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Purpose: to analyze the structure of hereditary pathology and the results of genetic studies in children in a specialized clinic.Results.1045 children from 79 regions of the Russian Federation were examined and treated in the pediatric department of congenital and hereditary diseases in 2018. There were 25% of patients from Moscow and Moscow region and 75% from other territories. After examination all patients were divided into 2 large cohorts: patients with hereditary diseases diagnosed by clinical and laboratory data (737 children; 70%) and patients with undifferentiated pathological conditions with unclear genesis at the time of discharge from the hospital (308 children; 30%). In the cohort of hereditary diseases there were the most numerous (about 100 children in each) groups of patients with Ehlers–Danlos syndrome, imperfect osteogenesis and rare heterogeneous genetic syndromes. The groups of rickets- like diseases, chromosomal syndromes and Rett syndrome included 50-70 patients. Other groups were smaller. Half of the hospitalized patients required genetic analysis. The highest percentage of molecular genetically / cytogenetically confirmed diagnoses was found in the groups of chromosomal diseases, rare genetic syndromes of lysosomal and mitochondrial diseases, Rett syndrome, and aminoacidopathy. It is worth mentioning that a primary diagnosis was not established during a genetic study in 57 children (18%) children from the general cohort of patients with hereditary diseases, so the researchers used other methods of analysis or bioinformatic revision of the results.Conclusion: The authors found a large variety of genetic diseases in children requiring examination and treatment in a specialized hospital. 1/5 of the examined children require additional genetic testing or repeated bioinformatic interpretation of the data.

Objective. To analyze the influence of clinical and biochemical markers on the diagnostic algorithm for hypoxic syndrome in children with genetic diseases of connective tissue.Characteristics of children and methods. There were examined 60 children were examined: 50 children with Ehlers–Danlossyndrome and 10 children with Marfan syndrome.Results. Constant fatigue, fast fatigue, low tolerance to physical exercises, pale skin, muscle hypotonia and headache are the most frequent symptoms of a hypoxic state in children with connective tissue dysfunction. At the biochemical level, hypoxic syndrome was characterized by signs of oxidative stress. The authors noted an decrease in pO2 , an increase in pCO2 in the circulating blood, an increase in the activity of anaerobic glycolysis with accumulation of lactate and pyruvate, a decrease in the synthesis of macroergs (ATP, ADP, AMP) and the activity of the mitochondrial respiratory enzymes, the emersion of mitochondrial insufficiency in the form of ripped red fibers (RRF) in myocytes , conglomerates of lipids, calcium, glycogen. There was an increased content of peroxidation products in the blood, urine and saliva.Conclusion. Periodic use of antihypoxants, drugs with detoxifying and immunomodulatory effect is justified for the treatment of children.

IXa glycogenosis is the most common of the currently known 15 types of glycogenosis. The disease has X-linked recessive inheritance, is caused by mutations in the PHKA2 gene localized on the short arm of X chromosome in the Хр22.13 region. The main manifestations of the disease: stunted growth, increased liver size, episodes of hypoglycemia, fasting ketosis, increased blood levels of cholesterol, low-density lipoproteins, triglycerides, liver transaminases. In many cases, the course of the disease can be relatively mild, which complicates early diagnosis and the timely administration of therapy. Clinical observations of two children from unrelated families with the same homozygous c.884G> A mutation (р.Arg295His, or R295H) in the PHKA2 gene are presented. The similarities and differences in clinical symptoms are emphasized, and the features of patient management are presented.

The article is devoted to the rare disease of the lysosomal storage disease group – Fabry’s disease. The disease is associated with the sphingolipids dysmetabolism, is caused by the accumulation of the globotriosylceramide (Gb 3 ) and othersphingolipidsin the organism tissues and cells; it is characterized by the progression and severity of the course. The diagnostic results of 6 patient children aged from 5 to 17 years are analyzed; 2 boys and 4 girls from 3 families. The hereditary burden with a large number of the disease cases, 16 patients in 3 families including 6 children, comes under notice. All 6 children were diagnosed with Fabry’s disease based on the genealogical analysis as well as biochemical and molecular genetic examination. The activity of α-galactosidase A enzyme in the blood leukocytes was significantly decreased in two boys, insignificantly decreased in two sisters, and was normal in two girls. When performing the molecular genetic analysis, 3 mutations in exon 5 of GLA gene were identified. It has been established that the damages of cardiovascularsystem and nervoussystem, kidneys and visual organ, depression of the perspiratory gland function shall be considered as the first clinical signs of the disease in the children; it seems likely that the angiokeratoma appearance is characteristic only for boys. The presence of the non-specific symptoms and signs of the connective tissue dysplasia is noteworthy. The emphasis is made towards the importance of the early Fabry’s disease diagnosis, as it is essential for the timely (prior to appearance of the clinical symptoms and signs) beginning of the pathogenic treatment with the enzyme replacement drug.

