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A Spectrum of Human Disorders with Inactivating GNAS Mutations


Inherited Human Diseases of Heterotopic Bone Formation

  • Authors: Eileen M. Shore, PhD; Frederick S. Kaplan, MD
  • CME Released: 8/10/2010
  • Valid for credit through: 8/10/2011
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Target Audience and Goal Statement

This activity is intended for pediatricians, orthopaedists, rheumatologists, geneticists, and other physicians who care for patients with diseases of heterotopic bone formation.

The goal of this activity is to describe the causes and clinical manifestations of FOP and POH.

Upon completion of this activity, participants will be able to:

  1. Describe the genetics and pathologic characteristics of fibrodysplasia ossificans progressiva (FOP)
  2. Apply knowledge of the clinical course of FOP in counseling patients and families
  3. Describe progressive osseous heteroplasia and its etiology


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  • Eileen M. Shore, PhD

    Associate Professor, Departments of Orthopaedic Surgery and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Co-Director, Center for Research in FOP and Related Disorders; Scientific Advisor, International Fibrodysplasia Ossificans Progressiva (FOP) Association; Progressive Osseous Heteroplasia (POH) Association


    Disclosure: Eileen M. Shore, PhD, has disclosed no relevant financial relationships.

  • Frederick S. Kaplan, MD

    Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine, Departments of Orthopaedic Surgery and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Co-Director, Center for Research in FOP and Related Disorders; Medical Advisor, International Fibrodysplasia Ossificans Progressiva (FOP) Association; Progressive Osseous Heteroplasia (POH) Association


    Disclosure: Frederick S. Kaplan, MD, has disclosed no relevant financial relationships.


  • Jenny Buckland

    Editor, Nature Reviews Rheumatology


    Disclosure: Jenny Buckland has disclosed no relevant financial relationships.

CME Author(s)

  • Charles P. Vega, MD

    Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine


    Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

  • Laurie E. Scudder, DNP, NP

    CME Accreditation Coordinator, Medscape, LLC


    Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

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    For Physicians

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Inherited Human Diseases of Heterotopic Bone Formation

Authors: Eileen M. Shore, PhD; Frederick S. Kaplan, MDFaculty and Disclosures

CME Released: 8/10/2010

Valid for credit through: 8/10/2011


Abstract and Introduction


Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extra skeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extra skeletal bone formation—fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.


The formation and maintenance of tissues and organ systems depend on the coordination of cellular events and mechanisms. In human genetic diseases, the normal functions of cells are perturbed by alterations in aspects of the expression, duration of signaling, structure or interaction (or combinations thereof) of cellular proteins during embryonic development or later in life (or both). Throughout life, bone formation is normally limited to the skeletal system. During embryogenesis, most skeletal elements, such as the long bones, form through endochondral ossification, in which cartilaginous skeletal anlagen are replaced by bone, while other elements, such as the skull, ossify directly through a process described as intramembranous ossification.[1]

Heterotopic ossification is a pathological condition in which bone forms in nonskeletal tissues.[2,3] Formation of this ectopic bone in soft tissues requires precursor cells that have the potential to differentiate into bone or cartilage (or both), a conducive tissue microenvironment, and an inducing event to initiate the cellular and molecular events that lead to bone formation. The heterotopic bone that forms is qualitatively normal endochondral or intramembranous bone, and develops through processes that parallel the events that occur during normal embryonic bone and skeletal formation, as well as those occurring in bone regeneration during fracture healing. The pathophysiology of heterotopic ossification is caused by dysregulation of cell-fate determination and inappropriate induction of the bone formation program.

Nonhereditary forms of heterotopic ossification are frequent complications of a number of common conditions, although the environmental or genetic factors that predispose some individuals to heterotopic ossification remain uncertain. Induction of nonhereditary heterotopic ossification is associated with certain types of severe tissue trauma, including injury to the spinal cord and brain, hip replacement surgery, severe burns, and high-energy war wounds; nonhereditary heterotopic ossification is also a complication of age-associated conditions such as atherosclerosis and pressure ulcers.[2-7] Nonhereditary forms of heterotopic ossification have been reviewed elsewhere[2,3] and will not therefore be discussed further in this article.

Two human genetic diseases of progressive and extensive heterotopic ossification are known: fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH).[8,9] Each of these conditions is caused by mutations in a single (different) gene, which indicates that these disease-causing genes are critical components of the regulatory mechanisms that direct cell-fate decisions and bone tissue and/or organ formation. In this Review, we compare and contrast the bone formation process that occurs in patients with FOP and POH, and discuss the relevance of the mutated pathways that underlie these conditions to normal bone and skeletal development.