Fibrodysplasia ossificans progressiva 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 limits 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.

Variants (also known as mutations) in the ACVR1 gene cause fibrodysplasia ossificans progressiva. This gene provides instructions for making 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.

Studies show that variants in the ACVR1 gene disrupt mechanisms that control the receptor's activity. As a result, the receptor is turned on when it normally should not be. Too much receptor activity causes overgrowth of bone and cartilage, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva.

Normal Function

The ACVR1 gene provides instructions for making the activin receptor type-1 (ACVR1) protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors. BMP receptors span the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This arrangement allows receptors to receive signals from outside the cell and transmit them inside to affect cell development and function.

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). This process occurs in normal skeletal maturation from birth to young adulthood.

The ACVR1 protein is normally turned on (activated) at appropriate times by molecules called ligands. Activation may occur when these ligands, such as BMPs or a protein called activin A, attach (bind) to the receptor or to other proteins with which it forms a complex. Another protein called FKBP12 can turn off (inhibit) ACVR1 by binding to the receptor and preventing inappropriate (leaky) activation in the absence of ligands.

Health Conditions Related to Genetic Changes

Fibrodysplasia ossificans progressiva

Variants (also known as mutations) in the ACVR1 gene cause fibrodysplasia ossificans progressiva, a disorder in which muscles and connective tissue such as tendons and ligaments are gradually replaced by bone (ossified). The formation of bone tissue outside the skeleton freezes joints and limits movement in affected individuals. The most common variant, which occurs in all individuals with the classic features of the condition, substitutes the protein building block (amino acid) histidine for the amino acid arginine at position 206 of the ACVR1 protein (written as Arg206His or R206H). Other variants in the ACVR1 gene cause rarer forms of the condition that can be more severe and often involve skeletal abnormalities, such as multiple abnormally formed fingers and toes. The variants that cause fibrodysplasia ossificans progressiva occur as a random (de novo) event during the formation of reproductive cells (eggs or sperm) in an affected person's parent or in early embryonic development. The genetic change is found in all of the affected person's cells.

Studies show that the R206H variant changes the shape of the ACVR1 protein. This shape change disrupts the binding of the inhibitor protein FKBP12. As a result, the receptor is constantly turned on (constitutively activated), even in the absence of ligands. Other ACVR1 gene variants result in a receptor protein that is turned on by ligands more easily than the normal version of the protein. Too much receptor activity causes overgrowth of bone and cartilage, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva. Although the same ACVR1 gene variants that cause fibrodysplasia ossificans progressiva are associated with a rare brain cancer (described below), people with fibrodysplasia ossificans progressiva do not have an increased risk of developing cancer.

Other disorders

Variants in the ACVR1 gene contribute to the development of a rare brain cancer in children called diffuse intrinsic pontine glioma (DIPG). Most people with DIPG have a particular genetic change in another gene, but a second variant in a different gene (such as ACVR1) is required for a tumor to develop. ACVR1 variants are found in around 25 percent of children with DIPG.

Most of the ACVR1 gene variants involved in DIPG are the same as those that cause fibrodysplasia ossificans progressiva (described above). However, in DIPG, the variant occurs during a person’s lifetime and is found only in cells that become cancerous. (This type of genetic change is called a somatic variant.) As in fibrodysplasia ossificans progressiva, the ACVR1 variant increases the activity of the ACVR1 receptor. In combination with other cellular changes, abnormal ACVR1 receptor activity can make cells grow and divide uncontrollably, leading to cancer.

Other Names for This Gene

• activin A receptor type I
• activin A receptor, type I
• activin A receptor, type II-like kinase 2
• activin A type I receptor
• activin A type I receptor precursor
• ActR-IA protein, human
• ACTRI
• ACVR1_HUMAN
• ACVR1A
• ACVRLK2
• ALK2
• hydroxyalkyl-protein kinase
• SKR1

Genomic Location

There is currently no definitive treatment. However, a brief course of high-dose corticosteroids, such as Prednisone, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue swelling seen in the early stages of fibrodysplasia ossificans progressiva. Other medications, such as muscle relaxants, mast cell inhibitors, and aminobisphosphonates, if appropriate, should be closely monitored by a physician. Surgery to remove heterotopic and extra-skeletal bone is risky and can potentially cause painful new bone growth.

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