Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred

Am J Med Genet. 2000 Aug 14;93(4):320-7. doi: 10.1002/1096-8628(20000814)93:4<320::aid-ajmg12>;2-r.


HHT type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutation in the ALK-1 gene, but the phenotype has not been well defined. We report on 51 members of an HHT 2 kindred with an ALK-1 gene mutation shown to be associated with the disorder. This ALK-1 mutation was detected in 38 kindred members who were evaluated systematically for associated vascular abnormalities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of those screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 38 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not detected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2. It also adds to the evidence suggesting that pulmonary AVMs are more common in HHT 1 than in HHT 2. We identify a higher prevalence of hepatic AVMs than previously reported in either HHT 1 or 2. This may be specific to the mutation in this kindred, but probably reflects the lack of routine screening for this manifestation. Even in this family in which all affected individuals have the same mutation, the clinical manifestations of HHT and their severity varied tremendously. Intrafamilial variation in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families when DNA testing is not available.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Anaplastic Lymphoma Kinase
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Epistaxis / etiology
  • Female
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases
  • Telangiectasia, Hereditary Hemorrhagic / diagnosis*
  • Telangiectasia, Hereditary Hemorrhagic / genetics


  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases