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Hereditary Hemorrhagic Telangiectasia

Rendu-Osler-Weber Syndrome
6 genes

Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by the presence of multiple arteriovenous malformations (AVMs). The findings generally depend on age, and the diagnosis is usually made after adolescence, although severe cases are described at an early age. The diagnosis is based on the presence of nosebleeds (epistaxis), skin or mucosal telangiectasia, visceral arteriovenous malformations, family history, or presence of a pathogenic mutation in some of the disease-related genes.

HereditaryHemorrhaicTelangiectasia Hereditary Hemorrhagic Telangiectasia
  • Patients with suspicion of HHT based on clinical data, such as: 1) spontaneous recurrent epistaxis, 2) cutaneous telangiectasia, 3) visceral lesions (arteriovenous malformations), and/or 4) first-degree relatives with those characteristics. These data are known as criteria of Curaçao.
  • It is especially useful in patients with probable (2 Curaçao criteria) or unlikely (0-1 criterion) diagnosis, as well as in patients who meet the Curaçao criteria and present some atypical form of the disease, which could suggest mutations in genes other than ENG or ALK1.
  • The genetic test can help to confirm or rule out the clinical diagnosis in these individuals. Sometimes, knowing the molecular diagnosis of the disease may provide information about prognosis, monitoring and management of the disease.
  • Furthermore, identifying the causative mutation is useful in familial genetic screening, since early detection of carriers allows for their clinical monitoring, while monitoring of non-carriers may be discontinued.
  • Finally, genetic diagnosis provides the possibility of offering prenatal or preimplantation diagnosis in pregnancies at risk of inheriting the disease.
  • International guidelines for the diagnosis and management of Hereditary Haemorrhagic Telangiectasia. J Med Genet 2011;48:73-87
  • McDonald J, et al. Hereditary Hemorrhagic Telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 2015 Jan 26;6:1
The performance of this panel is optimal for genetic confirmation of HHT, increasing with the number of clinical criteria of the disease. It is estimated that the probability of detecting a mutation in ENG or ALK1 genes is 85% in patients who meet the four Curaçao criteria, but is much smaller (less than 40%) in patients with an atypical presentation, for example without epistaxis. The current method – panel including 6 priority genes – avoids repeating new genetic studies, thus speeding up the delivery of results.The yield of the offered 6-gene panel allows the diagnosis of any of the genes defined so far. Mutation detection in these genes is done by Next Generation Sequencing (NGS), which is the currently recommended method and can detect previously undefined mutations. Both the clinical setting and the cosegregation study in relatives are of utmost importance for this, as they would support the pathological value of the detected mutation. In addition, knowing the cases described in the literature with a particular mutation will also contribute to its clinical interpretation.

Hereditary Hemorrhagic Telangiectasia Panel

6 genes

  • The two priority genes encompassing most mutations that have been identified in connection with HHT: ENG gene (defines HHT type 1, more related to pulmonary arteriovenous fistulas) and ALK1 (defines HHT type 2, with higher frequency of liver involvement).
  • The study of the SMAD4 gene, which defines an affectation of HHT associated with juvenile adenomatous polyposis.
  • All recently defined genes including new mutations that have been linked to disease.

ACVRL1, ENG, SMAD4, GDF2, SMAD1, BMPR2*

Notes on Genes

Priority Genes: These genes include >70% of the mutations that have been previously associated with the development of hypertrophic cardiomyopathy and/or their testing is recommended by the guidelines. Secondary genes: Other genes related to the disease. *Candidate genes: With no evidence, but likely to be related to the phenotype.