The article is devoted to a rare pathology from a group of accumulation diseases with an autosomal recessive type of inheritance – mucolipidosis II and IIIA types. The disease is characterized by a greater phenotypic similarity to mucopolysaccharidosis. Objective: analysis of genophenotypic parameters in Russian patients with mucolipidosis II and IIIA types. The activity of lysosomal enzymes in plasma (β-glucuronidase, total hexosaminidase and N-acetyl-α-D-glucosaminidase) was measured using a standard technique using chromogenic and fluorogenic substrates. Genomic DNA of peripheral blood leukocytes was isolated using a set of reagents Preb 100 (DIAtomTM). Amplification of all exons of the GNPTAB gene was carried out by polymerase chain reaction (PCR) followed by direct non-radioactive sequencing by Sanger. 50 patients aged from 1.5 to 10 years were examined. The clinical symptoms of the disease included: a Hurler-like phenotype, growth retardation, skeletal, cardiac and vascular damage, and CNS. Mucolipidosis type II (I-cell disease) was characterized by a more severe course. The clinical diagnosis was confirmed by the results of laboratory methods of investigation: normal parameters of renal excretion of glycosiminoglycans (GAG), high (5-15 times higher than normal) activity of lysosomal hydrolases in blood plasma and detection of mutations in the GNPTAB gene. 35 probands are completely genotyped. In 8 patients only 8 mutant alleles were detected; 7 mutations were not detected. Six new mutations in exons 1 (p.I31N; p.Q36P), 10 (p.L398P), 11 (p.W446X) and 13 (p.S738X; c.2250delT) were found, including a frequent mutation for Russian patients P.S738X (21% alleles). The most common (31.4% alleles) in the Russian cohort of patients was a known small deletion c. 3503_3504delTC, leading to a reading frameshift. A clinical observation of a child with type 2 mucolipidosis (I-cell disease) with typical symptomatology of the disease caused by two nonsense mutations of the GNPTAB gene is presented: p.S738X / p.R375X. In conclusion, it is emphasized that the identification of mutations of the GNPTAB gene provides prediction of the severity of the disease course, an understanding of the mechanisms of its development that will contribute to the development of pathogenetic treatment methods, improving the quality of life of patients and effective medical and genetic counseling.

The paper deals with a rare monogenic connective tissue disease from a group of fibrillinopathies with autosomal dominant inheritance — Beals syndrome caused by a mutation in the FBN2 gene. Attention is drawn to the high phenotypic similarity of this disease and Marfan syndrome (FBN1 gene mutation), which is associated with the almost complete identity of two proteins: fibrillin 1 and fibrillin 2.The paper describes a clinical case of a child with Beals syndrome and the typical manifestations of the disease: asthenic constitution, arachnodactyly of the hands and feet, congenital contractures of the large and small joints, chest deformity, kyphoscoliosis, talpes, and crushed ears. The investigators made a differential diagnosis with other connective tissue diseases, such as Marfan syndrome, Stickler syndrome, Ehlers–Danlos syndrome, homocystenuria, and arthrogryposis. DNA diagnosis verified the Beals syndrome in the proband. Exon 28 in the FBN2 gene showed the previously undescribed missense mutation of c.3719G>A, resulting in the amino acid substitution of cysteine for tyrosine (p.Cys1240Tyr) in the structure of the protein fibrillin 2. A de novo mutation occurred. There is evidence for its pathogenicity in the development of the clinical symptoms of the disease. The problems of effective medical genetic counseling in this family are discussed.

In the regions polluted with industrial or agricultural toxicants, dysmetabolic nephropathy is detected in every 2 or 3 children and this rate increases with age. Exogenous intoxication is not the only cause of dysmetabolic nephropathy; of no less importance are endogenous toxicants, such as oxidative stress products, excess of usual metabolites or emergence of unusual products of abnormal metabolism. The toxicants are ascertained to be able to change the conformation of protein molecules to give rise to additional ligand loci ensuring the aggressive uptake of trace elements that fix changes in protein molecules, making them antigenically alien to the body. Low molecular weight proteins with their changed structure, which penetrate through the basement membrane, are unrecognized by the reabsorption systems of proximal tubules and excreted with urine, determining the appearance of the most steady and age-increasing sign of dysmetabolic nephropathy – microproteinuria or trace elementuria.

