Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene–phenotype correlations

Authors

  • Takeo Nishida,

    1. Yale HHT Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
    2. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
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  • Marie E. Faughnan,

    Corresponding author
    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Division of Respirology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    3. Toronto HHT Program, Division of Respirology, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
    4. Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
    • St. Michael's Hospital, 30 Bond St, Toronto, ON, Canada M5B-1W8.
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  • Timo Krings,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Division of Neuroradiology, Department of Medical Imaging, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
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  • Murali Chakinala,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Pulmonary/Critical Care division, Department of Internal medicine, Washington University School of Medicine, St. Louis, Missouri
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  • James R. Gossage,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Georgia Health Sciences University, Augusta, Georgia
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  • William L. Young,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California–San Francisco, San Francisco, California
    3. Department of Neurological Surgery, University of California–San Francisco, San Francisco, California
    4. Department of Neurology, University of California–San Francisco, San Francisco, California
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  • Helen Kim,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California–San Francisco, San Francisco, California
    3. Department of Epidemiology and Biostatistics, University of California–San Francisco, San Francisco, California
    4. Institute for Human Genetics, University of California–San Francisco, San Francisco, California
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  • Tony Pourmohamad,

    1. Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California–San Francisco, San Francisco, California
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  • Katharine J. Henderson,

    1. Yale HHT Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
    2. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
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  • Stacy D. Schrum,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Pulmonary/Critical Care division, Department of Internal medicine, Washington University School of Medicine, St. Louis, Missouri
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  • Melissa James,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Georgia Health Sciences University, Augusta, Georgia
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  • Nancy Quinnine,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California–San Francisco, San Francisco, California
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  • Aditya Bharatha,

    1. Division of Neuroradiology, Department of Medical Imaging, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
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  • Karel G. terBrugge,

    1. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
    2. Division of Neuroradiology, Department of Medical Imaging, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
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  • Robert I. White Jr

    1. Yale HHT Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
    2. Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network**
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  • **The BVMC (U54NS065705) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through the NIH Office of Rare Diseases Research (ORDR)/National Center for Advancing Translational Sciences (NCATS) and the National Institute of Neurological Disorders and Stroke (NINDS).

  • How to Cite this Article: Nishida T, Faughnan ME, Krings T, Chakinala TK, Gossage JR, Young WL, Kim H, Pourmohamad T, Henderson KJ, Schrum SD, James M, Quinnine N, Bharatha A, terBrugge KG, White RIJ, 2012. Brain Arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene-phenotype correlations. Am J Med Genet Part A 158A: 2829–2834.

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. © 2012 Wiley Periodicals, Inc.

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