Hereditary Hemorrhagic Telangiectasia

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple types of arteriovenous malformations (AVMs) involving the skin, mucosal surfaces, and internal organs.
  • Also known as Osler-Weber-Rendu syndrome
  • Phenotypes
    • Although any type of AVM can occur with any HHT phenotype, HHT type 1 (HHT-1) has a higher risk for pulmonary and cerebral AVMs.
    • HHT type 2 (HHT-2) has a higher risk for hepatic AVMs.
    • Both HHT-1 and HHT-2 phenotypes have similar risk for gastrointestinal (GI) telangiectasias.
  • “Curaçao criteria” for diagnosis of HHT
    • Diagnosis is considered definite if 3 of 4 criteria are present and “possible” if 2 criteria are present.
    • Criteria:
      • Epistaxis
      • Multiple telangiectasias which are present at characteristic sites such as lips, oral cavity, fingers, and nose
      • Visceral lesions (such as pulmonary, hepatic, cerebral or spinal AVMs or GI telangiectasias)
      • Family history that includes a 1st-degree relative with HHT.

EPIDEMIOLOGY

Estimated to occur in 1 of 5,000 persons worldwide; however, prevalence varies in different parts of the world.

  • 1 in 1,331 people in Afro-Caribbean population, >12 years of age, in the Netherland Antilles
  • 1 in 5,000 to 8,000 people in Japan
  • 1 in 16,500 people in Vermont, United States

ETIOLOGY

  • During angiogenesis and wound healing, gene mutations associated with HHT affect transforming growth factor β (TGF β) signaling pathways involved with angiogenesis.
  • This increases the formation of abnormal connections between venules and arterioles, without the normal capillary bed separation.
  • Venule walls have qualitative issues with internal structure to handle increased flow, which leads to increased risk for hemorrhage.

RISK FACTORS

Genetics

  • Autosomal dominant with variable penetrance
  • Large majority of cases caused by endoglin gene (ENG) mutation, which leads to HHT-1, or by activin-like receptor kinase 1 (ALK1) gene (ACVRL1) mutation, which leads to HHT-2. Rare mutations involve GDF2 and RASA-1.
  • A subset of patients with HHT and juvenile polyposis (JP) (2% of cases) have mutations in SMAD4 gene leading to SMAD4 protein alternations.

COMMONLY ASSOCIATED CONDITIONS

  • JP
    • In 1980, a syndrome that combines JP and HHT was first described. Patients exhibit symptoms of both JP and HHT; however, the presence of JP and anemia are the predominant clinical features.
    • There is an increased risk for early onset colorectal cancer (CRC) with a mean age of 28 years for these patients with combined JP and HHT.
  • Migraine headaches
    • For patients with HHT and migraines, embolization of pulmonary AVMs (PAVMs) is associated with a decrease in presence of migraine episodes.
  • Deep vein thrombosis (DVT)
    • Patients with HHT are at increased risk for DVT.

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