Fibrodysplasia ossificans progressiva | Stone Man Syndrome

Fibrodysplasia ossificans progressiva | Stone Man Syndrome

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare connective tissue disease. The disease is caused by a mutation of the body's repair mechanism, which causes fibrous tissue (including muscle, tendon, and ligament) to be ossified spontaneously or when damaged.

Fibrodysplasia ossificans progressiva (FOP) is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone (ossified), 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 that restricts expansion of the lungs.

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.

Causes

he 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 gradual replacement of cartilage 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 under certain conditions and disrupt mechanisms 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.

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.

Approximately 1 person out of 2 million is afflicted with FOP. The disease is characterized by congenital skeletal malformations and heterotopic ossification (HO; bone growth outside of skeletal tissue). It is considered the most catastrophic form of HO, with episodic flare-ups leading to cumulative immobility. FOP is an autosomal dominant condition, with a 50% chance of a child developing the disease if 1 parent is positive. There are no differences in prevalence rates across racial or ethnic groups and geographical regions. The severe disability associated with FOP often results in poor reproductive fitness. To date there are fewer than 10 multigenerational families afflicted worldwide. A curious aspect of this condition is that the majority of diagnosed cases are spontaneous mutations with no apparent hereditary link.

FOP is linked to a mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. The ACVR1 gene is found in many tissues, including bone, muscle, and cartilage. Under normal circumstances it provides instructions for producing BMP receptors and helps control bone and muscle growth. It is influential in the gradual replacement of cartilage with bone that occurs over the course of normal human development. It has been suggested that the mutation may change the shape of BMP receptors and disrupt mechanisms that control the receptors’ activity, essentially leaving receptors in a constant “on” state.

FOP is one of the rarest diseases in the world. Students in medical school generally do not learn about FOP, and because of that it is often misdiagnosed.

 Common misdiagnoses are juvenile fibromatosis, lymphedema, and soft tissue sarcomas. In one such case, a young child around 3 years old had her right arm amputated because doctors feared that the growth was a cancerous tumor. Children often undergo harmful tests and biopsies that result in swelling, inflammation, and flare-ups. There is some literature describing successful surgical removal of bony growths, but in the overwhelming majority of cases, surgery only exacerbates the condition. Children should exercise caution when playing in order to minimize typical childhood accidents that can result in even minor trauma to muscles or soft tissue. In essence, children shouldn’t behave like children.

Reference

1. Angier N. Bone, a masterpiece of elastic strength. NY Times. April 28, 2009:D1. http://www.nytimes.com/2009/04/28/science/28angi.html.
2. Fibrodysplasia ossificans progressive. Genetics Home Reference Web site. August 13, 2012. http://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva.
3. History of FOP. Ifopa Web site. 2009. http://www.ifopa.org/es/history-of-fop.html.
4. Hutchison C. Turned to bone: rare condition locks victims in second skeleton. ABC News Web site.February 17, 2010. http://abcnews.go.com/Health/Wellness/fibrodysplasia-ossificans-progressiva-rare-condition-tissue-turns-bone-second-skeleton/story?id=9853121#.UC5_86D7bbI.