Fibrodysplasia ossificans progressiva (Paraosseous heterotopic ossification)

Fibrodysplasia ossificans progressiva (Paraosseous heterotopic ossification)

Diagnosis of progressive fibrodysplasia ossificans is carried out on the basis of patient examination, radiological and genetic studies. As a rule, the results of examination of patients depend on the age and severity of the disease. In children under 10-12 years of age, the main symptoms are areas of soft tissue compaction on the head, neck, and sometimes on the back. In older patients, foci of ossification can be located on any part of the body; there is often a sharp limitation of joint mobility and pronounced curvature of the spine.

Compactions of soft tissues lead to the appearance of characteristic bumps on the skin and often severely disfigure the patient with progressive fibrodysplasia ossificans. Sometimes, as an additional diagnostic method, they resort to a biopsy and subsequent histological examination of compaction foci, however, many experts are against this technique, since such an invasive procedure can provoke the development of a new focus of ossification.

X-ray examination in the early stages of the disease can detect congenital malformations of the musculoskeletal system - clinodactyly of the big toes, metaphyseal dysplasia, shortening of the long tubular bones of the extremities. As heterotopic ossification develops in the tendons, fascia, and intermuscular connective tissue septa, first single and then multiple shadows with bone density are revealed. In advanced cases of progressive fibrodysplasia ossificans, the shadows merge with each other and often make it difficult to visualize internal organs and other deeply located structures. Using modern genetics, it is possible to diagnose this condition by looking for mutations in the ACVR1 gene.

There is no specific treatment for progressive fibrodysplasia ossificans, and palliative therapy is sharply limited in its capabilities due to the childhood age of most patients and the specific reaction of the body. Numerous attempts to eliminate foci of heterotopic ossification surgically ended unsuccessfully - after the operation, due to tissue damage, the growth of compactions sharply increased. In the early stages of the disease, the development of pathological lesions can be slightly slowed down with the help of high doses of corticosteroid drugs and other drugs that inhibit inflammatory processes (NSAIDs, leukotriene inhibitors, mast cell blockers).

In recent years, the first laboratory data have been obtained regarding the specific treatment of fibrodysplasia ossificans progressiva - using special RNA, it was possible to inhibit the expression of the defective ACVR1 gene without affecting its healthy homologous copy in the stem cells of patients. Perhaps in the future this will make it possible to successfully treat patients suffering from this disease, or at least significantly improve their quality of life.

Progressive muscular dystrophies

Progressive muscular dystrophies (PMDs) are a heterogeneous group of inherited diseases characterized by progressive muscle weakness and skeletal muscle atrophy.

