How to diagnose Osler-Weber-Rendu syndrome (Hereditary Hemorrhagic Telangiectasia, HHT)?

Diagnosis of Osler-Weber-Rendu Syndrome (Hereditary Hemorrhagic Telangiectasia)

The diagnosis of Osler-Weber-Rendu syndrome (Hereditary Hemorrhagic Telangiectasia, HHT) should be based on the Curaçao criteria, with a definite diagnosis established when three or more criteria are present. 1

Curaçao Diagnostic Criteria

The Curaçao criteria include four major elements:

• Epistaxis: Spontaneous and recurrent nosebleeds 2
• Telangiectases: Multiple telangiectases at characteristic sites including lips, oral cavity, fingers, and nose 2
• Visceral lesions: Including pulmonary arteriovenous malformations (AVMs), hepatic AVMs, cerebral AVMs, spinal AVMs, or gastrointestinal telangiectases 2
• Family history: First-degree relative with HHT diagnosed using these criteria 2, 1

Diagnostic Classification

• Definite HHT: Three or more criteria present 2
• Possible/Suspected HHT: Two criteria present 2
• Unlikely HHT: Fewer than two criteria present 2

Genetic Testing

• Genetic testing should be performed to identify mutations in:

  • Endoglin (ENG) - HHT type 1 1, 3
  • Activin receptor-like kinase-1 (ACVRL1/ALK1) - HHT type 2 1, 3
  • SMAD4 - associated with juvenile polyposis-HHT overlap 1, 3

• Genetic testing is particularly important for:

  • Asymptomatic individuals from families with known HHT 1
  • Early diagnosis in children to enable appropriate screening 4
  • Determining the genetic subtype, which may predict organ-specific manifestations 3

Organ-Specific Screening

Liver Involvement

• Doppler ultrasonography is the recommended first-line imaging for liver involvement in all HHT patients 2
• Liver biopsy should be strictly avoided due to high risk of hemorrhage 2
• Liver involvement can be graded (0-4) based on:
  • Hepatic artery diameter
  • Peak flow velocity
  • Resistivity index
  • Presence of peripheral hepatic hypervascularization 2

Pulmonary Screening

• All HHT patients should undergo screening for pulmonary arteriovenous malformations 2, 1
• Recommended screening methods include:
  • Contrast echocardiography
  • Chest CT 1, 4

Cerebral Screening

• MRI of the brain is recommended to detect cerebral vascular malformations 1, 5
• Early detection is crucial to prevent complications such as stroke, intracranial hemorrhage, and brain abscess 3, 5

Gastrointestinal Evaluation

• Upper endoscopy is recommended to evaluate for gastrointestinal telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 1, 6
• Colonoscopy may be necessary to identify colonic AVMs 6, 7

Clinical Presentation Patterns

• Age-dependent penetrance: Symptoms typically develop progressively with age 3, 5
• Most common initial presentation: Recurrent epistaxis (90-95% of patients), often beginning in childhood 6, 3
• Common clinical manifestations:
  • Mucocutaneous telangiectases (typically appear in the second or third decade of life) 1, 3
  • Iron deficiency anemia (due to chronic bleeding) 6, 7
  • Symptoms related to organ-specific AVMs 2, 5

Important Considerations and Pitfalls

• Avoid liver biopsy: This is a critical pitfall to avoid in HHT patients due to high risk of hemorrhage 2
• Gender differences: Hepatic VMs are more common and symptomatic in females, with a male/female ratio of 1:2 to 1:4.5 2
• Genotype-phenotype correlation: The frequency and location of AVMs may vary depending on the specific gene mutation 2, 3
• Age-related expression: Some manifestations may not appear until adulthood, making early diagnosis challenging 1, 5
• Multisystem involvement: Comprehensive evaluation of multiple organ systems is necessary even in asymptomatic patients 4, 5

Referral Recommendations

• Patients diagnosed with HHT should be referred to a multidisciplinary team with expertise in HHT management 1
• Family members of affected individuals should undergo screening due to the autosomal dominant inheritance pattern 1, 4