Congenital familial osteopetrosis is a hereditary disease with different types of inheritance and clinical course, which is characterized by a violation of the processes of ossification of bones with their densification and a number of concomitant disorders. Symptoms of this condition are fragility of bone tissue (mild development of traumatic and pathological fractures), manifestations of severe anemia with hepatomegaly and splenomegaly, in some cases neurological disorders are noted due to traumatization of nerves passing through bone channels. The diagnosis of congenital familial osteopetrosis is based on the data of X-ray studies, the study of the patient’s hereditary history, molecular genetic and general clinical analyses. There is no specific treatment for this condition, in some cases, bone marrow transplantation can significantly improve the patient’s condition.
Congenital familial osteopetrosis (marble disease, Albers-Schoenberg syndrome) is a group of genetic disorders with similar clinical manifestations, consisting in compaction of bone tissue with a decrease in the diameter of bone marrow and other channels. One of the forms of this disease was first described in 1904 by the German surgeon G. Albers-Schoenberg, since then the most common (autosomal dominant) the type of congenital familial osteopetrosis bears his name. This condition affects both men and women with the same frequency, the occurrence depends on the type of pathology. Thus, the most severe autosomal recessive form of congenital familial osteopetrosis in its clinical manifestations has a frequency of 1:200,000-300,000, whereas types of disease with autosomal dominant inheritance occur in 1 person per 20,000 population. Another name for the pathology (marble disease) is due to the X-ray picture with it (granularity of bone tissue resembling marble and caused by foci of osteopetrosis), as well as increased fragility, but at the same time bone hardness. Congenital familial osteopetrosis is one of the most studied genetic diseases accompanied by hyperostosis.
The direct cause of all forms of congenital familial osteopetrosis is a violation of the functional activity of osteoclasts – cells responsible for the destruction of bone tissue elements. As a result, the balance between the formation and destruction of bones is disturbed, which is accompanied by an increase in the density of compact matter, a decrease in the lumen of bone marrow channels and other openings in the bones, a change in the shape of metaphyses. Despite osteosclerosis, skeletal elements in congenital familial osteopetrosis have increased fragility, which leads to frequent traumatic and pathological fractures, scoliosis and other forms of spinal deformity. The genetic and molecular nature of osteoclast dysfunction varies in different forms of the disease.
The most common autosomal dominant form of congenital familial osteopetrosis (Albers-Schoenberg syndrome) is caused by a mutation of the CLCN7 gene located on the 16th chromosome. It encodes sequences of one of the subunits of the chlorine-specific ion channel, which is especially common on the surface of osteoclast membranes. It participates in the formation of hydrochloric acid, which is necessary for the dissolution of calcium salts that make up bone tissue. As a result of a defect in the CLCN7 gene, the structure of the ion channel changes and leads to a violation of its function, as a result of which the release of hydrochloric acid is greatly reduced, which is the cause of congenital familial osteopetrosis.
Congenital familial osteopetrosis with an autosomal recessive type of inheritance is a more genetically heterogeneous condition, it can be caused by mutations of several genes. The classic type of this pathology, according to modern genetics, is due to a defect in the TCIRG1 gene localized on the 11th chromosome. The product of its expression is a protein called the “T-cell immune regulator”, and it is also one of the subunits of the transmembrane protein of osteoclast vacuoles, which exhibits the properties of an ATP-dependent proton pump. Along with a number of chlorine channels, it participates in the formation of hydrochloric acid, which, as with the autosomal dominant variant of congenital familial osteopetrosis, is necessary for the destruction of bone tissue and the functioning of osteoclasts. Mutations of the TCIRG1 gene cause about half of all cases of this form of the disease.
Other genetic defects are much less likely to lead to the development of congenital familial osteopetrosis with an autosomal recessive type of inheritance. Thus, approximately 10% of such patients have mutations of the CLCN7 gene associated with the dominant form of pathology – but the nature of the genetic defect is more pronounced and leads to the cessation of expression of chlorine-specific ion channel proteins. An even rarer type of congenital familial osteopetrosis is caused by a mutation of the OSTM1 gene located on the 6th chromosome – it encodes a protein of the same name involved in intracellular transmission of information in osteoclasts. As a result of this genetic defect, almost all functions of these cells are disrupted, even with the preserved ability to synthesize hydrochloric acid. According to some reports, there is a type of congenital familial osteopetrosis, which is transmitted by a sex–linked mechanism – geneticists associate it with mutations of the IBKG gene.
