What is HHT?
In the normal vasculature, extensive networks of small, thin-walled blood vessels known as capillaries bridge arteries and veins. Capillaries serve to slow blood flow and maximize delivery of oxygen to all cells in the body. If arteries improperly connect directly to veins, without an intervening capillary network, oxygen delivery to cells is impaired, and veins are prone to rupture.
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an inherited disorder characterized by a predisposition to development of direct connections between arteries and veins. When these connections occur in small vessels, such as in the skin or in the gastrointestinal tract, they are called telangiectasias. These appear as small red dots on the skin, particularly on the hands, face, lips and tongue. When they occur in larger vessels, most commonly in the brain, lungs, and liver of HHT patients, they are called arteriovenous malformations, or AVMs. Telangiectasias and AVMs tend to be very fragile and may easily rupture, leading to complications ranging from minor nosebleeds to hypoxemia (low oxygen levels in arterial blood) to hemorrhagic (bleeding) stroke, depending on the size and location of the vascular malformation.
How is HHT diagnosed?
HHT can be diagnosed by your doctor based on the “Curaçao Criteria:”
- Epistaxis (frequent nose bleeds)
- Telangiectasias (hands, face, lips, tongue)
- Visceral lesions: AVMs in lung, brain, or liver; GI tract telangiectasias
- Family history of the disease
If a patient presents with at least three of the four above diagnostic criteria, a diagnosis of HHT is definite, and AVM screening and genetic testing are strongly advised. If a patient presents with two of the four above diagnostic criteria, this indicates possible HHT and further tests should be performed to rule in or rule out HHT.
What causes HHT?
Approximately 80% of HHT patients carry a mutation in either ACVRL1 (activin receptor-like kinase I) or ENG (endoglin), with a much smaller percentage harboring a mutation in SMAD4. Each of these genes encodes a protein that participates in bone morphogenetic protein (BMP) signaling within endothelial cells, or the cells that line the inner surface of blood vessels. When this cellular communication system is disrupted, connections between arteries and veins do not form properly, and telangiectasias and AVMs can develop.
HHT is a haploinsufficiency: literally, this means that half (“haplo”) is not sufficient. We have two copies of each of 22 autosomal (non-sex) chromosomes, and thus two copies of every gene on each of those 22 chromosomes. HHT1 patients have one “normal” copy of the ENG gene on one copy of chromosome 9, and an abnormal or mutated copy of the ENG gene on the other copy of chromosome 9. The mutant ENG does not produce functional Endoglin protein. So HHT1 patients produce only half the normal amount of Endoglin protein, which is not enough to ensure development and maintenance of normal arterial-venous connections. HHT2 patients have one abnormal copy of ACVRL1 on chromosome 12, and juvenile polyoposis/HHT patients have one abnormal copy of SMAD4 on chromosome 18.
A parent with HHT has a 50% chance of passing on the disease-causing gene to his or her offspring.
Why is there so much variability in the age of onset and presentation of HHT?
The answer to this question is unsatisfying: we simply don’t know. Nearly all HHT patients will exhibit frequent nosebleeds, or epistaxis, with an average age of onset of 12 years; however, nosebleeds may begin in infancy or may not present until a patient reaches adulthood. Approximately 40% of HHT patients develop lung AVMs, whereas 5-20% develop brain AVMs. And although lung AVMs are more prevalent in HHT1 patients than in HHT2 patients, even within a particular HHT1 family, the members of which have the same exact mutation in the ENG gene, there is unexplained variability in the presence of lung AVMs. In short, although we know the genes that, when disrupted, are responsible for about 85% of HHT cases, and we can identify the precise mutations responsible for disease in each HHT family, we cannot use this information to predict the clinical outcome of HHT. In other words, there are unidentified stochastic factors at play that we need to understand in order to better manage HHT patients.