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fibrodysplasia ossificans progressiva
Wednesday 30 September 2009
Definition: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification in distinct anatomic patterns.
Early preosseous lesions in FOP are clinically and histologically indistinguishable from the lesions of aggressive juvenile fibromatosis (AJF).
Although the genetic defect in FOP is unknown, bone morphogenetic proteins (BMPs) 2 (BMP2) and 4 (BMP4) are plausible candidates genes.
The fibrodysplasia ossificans progressiva (FOP) is characterized by the association of skeletal abnormalities mainly in great toes, and enchondral ossifications in tendons and muscles.
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease of the connective tissue. A mutation of the body’s repair mechanism causes fibrous tissue (including muscle, tendon, and ligament) to be ossified when damaged. In many cases, injuries can cause joints to become permanently frozen in place.
Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with more bone.
Children born with FOP characteristically have deformed great toes, possibly missing a joint or simply presenting with a notable lump at the minor joint. The first "flare-up" that leads to the formation of FOP bones usually occurs before the age of 10.
FOP is considered a genetic disease because the bone growth progresses from the top downward, just as bones grow in fetuses. A child with FOP will typically develop bones starting at the neck, then on the shoulders, arms, chest area and finally on the feet.
Often, the tumor-like lumps that characterize the disease appear suddenly.
Physiopathology
Although the genetic defect in FOP is unknown, bone morphogenetic proteins (BMPs) 2 (BMP2) and 4 (BMP4) are plausible candidates genes.
BMP dysregulation seems to be the main underlying mechanism of the heterotopic ossifications. The genetic basis remain controversial between a mutation on chromosome 4 or 17.
The gene that causes ossification is normally deactivated after a fetus’ bones are formed in the womb, but in patients with FOP, the gene keeps working.
Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during apoptosis (self-regulated cell death), resulting in lymphocytes containing excess bone morphogenetic protein 4 (BMP4) provided during the immune system response.
Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes. BMP4 is a product that contributes to the development of the skeleton in the normal embryo.
Because the disease is so rare, the symptoms are often misdiagnosed as cancer. This leads doctors to order biopsies, which can actually exacerbate the growth of these lumps.
Synopsis
A loosely textured fibroblastic proliferation superficially resembling nodular fasciitis is apparent.
Spindled to stellate-shaped cells are deposited in a myxoid matrix and associated with dense collagen.
The proliferation is seen interdigitating between skeletal muscle fibers.
Differential diagnosis
childhood dermatomyositis with calcinosis (8106047)
myositis ossificans (1289774)
Links
See also
inherited ossifying diseases (15116703)
References
Fibrodysplasia ossificans progressiva: diagnosis and surgical management. Trigui M, Ayadi K, Zribi M, Triki Z, Keskes H. Acta Orthop Belg. 2011 Apr;77(2):139-44. PMID: 21667723
Inherited ossifying diseases. Job-Deslandre C. Joint Bone Spine. 2004 Mar;71(2):98-101. PMID: 15116703
Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva. Gannon FH, Kaplan FS, Olmsted E, Finkel GC, Zasloff MA, Shore E. Hum Pathol. 1997 Mar;28(3):339-43. PMID: 9042799
Differential diagnosis between fibrodysplasia ossificans progressiva and childhood dermatomyositis with calcinosis. Wu T, Chen SS. J Formos Med Assoc. 1993 Jun;92(6):569-76. PMID: 8106047
Myositis ossificans in childhood. Clapton WK, James CL, Morris LL, Davey RB, Peacock MJ, Byard RW. Pathology. 1992 Oct;24(4):311-4. PMID: 1289774
Fibrodysplasia ossificans progressiva. An 11-year-old boy treated with a diphosphonate. Bruni L, Giammaria P, Tozzi MC, Camparcola D, Scopinaro F, Imperato C. Acta Paediatr Scand. 1990 Oct;79(10):994-8. PMID: 2124774
Fracture in progressive ossifying fibrodysplasia. A case report. Nerubay J, Horoszowski H, Goodman RM. Acta Orthop Scand. 1987 Jun;58(3):289-91. PMID: 3630666
[Permanent constriction of the jaws due to progressive ossifying myositis] Seguin P, Delmas P, Bouvier R, Freidel M. Rev Stomatol Chir Maxillofac. 1987;88(3):190-5. French. PMID: 3112926
Fibrodysplasia ossificans progressiva: a distinctive bone-forming lesion of the soft tissue. Cramer SF, Ruehl A, Mandel MA. Cancer. 1981 Aug 15;48(4):1016-21. PMID: 6944142
[Apropos of myositis ossificans (progressive ossifying fibrodysplasia)] Sacrez R, Lévy M, Gigonnet JM, Langs A, Lahlou B, Walter JP, Stoerr E, Godar G. Pediatrie. 1969 Apr-May;24(3):313-23. French. PMID: 5795413
