Fibrodysplasia ossificans progressiva (FOP) is a very rare hereditary disorder characterized by progressive ossification of the skeleton. Even the smallest injuries trigger additional bone growth. There is not yet a causative treatment for this disease.
What is fibrodysplasia ossificans progressiva?
The term fibrodysplasia ossificans progressiva already indicates progressive bone growth. This occurs in spurts, and new bone can form from muscle or connective tissue even with the smallest trauma. The increasing ossification cannot be stopped. Only a slowing down of the bone growth is partly possible by medicinal treatment. Surgical interventions or infusions into the muscle should be avoided because they can initiate a new episode of ossification. The disease was first mentioned in 1692 by the French physician Guy Patin. In 1869, the physician Ernst Münchmeyer described the syndrome, which was subsequently also called Münchmeyer’s syndrome. Other names for fibrodysplasia ossificans progressiva (FOP) besides Münchmeyer syndrome include fibrodysplasia ossificans multiplex progressiva or myositis ossificans progressiva. FOP is genetically determined. Its incidence is 1 in 2 million. The extreme rarity of the disease results from the fact that it is an autosomal dominant mutation. A person affected by FOP usually has no offspring. Therefore, it is almost always new mutations. Currently, there are about 600 people worldwide known to have fibrodysplasia ossificans progressiva.
Causes
The cause of fibrodysplasia ossificans progressiva is a genetic defect in a gene on the long arm of chromosome 2. This gene encodes the so-called ACVR1 receptor. The ACVR1 receptor is responsible for normal skeletal development and growth of connective and supporting tissue. It is located mainly on the cells of transversely striated skeletal muscle and connective and cartilaginous tissue. The corresponding mutation can lead to permanent activation of the receptor. In the process, it constantly sends the signal for the formation of bone cells from muscle or connective tissue cells during growth processes in the course of normal growth and in the case of injuries. Normally, this signal is only switched on during skeleton formation during embryogenesis. However, the genetic defect prevents the signal from being turned off after fetal development. When it cannot be turned off, persistent ossification or ossification in spurts occurs. The mutation on this gene is inherited in an autosomal dominant manner. Thus, the offspring of an affected person would have a 50 percent chance of suffering from this disease. However, because people affected with FOP almost never have offspring, the observed cases are usually new mutations.
Symptoms, complaints, and signs
Fibrodysplasia ossificans progressiva is manifested after birth by twisting and shortening of the big toes. In 50 percent of cases, the thumbs are also shortened. The cervical vertebrae show malformations in more than 90 percent of cases. This leads to restricted mobility of the cervical spine already in the first years of life. In the further course of development, ossification takes place from top to bottom. After the cervical spine has solidified, the ossification process progresses to the extremities and the trunk. The disease progresses in relapses associated with inflammatory processes. Each relapse begins with swelling and heating of the corresponding part of the body. These swellings are very painful. Only after new bones are formed from muscle tissue in the affected area does the relapse end and the pain cease. Ossification also takes place with any minor injury to muscle tissue. Thus, falls, operations or injections into the muscle tissue are often triggers of a disease flare-up. However, the disease can progress both in relapses and continuously. Continuous bone growth can occur before and during puberty because increased body growth occurs during this time. Affected individuals are often wheelchair-bound after puberty because almost all joints are stiffened. Due to the limited mobility of the chest, respiratory problems may occur.There is a risk of life-threatening pneumonia.
Diagnosis
A tentative diagnosis of fibrodysplasia ossificans progressiva can be made as early as the typical shortening and twisting of the newborn’s big toes. A positive genetic test then confirms the diagnosis.
Complications
Fibrodysplasia ossificans progressiva results in significant complications in which the affected person’s body ossifies. This process occurs even with very mild and minor injuries, in which bone growth is directly stimulated. In most cases, the affected person suffers from the disease since birth, which presents itself through severely shortened thumbs. The cervical vertebrae are also affected by deformities. These finally solidify in the first years of life, with which the ossification of the body continues to progress into the lower region. In most cases, severe pain and swelling occur during the process of ossification. These disappear as soon as this is completed. The relapses are triggered mainly by minor injuries to the muscle tissue, so that the patient is extremely restricted in his movements and in his everyday life. Often, this results in respiratory problems and inflammation of the lungs. Unfortunately, it is not possible to treat fibrodysplasia ossificans progressiva causally. Treatment is mainly aimed at delaying the progression of the disease. Surgical removal is also not possible in this case. Life expectancy is significantly shortened by the disease and the quality of life is greatly reduced.
When should you go to the doctor?
If clearly recognizable abnormalities of the cervical spine or toes can be detected after the birth of the child, they should be discussed with a doctor. Stiffness of the joints or bones should be examined and treated immediately. If other abnormalities of the skeletal system are noted during the growth and development process of children, a physician should be consulted. If there are irregularities that appear in comparison to physical changes of peers, it is advisable to consult a physician. If parents or guardians can detect ossifications or twists in the child’s bone structure, these should be clarified by a doctor as soon as possible. Shortening of the fingers or thumb is considered unusual and should be referred to a physician. If swelling or bulging of the skin cannot be traced, a doctor should be consulted. If the changes in bone structure increase or spread to other parts of the body, a doctor’s visit is necessary. If the child complains of pain, shows behavioral abnormalities or loses zest for life, these are signs of serious complaints. If the child is aggressive for several days, refuses to eat several times or is unusually apathetic, a doctor should be consulted. If there are limitations of movement or problems with breathing, a visit to the doctor is necessary.
Treatment and therapy
Fibrodysplasia ossificans progressiva cannot be treated causally today. Only symptomatic treatments are possible. In this case, the course of the disease is not stopped but at least delayed by drug treatment. In drug therapy, the initial focus is on pain management during an attack. Anti-inflammatory drugs such as corticosteroids and non-steroidal anti-inflammatory drugs are used. Research is currently underway to develop a causative therapy using antibodies and signal transduction inhibitors against the ACVR1 receptor. However, this therapy is not yet ready for use. However, the additional bones must not be surgically removed because this would be followed by a new disease episode with much more ossification.
Outlook and prognosis
The prognosis of fibrodysplasia ossificans progressiva is negative. The progressive ossification of connective and supporting tissues means that the condition is continually worsening. In addition, there are only a few promising treatment approaches to date. According to current medical knowledge, the disease cannot be cured. Since fibrodysplasia ossificans progressiva occurs in episodes, research is trying to alleviate at least accompanying symptoms of inflammation. Drug research is intended to ensure that more can be done to counteract the progression of the disease in the future.Genetic research also plays a key role in this. Unfortunately, the disease is so rare that only about 700 cases are known worldwide. It is therefore unlikely that there will be sufficient research funding in the future. For those affected, the prospects of alleviating the consequences of the disease therefore remain poor. Above all, injuries of any kind must be prevented, since they lead to new bone formations. For affected children in particular, this means an enormous need for protection and a very restricted life. The increasing ossification, which progresses from top to bottom, also limits lung function at some point. By their mid-twenties, many sufferers are already in wheelchairs. Adults have an average life expectancy of 40 years. The more the chest ossifies, the harder it becomes to breathe. Eventually, sufferers can no longer be helped.
Prevention
Because fibrodysplasia ossificans progressiva is usually a new mutation, prevention is not possible. However, affected individuals should take every opportunity to delay the ossification process. This includes the absolute avoidance of injuries. Even bruises and overstretching or overuse of the muscles can trigger a disease flare-up. Injections into the muscle should be avoided. Surgery can be performed only in extreme emergencies. Cortisone treatment should be given for fresh injuries or relapses.
Aftercare
There are usually no special measures of aftercare available to the affected person with fibrodysplasia ossificans progressiva. Because this disease is genetic, the options for treatment are also severely limited, so that only purely symptomatic treatment can be given. If the patient wishes to have children, genetic counseling can also be performed to prevent the disease from being inherited by the descendants. The main focus is on early detection of fibrodysplasia ossificans progressiva. The treatment itself is carried out with the help of medication. The affected person should pay attention to a correct and regular intake of the medication and also follow the instructions of the doctor. In cases of doubt or ambiguity, a physician should always be contacted. Not infrequently, however, surgical interventions are necessary to alleviate the symptoms of fibrodysplasia ossificans progressiva. After such an operation, the patient should always rest and also take care of his body. In any case, it is necessary to refrain from exertion or from other stressful activities and occupations. Whether fibrodysplasia ossificans progressiva reduces the life expectancy of the affected person cannot be generally predicted.
Here’s what you can do yourself
In fibrodysplasia ossificans progressiva, there are usually no self-help options available to the affected person. In this case, the disease can also only be treated symptomatically, so causal therapy is not possible. Since the symptoms and complaints of this disease are further aggravated by injuries to the skeleton, these injuries must be prevented under all circumstances. For this reason, affected persons should take care during sports or activities. In most cases, further discomfort is treated with the help of medication and surgical interventions. If the affected person is dependent on painkillers, it is important not to take them over a long period of time. In the case of self-injections, care should be taken not to inject them directly into the muscle. Caution should also be exercised in the case of treatment with cortisone; accompanying visits to the doctor and regular intake are obligatory. Children should be taught about the consequences and limitations of fibrodysplasia ossificans progressiva to prevent any psychological problems that may arise. Meeting other sufferers can also have a positive effect on the child’s development.
