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AUTHOR AND EDITOR INFORMATION

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Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Robert A Schwartz is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

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

Editors: Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Jeffrey J Miller, MD, Associate Professor, Department of Dermatology, Penn State University, Milton S Hershey Medical Center; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author and Editor Disclosure

Synonyms and related keywords: fibrodysplasia ossificans progressive, FOP, myositis ossificans progressiva, myositis ossificans

INTRODUCTION

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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.

The eMedicine articles Myositis Ossificans and Heterotopic Ossification may be helpful.

Pathophysiology

The pathophysiology of FOP is unknown. It is an inherited autosomal dominant disorder with complete penetration but variable gene expressivity. Recent findings suggest that FOP maps to band 4q27-31, a region that contains at least 1 gene involved in the bone morphogenic protein (BMP) signaling pathway. BMPs are members of the transforming growth factor-beta superfamily and play a role in the development of bone and other tissues. The condition is multifocal, starting to develop usually after traumatization.

A number of mutations have been documented. A mutation of the noggin (NOG) gene in an FOP family has been described.1 The FOP gene in the 17q21-22 region had been observed with several mutations described in the NOG gene (located in 17q22) in 4 FOP patients, including the G91C mutation, which was transmitted dominantly in a Spanish FOP 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. Analysis showed that the patient was heterozygous for a mutation, G356D.2 A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic FOP.3 In this study, FOP was mapped to 2q23-24 by linkage analysis.

Frequency

International

The prevalence 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

FOP 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

The disease mainly occurs in whites, but it is also reported in blacks.

Sex

FOP 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

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


CLINICAL

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History

  • In most cases, FOP 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

  • 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.4
  • Mobility is restricted because of ankylosis of the spine and the rib cage.
  • FOP is sometimes associated with alopecia and deafness.

Causes

FOP is an idiopathic condition precipitated by trauma.


DIFFERENTIALS

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


WORKUP

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Lab Studies

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

Imaging Studies

  • Changes 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 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 FOP 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.


TREATMENT

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Medical Care

FOP should be diagnosed during the neonatal period.5 Early treatment 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; bisphosphonates and corticosteroids are only beneficial during the flares. Gene therapy may hold promise.

  • 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-2.6 Effective therapies for FOP may be based on blocking activinlike kinase-2 or blocking of activin receptor IA/activin-like kinase 2 signaling.7


MEDICATION

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No effective medical therapy is known.


FOLLOW-UP

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Complications

FOP is sometimes associated with alopecia and deafness.

Prognosis

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


MISCELLANEOUS

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Special Concerns

A special concern is recognizing classic clinical features of FOP prior to the appearance of heterotopic ossification, avoiding surgical interventions that may lead to irreversible iatrogenic harm.8


MULTIMEDIA

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Media file 1:  Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 2:  Typical hallus valgus deformity.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

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


REFERENCES

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Fibrodysplasia Ossificans excerpt

Article Last Updated: May 12, 2008