eMedicine Specialties > Dermatology > Pediatric Diseases

Fibrodysplasia Ossificans

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Slawomir Majewski, MD, Professor and Director, Department of Dermatology and Venereology, Warsaw School of Medicine, Poland; Sebastian S Majewski, MD, Consulting Staff, Department of Dermatology, Military Institute of Health Services, Warsaw, Poland; Stefania Jablonska, MD, Chairman, Professor Emeritus, Department of Dermatology, Warsaw School of Medicine, Poland
Contributor Information and Disclosures

Updated: Sep 4, 2009

Introduction

Background

Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling, autosomal dominant disease characterized by recurrent painful episodes of soft tissue swelling and the development of tumors in subcutis and muscle tissue. These lesions lead to heterotopic ossification, that is, true bone tissue formation in the axial musculature, the ligaments, the fascia, the aponeurosis, the tendons, and the joint capsules. A variety of congenital skeletal malformations of the hands and the feet, especially a hallus valgus deformity with microdactyly, also are characteristic.

Also see Fibrodysplasia Ossificans Progressiva (Myositis Ossificans) and Heterotopic Ossification.

Pathophysiology

The pathophysiology of fibrodysplasia ossificans progressiva is unknown. It is an inherited autosomal dominant disorder with complete penetration but variable gene expressivity. Findings suggest that fibrodysplasia ossificans progressiva maps to band 4q27-31, a region that contains at least 1 gene involved in the bone morphogenic protein (BMP) signaling pathway.1 BMPs are members of the transforming growth factor-beta superfamily and play a role in the development of bone and other tissues.2 The condition is multifocal, starting to develop usually after traumatization. The genetic cause of fibrodysplasia ossificans progressiva lies within the ACVR1 gene, which encodes a type I BMP transmembrane receptor. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.3 In one study, it was mapped to 2q23-24 by linkage analysis.4

A number of mutations have been documented. A mutation of the noggin (NOG) gene in a fibrodysplasia ossificans progressiva family has been described.5 The FOP gene in the 17q21-22 region had been observed with several mutations described in the NOG gene (located in 17q22) in 4 fibrodysplasia ossificans progressiva patients, including the G91C mutation, which was transmitted dominantly in a Spanish fibrodysplasia ossificans progressiva family. This mutation is a guanine to adenine change at nucleotide 283 (283G–>A) of the NOG gene and was transmitted by the affected mother to her 2 affected children. A novel mutation in the activin A type 1 receptor gene was described in one patient.6 Analysis showed that the patient was heterozygous for a mutation, G356D.7

Patients with fibrodysplasia ossificans progressiva–like heterotopic ossification and/or toe malformations have been described in 2 categories: fibrodysplasia ossificans progressiva–plus (classic defining features of fibrodysplasia ossificans progressiva plus one or more atypical features) and fibrodysplasia ossificans progressiva variants (major variations in one or both of the 2 classic defining features of fibrodysplasia ossificans progressiva)8 While the typical mutation was found in all cases of classic fibrodysplasia ossificans progressiva and most cases of fibrodysplasia ossificans progressiva–plus, novel ACVR1 mutations were identified in the fibrodysplasia ossificans progressiva variants and some with fibrodysplasia ossificans progressiva–plus.

Two unique mutations in the ACVR1 gene have also been identified in 2 fibrodysplasia ossificans progressiva patients from the United Kingdom with some atypical digit abnormalities and other clinical features.9 The resultant mutations were interpreted to result in local structural changes in the ACVR1 protein, as revealed by interrogating homology models of the native and mutated ACVR1 kinase domains.

Frequency

International

The prevalence of fibrodysplasia ossificans progressiva has been estimated at 1 case per 1.64 million persons in the United Kingdom. Fewer than 200 cases have been described worldwide.

Mortality/Morbidity

Fibrodysplasia ossificans progressiva usually starts in early infancy, although skeletal deformations are present at birth. The prognosis is poor because of the involvement of thoracic muscles, leading to restrictive lung disease.

