Fibrodysplasia Ossificans Progressiva

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What is fibrodysplasia ossificans progressiva?

Fibrodysplasia ossificans progressiva (FOP) is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone (ossify), forming bone outside the skeleton (extra-skeletal or heterotopic bone) that constrains movement. This process generally becomes noticeable in early childhood, starting with the neck and shoulders and proceeding down the body and into the limbs.

Extra-skeletal bone formation causes progressive loss of mobility as the joints become affected. Inability to fully open the mouth may cause difficulty in speaking and eating. Over time, people with this disorder may experience malnutrition due to their eating problems. They may also have breathing difficulties as a result of extra bone formation around the rib cage.

Any trauma to the muscles of an individual with fibrodysplasia ossificans progressiva, such as a fall or invasive medical procedures, may trigger episodes of muscle swelling and inflammation (myositis) followed by more rapid ossification in the injured area. Flare-ups may also be caused by viral illnesses such as influenza.

People with fibrodysplasia ossificans progressiva are generally born with malformed big toes. This abnormality of the big toes is a characteristic feature that helps to distinguish this disorder from other bone and muscle problems. Affected individuals may also have short thumbs and other skeletal abnormalities.

How common is fibrodysplasia ossificans progressiva?

Fibrodysplasia ossificans progressiva is a very rare disorder, believed to occur in approximately 1 in 2 million people worldwide. Several hundred cases have been reported.

What genes are related to fibrodysplasia ossificans progressiva?

Mutations in the ACVR1 gene cause fibrodysplasia ossificans progressiva.

The ACVR1 gene provides instructions for producing a member of a protein family called bone morphogenetic protein (BMP) type I receptors. The ACVR1 protein is found in many tissues of the body including skeletal muscle and cartilage. It helps to control the growth and development of the bones and muscles, including the process of cartilage being gradually replaced by bone (ossification) that occurs in normal skeletal maturation from birth to young adulthood.

Researchers believe that a mutation in the ACVR1 gene may change the shape of the receptor and disrupt its ability to attach (bind) to other molecules that control the receptor's activity. As a result, the receptor may be constantly turned on (constitutive activation). Constitutive activation of the receptor causes overgrowth of bone and cartilage and fusion of joints, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva.

How do people inherit fibrodysplasia ossificans progressiva?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases of fibrodysplasia ossificans progressiva result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. In a few cases, an affected person has inherited the mutation from one affected parent.

Source: National Institutes of Health

New myositis ossificans genetics findings from University of Pennsylvania, Department of Orthopaedic Surgery published

"However, the definitive contribution of hematopoietic cells to the pathogenesis of ectopic skeletogenesis remains obscure. We employed both careful clinical observation and in vivo murine transplantation studies to more precisely determine the contribution of hematopoietic cells to ectopic skeletogenesis. We identified a patient with fibrodysplasia ossificans progressiva who had undergone bone marrow transplantation for the treatment of intercurrent aplastic anemia twenty-five years earlier and investigated whether the clinical course of the fibrodysplasia ossificans progressiva had been influenced by bone marrow replacement or immunosuppression, or both. In complementary studies, we transplanted hematopoietic stem cells from constitutively expressing LacZ transgenic mice to identify the contribution of hematopoietic cells to BMP4-induced heterotopic ossification, a histopathologic model of fibrodysplasia ossificans progressiva. We found that replacement of hematopoietic cells was not sufficient to prevent ectopic skeletogenesis in the patient with fibrodysplasia ossificans progressiva but pharmacologic suppression of the apparently normal donor immune system following transplantation in the new host modulated the activity of the fibrodysplasia ossificans progressiva and diminished the expression of skeletal ectopia. In complementary murine transplantation studies, we found that cells of hematopoietic origin contributed to the early inflammatory and late marrow-repopulating stages of BMP4-induced heterotopic ossification but were not represented in the fibroproliferative, chondrogenic, or osteogenic stages of heterotopic ossification. Interestingly, both recombinant human BMP4 induction in an animal model and the dysregulated BMP signaling pathway in a patient with fibrodysplasia ossificans progressiva were sufficient to recruit at least two populations of cells, one of hematopoietic origin and at least one of non-hematopoietic origin, that contribute to the formation of an ectopic skeleton. Taken together, these findings demonstrate that bone marrow transplantation did not cure fibrodysplasia ossificans progressiva in the patient in this study, most likely because the hematopoietic cell population is not the site, or at least not the dominant site, of the intrinsic dysregulation of the BMP signaling pathway in fibrodysplasia ossificans progressiva. However, following transplantation of bone marrow from a presumably normal donor, immunosuppression of the immune system appeared to ameliorate activation of ectopic skeletogenesis in a genetically susceptible host," wrote F.S. Kaplan and colleagues, University of Pennsylvania, Department of Orthopaedic Surgery.

The researchers concluded: "Thus, cells of hematopoietic origin may contribute to the formation of an ectopic skeleton, although they are not sufficient to initiate the process alone."

Kaplan and colleagues published their study in the Journal of Bone and Joint Surgery (Hematopoietic stem-cell contribution to ectopic skeletogenesis. Journal of Bone and Joint Surgery, 2007;89(2):347-57).

For additional information, contact F.S. Kaplan, University of Pennsylvania School of Medicine, University of Pennsylvania School of Medicine, Dept. of Orthopaedic Surgery, Philadelphia, PA 19104-6081 USA.

The publisher's contact information for the Journal of Bone and Joint Surgery is: Journal Bone Joint Surgery Inc., 20 Pickering St., Needham, MA 02192, USA.

Keywords: United States, Philadelphia, Myositis Ossificans Genetics, Bone Marrow, Dermatology, Dysplasia, Genetics, Hematology, Hematopoietic, Heterotopic Ossification, Myositis Ossificans, Orthopedics, Surgery.

This article was prepared by Hematology Week editors from staff and other reports. Copyright 2007, Hematology Week via NewsRx.com.