Hereditary Hemorrhagic Telangiectasia - HHT

Diagnosis

Indications for Testing

  • Confirm hereditary hemorrhagic telangiectasia (HHT) in symptomatic individuals
  • Identify familial mutation in clinically affected individuals, enabling diagnostic testing of at-risk relatives

Criteria for Diagnosis

  • HHT
    • Diagnosis considered definite with ≥3 symptoms, suspected with 2 symptoms, and unlikely with a single symptom
    • Symptoms include the following
      • Recurrent epistaxis
      • Mucocutaneous telangiectasia, particularly on lips and hands
      • Internal arteriovenous malformations (AVMs)
      • First-degree relative with HHT
  • Juvenile polyposis syndrome (JPS)/HHT
    • Combination of symptoms meeting criteria for JPS and HHT
      • JPS diagnosed if any one of the following present
        • >5 juvenile polyps of colorectum
        • Multiple juvenile polyps of upper and lower GI tract
        • Any number of juvenile polyps and family history of juvenile polyps

Laboratory Testing

  • Genetic testing
    • ACVRL1, ENG, and BMP9
      • Mutation present – gene mutation predicted to cause HHT
      • For more information on ACVRL1 and ENG mutations, refer to ARUP and the HHT Foundation International's HHT mutation database
    • SMAD4
      • Mutation present – gene mutation predicted to cause JPS, JPS/HHT, or HHT
    • RASA1
      • Mutation present – gene mutation predicted to cause capillary malformation/arteriovenous malformation or RASA1-related disorder

Differential Diagnosis

Screening

  • Early identification and treatment of internal arteriovenous malformations (AVMs) significantly impacts outcome
  • Screening affected individuals early in life for lung and brain AVMs recommended

Clinical Background

Hereditary hemorrhagic telangiectasia (HHT) is characterized by multiple arteriovenous malformations (AVMs) and telangiectasia in specific locations. The most common symptom is nosebleeds.

Epidemiology

  • Age – variable; average onset in early teens
  • Sex – M:F, equal

Inheritance

Gene SymbolConditionInheritancePrevalenceDe novo mutations
ACVRL1/ALK1HHT type 2/HHT2AD~1/5,000Rare
BMP9/GDF2HHTSADUnknownUnknown
ENGHHT type 1/HHT1AD~1/5,000Rare
RASA1CM-AVM or RASA1-relatedAD~1/100,000 in northern Europeans~25%
SMAD4Juvenile polyposis/HHTADUnknown~25%

Clinical Presentation

  • HHT
    • Mucocutaneous telangiectasias – characteristic sites are lips, oral cavity, fingers, nose, and the upper gastrointestinal tract
    • Nosebleeds (epistaxis) – spontaneous and recurrent; occur in most patients by adulthood
    • Gastrointestinal bleeding – 20% of patients ≥50 years
    • Internal AVMs – characteristically found in the lungs, liver, brain, and occasionally the spine
      • Brain and lung AVMs
        • Source of significant morbidity and mortality
        • Complications resulting from AVMs in the lung (stroke and brain abscess) and the liver (high-output heart failure) – typically secondary to shunting associated with these lesions, not  hemorrhage
        • Usually congenital in HHT patients
    • Nasal and dermal telangiectasias – often not present until after the first decade
    • Patients commonly have a family history of HHT or epistaxis
  • Juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome – combines HHT and JPS
    • Polyps occur primarily in upper gastrointestinal tract
    • Juvenile refers to type of polyp rather than age of patient
    • Tested families with JPS/HHT have SMAD4 mutations

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Hereditary Hemorrhagic Telangiectasia (HHT) Panel, Sequencing Deletion/Duplication, 5 Genes 2009337
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Most comprehensive test to determine cause of a telangiectasia/AVM disorder

Genes tested – ENG, ACVRL1, SMAD4, RASA1, BMP9

Clinical sensitivity – disease dependent

Analytical sensitivity/specificity – >97%

Mutations in genes not tested, deep intronic or regulatory region mutations, and breakpoints of large deletions/duplications are not determined/evaluated