CLINICAL PICTURE

All PMD are characterized by muscle weakness of varying severity and muscle atrophy. The type of distribution of muscle weakness in PMD is one of the main diagnostic criteria. Each form of PMD is characterized by selective damage to certain muscles while sparing others nearby. In general, a typical myopathic symptom complex includes the following symptoms. • Symmetrical proximal muscle weakness of varying severity (muscle strength from 3-4 points in the early stages and up to 1-0 in the later stages of the disease), gradually developing muscle atrophy. • Govers' symptom: the patient, in order to rise from a squatting position, rests his hands on the floor, then rises, leaning his hands on his knees - “climbing on his own.” This early-onset symptom is caused by weakness of the muscles of the hips and pelvic girdle. • Difficulty walking up stairs - the patient helps himself with his hands. • “Duck” (waddling) gait associated with weakness of the pelvic girdle muscles. • Lumbar hyperlordosis, caused by weakness of the muscles of the pelvic girdle and back. • “Wing-shaped” scapula due to weakness of the serratus anterior muscle, as well as other muscles that fix the scapula. • Pseudohypertrophy of the calf muscles due to the development of connective tissue in them (muscle strength is reduced). • Walking on tiptoes due to Achilles tendon contractures. • Preservation of extraocular muscles, facial muscles. The myopathic symptom complex is most clearly identified in Duchenne and Becker PMD. • Duchenne PMD is characterized by an early onset of the disease (at 3-7 years), rapid progression, high CK levels, pronounced spontaneous activity according to needle EMG, and the absence of dystrophin in the muscles in immunohistochemical studies. As muscle weakness progresses, independent walking becomes difficult, and already at the age of 9-15, patients are forced to use a wheelchair, which provokes the development of kyphoscoliosis and osteoporosis. In the later stages, most patients develop dilated cardiomyopathy and weakness of the respiratory muscles. Intelligence is most often moderately reduced. • Clinical manifestations of Becker's PMD generally resemble those of the Duchenne form, but the course of the disease is milder: the onset occurs at a later age (from 2 to 21 years, on average 11 years), death occurs later (at 23-63 years ) . • Limb-girdle forms of PMD are also characterized by the development of a myopathic symptom complex. In terms of the age of onset of the disease, rate of progression and clinical manifestations, Erb's PMD resembles the Becker form, however, it is not characterized by cardiac pathology, in addition, the disease is noted in both boys and girls. In other limb-girdle forms, weakness of the facial muscles and cardiomyopathy are possible. • Landouzy-Dejerine PMD is characterized by severe weakness of the facial muscles (with the exception of a rare form without facial weakness), the symptom of “pterygoid” scapulae, weakness of the biceps and triceps brachii muscles with intact deltoid muscles, stepping. As a rule, the extraocular muscles (with the exception of one subtype) and the muscles of the tongue and pharynx, and the respiratory muscles remain intact. Some patients experience weakness of the pelvic girdle muscles (about 20% of patients are forced to use a wheelchair). Muscle atrophy is often asymmetrical. Many patients experience hearing loss, cardiomyopathy, or heart rhythm disturbances. • Emery-Dreyfus PMD is characterized by the presence of contractures (usually in the elbow, knee joints, and posterior neck muscles, due to which the head is slightly thrown back) and a scapulohumeral-peroneal distribution of muscle weakness and atrophy with preservation of the facial muscles. Cardiac arrhythmias and cardiomyopathy are common. The disease often debuts with contractures. • The main symptom of the ophthalmopharyngeal form is chronic progressive external ophthalmoplegia, followed by moderate bulbar syndrome. Subsequently, proximal muscle weakness develops in the arms and legs. • Distal myopathies are characterized by predominant weakness of the distal muscles. With Welander myopathy, the extensors of the hands are most affected; with Mioshi myopathy, the calf muscles are most affected: patients stand poorly on their toes and often stumble. With Govers' myopathy, tibial myopathy, the main symptom is stepping due to weakness of the peroneal muscle group, while Govers' myopathy is prone to further generalization: after 5-10 years, weakness of the hands and neck muscles is added, often about 1 toe and V on the arms . With tibial myopathy, which is common in Finland, isolated damage to the anterior tibial muscles is most often observed, and sometimes cardiomyopathy develops.

SYMPTOMS

With PMD Duchenne, Becker, limb-girdle forms, the most pronounced weakness is manifested in the lumbar-iliac muscles, muscles of the hips, deltoid, biceps and triceps muscles of the shoulder. Weakness in the distal muscles of the extremities is less pronounced. The facial muscles remain intact. Along with muscle weakness, hypotrophy of the affected muscles gradually develops, up to atrophy in the later stages. In this case, neighboring muscles can be completely clinically intact.

TREATMENT

Treatment should be carried out exclusively by a neurologist. Self-medication is unacceptable. There is currently no definitive treatment for PMD. The goal of treatment is to maintain muscle strength, prevent the development of contractures and joint deformities. Non-drug treatment Excessive physical activity, as well as insufficient physical activity, leads to an increase in muscle weakness. Daily exercise therapy helps maintain muscle tone and prevents the development of contractures. A physical therapy complex must include active and passive exercises, stretching exercises/contracture prevention exercises and breathing exercises. Active massage with muscle kneading can increase muscle weakness and fatigue, so a gentle massage is recommended. Patients tolerate physiotherapeutic treatment differently: some do not feel any improvement or even complain of increased muscle weakness. Surgical treatment In some cases, surgical treatment of contractures is possible, but it is necessary to remember the possibility of increasing muscle weakness during rehabilitation treatment (up to loss of the ability to walk). In some cases, implantation of a pacemaker is necessary.

Prospects for the treatment of fibrodysplasia were discussed at the 4th International Conference on FOP

One of these drugs is in the final, third phase of clinical trials. According to doctors, the creation of a drug to block the pathological mechanism of ossification will be a real revolution in the treatment of many rheumatic and other diseases, as it will help not only patients with FOP, but also tens of thousands of people with similar, but less severe musculoskeletal pathologies.

Experts reported this to doctors and journalists at the 4th International Conference on FOP , which was held in Moscow from July 30 to August 1, 2021, with the participation of leading international and Russian medical specialists in the field of diagnosis and treatment of FOP - rheumatologists, orthopedists , pediatricians, geneticists, as well as patients living with FOP and members of their families - a total of 30 families from regions of the Russian Federation came to Moscow. The conference was attended by 150 guests from different Russian cities, as well as other countries: Germany, USA, Japan, Belarus, Georgia, Kazakhstan, Ukraine, Moldova, Estonia.

