Hereditary Hemorrhagic Telangiectasia

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What is hereditary hemorrhagic telangiectasia?

Hereditary hemorrhagic telangiectasia is a disorder that results in the development of multiple abnormalities in the blood vessels.

In the circulatory system, blood carrying oxygen from the lungs is normally pumped by the heart into the arteries at high pressure. The pressure allows the blood to make its way through the arteries to the smaller vessels (arterioles and capillaries) that supply oxygen to the body tissues. By the time blood reaches the capillaries, the pressure is much lower. The blood then proceeds from the capillary beds into veins, through which it eventually returns to the heart.

In hereditary hemorrhagic telangiectasia, some arterial vessels flow directly into veins rather than into the capillaries. These abnormalities are called arteriovenous malformations. When they occur in superficial vessels, where they are visible as red markings on the skin, they are known as telangiectases (the singular is telangiectasia).

Without the normal buffer of the capillaries, the blood moves from the arteries at high pressure into the thinner walled, less elastic veins. The extra pressure tends to strain and enlarge these blood vessels, and may result in compression or irritation of adjacent tissues and frequent hemorrhages (episodes of severe bleeding). Nosebleeds are very common in people with hereditary hemorrhagic telangiectasia, and more serious problems may arise from hemorrhages in the brain, liver, lung, or other organs.

Forms of hereditary hemorrhagic telangiectasia include type 1, type 2 and type 3 hereditary hemorrhagic telangiectasia, and juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. People with type 1 tend to develop symptoms earlier than those with type 2, and are more likely to have lung involvement. Individuals with either form, however, can have severe lung involvement. Type 3 is a rarer form that may be associated with a higher incidence of malformed vessels in the liver. Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome is a condition that involves both arteriovenous malformations and a tendency to develop growths (polyps) in the gastrointestinal tract. There appears to be no increased likelihood of such polyps in types 1, 2 and 3.

How common is hereditary hemorrhagic telangiectasia?

The incidence of hereditary hemorrhagic telangiectasia is difficult to determine because the severity of symptoms can vary widely and some symptoms, such as frequent nosebleeds, are common in the general population. In addition, arteriovenous malformations may be associated with other medical conditions. Hereditary hemorrhagic telangiectasia is widely distributed, occurring in many ethnic groups around the world. It is believed to affect between 1 in 5,000 and 1 in 10,000 people.

What genes are related to hereditary hemorrhagic telangiectasia?

Mutations in the ACVRL1, ENG, and SMAD4 genes cause hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia type 1 is caused by mutations in the gene ENG. Type 2 is caused by mutations in the gene ACVRL1. Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome is caused by mutations in the gene SMAD4. All these genes produce proteins that are found in the lining of the blood vessels, and interact with growth factors that control their development. The gene involved in hereditary hemorrhagic telangiectasia type 3 is not known.

The mutations seen in these genes generally prevent the production of the associated protein, or result in the production of a defective protein that cannot fulfill its function. An individual inheriting a mutated gene from one parent will therefore have a reduced amount of the functional protein available in the tissue lining the blood vessels. This deficiency is believed to result in the signs and symptoms of hereditary hemorrhagic telangiectasia.

How do people inherit hereditary hemorrhagic telangiectasia?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person has one parent with the condition.

Source: National Institutes of Health

Data on hereditary hemorrhagic telangiectasia published by researchers at State University of Campinas, Hematology and Hemotherapy Center

"Ten patients were analyzed. Diagnosis of HHT was carried out by means of family history, recurrent bleeding, and the presence of multiple telangiectases lesions. Conformation-sensitive gel electrophoresis analyses with consistent abnormal migration patterns were cloned and sequenced using the MegaBace 1000 DNA automated analyzer. Three novel mutations were identified in the coding sequence of the ALK-1 gene in five patients and their families, which demonstrated clinical manifestations of HHT type 2. These mutations included a G insertion and a T deletion of single base pairs in exons 3 and 7, as well as missense mutations in exons 7 and 8 of the ALK-1 gene. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity," wrote A.M. Assis and colleagues, State University of Campinas, Hematology and Hemotherapy Center.

The researchers concluded: "We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2."

Assis and colleagues published their study in the Journal of Human Genetics (Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients. Journal of Human Genetics, 2007;52(3):237-43).

For additional information, contact A.M. Assis, State University of Campinas, Hemoglobin and Genome Laboratory, Hematology and Hemotherapy Center, Unicamp, R Carlos Chagas, 480, Cidade Universitaria Zeferino Vaz, Campinas, SP, Brazil.

Publisher contact information for the Journal of Human Genetics is: Springer-Verlag Tokyo, 3-3-13, Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan.

Keywords: Brazil, Campinas, Dermatology, Hematology, Hereditary Hemorrhagic Telangiectasia.

This article was prepared by Hematology Week editors from staff and other reports. Copyright 2007, Hematology Week via NewsRx.com.