Fibrodysplasia ossificans progressiva is a severe genetic disease characterized by metabolic disorders in the tissues of muscles, tendons and ligaments, which leads to the formation of calcinates in them. Symptoms of this condition are seals in the soft tissues of the neck, back and extremities, muscle hypotension, further pronounced deformities of the spine, stiffness of movements up to the disability of patients. Diagnosis is made on the basis of the data of the patient’s current status, X-ray and molecular genetic studies. Specific treatment of pathology does not exist today, but there are encouraging results of experiments on cell cultures of patients with this disease.
Fibrodysplasia ossificans progressiva (FOP, paraossal heterotopic ossification) is a rare genetic disease in which the processes of pathological ossification of tendons, fascia, intermuscular septa and other structures consisting of fibrous connective tissue occur. For the first time this condition was mentioned by the French doctor Guy Petit back in 1692, but its most complete description and study was made in the 70s of the XX century by the American geneticist Victor Mccusick, who gave the name to this disease.
Fibrodysplasia ossificans progressiva is most often the result of spontaneous germinative mutations, however, family cases of this pathology have also been described, while it is characterized by an autosomal dominant transmission mechanism with 100% penetrance. The incidence is estimated at about 1:1 800 000-2 000 000, the disease is equally likely to affect both boys and girls. A characteristic feature of fibrodysplasia ossificans progressiva is the fact that any attempts at surgical treatment of this condition (elimination of foci of ossification or relief of movements in the joints) lead to an explosive growth of new heterotopic areas of bone tissue.
The etiology of fibrodysplasia ossificans progressiva is a violation of the regulation of bone formation processes. In the embryonic period, a number of receptors are responsible for the development of bones, the work of which leads to the formation of solid connective tissue in the corresponding areas of the body. With the development of this disease, there is a mutation of the ACVR1 gene located on chromosome 2.
The expression product of this gene is a specific protein – activin receptor type 1. It belongs to a broader group of BMP receptors, which have the ability to bind substances-bone growth factors and transmit appropriate signals inside cells. The most common cause of fibrodysplasia ossificans progressiva is missense mutations (for example, Arg206His) in exon 6 of the ACVR1 gene. As a result of this genetic disorder, a defective form of activin-type 1 receptor is formed, which begins to form not only in the embryonic period and in osteoblasts in an adult, but also in fibrous connective tissue cells.
The further pathogenesis of fibrodysplasia ossificans progressiva has not been sufficiently studied due to the rarity of this condition. However, most researchers are inclined to believe that the defective receptor becomes capable of reacting not only to compounds from the BMP group (bone morphogenetic protein – bone morphogenesis proteins), but also to other substances, in particular, inflammatory factors. The proof of this theory is the fact that the foci of heterotopic ossification most often occur at the site of soft tissue damage – bruises, cuts, insect bites. In addition, during histological examination of pathological seals, moderate lymphocytic infiltration is always observed in them, which indicates the inflammatory or immune nature of the process.
Mutations of the ACVR1 gene lead not only to abnormal bone morphogenesis in children and adults, they also often cause a number of congenital malformations of the musculoskeletal system. The most common manifestations of fibrodysplasia ossificans progressiva of this type are microdactyly, varus curvature of the big toe (clinodactyly). Of other, rarer bone anomalies, fusion of the bodies of the cervical vertebrae, dysplasia of the metaphyses, fusion of the rib-vertebral joints are noted. Due to a combination of bone dysplasia and weakness of the muscular corset of the back, patients often develop severe curvature of the spine, which leads to secondary neurological disorders.
At birth, fibrodysplasia ossificans progressiva can manifest itself only by disorders of the formation of the bones of the fingers and toes, no other changes are detected. The onset of the disease is sudden, can occur for no apparent reason at the age of several months to 3-5 years. Usually, the first symptoms of this pathology are seals in the muscle tissues of the neck, back and arms, the dimensions of which can range from 1 to 10 centimeters. On palpation, the foci are painful, the skin above them is either unchanged or (in rare cases) hyperemic. With fibrodysplasia ossificans progressiva, such seals may appear at the site of bruises, cuts and other soft tissue injuries.
The gait of patients with fibrodysplasia ossificans progressiva, as a rule, is characterized by stiffness, small steps. The face is amimic against the background of tense neck and back muscles. As the number and size of seals increase, the volume of movements in the joints gradually decreases, leading to almost complete immobilization at the terminal stages of the disease. Often there are neurological pains caused by compression of the roots of the spinal nerves, complaints of a violation of skin sensitivity may also be received. All these manifestations of fibrodysplasia ossificans progressiva are gradually increasing and becoming more pronounced.
Cases are described when foci at the initial stage of development spontaneously dissolve (including under the influence of certain medications), but subsequently seals invariably reappear. Within 2-3 weeks, ossification occurs, after which their spontaneous or therapeutic resolution becomes impossible. In adult patients with fibrodysplasia ossificans progressiva, dozens of such foci are detected, which can merge with each other, forming a picture of the “second skeleton”. This circumstance, along with numerous deformities of bones, leads to deep disability of patients and often provokes the development of numerous disorders on the part of internal organs with subsequent fatal outcome.
Diagnosis and treatment
Diagnosis of fibrodysplasia ossificans progressiva is carried out on the basis of patient examination data, X-ray 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 foci 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 restriction of joint mobility, pronounced curvature of the spine.
Compaction of soft tissues leads to the appearance of characteristic bumps on the skin and often severely disfigure the patient with fibrodysplasia ossificans progressiva. Sometimes, as an additional diagnostic method, biopsy and subsequent histological examination of the foci of compaction are resorted to, but many experts oppose 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, dysplasia of the metaphyses, shortening of the long tubular bones of the limbs. With the development of heterotopic ossification in tendons, fascia, intermuscular connective tissue septa, first single and then multiple shadows with bone density are revealed. In far-reaching cases of fibrodysplasia ossificans progressiva, shadows merge with each other and often make it difficult to visualize internal organs and other deeply located structures. Using the methods of modern genetics, it is possible to diagnose this condition by searching for mutations in the ACVR1 gene.
There is no specific treatment for fibrodysplasia ossificans progressiva, and palliative therapy is severely limited in its capabilities due to the childhood age of most patients and the specific reaction of the body. Numerous attempts to eliminate the foci of heterotopic ossification surgically ended unsuccessfully – after surgery, due to tissue damage, the growth of seals sharply increased. In the early stages of the disease, it is possible to slow down the development of pathological foci a little with the help of high doses of corticosteroid drugs and other means that inhibit inflammatory processes (NSAIDs, leukotriene inhibitors, mastocyte blockers).
In recent years, the first laboratory data on the specific treatment of fibrodysplasia ossificans progressiva have been obtained – with the help of 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 allow us to successfully treat patients suffering from this disease, or, at least, significantly improve their quality of life.
Prognosis and prevention
The prognosis of fibrodysplasia ossificans progressiva is extremely unfavorable – the manifestations of the disease are steadily increasing, ectopic foci of ossification become larger and merge with each other, spinal deformities practically deprive the patient of mobility. As a rule, death occurs in 25-40 years from respiratory disorders, pneumonia, and other disorders of the internal organs. Cases of the development of foci of ossification in the masticatory muscles are described, which led to the inability to open the mouth and required urgent measures to organize the patient’s nutrition. Supportive treatment for fibrodysplasia ossificans progressiva can theoretically slow down the development of pathology, but in practice its effectiveness is very different in different patients. No methods of prevention of this rare genetic disease have been developed to date.