Race

Fibrodysplasia ossificans progressiva mainly occurs in whites, but it is also reported in blacks.

Sex

Fibrodysplasia ossificans progressiva is more common in females than in males. The observed male-to-male transmission of the disorder excludes X-linked inheritance. Because few individuals who are affected choose to have children, most patients are considered to have new mutations.

Age

Fibrodysplasia ossificans progressiva usually starts in early infancy; however, reports exist of in utero involvement and skeletal deformations are present at birth.

Clinical

History

  • In most cases, fibrodysplasia ossificans progressiva starts in early infancy with episodes of soft tissue swelling; however, reports exist of in utero involvement.
  • Ectopic bone formation is usually first evident in early childhood in children aged 2-6 years.
    • The main target is the axial musculature, but eventually ectopic bone formation occurs in the ligaments, the fascia, the aponeuroses, the tendons, and the joint capsules.
    • Involvement often demonstrates a proximal-to-distal predilection.
  • Most patients become bedridden by time they are in their 30s.

Physical

  • Fibrodysplasia ossificans progressiva lesions are characterized by painful, tender, rubbery, soft tissue indurations, usually precipitated by a trauma.
  • Lesions mainly develop in the paraspinal muscles of the back and in the limb girdles.
  • Some of the tumors undergo ossification, which can also affect the tendons, the ligaments, and the fascia.
  • Characteristics of diagnostic value are a hallus valgus deformity (present at birth), torticollis (due to involvement of the sternocleidomastoid muscle), joint immobilization (due to periarticular ossificans), and a thorax deformity (both lateral and anteroposterior).
  • Proximal tibial osteochondromas are a common phenotypic feature.10,11
  • Mobility is restricted because of ankylosis of the spine and the rib cage.
  • Fibrodysplasia ossificans progressiva is sometimes associated with alopecia and deafness.12
  • Aslan et al reported ankylosis of the jaw and van der Meij et al reported restricted mandibular movement, both associated with fibrodysplasia ossificans progressiva.13,14


Widespread tumors and indurations mainly in the s...

Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.

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Widespread tumors and indurations mainly in the s...

Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.



Typical hallus valgus deformity.

Typical hallus valgus deformity.

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Typical hallus valgus deformity.

Typical hallus valgus deformity.

Causes

  • Fibrodysplasia ossificans progressiva is an idiopathic condition precipitated by trauma.

More on Fibrodysplasia Ossificans

Overview: Fibrodysplasia Ossificans
Differential Diagnoses & Workup: Fibrodysplasia Ossificans
Treatment & Medication: Fibrodysplasia Ossificans
Follow-up: Fibrodysplasia Ossificans
Multimedia: Fibrodysplasia Ossificans
References
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References

  1. Feldman G, Li M, Martin S, et al. Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27-31. Am J Hum Genet. Jan 2000;66(1):128-35. [Medline].

  2. de la Pena LS, Billings PC, Fiori JL, Ahn J, Kaplan FS, Shore EM. Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J Bone Miner Res. Jul 2005;20(7):1168-76. [Medline].

  3. Shore EM, Glaser DL, Gannon FH. Osteogenic induction in hereditary disorders of heterotopic ossification. Clin Orthop Relat Res. May 2000;303-16. [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. Fontaine K, Semonin O, Legarde JP, Lenoir G, Lucotte G. A new mutation of the noggin gene in a French Fibrodysplasia ossificans progressiva (FOP) family. Genet Couns. 2005;16(2):149-54. [Medline].

  6. Nakajima M, Haga N, Takikawa K, Manabe N, Nishimura G, Ikegawa S. The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva. J Hum Genet. 2007;52(5):473-5. [Medline].

  7. Furuya H, Ikezoe K, Wang L, et al. A unique case of fibrodysplasia ossificans progressiva with an ACVR1 mutation, G356D, other than the common mutation (R206H). Am J Med Genet A. Feb 15 2008;146A(4):459-63. [Medline].

  8. Kaplan FS, Xu M, Seemann P, 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].

  9. Petrie KA, Lee WH, Bullock AN, et al. Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PLoS One. 2009;4(3):e5005. [Medline].