The rare hereditary diseases encountered in the practice of pediatricians, pediatric neurologists, and geneticists include Lesch—Nyhan syndrome associated with purine metabolic disorders caused by mutations in the HPRT1 gene encoding the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT deficiency gives rise to hyperuricemia, hyperuricemic nephropathy, and a CNS lesion reminiscent of dystonic or hyperkinetic infantile cerebral paralysis concurrent with a propensity to have autoaggressive behavior. The diagnosis is based on a range of history data, characteristic neurological symptoms, the detection of high blood and urine uric acid levels, and the identification of pathogenic mutagens in the HPRT1 gene. Early diagnosis contributes to timely therapy and assists in medical genetic counseling. The paper describes a clinical case of a boy with Lesch-Nyhan syndrome and elucidates the problems of diagnosis and treatment of this disease.

The paper gives the data available in the literature, which reflect the manifestations, diagnosis, and current treatments of the rare (orphan) inherited disease glycogen storage disease type II or Pomp disease in children, as well as its classification. The infant form is shown to be most severe, resulting in death from cardiovascular or pulmonary failure generally within the first year of a child’s life. Emphasis is laid on major difficulties in the differential and true diagnosis of this severe disease. Much attention is given to the new pathogenetic treatment — genetically engineered enzyme replacement drug Myozyme®. The authors describe their clinical case of a child with the juvenile form of glycogen storage disease type II (late-onset Pompe disease). Particular emphasis is laid on the clinical symptoms of the disease and its diagnostic methods, among which the morphological analysis of a muscle biopsy specimen by light and electron microscopies, and enzyme and DNA diagnoses are of most importance. The proband was found to have significant lysosomal glycogen accumulation in the muscle biopsy specimen, reduced lymphocyte acid α-1,4-glucosidase activity to 4,2 nM/mg/h (normal value, 13,0—53,6 nM/mg/h), described in the HGMD missense mutation database from 1000 G>A p.Gly334er of the GAA in homozygous state, which verified the diagnosis of Pompe disease.

То establish the diagnostic value of a change in the indicator coenzyme Qlo, its blood levels were tested in 15 children with mitochondrial diseases (Group 1). A comparison group consisted of 13 children with neurodegenerative diseases (Group 2). A control group included 29 healthy children of the same age. In Group 1 patients, the mean coenzyme Qlo level (0,56+0,06 mcmol/1) did not differ from that in the control group. However, these patients had a considerably lower coenzyme Q10/cholesterol ratio (0,10+0,01; /K0,001). The patients in the older age subgroup were found to have a significantly lower coenzyme Qlo level, which seems to reflect the progressive nature of the abnormality. There was a trend for the coenzyme Q10/cholesterol ratio to decline with age. Group 2 children had higher blood coenzyme Qlo levels (1,53+0,23; /K0,001) than Group 1 and an increased Q10/cholesterol ratio (0,31+0,04; /K0,001). It is advisable to continue the investigation to provide a rationale for using low coenzyme values as an additional criterion for the differential diagnosis of mitochondrial diseases.

The term phenylketonuria encompasses some genetically heterogeneous diseases from a group of hereditary amino acid metabolic disorders, the key biochemical sign of which is a steady increase in blood phenylalanine levels – hyperphenylalaninemia. Phenylketonuria is a most common disease of the above group; its rate in the Russian Federation is 1:7140 neonates. The rare causes of hyperphenylalaninemia include the cofactor (biopterin-deficient) forms associated with tetrahydrobiopterin deficiency, leading to the blocked metabolic pathways for converting phenylalanine to tyrosine and for synthesizing catecholamine and serotonin precursors (L-dopa and 5-hydroxytryptophan). The distinguishing feature of all cofactor forms of hyperphenylalaninemia is the inefficiency of an isolated low-protein diet. Cofactor therapy with sapropterin in combination with correction of neuromediatory disorders is used in the combination treatment of these patients. The paper presents a case history of a child with severe biopterin-deficient hyperphenylalaninemia resulting from a defect in the PTS gene. The clinical example illustrates difficulties associated with the diagnosis of cofactor hyperphenylalaninemia and with long individual dosage adjustments for medications.

The paper gives the data available in the literature, which reflect the manifestations, diagnosis, and treatments of the rare inherited disease Allgrove syndrome in children. Emphasis is placed on major difficulties in the differential and true diagnosis of this severe disease. The authors describe their clinical cases. Particular emphasis is laid on the clinical symptoms of the disease and on its diagnostic methods, among which the DNA diagnosis is of most importance. The probands were found to have mutations in the AAAS gene: in one case there was a mutation (c.856 C> T, p.Arg286Term) in homozygous state, which is described in the International Human Mutation Database (CM 10151); in other case there was a change in nucleotide sequence (c.709 delC), which is undescribed in the mutation and polymorphism databases and which leads to premature termination of the protein. It is shown that awareness of Allgrove syndrome among clinicians is low and the interdisciplinary approach is of importance.