Marina Yu. Yukina

Background. Primary adrenal insufficiency (PAI) is an endocrine disorder caused by the gradual destruction of all three layers of the adrenal cortex and characterized by insufficient secretion of cortisol and aldosterone. This condition significantly reduces patients’ quality of life, making its timely diagnosis crucial. Autoimmune disorders are the etiological factor in approximately 80% of PAI cases, making the search for predictive markers in innate immune genes one of the most promising areas for predicting the odds of developing PAI. Aims — to study the associations between single nucleotide polymorphisms in the TLR2 and TLR9 genes and the development of PAI. Methods. The study included 222 individuals: 72 patients with PAI and 150 controls. For the study, DNA was isolated from venous blood and subsequently analyzed using real-time PCR with fluorescently labeled probes. Statistical analysis of the results was performed using Fisher’s exact test (Fi), the χ2 test, the χ2 test with Yates’ correction, calculation of the odds ratio and 95% confidence interval. Results. The study revealed that the A allele (p 0.001) and the heterozygous genotype (p 0.001) of the rs5743708 polymorphism in the TLR2 gene were associated with the risk of developing PAI. Conversely, the homozygous genotype GG (p 0.001) reduced the odds of the pathology development by 11-fold. Analysis of the rs352140 single nucleotide polymorphism in the TLR9 gene also demonstrated an association between the A allele (p = 0.030) and the homozygous AA genotype (p = 0.0171) with the odds of developing PAI. Conclusions. Based on the data obtained in this and our previous study, a scheme was proposed that includes four polymorphic markers to predict the odds of developing 1-HH.

Congenital Adrenal Hyperplasia (CAH) is a group of diseases with an autosomal recessive inheritance pattern, which are caused by a defect in the enzymes involved in steroidogenesis in the adrenal cortex. Depending on the enzyme block variant, the spectrum of clinical manifestations of CAH varies from mild symptoms to potentially fatal disorders. The review provides a detailed analysis of the six main forms of CAH (lipoid hyperplasia, HSD3B2, CYP17A1, CYP21A2, CYP11B1, POR) with an in-depth description of their molecular basis, pathogenesis, and clinical and laboratory manifestations. Particular attention is paid to modern methods of genetic diagnosis of CAH, including analysis of the highly homologous CYP21A2 locus, prenatal and preimplantation diagnosis. Not only modern approaches to replacement therapy are described in detail, but also promising methods of treatment: corticotropin-releasing hormone receptor antagonists, gene- and cellbased technologies. The study's strength lies in its comprehensive analysis of the disease, spanning fundamental research to practical patient management, as applied to the realities of clinical practice in Russia.

Hypoglycemic syndrome (HGS) is a symptom complex that develops due to an imbalance in the blood glucose maintenance system with the development of hypoglycemia and is stopped by the administration of glucose. One of the most relevant methods at the present stage for the diagnosis of hereditary causes of HGS is whole exome sequencing. The description of two cases in the same family (mother and daughter) is presented, when using whole exome sequencing with the study of genes responsible for HGS, it became possible to establish an accurate diagnosis of a combined hereditary pathology (multi ple endocrine neoplasia type 1 syndrome (MEN1) and maturity-onset diabetes of the young 12 (MODY12)) and to determine a clear management strategy for patients. The presented family case highlights the importance of an extended genetic examination for an accurate diagnosis of the disease; confirms the need for MEN1 gene sequencing in young patients of the risk group, even if primary hyperparathyroidism has not yet manifested in them; once again demonstrates the variability of phenotypic penetrance of hereditary diseases (in particular MEN1 and MODY12); It recalls the expediency of considering the use of in vitro fertilization with preimplantation genetic testing in order to prevent the transmission of hereditary diseases to offspring; highlights the complexities of imaging diagnostics of neuroendocrine tumors

Background. Autoimmune thyroid diseases are the most common comorbid pathology of vitiligo. Presence of elevated levels of antibodies to the thyroid tissue in the blood of patients is one of the signs of autoimmune thyreopathies. In foreign studies, a higher detection rate of antithyroid antibodies has been established in patients with vitiligo compared to healthy people. In Russia, the frequency of antithyroid antibodies carriage in patients of this category has not been studied before. Objective. To evaluate the frequency of antibodies to thyroid peroxidase (AT-TPO) and thyroglobulin (AT-TG) carriage in patients with vitiligo as well as to identify factors associated with the carriage of antithyroid antibodies. Material and methods. During the study, 35 patients with vitiligo and 29 healthy volunteers were examined. The research protocol included determination of serum concentrations of thyroid-stimulating hormone, free thyroxine, AT-TPO and AT-TG, thyroid ultrasound. IBM SPSS Statistics software package (version 26.0) was used for statistical data analysis. Results. A higher frequency of AT-TPO, AT-TG carriage and simultaneous AT-TPO and AT-TG carriage has been established in patients with vitiligo compared to healthy volunteers (p<0.05). Mean levels of AT-TPO and AT-TG in patients were 13.6 and 9.7 times higher, respectively, than those of healthy volunteers. It has been found when performing a multidimensional logistic regression analysis that age of patient, vitiligo duration, area of depigmentation, late onset of the disease and vitiligo duration of 10 years or more are the independent factors associated with AT-TPO carriage. Age of patient, age of vitiligo manifestation, late onset of the disease and vitiligo duration of 10 years or more are independent factors associated with AT-TG carriage. Conclusion. The obtained results indicate the advisability of inclusion of the AT-TPO and AT-TG levels investigation in screening of vitiligo patients for early detection of autoimmune thyroid pathology along with the determination of thyroid hormone content.

