Fibrodysplasia ossificans progressiva (FOP)

(OMIM phenotype number #135100)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease of connective tissue characterized by congenital malformation of the great toes and disabling heterotopic ossification in characteristic extraskeletal sites (muscles, tendons, ligaments and connective tissues). This disease is the most disabling condition of heterotopic (extraskeletal) ossification in humans. The worldwide prevalence is approximately 1/2.000.000, without ethnic, racial, gender, or geographic predilection. FOP is usually misdiagnosed and mismanaged. Mutations in the ACVR1 gene were identified as a genetic cause of FOP. Most patients with FOP have the same recurrent single nucleotide change c.617G>A, p.R206H in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. At birth, children affected by FOP, appear normal except for congenital malformations of the great toes. Hypoplasia or aplasia and fibular deviation have been described in almost all patients and hypoplasia of the thumbs in about half of the patients. Other recurrent features include conductive hearing loss and teeth anomalies. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur, transforming skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone and causing limited motor function. Moreover, patients with atypical forms of FOP have been described. The heterotopic ossifications are progressive and lead to immobility of all major joints, and to respiratory insufficiency due to severe scoliosis.

Diagnosis: based on clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes: progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Currently, there is no cure for FOP and only treatment of the symptoms is available. High dose glucocorticoids (a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up) have a limited use in the management of the early inflammatory flare-ups. Preventative management include prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age.


ACVR1 gene, 2q24.1 (OMIM gene/locus number #102576).


Sporadic episodes of painful soft tissue swellings, occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue, sensorineural hearing loss, conductive hearing loss, widely spaced teeth, mental retardation, respiratory failure, intermittently progressive ectopic ossification and malformed big toes which are often monophalangic (hallux valgus, malformed first metatarsal, and/or monophalangism), flat, broad mandibular condyles, scoliosis, small cervical vertebral bodies, and proximal medial tibial osteochondromas.

Main biochemical alterations 

High ALP, high Ur OHP.


Fibrodysplasia ossificans progressiva (FOP)
Reproduced from Orphanet J Rare Dis 2011;6:80 under the terms of the Creative Commons Attribution License (CC BY)
Fibrodysplasia ossificans progressiva (FOP)
Reproduced by permission from Macmillan Publishers Ltd: Nat Genet 2006 May;38(5):525-7, copyright 2006.
Fibrodysplasia ossificans progressiva (FOP)
Fibrodysplasia ossificans progressiva (FOP)

Fig. (a) Extensive heterotopic ossification on the back of an patient with FOP; (b) three-dimensional reconstructed computed tomography (CT) scan of the back of a twelve-year old child showing extensive heterotopic ossification typical of FOP; Fig. (c, d) Images of hands and feet showing clinodactyly and hallux valgus deformities.

Reproduced from J Pediatr, Vol 166, Sharma A, Behar M, Heterotopic ossification in fibrodysplasia ossificans progressiva, Page 204, Copyright 2015, with permission from Elsevier.


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