Pediatric Fibrodysplasia Ossificans Progressiva (Myositis Ossificans) 

  • Author: Robert J Pignolo, MD, PhD; Chief Editor: Lawrence K Jung, MD   more...
 
Updated: Jul 30, 2009
 

Background

Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns.[1]

Extensive heterotopic ossification on the back of Extensive heterotopic ossification on the back of a patient with fibrodysplasia ossificans progressiva. Characteristic malformed great toes and hallux valCharacteristic malformed great toes and hallux valgus.

Most cases arise as a result of a spontaneous new mutation. Genetic transmission is autosomal dominant and can be inherited from either parent. Fibrodysplasia ossificans progressiva is the most catastrophic disorder of heterotopic ossification in humans. Flare-ups are episodic; immobility is cumulative.

Myositis ossificans is a misnomer, although the term myositis ossificans circumscripta continues to be used to describe nonhereditary forms of heterotopic ossification.

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Pathophysiology

Progressive postnatal heterotopic ossification in fibrodysplasia ossificans progressiva usually appears within the first decade of life as spontaneous or injury-induced exacerbations. The lesions are characterized by painful swellings in soft connective tissue, including tendons, ligaments, fascia, and skeletal muscle.[2]

Mounting evidence from all levels of investigation suggests involvement of the inflammatory component of the immune system in fibrodysplasia ossificans progressiva. The presence of macrophages, lymphocytes and mast cells in early fibrodysplasia ossificans progressiva lesions, macrophage and lymphocyte-associated death of skeletal muscle, flare-ups following viral infections, the intermittent timing of flare-ups, and the beneficial response of early flare-ups to corticosteroids support involvement of the innate immune system in the pathogenesis of fibrodysplasia ossificans progressiva lesions.

The genetic cause of fibrodysplasia ossificans progressiva was identified as a recurrent missense mutation in the GS activation domain of activin receptor Ia/activinlike kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, in all individuals with classic fibrodysplasia ossificans progressiva.[3, 4] Recently, additional mutations have been identified in the GS-domain and kinase domain of ACVR1 in individuals with atypical forms of fibrodysplasia ossificans progressiva.[5] Noggin mutations have been reported but cannot be substantiated and are erroneous.

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Epidemiology

Frequency

International

Fibrodysplasia ossificans progressiva is rare with a worldwide prevalence of approximately 1 case in 2 million individuals.

Race

No ethnic, racial, or geographic predisposition is noted.

Sex

No sex predisposition is noted.

Age

Most children with fibrodysplasia ossificans progressiva develop episodic, painful inflammatory soft tissue swellings (or flare-ups) during the first decade of life.[1, 6]

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Contributor Information and Disclosures
Author

Robert J Pignolo, MD, PhD  Assistant Professor of Medicine, Director, Ralston-Penn Clinic for Osteoporosis and Related Bone Disorders, Department of Medicine, Division of Geriatric Medicine, Associate Director, Structure-Function Biomechanical Core, Penn Center for Musculoskeletal Disorders, University of Pennsylvania School of Medicine

Robert J Pignolo, MD, PhD is a member of the following medical societies: American College of Physicians, American Geriatrics Society, American Society for Bone and Mineral Research, Gerontological Society of America, and National Osteoporosis Foundation

Disclosure: Nothing to disclose.

Coauthor(s)

Frederick S Kaplan, MD  Isaac and Rose Nassau Professor of Orthopedic Molecular Medicine, Chief, Division of Orthopedic Molecular Medicine, Director, Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine; Consulting Surgeon, Department of Orthopedic Surgery, Hospital of The University of Pennsylvania

Frederick S Kaplan, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Society for Bone and Mineral Research, American Society for Microbiology, Johns Hopkins Medical and Surgical Association, and Orthopaedic Research Society

Disclosure: Nothing to disclose.

Eileen M Shore, PhD  Research Associate Professor, Departments of Orthopaedic Surgery and Genetics, University of Pennsylvania School of Medicine

Eileen M Shore, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Human Genetics, and Royal Society of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David D Sherry, MD  Director, Clinical Rheumatology, Attending Physician, Pain Management, The Children's Hospital of Philadelphia; Professor of Pediatrics, University of Pennsylvania

David D Sherry, MD is a member of the following medical societies: American College of Rheumatology and American Pain Society

Disclosure: Nothing to disclose.

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Lawrence K Jung, MD  Chief, Division of Pediatric Rheumatology, Children's National Medical Center

Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Donald A Person, MD, and Mandar A Pattekar, MD, MS, to the original writing and development of this topic.

References

  1. Cohen RB, Hahn GV, Tabas JA, et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am. Feb 1993;75(2):215-9. [Medline].

  2. Kaplan FS, Glaser DL, Shore EM, et al. The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab. 2005;3:183-188.

  3. Kaplan FS, Groppe J, Pignolo RJ, Shore EM. Morphogen receptor genes and metamorphogenes: skeleton keys to metamorphosis. Ann N Y Acad Sci. Nov 2007;1116:113-33. [Medline].

  4. Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. May 2006;38(5):525-7. [Medline].

  5. Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. Mar 2009;30(3):379-90. [Medline].

  6. Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. Mar 2008;22(1):191-205. [Medline].

  7. Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age- and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. Apr 1994;243-8. [Medline].

  8. Schaffer AA, Kaplan FS, Tracy MR, et al. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome: clues from the BMP signaling pathway. Spine (Phila Pa 1976). Jun 15 2005;30(12):1379-85. [Medline].

  9. Deirmengian GK, Hebela NM, O'Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. Feb 2008;90(2):366-74. [Medline].

  10. Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. Jul 15 2008;146A(14):1788-96. [Medline].

  11. Pignolo RJ, Foley, KL. Non-hereditary heterotopic ossification. Implications for injury, arthropathy, and aging. Clin Rev Bone Miner Metabol. 2005;3:261-266.

  12. [Guideline] Morrison WB, Dalinka MK, Daffner RH, et al. Expert Panel on Musculoskeletal Imaging. Soft tissue masses. [online publication]. Reston (VA): American College of Radiology (ACR);. 2005;6 p.

  13. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. Nov 2005;116(5):e654-61. [Medline].

  14. Kaplan FS, Strear CM, Zasloff MA. Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. Jul 1994;238-47. [Medline].

  15. Kaplan FS, Xu M, Glaser DL, et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. May 2008;121(5):e1295-300. [Medline].

  16. Pignolo RJ, Suda RK, Kaplan FS. The fibrodysplasia ossificans progressiva lesion. Clin Rev Bone Miner Metabol. 2005;3:195-200.

 
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Extensive heterotopic ossification on the back of a patient with fibrodysplasia ossificans progressiva.
Characteristic malformed great toes and hallux valgus.
Tumorlike swellings on the back representing early fibrodysplasia ossificans progressiva (FOP) flare-ups.
Severe limb swelling seen with an fibrodysplasia ossificans progressiva (FOP) flare-up.
 
 
 
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