Hereditary haemorrhagic telangiectasia (Rendu–Osler–Weber disease)

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156 Hereditary haemorrhagic telangiectasia (Rendu–Osler–Weber disease)

Instruction

Examine the patient’s face and obtain a relevant history.

Perform a general examination.

Look at this patient’s face.

Salient features

History

• Does it run in the family (autosomal dominant)?

• Is there a history of GI bleeding?

• Is there a history of epistaxis?

• Is there a history of repeated blood transfusions?

• Is there a history of dyspnoea, fatigue, cyanosis or polycythaemia (pulmonary arteriovenous malformations)?

• Is there a history of headaches, subarachnoid haemorrhage (cerebral arteriovenous malformations)?

Examination

• Punctiform lesions and dilated small vessels present on the face, in particular around the mouth (Fig. 156.1)

• The patient may be pale (as a result of iron-deficiency anaemia).

image

Fig. 156.1 Hereditary haemorrhagic telangiectasia. (A) Lesions are commonly on or close to mucous membranes. (B) Lesions may occur anywhere on the body, such as on the fingers. The lesions are dilated capillaries, and they blanch if pressure is applied with a glass slide.

(With permission from Forbes, Jackson 2003.)

Proceed as follows:

• Look into the patient’s mouth and inspect the tongue and palate for telangiectasia.

• Examine the nail beds, arms, trunk for telangiectasia.

• Examine the chest for bruits (pulmonary arteriovenous malformations with a predilection for lower lobes).

• Look for signs of cardiac failure caused by left-to-right shunting and hepatic bruits (both from hepatic arteriovenous malformations) (N Engl J Med 2000;343:938–52).

Diagnosis

This patient has multiple telangiectasia around the mouth and on the tongue and lips (lesion), probably hereditary in nature (aetiology). The patient is severely anaemic, probably as a result of upper GI bleeding, and is currently receiving a blood transfusion (functional status).

Questions

What do you understand by the term telangiectasia?

Telangiectasia is a cluster of dilated capillaries and venules. The lesions blanch if pressure is applied with a glass slide. In hereditary haemorrhagic telangiectasia (HHT), the telangiectases consist of focal dilatations of postcapillary venules. Lesions are commonly on or close to mucous membranes but may occur anywhere on the body, such as on the fingers.

Mention a few conditions in which telangiectasia are seen

• Face:

• Those who work outdoors in a temperate or cold climate (e.g. farmers)
• In mitral stenosis
• Myxoedema
• Transitory phenomenon during pregnancy.

• Other sites:

• Secondary to irradiation
• Scleroderma (CREST syndrome)
• Dermatomyositis
• SLE
• Acne rosacea
• Lupus pernio
• Polycythaemia
• Necrobiosis lipoidica diabeticorum.

Advanced-level questions

What do you know about the genetics of hereditary telangiectasia?

Mutations have been identified in two genes encoding proteins expressed on vascular endothelial cells and involved in signalling by members of the transforming growth factor (TGF)-β superfamily: endoglin-β (chromosome 9q3; Nat Genet 1994;6:205–9) and activin receptor–like kinase 1 (ALK-1; Nat Genet 1996;13:189–95). Interestingly heterozygote endoglin knockout mice develop a phenotype (J Clin Invest 1999;104:1343–51) similar to that of humans who are heterozygous for a null mutation in the gene for endoglin-β. These heterozygous mice develop nose bleeds and cutaneous telangiectasia, and curiously the ears are more commonly affected than in human beings. In patients with this condition and juvenile polyposis there may be mutations in one gene—the MADH4 gene (also known as SMAD4). Pulmonary hypertension in association with hereditary haemorrhagic telangiectasia can involve mutations in ALK1 (N Engl J Med 2001;345:325).

What do you know about the pathology of the condition?

Skin

• The small telangiectasias are focal dilatations of postcapillary venules with prominent stress fibres in the pericytes along the luminal border.

• In fully developed telengiectasia, there is marked dilatation of the venules, which are also convoluted. They extend along the entire dermis, with excessive layers of smooth muscle devoid of elastic fibres. These often are directly connected to dilated arterioles.

• Mononuclear cells, predominantly lymphocytes, accumulate in the perivascular space.

Lungs, liver and brain

Arteriovenous malformations lack capillaries and consist of direct connections between arteries and veins.

What are the clinical criteria for diagnosing hereditary haemorrhagic telangiectasia?

Shovlin criteria:

• Recurrent epistaxis

• Telangiectasia at a site other than in the nasal mucosa

• Evidence of autosomal dominant inheritance

• Visceral involvement.

The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder (Am J Med Genet 2000;91:66–7).

What are the complications of hereditary telangiectasia?

• Epistaxis (usually begins by the age of 10 years and by age 21 in most; it becomes more severe in later decades in about two-thirds of affected patients) (N Engl J Med 1995;333:918–24)

• GI haemorrhage (usually does not manifest until the fifth or sixth decade). Arteriovenous malformations, angiodysplasias and telangiectasias are present in the stomach, duodenum, small bowel, colon and liver

• Symptomatic liver involvement: the typical clinical presentations include high-output heart failure, portal hypertension and biliary disease (N Engl J Med 2000;343:931)

• Iron-deficiency anaemia

• Haemoptysis, cyanosis, clubbing, cerebral abscess and embolic stroke from the pulmonary arteriovenous malformations

• Headache and subarachnoid haemorrhage

• High-output cardiac failure is almost always associated with shunts from the hepatic artery to the hepatic veins (N Engl J Med 2000;343:931–6).

How would you manage such patients?

• Anaemia: ferrous sulfate, multiple blood transfusions

• Epistaxis: oestrogen, cauterization, septal dermatoplasty, laser ablation and transcatheter embolotherapy of arteries leading to the nasal mucosa

• Cutaneous telangiectasia: cosmetic therapy with topical agents, laser ablation

• Pulmonary arteriovenous malformations: embolotherapy, surgical resection or ligation of arterial supply

• GI telangiectasia: blood transfusions, photocoagulation, oestrogen–progestogen therapy

• Brain and spinal cord arteriovenous malformations: embolotherapy, neurosurgery, stereotactic surgery

• Active bleeding: ε-aminocaproic acid (N Engl J Med 1994;330:1789, N Engl J Med 1994;330:j1822)

• Anti-vascular endothelial growth factor antibody, bevacizumab (N Engl J Med 2009;360:2143).

This condition was described by HJLM Rendu, a French physician, in 1896, by Sir William Osler in 1901 and by F Parkes Weber, a London physician, in 1936. Dr Claire Shovlin is a Senior Lecturer in NHLI Cardiovascular Sciences, and Honorary Consultant in Respiratory Medicine for Imperial College Healthcare NHS Trust (Hammersmith Hospital campus) research focus on gene identification of this condition.

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