Among the invited experts who made scientific presentations at the conference were Frederick Kaplan , considered the world's No. 1 expert in the study, diagnosis and treatment of FOP; Doctor of Medicine, Medical Director of the Department of Pediatrics at the Garmisch-Partenkirchen Clinic (Germany) Rolf Morhart ; Candidate of Medical Sciences, Head of the Pediatric Department of the Research Institute of Rheumatology named after. V.A. Nasonova RAMS Irina Nikishina ; Doctor of Medical Sciences, Professor of the State Budgetary Educational Institution of Higher Professional Education First Moscow State Medical University named after. THEM. Sechenova Natalya Golovanova and others.

The director of the Federal State Budgetary Institution “Medical Genetic Research Center of the Russian Academy of Medical Sciences”, the chief freelance specialist in medical genetics of the Ministry of Health of Russia, Sergei Kutsev, addressed the conference participants with a welcoming speech: “In Russia today, several programs have been adopted to support patients with rare diseases, in particular, the federal program “12 nosologies” “, within the framework of which the state covers all costs of treating patients with orphan diseases, there is also a program “24 nosologies”, funds for the implementation of which come from regional budgets. In mid-July, Speaker of the Federation Council of the Russian Federation Valentina Matvienko announced that from 2021, the purchase of drugs for the treatment of all orphan diseases will be fully financed from the federal budget. This will make expensive innovative therapies more accessible to all patients who need them.

Of course, systematic work is being carried out in terms of early diagnosis of orphan diseases. Currently, neonatal screening of orphan diseases in newborns in Russia is carried out for 5 nosologies, but in the coming years the program for identifying hereditary diseases will be improved and expanded to 30-40 nosologies, as experts insist.”

The goal of the conference organizers was to attract the attention of the scientific and medical community to the problem of heterotopic (extraskeletal) bone formation, exchange experience in the field of research and therapeutic approaches in the prevention and treatment of FOP and similar musculoskeletal pathologies, as well as talk about the prospects for innovative therapy and the possibilities of modern medicine .

Among rare (orphan) diseases, FOP is one of the most severe, leading to progressive disability. Symptoms of FOP appear most often in the first decade of life. Due to a genetic malfunction in the body, bone tissue (ossification) is formed where it should not be - inside muscles, tendons, ligaments and other connective tissue structures. The body is enveloped as if by a “second skeleton”; it becomes difficult for a person to breathe due to damage to the intercostal muscles and to chew solid food, as even the jaw muscles “turn to stone”. The patient becomes completely dependent on outside help.

“FOP is a catastrophic and so far incurable disease, but today we have great hope that in the next 1-2 years a drug will appear that will help stop the disease, and perhaps completely cure hundreds of patients with FOP who are so hoping to get out of captivity of one’s own bones, as one of my little patients from California said. The advances in science that have been achieved over the past 15 years of active research in the development of drugs to control FOP are impressive, and today we are closer than ever to creating a drug that will make the disease curable. The ACVR1 gene, “guilty” of the formation of extraskeletal ossification in FOP, was discovered in 2006, and since then active research in this direction has been carried out by the largest pharmaceutical laboratories in the USA, Japan and Europe. Currently, 13 pharmaceutical companies are developing a drug to treat FOP, but this disease is just the tip of the iceberg. Rheumatologists, cardiologists, surgeons, orthopedists, and other specialists around the world observe a huge number of patients who develop ectopic bone tissue (in atypical places). The discovery of the gene responsible for the development of FOP has stimulated scientists to work towards creating a drug to block the pathological mechanism of ossification, which will help hundreds of thousands of people with similar, but less severe musculoskeletal pathologies, accompanied by the growth of additional bone tissue,” said Frederick Kaplan.

We are talking about such nosologies as ankylosing spondylitis and other ankylosing spondylitis, myositis ossificans in injuries and burns, exostosis disease and others.

Currently, three innovative targeted drugs that control FOP are in different phases of clinical trials (CT), one of them is in the final, third phase of the CT. The preliminary results of the research are very encouraging for both doctors and their patients, Professor Kaplan said. Doctors hope to obtain a safe profile of the drug that can effectively treat children and adolescents, blocking the development of manifestations of FOP (formation of ossifications). Today, scientists know for sure that FOP is a pro-inflammatory disease, and this process can be blocked.

