Deficiency of the α-Subunit of the Stimulatory G Protein and Severe Extraskeletal Ossification

Authors

  • Mark C. Eddy,

    1. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, U.S.A.
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    • These authors contributed equally to this work.

  • Suzanne M. Jan de beur,

    1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
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    • These authors contributed equally to this work.

  • Suzanne M. Yandow,

    1. Department of Orthopedic Surgery, University of Utah School of Medicine and Shriners Hospital for Children, Salt Lake City, Utah, U.S.A.
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  • William H. McAlister,

    1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
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  • Eileen M. Shore,

    1. Department of Orthopedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
    2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
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  • Frederick S. Kaplan,

    1. Department of Orthopedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
    2. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
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  • Michael P. Whyte M.D.,

    Corresponding author
    1. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, U.S.A.
    2. Departments of Medicine, Pediatrics, and Genetics, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
    • Shriners Hospital for Children, 2001 South Lindbergh Boulevard, St. Louis, MO 63131, U.S.A.
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  • Michael A. Levine

    1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
    2. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
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  • Presented in part at the 2nd International Symposium on Fibrodysplasia Ossificans Progressiva, Philadelphia, Pennsylvania, U.S.A. October 29–31, 1995 [Calcif Tissue Int 1995;59:142] and the 2nd Joint Meeting of the American Society for Bone and Mineral Research and the International Bone and Mineral Society, San Francisco, California, U.S.A., December 1–6, 1998 [Bone 1998;23(Suppl 1):S544].

Abstract

Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the α-subunit of the G protein (Gsα) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsα deficiency.

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