

See Medical Care above.

Consultations

• A dermatologist may be consulted.
• An internal medicine specialist may be helpful.
• A neurologist may offer assistance.

Activity

• Patients should restrict their activity during episodes of acute bleeding.
• Patients with severe anemia should restrict their activity as well.

MEDICATION

Section 7 of 11  

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• References

Mild forms of HHT do not require treatment.

Drug Category: Iron salts

Iron replacement therapy provides symptomatic relief for anemia.

Drug Category: Hormones

Estrogen therapy may be beneficial in some women with HHT and may be used to decrease the amount of bleeding. Oral contraceptives have been shown to be more effective than estrogen alone in mucosal bleeding.

Drug Category: Antifibrinolytics

Used to enhance hemostasis when fibrinolysis contributes to bleeding.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• Most patients with HHT have a favorable prognosis.
• The prognosis depends on the degree of systemic involvement, especially involvement of the pulmonary, hepatic, and central nervous systems. Only 10% of patients die from complications of their disease.

Patient Education

• Educate patients about the possibility of their offspring having the disorder or being carriers.

MISCELLANEOUS

Section 9 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• The heritable nature of HHT requires diagnostic accuracy. Once the diagnosis is confirmed, encourage the family to undergo screening.
• A failure to screen for complications such as pulmonary AVMs and cerebral vascular malformations may lead to liability issues.

Special Concerns

• Antenatal treatment of women with HHT and pulmonary arteriovenous malformations may prevent potentially life-threatening fetomaternal complications.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

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.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Azuma H. Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia. J Med Invest. Aug 2000;47(3-4):81-90. [Medline].
• Byard RW, Schliebs J, Koszyca BA. Osler-Weber-Rendu syndrome--pathological manifestations and autopsy considerations. J Forensic Sci. May 2001;46(3):698-701. [Medline].
• Faughnan ME, Hyland RH, Nanthakumar K, Redelmeier DA. Screening in hereditary hemorrhagic telangiectasia patients. Chest. Aug 2000;118(2):566-7. [Medline].
• Fritzler MJ, Arlette JP, Behm AR, Kinsella TD. Hereditary hemorrhagic telangiectasia versus CREST syndrome: can serology aid diagnosis?. J Am Acad Dermatol. Feb 1984;10(2 Pt 1):192-6. [Medline].
• Goodenberger DM. Visceral manifestations of hereditary hemorrhagic telangiectasia. Trans Am Clin Climatol Assoc. 2004;115:185-99. [Medline].
• 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].
• Harrison DF. Use of estrogen in treatment of familial hemorrhagic telangiectasia. Laryngoscope. Mar 1982;92(3):314-20. [Medline].
• Isaacs E. Aminocaproic Acid.Pediatric Drug Dosage Handbook. Winnipeg Health Sciences Center and CSHP, 8th ed. Ottawa, Canada. 1998;161.
• Jakobi P, Weiner Z, Best L, Itskovitz-Eldor J. Hereditary hemorrhagic telangiectasia with pulmonary arteriovenous malformations. Obstet Gynecol. May 2001;97(5 Pt 2):813-4. [Medline].
• Maher CO, Piepgras DG, Brown RD, et al. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke. Apr 2001;32(4):877-82. [Medline].
• Manson D, Traubici J, Mei-Zahav M, et al. Pulmonary nodular opacities in children with hereditary hemorrhagic telangiectasia. Pediatr Radiol. Jan 5 2007;[Medline].
• Matsuo M, Kanematsu M, Kato H, et al. Osler-Weber-Rendu disease: visualizing portovenous shunting with three-dimensional sonography. AJR Am J Roentgenol. Apr 2001;176(4):919-20. [Medline].
• McDonald MT, Papenberg KA, Ghosh S. A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34. Nat Genet. Feb 1994;6(2):197-204. [Medline].
• Morphet JA. Osler-Weber-Rendu syndrome. CMAJ. Nov 7 2006;175(10):1243. [Medline].
• Pau H, Carney AS, Murty GE. Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): otorhinolaryngological manifestations. Clin Otolaryngol. Apr 2001;26(2):93-8. [Medline].
• 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].
• Soong HK, Pollock DA. Hereditary hemorrhagic telangiectasia diagnosed by the ophthalmologist. Cornea. Nov 2000;19(6):849-50. [Medline].
• Suga K, Ishikawa Y, Matsunaga N, et al. Liver involvement in hereditary haemorrhagic telangiectasia: assessment with 99Tcm-phytate radionuclide angiography and 123I-IMP transrectal portal scintigraphy. Br J Radiol. Oct 2000;73(874):1115-9. [Medline].
• Urushihara M, Furukawa S, Ota A, et al. Hemorrhagic telangiectasia with thrombocytopenia in a newborn infant. Pediatr Int. Dec 2000;42(6):693-5. [Medline].

Article Last Updated: Jan 26, 2007