In Russia and the CIS countries, about 70 patients with a confirmed diagnosis of FOP are currently registered, half of these patients are children. However, according to experts, in reality there are more patients in Russia and the CIS countries. Unfortunately, while FOP remains one of the most poorly understood diseases, the problem is that doctors - neonatologists, pediatricians, rheumatologists, orthopedists - are not sufficiently informed about this disease. Children are often misdiagnosed (up to 90% of cases) and given the wrong treatment, which catastrophically aggravates the course of the disease. An outbreak of the disease can be triggered by the most minor injury, any surgical intervention, even a simple injection: at the site of injury - in muscles, tendons - bone tissue (ossification) begins to spontaneously form, as the body's response to a traumatic intervention, which should not normally occur. On average, it takes 7 years for consultations and examinations before doctors realize that a person has FOP.

Irina Nikishina, Candidate of Medical Sciences, Head of the Pediatric Department of the Research Institute of Rheumatology named after. V.A. Nasonova RAMS: “FOP is a doubly orphan disease, which, unfortunately, does not have a medical specialty that could fully treat and monitor patients, which is why a lot of troubles happen to them. FOP has many similarities with rheumatic diseases, although it is not one. Therefore, most often such patients are observed and managed by rheumatologists, including in the pediatric department of our institute. It is these specialists who, as a rule, make a diagnosis and provide patients with the greatest help, because they know how to treat them and how not to harm them.”

The incidence of FOP varies, according to various sources, from 1 case per 1.3 to 2 million people, that is, it affects from 3,500 to 5,500 people worldwide. Currently, approximately 700 patients with FOP have been diagnosed in different countries.

Michelle Davis , Executive Director of the International Patients Organization IFOPA: “In 2015, we began working on creating an international registry of patients with FOP, the only list currently that includes all information about patients from all over the world, from all countries, including Russia. It doesn’t matter how old you are, where you live, how advanced your disease is, whether you are participating in a clinical trial or not. If you have an official diagnosis of FOP, then you should be on this register. Information can be sent through our website, which has now been translated into Russian. According to experts, the IFOPA registry is the most reliable database of patients with FOP.”

Source: Mail.ru Group

How it works[edit]

The first signs of the disease usually occur right in childhood; it is not known what the catalyst is, but there is a guess that first of all it is tissue damage, such as a bruise, sprain or fracture. The disturbed body will violently replace damaged muscle tissue with cartilage, which will result in compaction.

Due to the rarity of the disease, it can easily be confused with oncology, therefore, dear friend, most likely the district physician will send you with the lump to an oncologist (and not for a genetic test), the latter, without one hundred percent determining the nature of the lump, will send you for the sake of being on the safe side for surgical removal of the seal. What the FOP is just waiting for is to return with renewed vigor, because... It is believed that regenerative processes are involved in the ossification process. After a series of removals/remissions/relapses, perhaps Eureka will hit one of the treating doctors in the head and he will prescribe a genetic examination for you. As a result, the diagnosis will be made with almost one hundred percent probability, followed by free pain medication and sending home. In advanced cases, they can send you, and not just, but to a boarding school. Then anything is possible, for example, the first patient with FOP had fused teeth and had to make a technological hole so that the client could eat. What is characteristic and surprising is that the internal organs are almost not subject to the process of ostification.

Doctor, what will happen to me?[edit]

Most likely, everything will be very bad and the patient will be immortalized in granite during his lifetime. There is only one medicine - the rebel gene blocker Palovarotene is already on its way and is undergoing the third phase of clinical trials. This treatment belongs to a class of drugs that selectively target pathways involved in cartilage formation while effectively restoring normal endoskeleton growth. Among other things, after taking Palovarotene, rodents with injuries do not experience increased bone tissue growth. Judging by data from open clinical studies, the drug can already be fed to children. In addition, this Country may even undergo tests. But hardly.

As a consolation, we can say - but you are definitely not like everyone else.

Five minutes of the corrupt girl of capitalism[edit]

It would seem that given the frequency of the disease, you can simply forget about those suffering, just think, six hundred people out of 7 billion. And that’s not what happens. But it is precisely in this and not only this disease that the full potential of genetic engineering as such is truly revealed, because if you understand the nature of these mutations, you can not only reverse the process, but also gain a huge opportunity for the medicine of the future, including the regeneration of lost limbs. But this is already from the field of nanotechnology.