Which are the causes of Hereditary Hemorrhagic Telangiectasia?

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a genetic disorder caused by mutations in genes that regulate the formation of blood vessels, specifically the connections between arteries and veins. These mutations lead to the development of fragile, abnormal blood vessels called telangiectasias and arteriovenous malformations that are prone to bleeding.

What causes Hereditary Hemorrhagic Telangiectasia at a genetic level?

Hereditary Hemorrhagic Telangiectasia is primarily caused by mutations in genes belonging to the TGF-beta (Transforming Growth Factor-beta) signaling pathway. This pathway is essential for the proper development and maintenance of the structural integrity of blood vessels. When these genes are mutated, the body fails to create the appropriate "scaffolding" for capillaries, causing them to bypass the normal network and link arteries directly to veins. This results in high-pressure blood flow through vessels that are not designed to handle it, leading to the characteristic bleeding seen in Hereditary Hemorrhagic Telangiectasia.

Which specific genes are involved in Hereditary Hemorrhagic Telangiectasia?

The etiology of Hereditary Hemorrhagic Telangiectasia is linked to three primary genes, though research continues to identify rarer variants. The known genetic causes include:

• ENG (Endoglin): Mutations here cause HHT type 1.


• ACVRL1 (ALK1): Mutations here cause HHT type 2.


• SMAD4: Mutations here are associated with Juvenile Polyposis/HHT syndrome.


• GDF2 (BMP9): A rarer form sometimes classified as HHT type 5.

Approximately 85% to 90% of individuals with a clinical diagnosis of Hereditary Hemorrhagic Telangiectasia will have an identifiable mutation in one of these genes. If a patient does not show a mutation in these, it is possible they have a rare, undiscovered genetic variant, meaning the underlying cause is still being actively researched.

Are there environmental triggers or risk factors for HHT?

It is important to distinguish between the cause and triggers. The cause of Hereditary Hemorrhagic Telangiectasia is strictly genetic; you are born with it. However, because the blood vessels are structurally fragile, certain environmental factors can act as "triggers" that exacerbate symptoms. For example, local trauma to the nasal mucosa, dry air, or the use of blood-thinning medications (such as aspirin or anticoagulants) can significantly increase the frequency and severity of nosebleeds (epistaxis), which is the most common symptom of Hereditary Hemorrhagic Telangiectasia.

What is the current state of research into the etiology of HHT?

While the genetic basis of Hereditary Hemorrhagic Telangiectasia is well-documented, researchers are currently focused on why the disease presents so differently even among family members with the same mutation. This is known as "variable expressivity." Current studies are investigating the role of modifier genes, epigenetics, and the vascular microenvironment to understand why some patients develop severe arteriovenous malformations in the lungs or brain, while others primarily experience skin telangiectasias.

Next steps

• Consult with a genetic counselor to discuss family screening, as Hereditary Hemorrhagic Telangiectasia is an autosomal dominant condition, meaning there is a 50% chance of passing it to offspring.


• Request a referral to an HHT Center of Excellence for specialized screening of internal organs (brain, lungs, liver).


• Join the 141 members of the DiseaseMaps.org community to share experiences and learn about ongoing research.


• Maintain a medical log of bleeding episodes to share with your hematologist or vascular specialist.

Medical disclaimer: This information is for educational purposes only and does not constitute medical advice, diagnosis, or treatment; always seek the advice of your physician or other qualified health provider with any questions regarding a medical condition.

References

• NIH Genetic and Rare Diseases Information Center (GARD): Hereditary Hemorrhagic Telangiectasia.


• Orphanet: Rare Disease Database (ORPHA:774).


• OMIM (Online Mendelian Inheritance in Man): Entry #187300.


• Cure HHT (HHT Foundation International): Clinical Research and Patient Resources.