What is the workup for Hereditary Hemorrhagic Telangiectasia (HHT)?

From the Guidelines

The workup for Hereditary Hemorrhagic Telangiectasia (HHT) should begin with a thorough clinical evaluation based on the Curaçao criteria, followed by genetic testing for mutations in ENG, ACVRL1, or SMAD4 genes, as recommended by the Second International HHT Guidelines 1. Initial screening should include:

• Contrast echocardiography to detect pulmonary arteriovenous malformations (AVMs)
• Brain MRI with contrast to identify cerebral AVMs
• Abdominal CT or MRI to evaluate for hepatic AVMs Patients should also undergo upper endoscopy to assess for gastrointestinal telangiectasias if anemia or gastrointestinal bleeding is present. Pulmonary function tests and oxygen saturation measurements are important to evaluate for right-to-left shunting. Complete blood count should be monitored regularly to assess for anemia due to chronic bleeding. Family members of affected individuals should be offered genetic counseling and screening. This comprehensive approach is necessary because HHT can affect multiple organ systems with potentially serious complications including stroke, brain abscess, and high-output heart failure, and early detection of vascular malformations allows for preventive interventions before complications occur, as highlighted in the latest guidelines and studies 1.

Some key points to consider in the workup and management of HHT include:

• The use of the Curaçao criteria for clinical diagnosis
• The importance of genetic testing for mutations in ENG, ACVRL1, or SMAD4 genes
• The need for initial screening with contrast echocardiography, brain MRI, and abdominal CT or MRI
• The role of upper endoscopy in assessing for gastrointestinal telangiectasias
• The importance of monitoring for anemia and right-to-left shunting
• The need for genetic counseling and screening for family members of affected individuals.

Overall, a comprehensive approach to the workup and management of HHT is essential to prevent complications and improve outcomes for affected individuals, as supported by the latest evidence and guidelines 1.

From the Research

HHT Workup

The workup for Hereditary Hemorrhagic Telangiectasia (HHT) involves a combination of clinical evaluation and genetic testing.

• Clinical diagnostic criteria for HHT include:
  • Family history
  • Recurrent epistaxis
  • Telangiectasia
  • Visceral arteriovenous malformations (AVMs) 2, 3, 4
• Fulfillment of 3 or more of these criteria provides a definite diagnosis of HHT, whereas 2 criteria constitute a possible diagnosis of HHT 4
• Genetic testing can provide definitive diagnosis of HHT in all age groups, with mutations in the ENG and ACVRL1 genes causing approximately 85% of cases 2, 3
• Additional genes, such as SMAD4 and GDF2, have been identified in a smaller number of patients with a similar or overlapping phenotype to HHT 2, 5, 6
• A multi-gene next generation sequencing (NGS) HHT panel can be used to identify genetic mutations and facilitate gene discovery 2
• The combination of clinical features and gene detection can determine the etiology and classification of HHT, which is convenient for early diagnosis and prevention of the disease 5

Genetic Testing

Genetic testing for HHT typically involves sequencing of the coding regions of the ENG, ACVRL1, SMAD4, and GDF2 genes 5

• New putative genetic drivers of HHT have been identified, including variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1, and SMAD6 genes 6
• These variants should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations 6

Management

The management of HHT typically involves a multidisciplinary approach, including:

• Screening for visceral AVMs and telangiectasia
• Treatment of epistaxis and gastrointestinal bleeding
• Aggressive iron replacement with intravenous iron
• Medical treatments aimed at control of chronic bleeding, such as antifibrinolytic and antiangiogenic agents 4