Hereditary Hemorrhagic Telangiectasia And Its Underlying Genetic Causes

What Is Hereditary Hemorrhagic Telangiectasia?

Hereditary hemorrhagic telangiectasia (HHT) is a developmental condition which is marked by abnormal formation of blood vessels. Due to these defects, blood flows improperly throughout the body. Specifically, in HHT-affected individuals, oxygenated blood flows from the arteries into the veins. In healthy individuals, blood flows from arteries into capillaries and not veins. This improper blood flow can cause red marks, known as telangiectases, on the skin.

Blood flow anomalies caused by HHT can cause abnormally excessive pressure within veins, which can lead to nosebleeds and internal hemorrhaging. In the worst cases, such as when hemorrhaging occurs in the brain, for example, serious health conditions and even death can result.

There are four forms of HHT: type I, type II, type III, and juvenile HHT syndrome. The type I form is more likely to affect the brain and lungs than are the type I and II forms, which are more likely to affect the liver than is the type I form. Those who have juvenile HHT syndrome not only suffer from abnormally formed blood vessel but are also highly susceptible experiencing the formation of polyps in their digestive system.

It is estimated that about 1 in every 5,000 to 10,000 individuals suffers from HHT. HHT does not appear to be more prevalent among any sub-population of people than any other sub-population.

What Is Known About The Genetics Of Hereditary Hemorrhagic Telangiectasia?

Human molecular geneticists have determined that HHT is inherited in an autosomal dominant manner and that it is caused by one or mutations in any one of four genes, three of which are designated ENG, ACVRL1, and SMAD4. Specifically, mutations in ENG are causative of the type I form of HHT, mutations in ACVRL1 are causative of the type II form, and mutations in SMAD4 are causative of juvenile HHT syndrome. Molecular geneticists have yet to determine the gene that, when mutated, causes the type III form. However, studies toward identifying this culprit gene are on-going.

The proteins that are encoded for by the ENG, ACVRL1, and SMAD4 genes are different from each other in form and, while the protein encoded by SMAD4 is of a different function, the proteins encoded by ENG and ACVRL1 have similar functions. Specifically, in the case of ENG, its encoded product, a protein called endoglin, associates with various growth factors that are needed for proper development of blood vessels and also participates in the specialization of these vessels to become either veins or arteries. In the case of ACVRL1, its encoded protein associates with a protein called transforming growth factor beta. The association between these two proteins is what triggers certain cellular events that are needed for normal blood vessel development.

Finally, SMAD4’s encoded protein regulates the activity of certain genes that control the development of blood vessels. Specifically, the SMAD4 protein physically binds to these genes in the nucleus of the cell to either increase, decrease, or halt their activity.

This article is only meant to provide some basic information regarding the genetic condition known as Hereditary Hemorrhagic Telangiectasia. If you have any further questions regarding this inherited disorder, please contact your doctor or consult a genetic counselor.


Genetics Home Reference, National Institutes of Health, Hereditary Hemorrhagic Telangiectasia:

J. McDonald and R.E. Pyeritz, Gene Reviews, University of Washington, Hereditary Hemorrhagic Telangiectasia: