"Surgical attempts to remove heterotopic bone presents the risk of provoking painful and explosive new bone growth in persons with FOP."
Persons affected by FOP experience an inability to fully open their mouth, potentially causing eating and speaking difficulties.
Fibrodysplasia ossificans progressiva (FOP) is a disorder where a person's muscle and connective tissues, such as ligaments and tendons, are slowly replaced by bone through a process referred to as, 'ossification,' forming bone outside of their skeleton, constraining their ability to move. The process of ossification usually becomes noticeable during early childhood, beginning with the person's shoulders and neck, proceeding down their body into their limbs. The formation of extra skeletal bone causes a progressive loss of mobility as the person's joints become affected.
Persons affected by FOP experience an inability to fully open their mouth, potentially causing eating and speaking difficulties. As time passes, they can also experience malnutrition due to problems with eating, as well as breathing difficulties due to the formation of extra bone around their rib cage which restricts the expansion capabilities of their lungs. Any form of trauma to the muscles of persons with FOP, such as invasive medical procedures or a fall, might trigger episodes of inflammation and swelling, referred to as, 'myositis,' that are followed by an increase in ossification in the area of the person's body that has been injured. Persons with FOP can also experience flare-ups due to viral illnesses such as the flu.
One of the signs associated with FOP is malformation of the person's big toes. The abnormality of the person's big toes is a characteristic feature that assists in distinguishing the disorder from other types of muscle and bone problems. Persons affected by FOP may also have short thumbs, or additional skeletal abnormalities.
Causes of FOP
FOP is fortunately an extremely rare form of disorder; it is believed to occur in around one out of every two-million people in the world. Mutations in the ACVR1 gene cause fibrodysplasia ossificans progressiva (FOP). The ACVR1 gene provides instructions for the production of a member of protein family called, 'bone morphogenetic protein type I (BMP),' receptor's. The ACVR1 protein is found in a number of tissues in a person's body, including cartilage and skeletal muscle. The protein assists in controlling the development and growth of a person's muscles and bones, including the gradual replacement of cartilage by bone or, 'ossification,' that happens in average skeletal maturation as a person ages from birth to young adulthood.
Medical researchers believe a mutation in the ACVR1 gene might change the shape of the receptor in certain conditions, disrupting mechanisms which control the activity of the receptor. Due to this process, the receptor itself might remain in a consistent, 'on,' state. Remaining in such a state causes overgrowth of the person's bone and cartilage, fusion of their joints, and results in the signs and symptoms of fibrodysplasia ossificans progressiva (FOP).
Symptoms of FOP
FOP many times starts in the person's shoulders and neck, progressing along their back, trunk, and limbs. Malformation of the person's toes, which present as short, bent, and at times curved inward, are always a characteristic of FOP and are observable at the time of the person's birth. The malformation of the person's toes cause few problems, although they do serve as an early sign of FOP before the onset of ossification. While FOP is congenital, meaning that it begins prior to the person's birth, the ossification process does not begin before they are born.
Most people who are affected by FOP learn they have the disorder before they reach the age of ten. Inflammation and sometimes painful swelling, commonly in their back and shoulder areas, and at times involving their head or scalp, are usually initial signs of FOP. The swelling associated with FOP eventually clears up, although it leaves behind a new mature bone formation.
Individuals with FOP experience various rates of new bone formation. Some people experience rapid bone progression, while others experience a more gradual progression of bone formation. The rate of progression is something that cannot be predicted, although there seems to be a pattern to the progression. People with the disorder can experience bone formation that occurs in their shoulders, neck, and upper back early in their life, and in their knees and hips during their teenage years or early adulthood, for example.
The malformation of the person's toes are a characteristic sign of FOP, and are many times the very first sign of the disorder. While the sign is significant, it may not be recognized due to the rarity of the disorder. A conclusive diagnosis of FOP cannot be made based upon the presence of toe malformation alone. A conclusive diagnosis of FOP depends on genetic testing and observation of additional symptoms the person is experiencing that are associated with the disorder. An X-ray will show additional bone, for example.
Swelling that has the appearance of tumors on the person's neck and back areas usually appear before they reach the age of ten. If the person has experienced a physical trauma, they might also present with additional bone in the affected area of their body. At first the areas that have been affected can be red and painful, potentially hot to the touch; common symptoms of inflammation. Parents of children with FOP have also noted that their children experience a fever in addition to these symptoms.
