Osler-Weber-Rendu Syndrome

Synonyms: Hereditary Haemorrhagic Telangiectasia, HHT, HHT1 and Osler-Rendu-Weber disease.

This is a hereditary condition due to a mutation at gene location 9q34.1.¹ There is vascular dysplasia leading to telangiectasia and arteriovenous malformations of skin, mucosa, and viscera. It does not present at birth but bleeding from telangiectasia may present in the teens. Cutaneous telangiectasia do not present until adult life. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain. There is evidence of genetic heterogeneity.

It is inherited as an autosomal dominant trait with high penetrance as 97% have symptoms.²
Prevalence is between 1 in 5,000 and 1 in 8,000 population.³

It most commonly presents with recurrent epistaxis, usually in the teenage years. Most (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, 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 to 40%. There may be telangiectasia and AV malformations (AVM) 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 AV malformations occur in 14 to 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 CNS, 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 wrist in 41% and the face in 33%.² They do not tend to be a serious problem with regard to haemorrhage.
• Vascular malformation of the urinary tract are rare, in one series being present in just 2 of 324 cases.²

CREST syndrome, von Willebrand disease.

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

Diagnosis is made if at least 3 of the following are present:

• Epistaxes
• Telangiectasia
• Visceral lesions
• Appropriate family history

• Osler-Weber-Rendu type 2 (HHT2) is a distinct but very similar disorder, mapped to chromosome 12. Hereditary haemorrhagic telangiectasia is associated with pulmonary arterial hypertension.⁵
• Juvenile polyposis with hereditary haemorrhagic telangiectasia 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

• 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. 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 beneficial⁸ 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 SERMs also have mixed effects. There is no evidence as to whether lower doses of oestrogens, as are used in HRT, 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.

As explained above, haemorrhage is the major concern. The effects depend upon site and size. Cirrhosis occurs in a small number.

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

The condition was first described by Henry Gawen Sutton (1836-1891) in 1864 and 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.