eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Fibrodysplasia Ossificans Progressiva (Myositis Ossificans)

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

Updated: Jul 30, 2009

Introduction

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
 

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.

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.

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

Clinical

History

• Individuals with fibrodysplasia ossificans progressiva (FOP) appear normal at birth except for characteristic malformations of the great toes, which are present in all classically affected individuals.
• Episodic, painful soft tissue swellings or exacerbations usually develop in the preteen years.⁷
• Although some exacerbations spontaneously regress, most transform soft connective tissues (including aponeuroses, fascia, ligaments, tendons, and skeletal muscles) into mature bone.
• Minor trauma (eg, intramuscular immunizations; mandibular blocks for dental work; muscle fatigue; blunt muscle trauma from bumps, bruises, falls) or influenza-like viral illnesses can trigger painful new flare-ups of fibrodysplasia ossificans progressiva, leading to progressive heterotopic ossification (HO).
• Most patients with fibrodysplasia ossificans progressiva are confined to a wheelchair by the third decade of life and require lifelong assistance in performing activities of daily living.
• The severe disability of fibrodysplasia ossificans progressiva results in low reproductive fitness.

Physical

• Two clinical features define classic fibrodysplasia ossificans progressiva: malformations of the great toes and progressive heterotopic ossification.
• Heterotopic bone replaces skeletal muscle and connective tissues.
• Heterotopic ossification in fibrodysplasia ossificans progressiva progresses in characteristic anatomic and temporal patterns that mimic the patterns of normal embryonic skeletal formation. Heterotopic ossification is typically seen first in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions.
• Several skeletal muscles, including the diaphragm, tongue, and extraocular muscles, are spared from fibrodysplasia ossificans progressiva. Cardiac muscle and smooth muscle are also spared from heterotopic ossification.
• Stiffness of the neck is an early finding in most patients and can precede the appearance of heterotopic ossification at that site.
• Characteristic anomalies of the cervical spine include large posterior elements, tall narrow vertebral bodies, and fusion of the facet joints between C2 and C7.⁸ Although the cervical spine often becomes ankylosed early in life, any minimal residual movement may eventually result in painful arthritic symptoms.
• Other skeletal anomalies commonly associated with fibrodysplasia ossificans progressiva include short malformed thumbs, clinodactyly, short broad femoral necks, and proximal medial tibial osteochondromas.⁹
• Severe weight loss may result following ankylosis of the jaw.
• Pneumonia and right-sided heart failure are complications of rigid fixation of the chest wall.

• Search for CME/CE on This Topic »