McCune-Albright syndrome (MAS) is a rare genetic disorder which is caused by somatic mutations in the GNAS gene. Clinical symptoms of MAS include café-au-lait skin pigmentation, fibrous dysplasia, and autonomous endocrine hyperfunction. Somatic character of the gene defects determines wide variety of syndrome manifestations, from mild forms with minimum presentation to severe conditions with aggressive course. Potential multicomponent form of the MAS syndrome necessitates the dynamic monitoring, including regular screening for possible components of the disease. Therefore, additional methods specifying the diagnosis of MAS syndrome, especially of its suppressed forms, should facilitate selection of patient management strategy and monitoring rate and/or complete exclusion of the diagnosis. Molecular genetic verification of the diagnosis may be one of these methods.

Objective — the study was aimed at evaluating massive parallel sequencing (next generation sequencing, NGS) and real-time polymerase chain reaction using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR) in the diagnosis of somatic mutations R201C and R201H in the GNAS gene based on DNA obtained from the peripheral blood.

Material and methods. The study included patients diagnosed with and suspected for MAS syndrome. Molecular genetic testing of R201C and R201H mutations in the GNAS gene based on DNA extracted from peripheral blood leukocytes was carried out by Next generation sequencing (NGS) and real-time polymerase chain reaction methods using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR). Based on clinical data, patients were divided into groups depending on the severity of the disease and the number of MAS manifestations. The results were evaluated by comparing the rate of detected molecular genetic defects in the formed groups of patients.

Results. Molecular genetic study included 39 children with MAS syndrome and 6 children with suspected MAS. R201C and R201H mutations in GNAS gene were detected in 16 patients with severe to moderate MAS 16 (41%) 39. No mutations were detected in other MAS patients and patients with suspected MAS.

Conclusion. NGS and CAST-PCR methods can detect the presence of mutant alleles R201C and R201H of GNAS gene in DNA samples obtained from the blood in the case of severe to moderate MAS syndrome, but they cannot be recommended for MAS diagnosis based on the peripheral blood samples in children with mild signs of the syndrome or suspected diagnosis.

Objective — the research was aimed at studying clinical and molecular genetic characteristics of the most common subtypes of MODY (1—3) detected by NGS.

Material and methods. The study included 312 patients (162 boys and 150 girls) aged 3 months to 25 years with suspected MODY. Inclusion criteria were as follows: carbohydrate metabolism disorders of varying severity, negative titer of ICA, IA2, and GAD autoantibodies, preserved secretion of endogenous insulin. NGS technique was used for molecular genetic studies. Custom DNA Panel was used for the multiplex PCR and sequencing using the Ion Ampliseq technique. Custom Diabetes Panel included 28 genes (13 MODY candidates genes and other diabetes-associated genes). Non-synonymous mutations that were not previously described were rated as «probably pathogenic» if they had minor allele frequency of <0.1% and «pathogenic» when assessed against the ANNOVAR database.

Results. Mutations in MODY candidate genes were detected in 178 (57.1%) probands. Of these, 99 mutations in GCK99 gene were found in 129 (41.4%) probands and 77 relatives, 20 mutations in HNF1A gene were found in 19 (6.1%) probands and 14 relatives, 8 mutations in HNF4A gene — in 9 (2.9%) probands and 3 relatives. All detected mutations were heterozygous. MODY1 subtype was not previously described in the Russian Federation.

Conclusions. The Russian population is dominated by MODY2 subtype. Only MODY2 is characterized by typical clinical presentation. NGS is a highly effective method in the diagnosis of MODY.

Hypoparathyroidism is one of the major symptoms of type 1 autoimmune polyglandular syndrome. Currently, vitamin D preparations are the treatment of choice for hypoparathyroidism of any etiology. The treatment with these medications is quite effective to normalize and maintain calcium level. The world experience in application of the recombinant parathyroid hormone for the treatment of hypoparathyroidism is very limited and indications for its use are not determined. However, there are increasingly more publications reflecting the experience in treatment of patients with hypoparathyroidism with the parathyroid hormone.

