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The Biology and Genetics of HHT

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Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic condition caused by mutations in the ENG, ACVRL1, or SMAD4 genes. You have a 50% chance of passing it to each child. Genetic testing confirms your specific subtype and helps determine the best screening plan for you and your family.

Key Takeaways

  • • HHT is caused by genetic mutations that disrupt the TGF-beta pathway, leading to fragile blood vessels and AVMs.
  • • HHT Type 1 (ENG gene) increases the risk of lung and brain AVMs, while HHT Type 2 (ACVRL1 gene) often involves liver AVMs.
  • • The rare SMAD4 mutation causes HHT combined with Juvenile Polyposis Syndrome, requiring additional colon cancer screenings.
  • • HHT has an autosomal dominant inheritance pattern, meaning there is a 50% chance of passing the condition to each child.
  • • Even if genetic testing does not detect a mutation, a clinical diagnosis of HHT remains valid and screenings should continue.

HHT is a genetic condition, which means the “instruction manual” for your body contains a specific typo that affects how your blood vessels are built. Understanding the biology of HHT can help you make sense of why your symptoms occur and why certain screenings are necessary [1][2].

The Blueprint: TGF-beta and Angiogenesis

In a typical body, a specialized signaling system called the TGF-beta pathway acts like a construction foreman for blood vessels [2][3]. It sends signals that tell blood vessels when to grow, when to stop growing, and how to stay strong and stable. This process of building and maintaining blood vessels is called angiogenesis [2][3].

In HHT, a mutation (a change in the gene) causes a “loss of function.” This means one of your genes isn’t producing enough of the protein needed for that construction foreman to do its job properly [2][4]. Without enough of these proteins, blood vessels don’t mature or stabilize correctly. Instead of forming a neat network of tiny capillaries, the arteries and veins connect directly, creating the fragile “short circuits” known as telangiectasias and AVMs [2][3].

The Genetic Subtypes

There are three primary genes associated with HHT. Knowing which one you have can provide clues about your specific health risks:

  • HHT Type 1 (ENG gene): Mutations in the ENG gene are the most common. People with HHT1 have a higher likelihood of developing AVMs in the lungs and brain [5][6].
  • HHT Type 2 (ACVRL1 gene): Mutations in the ACVRL1 gene (also called ALK1) are also very common. While lung and brain AVMs can still occur, HHT2 is often associated with a higher risk of AVMs in the liver [7][8].
  • HHT-JPS (SMAD4 gene): This is a rare subtype (about 1–3% of cases) [9][10]. It combines the symptoms of HHT with Juvenile Polyposis Syndrome (JPS), a condition that causes polyps to grow in the gastrointestinal tract. People with this mutation require additional screenings, such as colonoscopies, because of an increased risk of colon cancer [11][12].

How HHT is Inherited

HHT follows an autosomal dominant inheritance pattern. This sounds complicated, but it means two simple things:

  1. It only takes one copy: You only need to inherit the mutated gene from one parent to have the condition [1][13].
  2. 50/50 Chance: If you have HHT, there is a 50% chance with each pregnancy that you will pass the gene on to your child [1][14]. It does not “skip” generations; if a child does not inherit the gene, they cannot pass it to their own children [1].

The Power of Genetic Testing

Genetic testing is a simple blood or saliva test that can confirm your diagnosis by finding the specific mutation [15][16].

  • For You: It confirms your diagnosis and can help tailor your screening plan based on your subtype (HHT1, HHT2, or SMAD4) [17][18].
  • For Your Family: Once your mutation is found, other family members can be tested for that exact same mutation [15][19]. This allows them to know for sure if they have HHT, even if they don’t have symptoms yet, so they can begin life-saving screenings [13][1].

Note on “Negative” Genetic Tests

It is important to know that about 10-15% of patients who clearly meet the clinical Curaçao criteria will test negative for the known genetic mutations [20][13]. If your genetic panel comes back with “no mutation detected,” do not panic; your clinical diagnosis still stands, and your screening should continue as planned.

Frequently Asked Questions

What are the different genetic subtypes of HHT?
The three primary subtypes of HHT are caused by different gene mutations. HHT1 involves the ENG gene, HHT2 involves the ACVRL1 gene, and a rare subtype involves the SMAD4 gene. Knowing your subtype helps your doctor understand which organs are most at risk for AVMs.
What are the chances of passing HHT to my children?
HHT follows an autosomal dominant inheritance pattern, which means there is a 50% chance of passing the mutated gene to each child. You only need to inherit one copy of the mutated gene from one parent to have the condition, and it does not skip generations.
Do I still have HHT if my genetic test is negative?
Yes, it is possible to have a negative genetic test but still have HHT. About 10% to 15% of patients who clearly meet the clinical criteria for HHT will not have a known genetic mutation detected. If this happens, your clinical diagnosis stands and you should continue your routine screenings.
What is the SMAD4 gene mutation in HHT?
The SMAD4 mutation causes a rare form of HHT combined with Juvenile Polyposis Syndrome (JPS). This condition causes polyps to grow in the gastrointestinal tract, increasing the risk of colon cancer. Patients with this specific mutation require additional screenings, such as regular colonoscopies.
Why is genetic testing for HHT important for my family?
Once your specific HHT gene mutation is identified, your family members can be tested for that exact same mutation. This allows relatives to know definitively if they have HHT, even before symptoms appear, so they can begin life-saving screenings for hidden AVMs.

Questions for Your Doctor

  • • Which specific gene mutation (ENG, ACVRL1, or SMAD4) do I have, and how does that influence my screening schedule?
  • • Since I have the HHT mutation, what is the best age to test my children?
  • • If my genetic test comes back negative but I meet the Curaçao criteria, does that mean I don't have HHT?
  • • Do I need to see a genetic counselor to explain these results to my siblings and parents?
  • • If I have the SMAD4 mutation, when should I start having screening colonoscopies?

Questions for You

  • • Has anyone else in my family been diagnosed with HHT or had frequent, unexplained nosebleeds?
  • • How would knowing my specific genetic subtype (HHT1 vs. HHT2) change how I feel about my long-term health monitoring?
  • • Am I comfortable sharing my genetic results with my biological relatives so they can seek testing?

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References

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This page explains the genetics of HHT for educational purposes only. Always consult a genetic counselor or your healthcare provider to interpret your specific genetic test results and coordinate family screening.

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