Background: Hereditary hypoparathyroidism (hypoPT) is a rare endocrine disorder caused by absent or insufficient parathyroid hormone secretion. Genetic forms are uncommon and frequently underdiagnosed, particularly when clinical onset is atypical.Purpose: We present three cases of genetic hypoPT caused by CASR, GNA11, and GATA3 mutations, highlighting diagnostic challenges and management approaches.Methods: Clinical data, biochemical results, and genetic findings were collected for three female patients with early-onset, nonsurgical hypoPT. Each case was evaluated for presenting symptoms, comorbidities, treatment responses, and outcomes. Relevant literature and guidelines were reviewed for context and management recommendations.Results: All patients exhibited chronic hypocalcemia, hyperphosphatemia, and low PTH without prior neck surgery. Initial manifestations were atypical, delaying diagnosis until adolescence or adulthood. Case 1 (CASR mutation) presented with seizure-like episodes misdiagnosed as epilepsy, and partial response to calcium–vitamin D therapy. Case 2 (GNA11 mutation) showed Raynaud’s phenomenon, dermatologic symptoms, and treatment intolerance without nephrocalcinosis. Case 3 (GATA3 mutation) had early deafness, later renal impairment, and fluctuating calcium levels. Genetic testing confirmed pathogenic variants, and individualized management with active vitamin D analogs achieved partial biochemical control. All patients remain under multidisciplinary follow-up with stabilization of neurological complications and monitoring of renal status. Conclusion: Genetic causes of hypoPT should be suspected in patients with early-onset or atypical presentations in the absence of neck surgery. Timely genetic testing confirms the diagnosis and determines personalized therapy. Management requires careful titration of calcium and active vitamin D to avoid complications and may benefit from emerging treatments (long-acting PTH analogs). Early recognition and tailored interventions can improve patient outcomes and quality of life.

Aim: search for new genetic predictors of autoimmune adrenal insufficiency (AAI). Materials and methods: In n=54 patients with AAI (isolated and as part of type 2 autoimmune polyglandular syndrome (APS-2; group 1)) and n=32 healthy individuals (group 2) we analyzed polymorphisms in IL28B (rs12979860, rs8099917), TLR9 (rs5743836, rs352140), TLR2 (rs5743708). Results: In group 1, compared with group 2, a predominance of CT genotype of rs12979860 polymorphism of IL28B (p=0.024), and T allele of rs5743836 polymorphism of TLR9 (p=0.044) was revealed. The allele C of rs5743836 polymorphism of TLR9 (p=0.044) was more common in group 2 than in group 1. With respect to other genotypes, alleles and haplotypes, no significant differences (or differences at the level of statistical trend) were found between groups 1 and 2. Conclusion: Thus, it is possible that the CT genotype according to the polymorphic locus rs12979860 of the IL28B gene and the allele T of the rs5743836 polymorphism of the TLR9 gene are prognostic markers that increase the likelihood of developing AAI due to violation the peripheral immune tolerance (IT), whereas the allele C of the rs5743836 polymorphism of the TLR9 gene performs a protective role in this disease in the Russian population.

This study investigated the IgA antibodies targeting bovine serum albumin (BSA) in 27 adult celiac disease (CD) patients adhering to a gluten-free diet (GFD), compared to 123 controls (including individuals with autoimmune disorders, those with gastrointestinal cancers, and healthy donors). Serum samples were evaluated using a multiplex assay based on a microarray comprising 66 immobilized antigens, including autoantigens associated with autoimmune diseases, different albumins, cytokines, and inflammatory markers. Elevated IgA-BSA levels were detected in 22% of CD patients versus 3.25% of controls. IgA-BSA did not cross-react with milk proteins like casein, β-lactoglobulin, and γ-globulin, nor with autoantigens and human albumin, ruling out autoimmunity against self-proteins. The observed cross-reactivity with porcine albumin suggests that antibodies target epitopes shared by bovine and porcine albumin. Increased IgA-BSA levels may interfere with immunoassays performed using BSA as a stabilizer, necessitating protein-free buffers to avoid false results when testing CD patients. Elevated IgA-BSA levels may reflect ongoing gut barrier dysfunction in CD patients on a GFD, allowing dietary proteins like BSA to trigger immune responses. This study identifies a novel immune response in CD patients on a GFD, emphasizing the need for tailored diagnostic approaches (BSA-free assays) and further research into the clinical and dietary implications of IgA-BSA elevation.

