- Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD more...
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. 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.
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. BMPs are members of the transforming growth factor-beta superfamily and play a role in the development of bone and other tissues. 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. In one study, it was mapped to 2q23-24 by linkage analysis.
A number of mutations have been documented. A mutation of the noggin (NOG) gene in a fibrodysplasia ossificans progressiva family has been described. 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. Analysis showed that the patient was heterozygous for a mutation, G356D.
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) 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 . A patient from Japan with an ACVR1 gene mutation had normal development until age 17 years and a mild clinical course. 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.
A novel ALK2 mutation, L196P, was identified in a mild form of fibrodysplasia ossificans progressiva.
The prevalence of fibrodysplasia ossificans progressiva has been estimated at 1 case per 1.64 million persons in the United Kingdom. Fewer than 200 cases have been described worldwide.
Fibrodysplasia ossificans progressiva mainly occurs in whites, but it is also reported in blacks.
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.
Fibrodysplasia ossificans progressiva usually starts in early infancy; however, reports exist of in utero involvement and skeletal deformations are present at birth.
The prognosis for fibrodysplasia ossificans progressiva is poor because of the involvement of thoracic muscles and restrictive lung disease. 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.
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