  10. 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].

  11. Chichareon V, Arpornmaeklong P, Donsakul N. Fibrodysplasia ossificans progressiva and associated osteochondroma of the coronoid process in a child. Plast Reconstr Surg. Apr 1999;103(4):1238-43. [Medline].

  12. Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva. Am J Audiol. Jun 1999;8(1):29-33. [Medline].

  13. Aslan G, Celik F, Gorgu M. Unusual ankylosis of the jaw due to fibrodysplasia ossificans progressiva. Ann Plast Surg. Nov 1999;43(5):576-8. [Medline].

  14. van der Meij EH, Becking AG, van der Waal I. Fibrodysplasia ossificans progressiva. An unusual cause of restricted mandibular movement. Oral Dis. Mar 2006;12(2):204-7. [Medline].

  15. Jeziorska M, Dabska M, Buraczewski J. [Myositis ossificans (clinico-pathological entity often diagnosed erroneously as malignant tumor)]. Nowotwory. Apr-Jun 1980;30(2):183-94. [Medline].

  16. Dzukou T, Barbier C, Spyckerelle C, Labarriere F, Vittu G, Kremp O. [Fibrodysplasia ossificans progressiva in children. The interest of early diagnosis and treatment]. Presse Med. Mar 12 2005;34(5):373-7. [Medline].

  17. Kaplan FS, Glaser DL, Pignolo RJ, Shore EM. A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton. Expert Opin Biol Ther. May 2007;7(5):705-12. [Medline].

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  20. Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB. Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neurosurg Pediatr. Jan 2008;1(1):91-4. [Medline].

  21. Ali NS, Qureshi R. A 3 year old girl with fibrodysplasia ossificans progressiva. J Pak Med Assoc. Sep 1999;49(9):223-5. [Medline].

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  26. Lucotte G, Semonin O, Lutz P. A de novo heterozygous deletion of 42 base-pairs in the noggin gene of a fibrodysplasia ossificans progressiva patient. Clin Genet. Dec 1999;56(6):469-70. [Medline].

  27. Magryta CJ, Kligora CJ, Temple HT, Malik RK. Clinical presentation of fibrodysplasia ossificans progressiva: pitfalls in diagnosis. J Pediatr Hematol Oncol. Nov-Dec 1999;21(6):539-43. [Medline].

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  30. Puzas JE, Miller MD, Rosier RN. Pathologic bone formation. Clin Orthop Relat Res. Aug 1989;269-81. [Medline].

  31. Smith R. 61st ENMC-sponsored international workshop: Fibrodysplasia (myositis) ossificans progressiva (FOP), 10-12th July 1998, Naarden, The Netherlands. Neuromuscul Disord. Oct 1999;9(6-7):434-5. [Medline].

  32. Sy MH, Diouf A, Diallo BK, et al. [Fibrodysplasia ossificans progressiva or Munchmeyer disease apropos of 2 cases]. Dakar Med. 1999;44(1):126-30. [Medline].

  33. Virdi AS, Shore EM, Oreffo RO, et al. Phenotypic and molecular heterogeneity in fibrodysplasia ossificans progressiva. Calcif Tissue Int. Sep 1999;65(3):250-5. [Medline].

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Further Reading

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Keywords

fibrodysplasia ossificans, fibrodysplasia ossificans progressiva, FOP, myositis ossificans progressiva, myositis ossificans

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Slawomir Majewski, MD, Professor and Director, Department of Dermatology and Venereology, Warsaw School of Medicine, Poland
Disclosure: Nothing to disclose.

Sebastian S Majewski, MD, Consulting Staff, Department of Dermatology, Military Institute of Health Services, Warsaw, Poland
Disclosure: Nothing to disclose.

Stefania Jablonska, MD, Chairman, Professor Emeritus, Department of Dermatology, Warsaw School of Medicine, Poland
Disclosure: Nothing to disclose.

Medical Editor

Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France
Jean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology and American Dermatological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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