Test Directory

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by telangiectases and arteriovenous malformations (AVMs) of the skin, mucosa and viscera.  Epistaxis is the most frequent presenting finding.  Gastrointestinal bleeding and telangiectases on the face, lips, tongue, fingers, and chest are other common clinical features.  AVMs within the lungs, liver, and brain are a significant cause of morbidity. Pulmonary AVMs lead to morbidity via direct hemorrhage, heart failure, or shunting of emboli with subsequent brain abscess formation or stroke.  AVMs involving the liver can result in hyperdynamic circulation and cause high output heart failure.  Additionally, intrahepatic arteriovenous shunts may lead to cirrhosis and resultant bleeding esophageal varices.  Cerebrovascular malformations causing intracranial hemorrhage also occur.  Other organs known to be affected by telangiectasia or AVMs include the bladder, eyes and kidneys. HHT is caused by mutations in the ENG (HHT1; MIM 187300), ACVRL1 (HHT2; MIM 600376) and GDF2 (HHT5; MIM 615506) genes. ENG encodes endoglin, a cell surface coreceptor which is a component of the transforming growth factor beta receptor complex. ACVRL1 (ALK1) encodes activin A receptor type II-like 1, a serine-threonine kinase receptor  for the transforming growth factor beta superfamily of ligands.  GDF2 encodes BMP9, a ligand for endoglin and ALK1. Approximately, 85% of individuals with HHT have mutations in ENG or ACVRL1.A small percentage of HHT patients with HHT have mutations in GDF2.  An additional 1-2% of patients with HHT have mutations in the SMAD4 gene. In addition to HHT, patients with SMAD4 mutations typically have juvenile polyposis (juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome). Some differences in the clinical manifestations of HHT1 and HHT2 have been reported.  An earlier onset of nasal and oral mucosal telangiectases, accompanied by epistaxis, and a higher incidence of pulmonary AVMs occurs in HHT1. A higher incidence of liver involvement and an earlier onset and increased frequency of dermal lesions occurs in HHT2.  The prevalence of certain findings may also be sex dependent. In HHT1 more women than men have pulmonary AVMs, hepatic AVMs and skin telangiectases, especially on the face.  HHT is completely penetrant by age 40. The overall incidence of HHT in North America is estimated at 1:10,000. However, it is likely that this is an underestimate. Mutations in ACVRL1 have been described in a subset of patients with hereditary hemorrhagic telangiectasia and pulmonary hypertension that is clinically and histologically indistinguishable from primary pulmonary hypertension.  Pulmonary arterial malformations appear to be rare in these patients.