Congenital family – a hereditary disease with different types of inheritance and a clinical current which is characterized by violation of processes of an ossifikation of bones with their consolidation and a number of the accompanying violations. Symptoms of this state are fragility of a bone tissue (easy development of traumatic and pathological changes), displays of heavy anemia with gepato-and the splenomegaliya, in some cases notes neurologic violations because of a travmatization of the nerves passing through bone channels. Diagnostics of a congenital family osteopetroz is based on data of radiological researches, studying of the hereditary anamnesis of the patient, molecular and genetic and general clinical analyses. Specific treatment of this state does not exist, it is in certain cases considerable transplantation of marrow can improve a condition of the patient.
Congenital family (a marble disease, Albers-Schoenberg's syndrome) – group of genetic disorders with similar clinical manifestations, consisting in consolidation of a bone tissue with reduction of diameter of marrowy and other channels. One of forms of this disease was for the first time described in the 1904th year by the German surgeon Mr. Albers-Schoenberg, since then the most widespread (autosomno-prepotent) type of a congenital family osteopetroz bears his name. This state with an identical frequency strikes both men, and women, occurrence depends on a kind of pathology. So, the heaviest on the clinical manifestations an autosomno-recessive form of a congenital family osteopetroz has the frequency 1:200 000-300 000 whereas disease types with autosomno-prepotent inheritance occur at the 1st person on 20 000 population. Other name of pathology (marble disease) is caused by a radiological picture at it (the granularity of a bone tissue reminding marble and caused by the centers of an osteopetroz), and also the increased fragility, but in too time the hardness of bones. Congenital family is one of the most studied genetic diseases which are followed giperostozy.
Reasons of a congenital family osteopetroz
Violation of functional activity of osteoklast – the cages which are responsible for destruction of elements of a bone tissue is an immediate cause of all forms of a congenital family osteopetroz. As a result of it the balance between education and destruction of bones is broken that is followed by increase in density of compact substance, reduction of a gleam of marrowy channels and other openings in bones, change of a form of metafiz. Despite an osteosclerosis, skeleton elements at a congenital family osteopetroz have the increased fragility that leads to frequent traumatic and pathological fractures, scolioses and other forms of deformation of a backbone. The genetic and molecular nature of violation of work of osteoklast is not identical at various forms of a disease.
The most often found autosomno-prepotent form of a congenital family osteopetroz (Albers-Schoenberg's syndrome) is caused by a mutation of a gene of CLCN7 located on the 16th chromosome. It codes the sequences of one of subjedinitsa chlorine - a specific ion channel which is especially extended to surfaces of membranes of osteoklast. He participates in process of formation of hydrochloric acid which is necessary for dissolution of the salts of calcium which are a part of a bone tissue. As a result of defect of a gene of CLCN7 the structure of an ion channel changes and leads to violation of its function therefore release of hydrochloric acid strongly decreases, as is the reason of a congenital family osteopetroz.
Congenital family with autosomno-recessive type of inheritance represents more genetically a heterogeneous state, it can be caused by mutations of several genes. The classical type of this pathology, according to modern genetics, is caused by defect of a gene of TCIRG1 localized on the 11th chromosome. A product of its expression is the protein under the name of "The T-cellular immune regulator", and it represents one of subjedinitsa of the transmembrane protein a vacuole of osteoklast showing ATP-dependent properties of the proton pump. Along with a number of chloric channels, he participates in formation of hydrochloric acid which, as well as at autosomno-prepotent option of a congenital family osteopetroz is necessary for destruction of a bone tissue and functioning of osteoklast. Mutations of a gene of TCIRG1 cause about a half of all cases of this form of a disease.
Other genetic defects lead to development of a congenital family osteopetroz with autosomno-recessive type of inheritance much less often. So, approximately at 10% of such patients mutations of a gene of CLCN7 associated with a prepotent form of pathology – but at the same time the nature of genetic defect which was more expressed come to light and leads to the termination of an expression of proteins chlorine - a specific ion channel. Even more rare type of a congenital family osteopetroz is caused by a mutation of a gene of OSTM1 located on the 6th chromosome – it codes the protein of the same name participating in intracellular information transfer in osteoklasta. As a result of this genetic defect practically all functions of these cages, even are broken at the kept ability to synthesize hydrochloric acid. According to some information, there is a kind of a congenital family osteopetroz which is transferred on the mechanism linked to a floor – doctors geneticists connect it with IBKG gene mutations.
