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Pediatric Fibrodysplasia Ossificans Progressiva (Myositis Ossificans) Differential Diagnoses

  • Author: Robert J Pignolo, MD, PhD; Chief Editor: Lawrence K Jung, MD  more...
 
Updated: Oct 26, 2015
 
 

Diagnostic Considerations

Fibrodysplasia ossificans progressiva (FOP) must be distinguished from other genetic conditions of heterotopic ossification (HO), as well as from nonhereditary heterotopic ossification (NHHO).

  • Progressive osseous heteroplasia (POH) is a rare genetic condition of progressive ectopic ossification.[12]
    • POH is clinically defined by cutaneous ossification that characteristically presents during childhood and progresses to involve subcutaneous and deep connective tissues, including muscle and fascia, in the absence of multiple features of Albright hereditary osteodystrophy (AHO) or hormone resistance.
    • Fibrodysplasia ossificans progressiva is distinguished from POH by the lack of cutaneous ossification, the presence of congenital malformation of the great toes, and preosseous tumorlike inflammation or “flare-ups.”
    • POH is one of numerous related genetic disorders, including AHO, pseudohypoparathyroidism (PHP), and osteoma cutis (OC), which share the common features of superficial ossification and association with inactivating mutations of GNAS, the gene that encodes the alpha subunit of the G-stimulatory protein of adenylyl cyclase.
  • NHHO follows trauma or other injury in most cases.[13] It can be observed at any age but is rare in children younger than 10 years. In children and young adults, sites of extraskeletal ossification tend to be periarticular or at the sites of blunt trauma or localized injury. NHHO presents as a painful soft tissue mass, which can be easily confused with malignant lesions such as osteosarcoma and soft tissue sarcoma.[14] Diagnosis of this condition may be difficult and requires radiological or histological findings after genetic conditions of heterotopic ossification have been excluded.
  • Fibrodysplasia ossificans progressiva is commonly misdiagnosed as aggressive juvenile fibromatosis, lymphedema, or soft tissue sarcoma.[15] The misdiagnosis of fibrodysplasia ossificans progressiva approaches 90% in individuals with fibrodysplasia ossificans progressiva worldwide. The correct diagnosis of fibrodysplasia ossificans progressiva can be made clinically, even before radiographic evidence of heterotopic ossification is seen, if soft tissues lesions are associated with symmetrical malformations of the great toes. Children often undergo unnecessary and harmful diagnostic biopsies that exacerbate the progression of the condition. This can be particularly dangerous at any anatomic site but especially so in the neck, back, or jaw where asymmetric heterotopic ossification can lead to rapidly progressive spinal deformity, exacerbation of thoracic insufficiency syndrome, or rapid ankylosis of the temporomandibular joints.
  • Other possibilities to consider include lymphoma, desmoids tumors, isolated congenital malformations, brachydactyly (isolated), and juvenile bunions.

Differential Diagnoses

 
 
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, 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, Orthopaedic Research Society, Johns Hopkins Medical and Surgical Association

Disclosure: Nothing to disclose.

Eileen M Shore, PhD Research 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, 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 Chief, Rheumatology Section, Director, Amplified Musculoskeletal Pain Program, The Children's Hospital of Philadelphia; Professor of Pediatrics, University of Pennsylvania School of Medicine

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

Disclosure: Nothing to disclose.

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, New York Academy of Sciences

Disclosure: Nothing to disclose.

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. 1993 Feb. 75(2):215-9. [Medline].

  2. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011. 6:80. [Medline].

  3. Kaplan FS, Groppe J, Pignolo RJ, Shore EM. Morphogen receptor genes and metamorphogenes: skeleton keys to metamorphosis. Ann N Y Acad Sci. 2007 Nov. 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. 2006 May. 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. 2009 Mar. 30(3):379-90. [Medline].

  6. Madhuri V, Santhanam M, Sugumar LK, Rajagopal K, Chilbule SK. Classical and atypical Fibrodysplasia Ossificans Progressiva in India. Ann Hum Genet. 2015 Jul. 79 (4):245-52. [Medline].

  7. Haupt J, Deichsel A, Stange K, Ast C, Bocciardi R, Ravazzolo R, et al. ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant. Hum Mol Genet. 2014 Oct 15. 23 (20):5364-77. [Medline]. [Full Text].

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

  9. 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. 1994 Apr. 243-8. [Medline].

  10. 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). 2005 Jun 15. 30(12):1379-85. [Medline].

  11. 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. 2008 Feb. 90(2):366-74. [Medline].

  12. 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. 2008 Jul 15. 146A(14):1788-96. [Medline]. [Full Text].

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

  14. [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:

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

  16. 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. 1994 Jul. 238-47. [Medline].

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

  18. 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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