Synonyms: hereditary haemorrhagic telangiectasia, HHT, HHT1 and Rendu-Osler-Weber disease

In Osler-Weber-Rendu syndrome there is vascular dysplasia leading to telangiectasia. There are also arteriovenous malformations (AVMs) of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain.

Genetics

This is an hereditary condition due to a mutation at gene location 9q34.1.¹ There is evidence of genetic heterogeneity. It is inherited as an autosomal dominant trait with high penetrance, as 97% have symptoms.²

Epidemiology

Prevalence is between 1 in 5,000 and 1 in 8,000 population.³

Presentation

It does not present at birth but commonly presents with recurrent epistaxis, usually in the teenage years. (62%) are diagnosed by age 16, with over 90% of these presenting with nosebleeds.⁴ They develop mucocutaneous lesions, usually involving the nasal mucosa, lips and tongue. These lesions are sharply demarcated red-purple macules, papules or spider-like lesions comprising a mat of tortuous vessels. These can also occur in the conjunctiva, upper respiratory tract, gastrointestinal (GI) tract, bladder, vagina, bronchi, brain and liver. Cutaneous telangiectasia are often not evident until between 20 and 30 years of age.

Other associated features

• In the GI tract, abnormalities are present in 11-40%. There may be telangiectasia and arteriovenous malformations (AVMs) causing acute haemorrhage or chronic slow bleeding with resulting iron deficiency anaemia. In one series, GI bleeding occurred in 16% and half of these required transfusion.⁴
• In the respiratory system, AVMs occur in 14-30%, presenting as dyspnoea, cyanosis, bruits, clubbing and paradoxical cerebral emboli that may cause stroke and cerebral abscess.
• In the liver, AVMs can cause high-output cardiac failure or cirrhosis due to hepatic vascular abnormalities, fibrosis, and portacaval shunts. In a large series, there was liver disease in 8% of patients, representing 27 individuals. Of these, 17 had cirrhosis and 5 died as a result.²
• In the central nervous system, AVMs, cavernous angiomas and aneurysm may result in headache, seizures or epilepsy, intracranial haemorrhage and stroke.
• Lesions of the skin do not usually develop until the 20s. They affect the hands and wrists in 41% and the face in 33%.² They do not tend to be a serious problem with regard to haemorrhage.
• Vascular malformations of the urinary tract are rare, in one series being present in just 2 of 324 cases.²

Differential diagnosis

• CREST syndrome (= calcinosis, Raynaud's disease, (o)esophageal dysmotility, sclerodactyly, telangiectasia).
• Von Willebrand's disease.

Investigations

• Capillary microscopy (examining the capillary pattern of the fingernail; this can be useful in screening for hereditary haemorrhagic telangiectasia (HHT), as most patients have detectable abnormalities before development of other signs).
• CT, MRI scanning and possibly angiography are used to identify lesions.

Diagnosis

Diagnosis is made if at least three of the following are present:

• Epistaxes
• Telangiectasia
• Visceral lesions
• Appropriate family history

Associated diseases

• Osler-Weber-Rendu type 2 - hereditary haemorrhagic telangiectasia type 2 (HHT2) - is a distinct but very similar disorder, mapped to chromosome 12. HHT2 is associated with pulmonary arterial hypertension.⁵
• Juvenile polyposis with HHT syndrome⁶ has been reported in a few families. There is inherited haemorrhagic telangiectasia associated with juvenile polyposis coli and colorectal cancer. The gene defect is on chromosome 18.
• A third type has also been described that is mapped to chromosome 5 and is called HHT3.⁷

Management

• Acute haemorrhage may require treatment including blood transfusion and attempts to stem the flow.
• Surgical or laser ablation may be required as an emergency or elective procedure. Arteriovenous malformations (AVMs) may need embolisation, ligation of the blood supply or resection.
• Septoplasty of the nose may be required.
• Liver transplantation or stereotactic intracranial radiosurgery may be indicated.
• For some years it has been noticed that oestrogens seem to have a beneficial effect on the lesions.

Oestrogen therapy

Oestrogens provoke squamous metaplasia of the epithelium. Oestrogens with progestogens (oral contraceptives) are beneficial in women of reproductive years.⁸ Anti-oestrogen, such as tamoxifen, is also beneficial although the term anti-oestrogen may be naive. Tamoxifen is an oestrogen antagonist on the breast but has agonist properties for bone and endometrium. The selective oestrogen receptor modulators (SERMs) also have mixed effects. There is no evidence as to whether lower doses of oestrogens, as are used in hormone replacement therapy, are also beneficial.⁸

There is evidence that not everyone will respond and there may be advantage in taking a nasal biopsy and assessing the tissue for oestrogen-binding sites.⁹ Therapy may be offered on the basis of receptor status.

Oestrogens also have benefit when used in men but predictable adverse events will occur.

Complications

As above, haemorrhage is the major concern. The effects depend upon site and size.

Cirrhosis occurs in a small number.

Prognosis

Usually there is no effect on lifespan unless there is severe haemorrhage, although cirrhosis may shorten life.

Historical notes

The condition was first described by Henry Gawen Sutton (1836-1891) in 1864. The following year, Benjamin Babington (1794-1866), in a paper in The Lancet, noted that it was familial. Henri Jules Louis Marie Rendu (1844-1902) was the first to differentiate the condition from haemophilia (1896). Osler (1849-1919) raised the profile of the disease by subsequently describing a family with nosebleeds, multiple telangiectasia of the skin and mucous membranes, in 1901. F. Parkes Weber (1863-1962) described later cases of angiomas.

Document references

1. Telangiestasia, hereditary haemorrhagic, Online Mendelian Inheritance In Man (OMIM)
2. Plauchu H, de Chadarevian JP, Bideau A, et al; Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989 Mar;32(3):291-7. [abstract]
3. Begbie ME, Wallace GM, Shovlin CL; Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J. 2003 Jan;79(927):18-24. [abstract]
4. Porteous ME, Burn J, Proctor SJ; Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992 Aug;29(8):527-30. [abstract]
5. Hereditary hemorrhagic telangiectasia type 2, Online Mendelian Inheritance in Man (OMIM)
6. Juvenile polyposis with hereditary hemorrhagic telangiectasia, Online Mendelian Inheritance in Man (OMIM)
7. Hereditary hemorrhagic telangiectasia type 3, Online Mendelian Inheritance in Man (OMIM)
8. Jameson JJ, Cave DR; Hormonal and antihormonal therapy for epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 2004 Apr;114(4):705-9. [abstract]
9. Pau H, Carney AS, Walker R, et al; Is oestrogen therapy justified in the treatment of hereditary haemorrhagic telangiectasia: a biochemical evaluation. Clin Otolaryngol Allied Sci. 2000 Dec;25(6):547-50. [abstract]

Internet and further reading

• Soriano PA et al; Osler-Weber-Rendu Disease, eMedicine, Dec 2008

Acknowledgements