Pediatric Fibrodysplasia Ossificans Progressiva (Myositis Ossificans) 

Updated: Aug 14, 2018
Author: Robert J Pignolo, MD, PhD; Chief Editor: Lawrence K Jung, MD 

Overview

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]

Extensive heterotopic ossification on the back of Extensive heterotopic ossification on the back of a patient with fibrodysplasia ossificans progressiva.
Characteristic malformed great toes and hallux val Characteristic malformed great toes and hallux valgus.

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, 6, 7] Noggin mutations have been reported but cannot be substantiated and are erroneous.

Epidemiology

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, 8]

 

Presentation

History

See the list below:

  • 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.[19]

  • Episodic, painful soft tissue swellings or exacerbations usually develop in the preteen years.[9]

  • 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

See the list below:

  • Two clinical features define classic fibrodysplasia ossificans progressiva: malformations of the great toes and progressive heterotopic ossification.

  • Among patients with fibrodysplasia ossificans progressiva–like HO and/or toe malformations, a small number of patients have clinical features unusual for fibrodysplasia ossificans progressiva.[5] These atypical fibrodysplasia ossificans progressiva patients are categorized as 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, such as normal great toes or severe reduction deficits of digits).

  • 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.[10] 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.[11]

  • 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.

 

DDx

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

 

Workup

Laboratory Studies

See the list below:

  • Routine biochemical evaluations of bone mineral metabolism are usually normal in patients with fibrodysplasia ossificans progressiva (FOP), although the serum alkaline phosphatase activity and the erythrocyte sedimentation rate may be increased, especially during disease flare-ups.

  • Urinary basic fibroblast growth factor levels may be elevated during disease flare-ups coinciding with the preosseous angiogenic phase of early fibroproliferative lesions.

Imaging Studies

See the list below:

  • Radiographic and bone scan findings suggest normal modeling and remodeling of the heterotopic skeleton.[16]

  • Bone scan findings are abnormal before heterotopic ossification (HO) can be detected on conventional radiography.

  • CT and MRI have been used to study early lesions. Although these evaluation methods are generally superfluous from a diagnostic standpoint, they can provide a useful and 3-dimensional perspective of the disease process. The definitive diagnosis of fibrodysplasia ossificans progressiva can be made by simple clinical evaluation that associates rapidly appearing soft tissue lesions with malformations of the great toes.

Procedures

See the list below:

  • Definitive genetic testing of fibrodysplasia ossificans progressiva is now available.[17] Clinical suspicion of fibrodysplasia ossificans progressiva early in life on the basis of malformed great toes can lead to early clinical diagnosis, confirmatory diagnostic genetic testing (if appropriate), and the avoidance of harmful diagnostic and treatment procedures.[15] At the present time, genetic testing is available on a clinical and research basis at several laboratories.

  • Intramuscular injections must be avoided. Routine childhood diphtheria-tetanus-pertussis immunizations administered by intramuscular injection pose a substantial risk of permanent heterotopic ossification at the site of injection, as do arterial punctures, whereas measles-mumps-rubella immunizations administered by subcutaneous injection and routine venipuncture pose no significant risk.

  • Permanent ankylosis of the jaw may be precipitated by minimal soft tissue trauma during routine dental care. Assiduous precautions are necessary in administering dental care to anyone who has fibrodysplasia ossificans progressiva. Overstretching of the jaw and intramuscular injections of local anesthetic must be avoided. Mandibular blocks cause muscle trauma that leads to heterotopic ossification, and local anesthetic drugs are extremely toxic to skeletal muscle.

  • Individuals with fibrodysplasia ossificans progressiva have developmental anomalies of the temporomandibular joints (TMJs). Spontaneous or posttraumatic ankylosis of the temporomandibular joints is common and leads to severe disability with resultant difficulties in eating and poor oral hygiene. Great care must be taken not to provoke flare-ups of the temporomandibular joints. Preventive oral and dental health care measures are essential in patients with fibrodysplasia ossificans progressiva, especially during childhood years. Periodontic and preventative oral care is crucial to prevent long-term dental and oral complications in patients with fibrodysplasia ossificans progressiva.

  • Patients with fibrodysplasia ossificans progressiva have limited options for dental anesthesia. Mandibular blocks are contraindicated because they lead to ossification of the pterygoid muscles and rapid ankylosis of the temporomandibular joints. Infiltration anesthesia is difficult in the mandibular posterior molar areas of permanent teeth. Successful anesthesia in mandibular primary teeth can be achieved by infiltration through the dental pulp. Interligamentary infiltration may be helpful, if performed carefully. However, in some patients, this type of local anesthesia may not be possible. General anesthesia with awake nasotracheal fiberoptic intubation may be needed for dental care in patients with fibrodysplasia ossificans progressiva.

  • Hearing impairment is a common feature of fibrodysplasia ossificans progressiva and occurs in approximately 50% of patients. The onset is usually in childhood and may be slowly progressive. Hearing loss is usually conductive in nature and may be due to middle ear ossification; however, in some patients, the hearing impairment is neurologic in nature. Children with fibrodysplasia ossificans progressiva should generally have audiology evaluations every other year; more often, if necessary. Hearing aids are often helpful and can diminish developmental problems due to hearing loss.

Histologic Findings

See the list below:

  • Histopathologic studies of fibrodysplasia ossificans progressiva lesions reveal monocytic and lymphocytic infiltration into skeletal muscle followed by widespread myocyte degeneration, fibroproliferation, chondrogenesis, and osteogenesis.[18]

  • All stages of histological development are present in the fibrodysplasia ossificans progressiva lesion within days of its induction, indicating that different regions mature at different rates.

