eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Fibrodysplasia Ossificans Progressiva (Myositis Ossificans): Differential Diagnoses & Workup

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

Differential Diagnoses

Juvenile fibromatosis
Osteosarcoma

Other Problems to Be Considered

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.¹⁰
  • 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.¹¹ 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.¹² 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.¹³ 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.

Workup

Laboratory Studies

• 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

• Radiographic and bone scan findings suggest normal modeling and remodeling of the heterotopic skeleton.¹⁴
• 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

• Definitive genetic testing of fibrodysplasia ossificans progressiva is now available.¹⁵ 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.¹³ 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

• Histopathologic studies of fibrodysplasia ossificans progressiva lesions reveal monocytic and lymphocytic infiltration into skeletal muscle followed by widespread myocyte degeneration, fibroproliferation, chondrogenesis, and osteogenesis.¹⁶
• 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.

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