What is fibrodysplasia ossificans progressiva?

Risk Factors

Most cases of FOP are sporadic and result from a new gene mutation. FOP is inherited as an autosomal dominant trait. Only a few multigenerational families exist, due to the low reproductive fitness. Though patterns are difficult to discern due to the rarity of the disease, FOP occurs more often in females than in males.

Etiology and Genetics

FOP is characterized by a progressive transformation of skeletal muscle and connective tissue into ectopic bone. This process of one tissue type being transformed into another is a clinical feature unique to FOP. It is similar to the formation of bone in the developing fetus and during the healing of a fracture. This normal process, called endochondral ossification, involves the formation of bone from a cartilage model. In FOP, this same process occurs in the wrong places and at the wrong time. Progenitor cells in connective tissue and skeletal muscle are transformed into endochondral bone to form a second skeleton. This process of heterotopic ossification occurs in similar anatomic and temporal patterns to that seen in the fetus, beginning in the head, neck, and shoulders and progressing caudally to the hips and distally through the limbs. It characteristically spares the face, eyes, heart, and tongue. Heterotopic ossification is also induced by tissue injury and inflammation.

The transformation process in FOP has been well characterized. A flareup begins with the appearance of a painful connective tissue swelling. T lymphocytes migrate into the skeletal muscle and cause cell destruction. B lymphocytes then proliferate around blood vessels and stimulate the formation of new vessels. The final stages include cartilage and endochondral bone formation. These stages are similar to embryonic skeletal development and early fracture healing, except for the involvement of inflammatory cells.

Bone morphogenetic proteins (BMPs) are a family of extracellular signaling proteins that regulate cell differentiation in a variety of tissues. BMPs act by binding specific receptors in the cell membrane of target cells, resulting in the activation of an intracellular signaling pathway. Activin receptor type I (ACVR1) is one type of BMP receptor found in many tissues of the body, including skeletal muscle and cartilage. Binding of BMPs to the ACVR1 receptor results in activation of the BMP signaling pathway and transcription of genes required for cartilage and bone cell differentiation.

FOP is caused by a mutation of the gene that encodes the ACVR1 receptor. The ACVR1 gene is located at chromosome band 2q23-q24. All patients with the classic features of FOP have the same R206H mutation in one copy of the gene. This mutation causes the substitution of histidine for arginine in a glycine/serine-rich domain of the receptor. Studies predict that this amino acid substitution leads to a change in the shape of the receptor that alters its sensitivity and function. FOP cells demonstrate constant activation of the ACVR1 receptor and dysregulated BMP signaling pathways, resulting in excessive cartilage and bone cell differentiation.

Symptoms

All patients with FOP are born with a characteristic malformation of the great toe. Heterotopic ossification begins in early childhood with an episode of painful soft tissue swelling, followed by metamorphosis into ectopic bone. These episodes, called flare-ups, occur intermittently throughout life, resulting in progressive fusion of the joints and spine in fixed positions and associated immobility.

Screening and Diagnosis

The clinical diagnosis of FOP is based on the presence of heterotopic ossification in characteristic anatomic patterns and the presence of the great toe malformation. Plain radiographs may also demonstrate the presence of extraskeletal bony lesions, and other minor bone malformations, including cervical spine abnormalities and tibial osteochondromas. The soft tissue swellings of FOP are often misdiagnosed as cancer; however, a biopsy is not necessary for diagnosis and will trigger a flare-up. Definitive testing for FOP is based on DNA testing of the ACVR1 gene for the specific R206H mutation.

Treatment and Therapy

At the present time, there is no medication or therapy that can stop the progressive formation of ectopic bone in FOP patients. Medical management is limited to symptomatic relief of painful flare-ups. Supportive care is important for the progressive disability resulting from spinal deformity and joint immobilization, restrictive cardiopulmonary function, recurrent pulmonary infections, hearing loss, and poor nutrition. Future therapy may involve medications that decrease ACVR1 receptor activation, in addition to the identification of affected children before the onset of heterotopic ossification.

Prevention and Outcomes

Unnecessary surgical procedures, injections, and dental procedures are contraindicated; falls and injuries should be prevented. Patients are wheelchair bound before age thirty. Progressive immobility of the chest wall leads to thoracic insufficiency syndrome and life-threatening pulmonary complications. The average life span is forty-five years.

Bibliography

Gorlin, R. J., M. M. Cohen, and R. C. M. Hennekam. Syndromes of the Head and Neck. 4th ed. New York: Oxford UP, 2001. Print.

Kaplan, F. S., E. M. Shore, and J. M. Connor. “Fibrodysplasia Ossificans Progressiva.” Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. Ed. P. M. Royce and B. U. Steinmann. 2d ed. New York: Wiley, 2002. Print.

Kaplan, F. S., M. Xu, D. L. Glaser, et al. “Early Diagnosis of Fibrodysplasia Ossificans Progressiva.” Pediatrics 121.5 (2008): e1295-1300.

Lowery, Jonathan W., and V. Rosen. “Allele-Specific Interference in FOP: Silencing the FOP Gene.” Gene Therapy 19 (2012): 701–02. Print.

Schwartz, Robert A. “Fibrodysplasia Ossificans.” Medscape. WebMD, 7 May 2014. Web. 23 July 2014.

Thakker, Rajesh V., John A. Eisman, Takashi Igarashi, and Michael P. White. Genetics of Bone Biology and Skeletal Disease. London: Academic, 2013. Print.