The fact that FOP is so rare finds a number of doctors incorrectly diagnosing children with the disorder. The process of diagnosing FOP can take months, or even years because of its rarity and unfamiliarity on the part of doctors. Explanations that families are commonly provided with include fibromatosis and cancer. A misdiagnosis or delays in achieving a diagnosis can cause harm to those affected by FOP, leading to inappropriate testing such as biopsies that may cause flare-ups and permanent immobility, as well as other treatments that are inappropriate such as chemotherapy.
Treatment of FOP
Unfortunately, medical science has not discovered a proven, effective treatment for FOP. Increased understanding of the underlying cause of FOP is leading to medication-based means for the treatment of the disorder. The unpredictable nature of FOP often makes it hard to assess any therapeutic intervention because the symptoms of the disorder come and go. Determining if any particular form of treatment has really been successful or not is made more difficult through the fact that it is hard to tell if the person's flare-up has simply run its course.
The flare-ups people with FOP experience are both unpredictable and sporadic; the rate at which the disease progresses in individuals is equally varied. A number of studies on the natural history of FOP have shown that attempts to predict the duration, occurrence, or severity of an FOP flare-up is impossible, although characteristic anatomic patterning is something that has been described.
A brief course of high-dose corticosteroids, started within twenty-four hours of a flare-up, might assist in the reduction of intense tissue edema and inflammation people with FOP experience during the early stages of the disease. The use of corticosteroids is something that should be restricted to very early treatment of flare-up symptoms affecting the person's jaw, major joints, or submandibular area. Corticosteroids are not something that should be used for treatment of flare-ups involving the person's neck, back, or trunk because of the long duration and recurring nature of the flare-ups, as well as the difficulties with assessing the true onset of the flare-ups.
The dose of corticosteroids a doctor administers to a person with FOP depends on the person's body weight. The dose is usually administered as a single dose over no more than a four day period of time. The potential danger associated with flare-ups and FOP in a person's submandibular region may find a doctor administering corticosteroids for a slightly longer period of time and tapering the dose for the duration of the flare-up until the acute swelling has subsided. The the corticosteroids are discontinued, a non-steroidal anti-inflammatory drug (NSAID), or cox-2 inhibitor combined with a leukotriene inhibitor, might be prescribed for symptoms of the flare-up. A doctor may use mast cell inhibitors and amino-bisphosphonates as well.
FOP flare-ups, particularly around the knees and hips, can be extremely painful and might require a course of narcotic analgesia in combination with the use of NSAID's, cox-2 inhibitors, and either oral or intravenous glucocorticoids. Other types of transient pain syndromes can be caused by neuropathies resulting from acute flare-ups, inflammation of osteochondromas, transient bursitis, muscle fatigue, or arthritis. People with FOP can experience metabolic changes to relatively healthy skeletal muscle, leading to muscle spasms and fiber shortening. Muscle relaxants such as cyclobenzaprine, lioresal, or metaxalone can help to decrease muscle spasm and help the person to maintain their levels of activity.
Surgical attempts to remove heterotopic bone presents the risk of provoking painful and explosive new bone growth in persons with FOP. Biopsies of FOP lesions are something that is never indicated because they can cause additional heterotopic ossification in the person being biopsied. Falls on the part of persons with FOP may lead to serious injury and flare-ups as well.
People with FOP have a self-perpetuating fall cycle.
Minor soft tissue trauma many times leads to severe exacerbations of the disorder, resulting in ossification and joint ankylosis. The resulting mobility restriction from joint ankylosis impairs the person's balancing abilities, causing instability resulting in more falls, with the potential for head injuries, concussions, loss of consciousness, back and neck injuries and more. Children with FOP should pursue less physically interactive play, it may be helpful. They should completely avoid high-risk circumstances, it can help them to avoid falls.
Palovarotene for Treatment of Fibrodysplasia Ossificans Progressiva
Clementia Pharmaceuticals, Inc. announced today (21 Nov., 2014) that the European Medicines Agency (EMA) has granted Orphan Medicinal Product Designation for palovarotene, the company's lead product candidate, for the treatment of fibrodysplasia ossificans progressiva (FOP). Palovarotene, an investigational retinoic acid receptor gamma agonist, is currently in a Phase 2 clinical trial in patients with FOP and was previously designated an orphan drug by the U.S. Food and Drug Administration. Clementia recently announced the launch of a 12-month, open-label extension study for patients with FOP who complete the 12-week, randomized, double-blind, placebo-controlled study of palovarotene.
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