SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
print        

Hereditary Hemorrhagic Telangiectasia (HHT)

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Hereditary hemorrhagic telangiectasia (HHT) results from the presence of multiple arteriovenous malformations (AVMs) in which intervening capillaries between arteries and veins are absent, resulting in direct connections between arteries and veins. Small AVMs or telangiectases near the skin surface and surface of oral and gastrointestinal (GI) mucosa membranes often rupture and bleed with minor trauma. Large AVMs often cause more severe symptoms when they occur in brain, lung, GI tract or more rarely liver and spine. Complications from bleeding or shunting may be sudden and catastrophic.

HHT is an autosomal dominant disorder which can be divided into two clinically indistinct forms based on the protein defect: HHT1 is caused by defects in the endoglin protein encoded by the ENG gene located on chromosome 9 at 9q34.1 while HHT2 is caused by defects in the serine/threonine receptor kinase R3 encoded by the ACVRL1 (ALK1) gene located on chromosome 12 at 12q11-q14. Approximately 80-90% of all mutations causing HHT1 or HHT2 are point mutations or small insertions/deletions. Deletions in the ENG gene may also cause up to 10% of HHT.

HHT is present when an individual has one copy of the defective gene (ENG or ACVRL1). Silent carriers may not be affected themselves by HHT, however, they may transmit the defective gene to their offspring. There is a 50% chance that their baby will have the gene for HHT and thus may develop symptoms at some stage in their life. There is a 50% chance that the baby will not have HHT.

Who should be tested

  • individuals with a clinical indication of HHT
  • parents, siblings and non-manifesting relatives of individuals with HHT

Testing Methodology

Direct Mutation Analysis: his assay consists of two stages:

  • Direct sequence analysis to identify any point mutations or small insertions/deletions
  • Dosage analysis to detect deletions in the ENG or ACVRL1 (ALK1) gene.

In families where an ENG or ACVRL1 (ALK1) mutation has previously been identified, samples from relatives are analyzed for only the family mutation.

Test Sensitivity: Approximately 90% of all ENG or ACVRL1 (ALK1) mutations can be detected by molecular analysis. Approximately 10% of the mutations causing HHT cannot be detected by current testing procedures in place in the Molecular Diagnostics Laboratory.

  • For example, of 10 people diagnosed with HHT, molecular analysis will identify the ENG or ACVRL1 (ALK1) mutations in approximately 9 of them, but will not detect any mutations in one.

Potential Outcomes & Interpretation of Test Results

ENG or ACVRL1 Gene Mutations
allele 1 / allele 2

Explanation

none detected / none detected

  • This result does not support a diagnosis of Hereditary hemorrhagic telangiectasia

mutation detected / none detected

  • This result supports a diagnosis of Hereditary hemorrhagic telangiectasia.

Cautions

  • Current molecular testing will not detect all possible mutations in the ENG or ACVRL1 (ALK1) genes. A negative test, therefore, does not rule out the diagnosis of HHT, nor eliminate the possibility the individual is a carrier.
  • It is helpful to first identify the mutations in an affected family member or in the parent of the affected family member. If the familial mutation can be identified in this way, the molecular test is conducted only for the familial mutation.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information: