Fibrodysplasia Ossificans 

Updated: Sep 16, 2019
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

Overview

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.[1] 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.[2] BMPs are members of the transforming growth factor-beta superfamily and play a role in the development of bone and other tissues.[3] 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.[4] In one study, it was mapped to 2q23-24 by linkage analysis.[5]

A number of mutations have been documented. A mutation of the noggin (NOG) gene in a fibrodysplasia ossificans progressiva family has been described.[6] 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.[7] Analysis showed that the patient was heterozygous for a mutation, G356D.[8]

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)[9] 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[10] . A patient from Japan with an ACVR1 gene mutation had normal development until age 17 years and a mild clinical course.[11] 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.

Impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may activate osteogenic BMP-signaling in extraskeletal sites, leading to delayed and progressive ectopic bone formation.[12]

A novel ALK2 mutation, L196P, was identified in a mild form of fibrodysplasia ossificans progressiva.[13]

Etiology

Fibrodysplasia ossificans progressiva is an idiopathic condition precipitated by trauma.

Epidemiology

Frequency

The prevalence of fibrodysplasia ossificans progressiva has been estimated at 1 case per 1.64 million persons in the United Kingdom. A prevalence of 1.36 per million inhabitants has been calculated for France.[14] Fewer than 200 cases have been described worldwide.

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.

Prognosis

The prognosis for fibrodysplasia ossificans progressiva is poor because of the involvement of thoracic muscles and restrictive lung disease.[15] 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.

 

Presentation

History

In most cases, fibrodysplasia ossificans progressiva starts in early infancy with episodes of soft tissue swelling; however, reports exist of in utero involvement. It may be first evident in an infant as recurrent diffuse soft-tissue scalp and periorbital swelling.[16]

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. Approximately half of the flare-ups seem to be spontaneous, while the other half appear to be trauma related.[17]

Most patients become bedridden by time they are in their 30s.

Chronic neurological symptoms are common in these patients.[18] These findings include neuropathic pain, especially in females (15%). Many had other sensory abnormalities.

Physical Examination

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).

Fibrodysplasia ossificans progressiva limited to the maxillofacial region has been described.[19] It may produce a fusion between the mandibular ramus and the zygomatic complex and trismus.

All proximal tibial osteochondromas are a common phenotypic feature.[20, 21] Mobility is restricted because of ankylosis of the spine and the rib cage.

Fibrodysplasia ossificans progressiva is sometimes associated with alopecia and deafness.[22]

Aslan et al reported ankylosis of the jaw and van der Meij et al reported restricted mandibular movement, both associated with fibrodysplasia ossificans progressiva.[23, 24]

Note the images below.

Widespread tumors and indurations mainly in the sc 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.

Complications

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

Patients should be protected by surgical procedures, including biopsies if possible, to avoid harming them.[25]

 

DDx

Diagnostic Considerations

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

  • 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[26]

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

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.[27]

Differential Diagnoses

 

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).

CT scanning is the best method for detection of early fibrodysplasia ossificans progressiva lesions.[28] Bone scintigraphy shows an increased uptake of radiolabeled diphosphonate before ossification can be demonstrated by radiographic examination.

CT evaluation may demonstrate heterotopic ossification of the pterygoid muscles, a likely cause jaw restriction and retrognathia in older patients.[29]

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. Note the image below.

Proliferation of fibroblasts within the muscle wit 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.[30] 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.[31] 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.[32]

One report (involving 3 patients) suggested that a combined formulation of propranolol and ascorbic acid (known as FOPCon) may be beneficial in the prophylaxis of flare-ups.[33] However, the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) recommends that FOPCon not be promoted as or purported to be a definitive therapy for fibrodysplasia ossificans progressiva.[34] The IFOPA has determined the evidence for efficacy and safety is insufficient. The organization strongly recommends caution for both patients and medical practitioners against making therapeutic conclusions for current practice; however, it suggests further insights may be gained from continued investigation and validation. Further, until the safety and efficacy of FOPCon has been further investigated, it should be considered investigational and patients receiving it should be treated under protocols associated with formal clinical trials, including discussion of potential risks and benefits.

A summary of the IFOPA treatment guidelines for medical professionals is as follows[35] :

  • Deep tissue trauma: Deep tissue trauma must be avoided. This includes intramuscular injections, if at all possible.
  • Stabilization and treatment: For stabilization and procedures, venipuncture, subcutaneous medications, and intravenous medications are acceptable; again, intramuscular infections should be avoided if possible.
  • Intubation precautions: Significant precautions should be taken with intubation procedures. The jaw should be protected. Expert anesthesiologist consultation should be obtained because the jaw and neck may be completely or partially locked.
  • Further consultations: It is strongly recommended to obtain further consultations with expert physicians regarding the significant potential risks of any surgical or medical interventions being considered.

A complete version of these guidelines is available at The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations.

Surgical Care

Patients with fibrodysplasia ossificans, a rare disorder, may require oral surgical and anesthetic procedures to control oral pain. The importance of a minimally invasive surgical technique and appropriate anesthetic management has been stressed.[36]

The experience using general anesthesia has been favorable, with awake nasal fiberoptic intubation evaluated as desirable for airway management.[37]

 

Medication

Medication Summary

No effective medical therapy is known for fibrodysplasia ossificans progressiva.[38] Rituximab has been used.[39]