Type 1 autoimmune polyglandular syndrome is characterized by multiform clinical manifestations and for this reason it is often difficult to achieve compensation using replacement therapy. Autoimmune enteropathy often develops, which leads to severe malabsorption of nutrients and drugs in the intestine and inefficient replacement therapy, which necessitates a special approach and additional recommendations for the treatment of these patients with combined pathology of several organs and systems. This article describes the first Russian experience in the use of teriparatide pump therapy in a female patients with hypoparathyroidism as a part of severe autoimmune polyglandular syndrome.

Until recently, in was believed that degradation of insulin is the main function of the kidneys in maintaining glucose homeostasis. The results of numerous studies showed that the kidneys are involved in filling the energy needs of the body due to the following three key processes: gluconeogenesis, uptake and reabsorption of glucose molecules. The characteristic feature of gluconeogenesis that occurs in the kidneys lies in the fact that it depends on the time elapsed since the last meal. Thus, gluconeogenesis that occurs in the cortical substance of the kidneys provides up to 90% of the glucose entering the blood in the post-absorptive period and up to 60% in the postprandial period. Glucose reabsorption from the glomerular filtrate occurs in the proximal convoluted tubules assisted by sodium-glucose cotransporters, sodium-glucose cotransporters 2 (SGLT2) being the most important of them. It is known that the cells of the proximal convoluted tubules of the kidneys in patients with type 2 diabetes mellitus (DM2) contain significantly more SGLT2 proteins compared to those of healthy individuals. The discovery of the important role of the kidneys in glucose homeostasis led to investigation of the new links in DM2 pathogenesis and the development of a promising approach to its treatment using SGLT2 inhibitors.

Screening using the Fracture Risk Assessment Tool (FRAX) is recommended in all postmenopausal woman and mеn over 50 (A1) in order to identify individuals with high probability of fractures. It is recommended to diagnose osteoporosis and start treatment in patients with fragility fracture of large bones of the skeleton and/or high individual probability of major fragility fractures (FRAX) and/or detected decrease in bone mineral density (BMD) up to –2.5 T-score as assessed by DXA in the femoral neck and/or lumbar vertebrae (A1). Patients with back pain, lifetime height loss of 4 cm or height loss of 2 cm since a previous medical examination, those who receive glucocorticoids, patients with long lasting decompensated type 2 diabetes mellitus, or those receiving insulin therapy, as well as patients who were previously diagnosed with fragility fractures at the other sites are advised to underwent standard lateral X-ray imaging of the spine (Th4—L5) in order to verify the presence of compression vertebral fractures (B1).

Dual-energy X-ray absorptiometry (DXA) is recommended for individuals whose 10-year probability of major osteoporotic fracture (FRAX) falls within the medium risk group (B1). It is recommended to include the trabecular bone score (TBS) the FRAX algorithm in order to improve the sensitivity of this method (B1).

Laboratory testing is recommended for the differential diagnosis with other causes of increased skeletal fragility in all patients with newly diagnosed osteoporosis and when previously prescribed antiosteoporostic treatment was ineffective (B1).

Bisphosphonates (BPs), antibodies to receptor activator of nuclear factor kappa-beta ligand (RANKL) (denosumab), or parathyroid hormone analogue (teriparatide) are equally recommended to prevent fragility fractures and increase BMD in patients with osteoporosis (A1). Denosumab is also recommended to prevent BMD loss and fractures in females receiving aromatase inhibitors therapy for breast cancer and males with prostate cancer receiving hormone-deprivation therapy and having no bone metastases (A1). Since teriparatide has the anabolic effect, it is recommended as the first line treatment in patients with severe osteoporosis having history of vertebral fractures, in the individuals with very high risk of fragility fractures, or in the cases when antiresorptive treatment was ineffective (B1). All medications for treatment of osteoporosis are recommended in combination with calcium and vitamin D supplements (A1).