Course:MEDG550/Student Activities/HHT

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Hereditary hemorrhagic telangiectasia (HHT), also called Osler–Weber–Rendu syndrome, is a genetic condition in which blood vessels do not develop properly.[1] Abnormal blood vessel formation causes individuals with HHT to have blood vessel walls that can be fragile and more prone to breakage (hemorrhage), putting them at risk for bleeding and low iron (anemia).[1]

The most common features of HHT include frequent nosebleeds, broken blood vessels near the skin surface that look like red spots or lines (known as telangiectasias), and abnormal connections between arteries and veins in internal organs (known as arteriovenous malformations or AVMs).[2]

HHT occurs in approximately 1 out of every 5,000 to 10,000 people.[3][4][5][6]However, it may be more common as some people with HHT go undiagnosed.

Clinical Characteristics

People with HHT can experience some variability in symptoms that can begin at different ages throughout their lives. This variability is present even among family members with HHT.[7]

Frequent and spontaneous nosebleeds that start in childhood are the most common symptom of HHT, affecting 90% of people with HHT.[7]

Telangiectasias, broken blood vessels near the skin surface that look like red to purplish spots or lines, are often seen on the lips, fingers, nose, or inside the mouth.[7] These areas often turn white when pressure is applied to them. Telangiectasias can also develop inside walls of the digestive tract and cause chronic bleeding. Telangiectasias are common features of HHT, but often do not form until an individual is 30 years old or later and they can increase with age.

Arteriovenous malformations or AVMs, abnormal connections between arteries and veins in internal organs that lack capillaries, are commonly found in the lungs, liver, and brain.[7] Capillaries are tiny blood vessels that pass blood between arteries and veins. People with HHT normally will have an AVM in at least one of these areas. AVMs can also be found more rarely in the spine.

Blood loss from nosebleeds and bleeding from internal organs can lead to low iron and symptoms of anemia.[7] The most serious complications of HHT result from bleeding due to blood vessel rupture (called a hemorrhage) or blood clots in AVMs, particularly AVMs in the lungs or brain. However, most people with HHT will not have serious complications.

Diagnosis

The Curaçao criteria for diagnosis of HHT. (A) Multiple telangiectasias at characteristic sites. (B) AVMs in the lungs (pulmonary), brain (cerebral), liver (hepatic) or spinal cord. (C) Frequent spontaneous nosebleeds. (D) An example of a family history of HHT (affected family members in red and unaffected family members in blue).[8]

In order to have a definite diagnosis of HHT, an adult has to have three or more of the following features associated with HHT.[9] If an individual only has two of these features, then a diagnosis of HHT is only ‘possible’ or ‘suspected’. Having less than two of these features makes it unlikely that the person has HHT.

The Curaҫao Criteria for HHT Diagnosis:[9]

1.      Frequent spontaneous nosebleeds

2.      Multiple telangiectasias on the lips, mouth, fingers, or nose

3.      Identified AVMs in the digestive tract, lungs, liver, brain, or spine

4.      A first-degree family member (parents, siblings, or children) that has a diagnosis of HHT

This criteria for diagnosing HHT does not apply to children with HHT because children may have the condition but have not yet developed symptoms of HHT.[1]

Another way to make a diagnosis of HHT is based on genetic testing to identify mutations in genes associated with HHT (see Genetic Testing).

Management

Medical management of HHT differs from person-to-person and is dependent on their unique symptoms. Individuals with HHT should be managed by health care providers familiar with HHT. Management can include:[2][10]

-         Evaluation of medical and family history

-         Physical exam that includes looking for telangiectasias

-         Blood tests for low iron and anemia

-         Imaging and/or testing of the lungs, brain, and liver to identify AVMs

Screening

Family members not displaying symptoms of HHT may still have the condition without realizing it because features of HHT may not have developed yet or the condition may only be affecting their internal organs. In this case, screening for symptoms of HHT is important to avoid potential complications of HHT in individuals not yet diagnosed.[2]

Screening can include yearly evaluation by health care providers familiar with HHT, regular blood tests for iron deficiency anemia, examination for lung AVMs every 5 years, and brain imaging to look for AVMs. At risk children should also be screened for AVMs in the lung and brain.[2]

If an HHT gene mutation has already been identified in a family, genetic testing can be performed to identify other family members that may be at risk of developing symptoms of HHT.

Genetics

Autosomal_Dominant_Inheritance
Autosomal dominant inheritance pattern. The affected father has a 50% chance of passing the condition on to an affected child.

Genes are regions of DNA that provide instructions for building structures or performing tasks within our bodies. We each inherit two copies of every gene, one from each parent. Genes can acquire different changes that prevent them functioning properly and cause disease, which are called mutations. Mutations in these four genes are known to cause HHT: ACVRL1, ENG, GDF2, SMAD4.[11] These genes are important for proper development of blood vessels.[11] There are potentially other genes that can cause HHT that have not yet been identified.[1]

HHT is passed through a family in an autosomal dominant pattern. In autosomal dominant inheritance, only one of the two copies of a gene needs to be not working for an individual to develop the genetic condition. It can affect both males and females. Individuals with HHT have a 50% chance of passing on the condition to each of their children.

Individuals that receive two copies of the not working gene often do not survive pregnancy. This may occur in families where both parents have HHT and genetic counselling is advised.

Some individuals with HHT may not have any family members with the same condition. In these cases, it is possible that a new mutation causing HHT arose in that individual when they were conceived, and the condition was not inherited from a parent.

Genetic Counselling

Genetic counselling can aid individuals and families in gaining a better understanding of the genetics of their condition. Genetic counsellors help individuals understand how a condition may be passed through their family, discuss options available for genetic testing, explain genetic test results, provide risk assessments, facilitate decision-making, provide emotional support, and connect patients with available resources.

Genetic Testing

Genetic testing can be done for people with a clinical diagnosis of HHT to identify a genetic mutation that is causing the condition. Certain symptoms of HHT are seen more commonly in association with specific gene mutations.[7] This information may be important for modifying how their HHT is managed by their health care team.[7] Additionally, genetic testing can be valuable for individuals with ‘possible’ or ‘suspected’ HHT to confirm an HHT diagnosis. [7]

Patient Resources

For additional information on HHT from the CDC: https://www.cdc.gov/ncbddd/hht/index.html

Find an HHT Clinic in your community: https://directory.curehht.org/hht-centers

Patient Organizations

Cure HHT

HHT Canada

References

  1. ↑ 1.0 1.1 1.2 1.3 McDonald J, Pyeritz RE. Hereditary Hemorrhagic Telangiectasia. 2000 Jun 26 [Updated 2017 Feb 2]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1351/
  2. ↑ 2.0 2.1 2.2 2.3 McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Genet Med. 2011. doi:10.1097/GIM.0b013e3182136d32
  3. ↑ Bideau A, Brunet G, Heyer E, Plauchu H, Robert JM. An abnormal concentration of cases of rendu-osler disease in the valserine valley of the French jura: A genealogical and demographic study. Ann Hum Biol. 1992. doi:10.1080/03014469200002112
  4. ↑ Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: A population-based study of prevalence and mortality in Danish patients. J Intern Med. 1999. doi:10.1046/j.1365-2796.1999.00398.x
  5. ↑ Marchuk DA, Guttmacher AE, Penner JA, Ganguly P. Report on the workshop on Hereditary Hemorrhagic Telangiectasia, July 10-11, 1997. Am J Med Genet. 1998;76:269–73.
  6. ↑ Dakeishi M, Shioya T, Wada Y, et al. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat. 2002. doi:10.1002/humu.10026
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: A clinical and scientific review. Eur J Hum Genet. 2009. doi:10.1038/ejhg.2009.35
  8. ↑ Botella LM, Albiñana V, Ojeda-Fernandez L, Recio-Poveda L, Bernabéu C. Research on potential biomarkers in hereditary hemorrhagic telangiectasia. Front Genet. 2015. doi:10.3389/fgene.2015.00115
  9. ↑ 9.0 9.1 Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for Hereditary Hemorrhagic Telangiectasia (Rendu- Osler-Weber Syndrome). Am J Med Genet. 2000. doi:10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P
  10. ↑ Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020. doi:10.7326/m20-1443
  11. ↑ 11.0 11.1 McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: Genetics and molecular diagnostics in a new era. Front Genet. 2015. doi:10.3389/fgene.2015.00001
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