Hereditary Hemorrhagic Telangiectasia - HHT

Diagnosis

Indications for Testing

• Clinical symptoms compatible with diagnosis of HHT or JPS/HHT
• Offer diagnostic genetic testing to do the following
  • Confirm the diagnosis in symptomatic individuals
  • Identify genetic mutations in an affected family member in order to offer diagnostic testing for at-risk relatives (ie, children)
  • Confirm or rule out HHT in at-risk relatives of individuals with a confirmed diagnosis

Criteria for Diagnosis

• HHT
  • Symptoms include the following
    • Recurrent epistaxis
    • Mucocutaneous telangiectasia, particularly on lips and hands
    • Internal AVMs
    • First-degree relative with HHT
  • Diagnosis considered definite with ≥3 symptoms, suspected with 2 symptoms, and unlikely with a single symptom
• JPS/HHT
  • Combination of symptoms meeting criteria for JPS and HHT
    • JPS diagnosed if any one of the following present
      • More than five 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 and ENG
    • Positive result – detected gene mutation predicted to cause HHT
  • SMAD4
    • Positive result – detected gene mutation predicted to cause JPS, JPS/HHT or HHT

Differential Diagnosis

• Telangiectasias
  • Capillary malformation-AVM syndrome
  • CREST syndrome
  • Hereditary benign telangiectasia
• Bleeding
  • von Willebrand disease 
  • Other factor deficiencies 

Screening

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

• Prevalence – 1-5/10,000
• Age – variable; average onset in early teens
• Sex – M:F, equal

Inheritance

• Autosomal dominant (penetrance approaches 100% by age 40); de novo mutations are rare
• Endoglin (ENG) or activin A receptor type II-like 1 (ACVRL1)

Pathophysiology

• Mutations in the ENG or ACVRL1 gene are the cause in 85% of cases
• Mutations in the SMAD4 gene are thought to cause ~2% of HHT
  • At least two additional HHT genes are suggested by linkage analysis in several large kindreds
• AVMs and telangiectases are blood vessels with missing capillary beds, resulting in direct artery-to-vein connections
• Small AVMs are called telangiectasias

Clinical Presentation

• HHT
  • Mucocutaneous telangiectasias –  characteristic sites are lips, oral cavity, fingers, nose and the upper gastrointestinal tract
  • Nosebleeds (epistaxis) – spontaneous and recurrent; will occur in most patients by adulthood
  • Gastrointestinal bleeding found in 20% of patients after age 50
  • Internal AVMs – characteristically found in the lungs, liver, brain and occasionally the spine
    • Brain and lung AVMs are a source of significant morbidity and mortality
    • Complications resulting from AVMs in the lung (stroke and brain abscess) and the liver (high-output heart failure) are typically secondary to shunting associated with these lesions, not  hemorrhage
    • Brain and lung AVMs are usually congenital in HHT patients, but nasal and dermal telangiectasias are 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 the upper gastrointestinal tract
    • Juvenile refers to type of polyp rather than age of patient
  • Tested families with JPS/HHT have SMAD4 mutations

Treatment

• Method of treatment for telangiectasia and AVMs is organ dependent
  • Methods include laser coagulation, transcatheter embolization, resection and stereotactic radiosurgery

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Sequencing 0051381 Method: Polymerase Chain Reaction/Sequencing	Confirm suspected HHT in individuals serving as the test index for a familial mutation
Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Deletion/Duplication 0051348 Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification	Confirm suspected HHT in individuals when no familial mutation was identified by previous sequencing Confirm suspected HHT in individuals after a familial duplication or deletion is identified
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