The severity of the symptoms of congenital familial osteopetrosis and the severity of its course is strongly dependent on the form of this disease. The earliest and most obvious manifestations are autosomal recessive types of this pathology, which manifest themselves immediately at birth, and in some cases intrauterine at the final stages of bearing a child. The leading manifestation at this stage of the development of congenital familial osteopetrosis is severe anemia caused by a deficiency of red bone marrow due to narrowing of the bone marrow channels. It leads to numerous secondary disorders – hepatomegaly and splenomegaly, which have a progressive character, pallor of the skin, signs of oxygen starvation of tissues. Often, infants suffering from congenital familial osteopetrosis are diagnosed with hydrocephalus, in the future many patients lose their hearing and vision due to narrowing of the skull openings through which the corresponding nerves pass. The face of such patients has characteristic features – widely spaced eyes, a depressed bridge of the nose, thick and disproportionate lips. Numerous disorders in the autosomal recessive form of congenital familial osteopetrosis tend to progress, which often leads to the death of patients before they reach 3-8 years.
In contrast to the malignant course of the above-described form of the disease, congenital familial osteopetrosis with an autosomal dominant type of inheritance is often also called benign due to much weaker manifestations. Most often, the first signs of pathology are detected no earlier than 15-18 years, but with age they can intensify and progress. The leading symptoms in this case are an increased frequency of fractures due to the fragility of bones due to osteopetrosis. Anemia is also often diagnosed, but it has a moderate character, neurological disorders caused by nerve damage in the bone channels are quite rare. Based on clinical data, it was possible to identify two types of congenital familial osteopetrosis with an autosomal dominant type of inheritance – the first type most severely affects the bones of the cranial vault, while the second is characterized by predominant involvement of the spine and pelvic bones. According to medical statistics, almost half of patients with the dominant variant of congenital familial osteopetrosis have an asymptomatic course, the presence of pathology is detected accidentally during X-ray or genetic studies.
Diagnosis and treatment
To diagnose congenital familial osteopetrosis, X-ray techniques, general blood tests, molecular genetic studies, and the study of the patient’s hereditary history are used. Radiographs reveal a general compaction of bone tissue (diffuse osteosclerosis), the severity of which is greater in autosomal recessive variants of the disease. In some elements of the skeleton (phalanges of the fingers, iliac bones, vertebrae), osteopetrosis has a focal character, creating a characteristic X-ray picture known as “bone in bone”. In long tubular bones, the shape of metaphyses and the size of the medullary canal change – from a slight decrease in the benign type of congenital familial osteopetrosis to almost complete disappearance in recessive. Radiographs can also show signs of hydrocephalus, curvature of the spine, in adults – traces of numerous healed fractures.
In blood tests, a sharp decrease in the level of erythrocytes and hemoglobin is determined, indicators relative to other cellular elements often decrease. In children with a recessive form of congenital familial osteopetrosis, this may be life-threatening, whereas in adults (autosomal dominant form) anemia is poorly expressed or not detected at all. Molecular genetic studies are most often reduced to direct sequencing of the TCIRG1 gene, mutations of which lead to a malignant type of this disease. The reason for such an analysis is, in addition to the characteristic clinical picture, the presence of such manifestations in relatives of the patient’s parents – this may indicate an autosomal recessive nature of the transmission of the disease.
Specific treatment of autosomal recessive forms of congenital familial osteopetrosis (as well as dominant ones) has not been developed – some researchers point to bone marrow transplantation as such. Since some osteoclasts are a variant of tissue macrophages (that is, they have a bone marrow origin), this method of treatment is able to improve the patient’s condition by “replacing” their own cells with donor osteoclasts without genetic defects. Indeed, in a number of cases of congenital familial osteopetrosis, bone marrow transplantation led to improvement, but no examples of complete recovery were recorded. The remaining therapeutic measures have a supportive and symptomatic character – the use of antianemic agents (iron preparations, erythropoietins), vitamin D, physical therapy and gymnastics. In the autosomal dominant form of congenital familial osteopetrosis, a noticeable improvement is observed with spa treatment.
Prognosis and prevention
The prognosis of congenital familial osteopetrosis caused by autosomal recessive mutations of the TCIRG1, CLCN7 and OSTM1 genes is extremely unfavorable – without bone marrow transplantation, death occurs in childhood due to anemia, neurological disorders and various infections. If the transplantation was still carried out, in the future everything depends on the survival rate of donor cells and the degree of disorders in the patient’s body. More benign dominant variants of congenital familial osteopetrosis have a more favorable prognosis for life, but pathological fractures are a potential threat. Therefore, patients should avoid highly traumatic industries, active sports, and be regularly examined by an orthopedist and hematologist for complications and progression of symptoms of the disease.