Hereditary Hemorrhagic Telangiectasia

At a glance

Autosomal dominant mucocutaneous and visceral fibrovascular dysplasia in which telangiectasia, arteriovenous malformations, and vascular aneurysms may be widely distributed throughout the cardiovascular system. It is usually recognized as a “triad” of telangiectasia, recurrent epistaxis, and a family history of the disorder. The telangiectasias are located on the skin and mucosa of the nose and gastrointestinal tract. Epistaxis is the most common problem. The presence of arteriovenous malformations is predominant in the lungs (50%), liver (30-70%), and the brain (10%), with a very small proportion (<1%) in the spinal cord.

Synonym

Osler-Rendu-Weber (ORW) Disease; Rendu-Osler Disease; Osler-Rendu Disease; Osler-Rendu-Weber Syndrome.

History

The disease carries the names of Sir William Osler, Henri Jules Louis Marie Rendu, and Frederick Parkes Weber, who described it in the late 19th and early 20th centuries.

Classification

The different types of Osler-Rendu-Weber Disease are classified according to either the gene map locus or, clinically, the presence or absence of pulmonary arteriovenous malformations.

• ORW I: Presence of pulmonary malformation with polycythemia and clubbing; mutation on the long arm of chromosome 9.

• ORW II: Absence of pulmonary malformation; gene map location is 12q11-q14.

• ORWIII: Unlinked to either chromosome 9 or 12, in which the frequency of pulmonary arteriovenous fistulas is intermediate between the two first types. Patients seem to be more prone to have liver vascular malformations.

Incidence

Hereditary Hemorrhagic Telangiectasia (HHT) is widely distributed, occurring in many ethnic groups around the world. The presence of hemorrhagic telangiectasia affects between 1 in 5,000 and 1 in 10,000 people. The incidence of HHT with arteriovenous malformations (AVMs) is estimated at 1:100,000 in the general population, but in some areas of the world the estimate is 1:40,000, and in Vermont, US, the estimate is 1:16,500. The difference in incidence observed probably is a result of the different subtypes.

Genetic inheritance

All types of hereditary telangiectasia are autosomal dominant with some genetic heterogeneity but highly penetrant. The candidate genes are the genes for endoglin, CLO5A1 (type V collagen), and ZNF79, which all map to the long arm of chromosome 9.

Pathophysiology

The disease seems to result from the combination of defective perivascular connective tissue, insufficient smooth muscle contractile element, endothelial cell junction defects, and increased endothelial tissue plasminogen activator impairing thrombus formation in case of vascular damage.

Diagnosis

Hereditary telangiectasia is a vascular dysplasia leading to telangiectasias and arteriovenous malformations of skin, mucosa, and viscera (especially tongue, lips, face, ears, and fingers), with ...