Some small deletions or insertions may not be detected by massively parallel sequencing

Copy-number variants <1,000 base pairs may not be detected in targeted genes

Diagnostic errors may occur due to rare sequence variations

 
Hereditary Hemorrhagic Telangiectasia (HHT) Sequencing, 5 Genes 2009342
Method: Massive Parallel Sequencing

Acceptable test to determine cause of a telangiectasia/AVM disorder

Genes tested – ENG, ACVRL1, SMAD4, RASA1, BMP9

Clinical sensitivity – disease dependent

Analytical sensitivity/specificity – >97%

Mutations in genes not tested, deep intronic or regulatory region mutations, and breakpoints of large deletions/duplications are not determined/evaluated

Some small deletions or insertions may not be detected by massively parallel sequencing

Copy-number variants <1,000 base pairs may not be detected in targeted genes

Diagnostic errors may occur due to rare sequence variations

 
Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Sequencing and Deletion/Duplication with Reflex to Juvenile Polyposis (SMAD4) Sequencing and Deletion/Duplication 2009008
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Appropriate test when clinical/family history is classic for HHT

Reflex – if results of test do not explain clinical scenario, SMAD4 sequencing and deletion/duplication testing is performed

Clinical sensitivity – ~85%

Analytical sensitivity – 99% for sequencing; 90% for MLPA

Analytic specificity – 99% for sequencing and 98% for MLPA

Breakpoints of large deletions/duplications cannot be determined

Regulatory region, intronic mutations, and mutations in genes other than ENG and ACVRL1 will not be detected

Diagnostic errors may occur due to rare sequence variations

 
Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Sequencing and Deletion/Duplication 0051382
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Acceptable test when clinical/family history is classic for HHT

Clinical sensitivity – ~85%

Detects only  ENG and ACVRL1 gene mutations

Rare diagnostic errors can occur due to primer and probe site mutations

Gene mutations of uncertain significance are common in ENG and ACVRL1

Breakpoints of large deletions/duplication cannot be determined

If negative, consider Juvenile Polyposis Sequencing and Deletion/Duplication testing

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing
Confirm or exclude HHT in an individual with a previously identified familial mutation

Rare diagnostic errors can occur due to primer site mutations

 
Familial Mutation, Targeted Sequencing, Fetal 2001980
Method: Polymerase Chain Reaction/Sequencing

Confirm or exclude HHT in a fetus when a familial mutation has previously been identified

Accuracy considered >99%

Rare diagnostic errors can occur due to primer site mutations

 
Juvenile Polyposis (SMAD4) Sequencing and Deletion/Duplication 2001971
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Use if medical or family history includes gastrointestinal polyposis

Use when HHT is suspected clinically, but testing of ACVRL1 and ENG genes is negative

Rare diagnostic errors can occur due to probe site mutations

Breakpoints for large deletions/duplications will not be determined

 
RASA1-Related Disorders (RASA1) Sequencing and Deletion/Duplication 2007852
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Appropriate if cutaneous vascular lesions include capillary malformations

Rare diagnostic errors can occur due to probe site mutations

Breakpoints for large deletions/duplications will not be determined

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Sequencing 0051381
Method: Polymerase Chain Reaction/Sequencing

Alternative test when clinical/family history is classic for HHT

If negative, order HHT Deletion/Duplication testing

Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Deletion/Duplication 0051348
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification
Use if ACVRL1 and ENG sequencing test is negative
Juvenile Polyposis (SMAD4) Deletion/Duplication 2001976
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Confirm JPS or JPS/HHT syndrome in symptomatic individuals

Confirm HHT in symptomatic individuals when no mutation was previously detected in the ENG and ACVRL1 genes

Vascular Malformations Panel, Sequencing and Deletion/Duplication, 14 Genes  2007384
Method: Massive Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred test to confirm clinical diagnosis of a blood vessel disorder

Vascular Malformations Sequencing, 14 Genes  2007390
Method: Massive Parallel Sequencing

Acceptable test to confirm clinical diagnosis of a blood vessel disorder