Symptoms of a congenital family osteopetroz
Expressiveness of symptoms of a congenital family osteopetroz and weight of its current is in strong dependence on a form of this disease. Autosomno-recessive types of this pathology which are shown at once at the birth, and in certain cases and vnutriutrobno at the final stages of incubation of the child possess the earliest and obvious manifestations. The leading manifestation at this stage of development of a congenital family osteopetroz is the hardest anemia caused by deficiency of red marrow because of narrowing of marrowy channels. It leads to numerous secondary violations – gepato-and the splenomegaliya having the progressing character, pallor of integuments, signs of oxygen starvation of fabrics. Quite often at the babies suffering from a congenital family osteopetroz define hydrocephaly, further many patients lose hearing and sight because of narrowing of openings of a skull through which there pass the corresponding nerves. The face of such patients has characteristics – widely placed eyes, the pressed nose bridge, full and disproportional lips. Numerous violations at an autosomno-recessive form of a congenital family osteopetroz tend to progressing that quite often leads to the death of patients before achievement of 3-8 years by them.
Unlike a malignant current of the above described form of a disease, congenital family with autosomno-prepotent type of inheritance quite often is also called good-quality for the reason much more weakly than the expressed manifestations. Most often the first symptoms of pathology come to light not earlier than 15-18 years, but with age they can amplify and progress. As the leading symptoms at the same time the increased frequency of changes caused by fragility of bones because of an osteopetroz acts. Also anemia is quite often diagnosed, but it has the moderate character, neurologic violations caused by injury of nerves to bone channels are rather rare. On the basis of clinical data it was succeeded to reveal two kinds of a congenital family osteopetroz with autosomno-prepotent type of inheritance – the first type most strongly affects skull arch bones whereas the second is characterized by primary involvement of a backbone and pelvic bones. According to medical statistics, almost at a half of patients with prepotent option of a congenital family osteopetroz the asymptomatic current is noted, existence of pathology is revealed incidentally at radiological or genetic researches.
Diagnostics and treatment of a congenital family osteopetroz
Apply radiological techniques, the general blood tests, molecular and genetic researches, studying of the hereditary anamnesis of the patient to diagnostics of a congenital family osteopetroz. On roentgenograms reveal the general consolidation of a bone tissue (a diffusion osteosclerosis) which expressiveness is more at autosomno-recessive options of a disease. In some elements of a skeleton (phalanxes of fingers, podvzdoshny bones, vertebras) has focal character, creating the characteristic radiological picture known as "a bone in a bone". In long tubular bones the form of metafiz and the sizes of the marrowy channel – from insignificant reduction changes at good-quality type of a congenital family osteopetroz before almost total disappearance at recessive. On roentgenograms symptoms of hydrocephaly, a backbone curvature can also come to light, adults have traces of the numerous begun to live changes.
In blood tests sharp decrease in level of erythrocytes and hemoglobin is defined, indicators concerning other cellular elements quite often decrease. At children with a recessive form of a congenital family osteopetroz it can have zhizneugrozhayushchy character whereas at adults (an autosomno-prepotent form) anemia is expressed poorly or it is not found at all. Molecular and genetic researches most often come down to a direct sekvenirovaniye of a gene of TCIRG1 which mutations lead to malignant type of this disease. Are the cause for such analysis, besides a characteristic clinical picture, presence of similar manifestations at relatives of parents of the patient – it can indicate the autosomno-recessive nature of transfer of a disease.
Specific treatment of autosomno-recessive forms of a congenital family osteopetroz (as well as prepotent) is not developed – some researchers as that point to transplantation of marrow. As some osteoklasta are option of fabric macrophages (that is, have a marrowy origin) such method of treatment is capable to improve a condition of the patient due to "replacement" of own cages with donor osteoklasta without genetic defects. Really, in some cases transplantation of marrow led a congenital family osteopetroz to improvement, but was not recorded examples of an absolute recovery. Other therapeutic actions have the supporting and symptomatic character – application of antianemichesky means (medicines of iron, erythropoietins), vitamin D, physiotherapy exercises and gymnastics. At an autosomno-prepotent form of a congenital family osteopetroz noticeable improvement is observed at sanatorium treatment.
Forecast and prevention of a congenital family osteopetroz
The forecast of the congenital family osteopetroz caused by autosomno-recessive mutations of genes of TCIRG1, CLCN7 and OSTM1, extremely adverse – without transplantation of marrow a lethal outcome comes in the childhood because of anemia, neurologic violations and various infections. If transplantation nevertheless was carried out, further everything depends on survival of donor cages and extent of violations in the patient's organism. More good-quality prepotent options of a congenital family osteopetroz have more favorable forecast for life, but the potential threat is made by pathological changes. Therefore patients should avoid high-traumatic productions, occupations active sports, to be examined regularly by the orthopedist and the hematologist regarding complications and progressing of symptoms of a disease.