  • Although heterotopic bone formation in fibrodysplasia ossificans progressiva is similar in some respects to bone formation in embryonic skeletal development and postnatal fracture healing, important differences include the lack of inflammation in embryonic skeletal induction and the relative absence of lymphocytic inflammatory cells in early fracture healing.

 

Treatment

Medical Care

Flare-ups of fibrodysplasia ossificans progressiva (FOP) are sporadic and unpredictable, and the rate of individual disease progression widely varies. Several large studies on the natural history of fibrodysplasia ossificans progressiva have confirmed that predicting the occurrence, duration, or severity of an fibrodysplasia ossificans progressiva flare-up is impossible, although characteristic anatomic patterning has been described.

A brief description of agents to be considered during a fibrodysplasia ossificans progressiva exacerbation is below. For a complete description, including dosing and potential major side effects, refer to the current treatment guidelines at International Fibrodysplasia Ossificans Progressiva.

Flare-ups

Widespread favorable anecdotal reports from the fibrodysplasia ossificans progressiva community suggest that a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. The use of corticosteroids should be restricted to the extremely early symptomatic treatment of flare-ups that affect major joints, the jaw, or the submandibular area. Corticosteroids should not generally be used for the symptomatic treatment of flare-ups that involve the back, neck, or trunk due to the long duration and recurring nature of these flare-ups and the difficulty in assessing the true onset of such flare-ups.

The dose of corticosteroids depends on body weight. A typical dose of prednisone is 2 mg/kg/d, administered as a single daily dose for no more than 4 days. The potentially dangerous nature of flare-ups in the submandibular region may dictate a slightly longer use of corticosteroids with an appropriate taper for the duration of the flare-up or until the acute swelling subsides.

When prednisone is discontinued, a nonsteroidal anti-inflammatory drug (NSAID) or cox-2 inhibitor (in conjunction with a leukotriene inhibitor) may be used symptomatically for the duration of the flare-up.

The use of mast cell inhibitors and aminobisphosphonates are less well-defined and should be used at the physician’s discretion.

Pain management

Many fibrodysplasia ossificans progressiva flare-ups, especially those around the hips and knees, are extremely painful and may require a brief course of well-monitored narcotic analgesia in addition to the use of NSAIDs, cox-2 inhibitors, and oral or intravenous glucocorticoids. Other types of transient pain syndromes may be caused by neuropathies resulting from acute flare-ups, transient bursitis, inflammation of osteochondromas, arthritis, and muscle fatigue.

Muscle relaxants

Areas of relatively healthy skeletal muscle bordering the acute fibrodysplasia ossificans progressiva lesion are subject to metabolic changes that lead to muscle spasm and fiber shortening. The judicious short-term use of muscle relaxants such as cyclobenzaprine (Flexeril), metaxalone (Skelaxin), or Lioresal (Baclofen) may help to decrease muscle spasm and maintain more functional activity.

Surgical Care

Attempts to surgically remove heterotopic bone risks provoking explosive and painful new bone growth. Biopsies of fibrodysplasia ossificans progressiva lesions are never indicated and may cause additional heterotopic ossification.

Activity

Falls suffered by patients with fibrodysplasia ossificans progressiva can lead to severe injuries and flare-ups. Patients with fibrodysplasia ossificans progressiva have a self-perpetuating fall cycle. Minor soft tissue trauma often leads to severe exacerbations of fibrodysplasia ossificans progressiva, which result in heterotopic ossification and joint ankylosis. Mobility restriction from joint ankylosis severely impairs balancing mechanisms and causes instability, resulting in more falls. Compared with people who do not have fibrodysplasia ossificans progressiva, falls in those with fibrodysplasia ossificans progressiva are more likely to result in severe head injuries, loss of consciousness, concussions, and neck and back injuries due to the inability to use the upper limbs to absorb the impact of a fall and to anatomic abnormalities of the cervical spine in individuals with fibrodysplasia ossificans progressiva.

For children, redirection of activity to less physically interactive play may be helpful. Complete avoidance of high-risk circumstances may reduce falls but may also compromise a patient’s functional level and independence and may be unacceptable to many.

 

Medication

Anti-inflammatory Agent

Class Summary

Corticosteroids are indicated as first-line treatment at beginning of flare-ups.

Prednisone

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

 

Follow-up

Deterrence/Prevention

See the list below:

  • If a parent has fibrodysplasia ossificans progressiva (FOP), the chance that a child will have fibrodysplasia ossificans progressiva is 50%. In addition to the usual risks that any woman might encounter during pregnancy, a woman with fibrodysplasia ossificans progressiva has additional concerns that must be carefully considered, including substantial life-threatening risks to both the mother and child.

  • Present and future rehabilitation approaches should be focused on enhancing activities of daily living. Occupational therapy and vocational education consultations may be extremely useful. Passive range of motion must be avoided, as it likely leads to disease exacerbations.

  • Measures to prevent falls should be directed at modification of activity, improvement in household safety, use of ambulatory devices (such as a cane, if possible), and use of protective headgear.

  • Prophylactic measures to maximize pulmonary function, minimize respiratory compromise, and prevent influenza and pneumonia are helpful in decreasing the morbidity and mortality from thoracic insufficiency syndrome.

Prognosis

See the list below:

  • As heterotopic bone accumulates in fibrodysplasia ossificans progressiva, range of motion is progressively lost, leading to near complete immobility.

  • Patients with fibrodysplasia ossificans progressiva develop thoracic insufficiency syndrome (TIS) that can lead to life-threatening complications. Pneumonia and right-sided heart failure are the major life-threatening hazards that result from TIS in patients with fibrodysplasia ossificans progressiva.

  • The median age of survival is approximately 41 years, and death often results from complications of TIS.