Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations

Am J Med Genet A. 2012 Nov;158A(11):2829-34. doi: 10.1002/ajmg.a.35622. Epub 2012 Sep 18.

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2-50) and 18 ± 21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Adolescent
  • Adult
  • Aged
  • Antigens, CD / genetics
  • Arteriovenous Fistula / complications*
  • Arteriovenous Fistula / diagnosis
  • Arteriovenous Fistula / genetics*
  • Child
  • Child, Preschool
  • Endoglin
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracranial Arteriovenous Malformations / complications*
  • Intracranial Arteriovenous Malformations / diagnosis
  • Intracranial Arteriovenous Malformations / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Receptors, Cell Surface / genetics
  • Smad4 Protein / genetics
  • Telangiectasia, Hereditary Hemorrhagic / complications*
  • Telangiectasia, Hereditary Hemorrhagic / diagnosis
  • Telangiectasia, Hereditary Hemorrhagic / genetics*
  • Young Adult

Substances

  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Intracellular Signaling Peptides and Proteins
  • NMI protein, human
  • Receptors, Cell Surface
  • Smad4 Protein
  • ACVRL1 protein, human
  • Activin Receptors, Type II