Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. Specifically, this disorder causes the body’s skeletal muscles and soft connective tissues to undergo a metamorphosis, essentially a transformation into bone, progressively locking joints in place and making movement difficult or impossible. Patients with FOP have malformed big toes that are present at birth (congenital). Other skeletal malformations may occur. The abnormal episodic development of bone at multiple soft tissue sites frequently leads to stiffness in affected areas, limited movement, and eventual ankylosis (fusion) of affected joints (neck, back, shoulders, elbows, hips knees, wrists, ankles, jaw – often in that order).

Episodic flare-ups (inflammatory soft tissue swellings) of FOP usually begin during early childhood and progress throughout life. Most cases of FOP occur as the result of a sporadic new mutation and the genetic mutation that results in this disorder has been identified. FOP is caused by the mutation of a gene (ACVR1) in the bone morphogenetic protein (BMP) pathway, which is important during the formation of the skeleton in the embryo and the repair of the skeleton following birth.

Signs & Symptoms

All individuals with classic FOP have malformations of the great toes and, in approximately 50% of patients, the thumbs. These changes in the skeleton are present at birth (congenital) and are the first clinical signs of this disorder. The most common skeletal malformation associated with FOP is a shortened great toe with a malformed distal first metatarsal and a missing or abnormal first phalanx and/or interphalangeal joint. Other malformations of the toes and fingers may include inward turning of the great toe toward the other toes (hallux valgus), abnormally short fingers and toes (microdactyly), and/or permanent fixation of the fifth finger in a bent position (clinodactyly). Other congenital signs of FOP include proximal medial tibial osteochondromas, malformation of the upper part of the spinal column (cervical vertebrae), and an abnormally short broad neck of the bone in the thigh that extends from the knee to the pelvis (femur).

Progressive bone formation in connective tissues (heterotopic ossification) usually occurs during early childhood, and progresses throughout life. The abnormal development of bone may occur spontaneously but often occurs following an episode of soft tissue injury or a viral illness. The first sign of heterotopic ossification is the appearance of firm tender swellings on certain parts of the body, especially the back, neck, and/or shoulders. These soft tissue swellings mature through a cartilage-to-bone (endochondral) pathway to form mature heterotopic bone. The ectopic bone growth usually involves tendons, ligaments, skeletal muscle tissue, and connective tissues such as fascia and aponeuroses. In many cases, pain and stiffness occurs in these areas. On some occasions, a low-grade fever may herald the development of these swellings. Although the swellings eventually regress, they usually harden into mature bone as they decrease in size.

In the affected areas, bone slowly replaces connective tissue. The neck, back, chest, arms, and legs are usually the first areas affected. The disease eventually affects the hips, ankles, wrists, elbows, shoulders, and/or jaw as well as the abdominal wall. In some affected individuals, the progression of bone development may be rapid; in others, the process may be gradual. Even among identical twins, the disease progression may vary greatly, reflecting different environment impacts such as traumatic episodes.

Chronic swelling in various parts of the body is a common physical characteristic of individuals with FOP. Swelling may occur coordinately with the abnormal bone formation that characterizes FOP, or it may occur when recently-formed bone presses on lymphatic vessels, obstructing the flow of tissue fluid. In addition, swelling may also be caused by a lack of pumping action within the hardened (ossified) muscle and can cause blood and tissue fluids to pool in a limb (e.g., arms and/or legs).

Abnormal development of bone eventually leads to stiffness and limited movement of affected joints. If the jaw is involved, affected individuals may have trouble eating and/or speaking. In addition, abnormal development of bone may lead to progressive deformity of the spine including side-to-side (scoliosis) and, in some cases, front-to-back curvature of the spine (kyphosis). As is the case for skeletal bone, the bone that develops in abnormal areas may fracture and then undergo fracture repair. As the disease progresses, individuals with FOP experience increasingly limited mobility that causes problems with balance, difficulty walking and/or sitting, and/or severely restricted movement.

FOP may eventually result in complete immobilization. Affected individuals may experience progressive pain and stiffness in affected areas, complete fusion of the spine, and/or pain in affected areas of the body caused by abnormal bony growths that compress the nerves in these areas (entrapment neuropathies). As mobility begins to deteriorate, affected individuals may exhibit an increased susceptibility to respiratory infection or right sided congestive heart failure. Hearing impairment is seen in approximately 50% of affected individuals. In some cases of more severe forms of variant FOP, individuals may exhibit hair loss or mild cognitive delay.

One in every two million people are diagnosed with Fibrodysplasia Ossificans Progressiva.The disease mostly begins in childhood, usually diagnosed before age ten.  Nearly 90% of the time the disease is misdiagnosed and mismanaged by physicians or other health care providers. However, there have been 800 confirmed cases in the world and 285 in the United States.67% undergo invasive procedures for diagnosis and treatment such as, an osteotomy, blood sample, or an MRI. Fibrodysplasia Ossificans Progressiva has not been shown to be linked with any specific gender, ethnicity or race.

FOP is caused by a mutation in the ACVR1 gene. This gene is involved in growth and development of bones. The mutation allows them to grow unchecked. The gene can be inherited from one parent, but in most cases of FOP, it’s a new mutation in a person with no family history of the disease.

There are no known effective treatments for FOP but clinical trials are underway. Certain types of drugs have been used to relieve pain and swelling associated with FOP during acute flare-ups (most notably corticosteroids) and non-steroidal anti-inflammatory medication between flare-ups.

Diagnosis

Misdiagnosis of FOP is common but can be avoided simply by examining the individual’s toes for the characteristic feature, short great toes. The diagnosis may be confirmed by a thorough clinical evaluation, characteristic physical findings, and sequencing of the ACVR1 gene.

Standard Therapies

Treatment

Biopsies should be avoided when FOP is suspected because these tests may result in rapid bone formation in those areas where tissue is removed. Intramuscular injections (e.g., immunizations) must be avoided, and dental therapy should preclude injections of local anesthetics and stretching of the jaw. In addition, individuals should avoid any situations, such as falls, that may cause blunt trauma, since trauma may cause abnormal bone development in most cases. Various viral illnesses including influenza and influenza-like illnesses may provoke flare-ups of the condition.

In affected individuals with an increased susceptibility to respiratory infections due to progressive mobility impairment, steps may be taken to prevent infection, such as preventative (prophylactic) antibiotic therapy.

There are no known effective treatments for FOP but clinical trials are underway. Certain types of drugs have been used to relieve pain and swelling associated with FOP during acute flare-ups (most notably corticosteroids) and non-steroidal anti-inflammatory medication between flare-ups.

Affected individuals may benefit from occupational therapy. Special shoes, braces, and other devices that assist in walking and weight-bearing have been used to help people with FOP. Affected individuals may have their physicians contact an occupational therapist who can help obtain special devices or tools to assist them in daily activities.

Genetic counseling may be of benefit for families with inheritance of FOP. A team approach for infants diagnosed with FOP will also be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.

Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients.

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