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Fibrodysplasia Ossificans

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
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

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.




Typical hallus valgus deformity.

Typical hallus valgus deformity.


Causes

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

Differential Diagnoses

Osteoma Cutis

Other Problems to Be Considered

Many systemic conditions are associated with cutaneous calcification, and many of them may secondarily ossify.

Dystrophic calcification (eg, scleroderma; calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia [CREST] syndrome; panniculitis; Ehlers-Danlos syndrome; Werner syndrome; some cutaneous neoplasms; after traumatization)

Metastatic calcification15
Iatrogenic calcification (as a complication of intravenous calcium chloride and calcium gluconate therapy)

Workup

Laboratory Studies

  • The clinical presentation (especially the additional presence of a hallus valgus deformity) is suggestive of fibrodysplasia ossificans progressiva (FOP).
  • Routine biochemical study results of mineral metabolism are usually within the reference range.
  • In fibrodysplasia ossificans progressiva, increased alkaline phosphatase levels are characteristic for children (physiologic growth of the bones).

Imaging Studies

  • Changes associated with fibrodysplasia ossificans progressiva include abnormal formation of the great toe, abnormally shaped long bones with exostoses, and developmental fusion of cervical vertebrae.
  • The most characteristic features are areas of bony masses penetrating into muscles (mainly the paraspinal region).
  • Computed tomography is the best method for detection of early fibrodysplasia ossificans progressiva lesions.
  • Bone scintigraphy shows an increased uptake of radiolabeled diphosphonate before ossification can be demonstrated by radiographic examination.

Procedures

  • A biopsy is generally not indicated in fibrodysplasia ossificans progressiva because of the frequent development of the lesions in the traumatization area.

Histologic Findings

Histologic examination shows a pronounced proliferation of fibroblasts within the muscles in several areas, leading to destruction of muscle fibers. Predominate mononuclear cell infiltrates are present within the muscles and in the subcutaneous connective tissue, with extensive proliferation of connective tissue fibroblasts replacing damaged muscle fibers, plus areas of newly formed bone tissue. In the center of fibrous material, bone or cartilage tissue may be detected. The well-developed osseous lesions show a typical picture of mature bone with Haversian systems. The muscle fibers usually secondarily degenerate. Smooth muscles are not involved.

Proliferation of fibroblasts within the muscle wi...

Proliferation of fibroblasts within the muscle with partial replacement of the muscle fibers.


Treatment

Medical Care

Fibrodysplasia ossificans progressiva (FOP) should be diagnosed during the neonatal period.16 Early treatment of fibrodysplasia ossificans progressiva helps avoid the factors of aggravation, slow the progression of the disease, and provide the children with improved quality of life. No effective medical therapy is known for fibrodysplasia ossificans progressiva; bisphosphonates and corticosteroids are only beneficial during the flares. Gene therapy may hold promise in fibrodysplasia ossificans progressiva treatment.

  • Systemic steroids are sometimes used for acute flare-ups.
  • Iontophoresis with steroids or acetic acid may improve diminished range of motion.
  • The discovery of the FOP gene reveals a highly conserved target in the transforming growth factor-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small-molecule signal transduction inhibitors for activinlike kinase-2.17 Effective therapies for fibrodysplasia ossificans progressiva may be based on blocking activinlike kinase-2 or blocking of activin receptor IA/activin–like kinase 2 signaling.18

Medication

No effective medical therapy is known for fibrodysplasia ossificans progressiva. Rituximab has been used.19

Follow-up

Complications

Fibrodysplasia ossificans progressiva (FOP) is sometimes associated with alopecia and deafness.

Prognosis

The prognosis for fibrodysplasia ossificans progressiva is poor because of the involvement of thoracic muscles and restrictive lung disease. Most fibrodysplasia ossificans progressiva patients are bedridden by the time they are in their 30s, and they usually die before they reach age 40 years.

Miscellaneous

Special Concerns

A special concern is recognizing classic clinical features of fibrodysplasia ossificans progressiva prior to the appearance of heterotopic ossification, avoiding surgical interventions that may lead to irreversible iatrogenic harm.20

Multimedia

Widespread tumors and indurations mainly in the s...

Media file 1: Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.

Typical hallus valgus deformity.

Media file 2: Typical hallus valgus deformity.

Proliferation of fibroblasts within the muscle wi...

Media file 3: Proliferation of fibroblasts within the muscle with partial replacement of the muscle fibers.

References

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  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].

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  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].

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  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].

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Keywords

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

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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