A clinical case of neurofibromatosis 1 type in combination with pheochromocytoma in a 53-year-old woman with no family history of the disease is described. The diagnosis of neurofibromatosis 1 type was established on the basis of signs of the disease (glioma of the right optic nerve, epilepsy, hypertension, Lish nodules, osteoporosis). The diagnosis of pheochromocytoma was established according to the data of a multiple increase in the level of free metanephrines and normetanephrines in daily urine, a malignant CT phenotype of a tumor of the left adrenal gland, and confirmed by a pathomorphological examination. During genetic analysis, a variant HG38 not previously described in the literature in the heterozygous state was found in the NF1 gene in exon 38, leading to deletion of 4 nucleotides and a shift in the reading frame with a coverage depth of 170x. The variant is not found in the gnomAD population frequency database and most likely leads to loss of function of the corresponding copy of the gene, which makes it possible to attribute the pheochromocytoma in this case to the 2nd cluster of genetic abnormalities in paragangliomas. This case highlights the importance of timely diagnosis of neurofibromatosis type 1 to determine further follow-up and treatment plan. It also demonstrates the effectiveness of cooperation between specialists from different medical fields in the diagnosis and treatment of tumors secreting catecholamines, which can occur with neurofibromatosis 1 type.

BACKGROUND: Currently, an annual study of venous glucose after night fasting is carried out to detect hypoglycemia for diagnosis the recurrence of insulinoma. However, hypoglycemia cannot always be achieved after night fasting if tumor is small. Previously continuous glucose monitoring (CGM) in diagnosis of recurrence of insulinoma was evaluated in small samples.AIM: To evaluate the effectiveness of CGM in interstitium for the diagnosis of recurrent insulinoma (hypoglycemia) after surgery.METHODS: Adult patients who underwent surgery for insulinoma and with remission in the early postoperative period were included. The glucose level in the interstitium was studied by CGM for a maximum of 14 days, and a single venous blood glucose test was performed after a night fasting. If hypoglycemia was detected by any method, a long-term fasting test to confirm the recurrence of hypoglycemic syndrome and imaging diagnostics to identify insulinoma were performed.RESULT: The study included 29 patients after surgical treatment of insulinoma 3-69 months ago. Normoglycemia was determined in 28 patients after night fasting, while one had hypoglycemia, subsequently confirmed by a long-term fasting test. During the CGM, 25 patients had normoglycemia throughout the entire study period, while hypoglycemia was detected in 4 patients, and among them subsequent long-term fasting test confirmed it in three cases. During instrumental examination, pancreatic formation, different in location from the primary tumor, was detected in these three patients. Thus, the sensitivity of CGM relative to reference night fasting test is 100%, 95% CI (3%; 100%), specificity 89% (72%; 98%), positive predictive value 25% (1%; 81%), negative predictive value 100% (86%; 100%). During CGM no adverse events were detected.CONCLUSIONS: CGM can be used effectively and safely to rule out hypoglycemia; and positive cases require subsequent long-term fasting test.

Background/Objectives: The aim of this study was to evaluate the avidity of thyroid autoantibodies (Abs) in sera of patients with autoimmune thyroid disease (AITD) and thyroid autoantibody carriers without diagnosed AITD. Methods: A hydrogel microarray-based multiplex assay with the chaotrope destruction stage was developed to measure the avidity of thyroid disease-associated autoantibodies, including those targeting thyroperoxidase (TPO), thyroglobulin (Tg), and other minor antigens. Results: Evaluation of the assay in three independent cohorts of patients, totaling 266 individuals with and without AITD, demonstrated the heterogeneous avidity of autoantibodies to thyroid proteins. For the confirmation study, the median avidity index (AI) for AbTg was 29.9% in healthy autoantibody carriers, 52.6% for AITD patients, and 92.7% for type 1 diabetes (T1D) thyroid autoantibody carriers. The median AI for AbTPO was 39.9% in healthy carriers, 73.4% in AITD patients, 83.2% in T1D thyroid autoantibody carriers, and 98.5% in AITD patients with thyroid neoplasm. In patients with Hashimoto’s thyroiditis and known disease duration, changes in the avidity maturation of AbTPO over time were demonstrated. Conclusions: Longitudinal studies of TPO- and/or Tg-positive healthy individuals (with an interval of 1–2 years between visits) are needed to evaluate the maturation of autoantibody avidity during the asymptomatic phase and to assess the potential of autoantibody avidity as a prognostic marker for disease development.