History

In most cases, fibrodysplasia ossificans progressiva 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.

Chronic neurological symptoms are common in these patients.[13] These findings include

neuropathic pain, especially in females (15%). Many had other sensory abnormalities.

Physical

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.[14] It

may produce a fusion between the mandibular ramus and the zygomatic complex and trismus.

All proximal tibial osteochondromas are a common phenotypic feature.[15, 16]Mobility is restricted

because of ankylosis of the spine and the rib cage.

Fibrodysplasia ossificans progressiva is sometimes associated with alopecia and deafness.[17]

Aslan et al reported ankylosis of the jaw and van der Meij et al reported restricted mandibular

movement, both associated with fibrodysplasia ossificans progressiva.[18, 19]

Note the images below.

Widespread tumors and indurations mainly in the scapular area, found

on radiographic examination to consist of heterotopic bone formation.

Typical hallus valgus deformity.

Causes

Fibrodysplasia ossificans progressiva is an idiopathic condition precipitated by trauma.

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.[1] BMPs are

members of the transforming growth factor-beta superfamily and play a role in the development

of bone and other tissues.[2] 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.[3] In one study, it was mapped to 2q23-24 by linkage analysis.[4]

A number of mutations have been documented. A mutation of the noggin (NOG) gene in a

fibrodysplasia ossificans progressiva family has been described.[5] TheFOP 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 NOGgene 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.[6] Analysis showed that the patient was

heterozygous for a mutation, G356D.[7]

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)[8] 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[9] . A patient from Japan with an ACVR1 gene mutation had normal development

until age 17 years and a mild clinical course.[10] 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.[11]

A novel ALK2 mutation, L196P, was identified in a mild form of fibrodysplasia ossificans

progressiva.[12]