Contribution of BARD1 gene to male breast cancer- report of a family with different types of cancer.

This case illustrates the challenges in the diagnosis of a rare disease with an intricate orientation, requiring an in-depth medical history review and a comprehensive series of laboratory tests with genetic confirmation. The patient presented with myoclonic jerks associated with hypoglycaemia and proximal tubulopathy. A fasting functional test was performed to investigate the origin of the hypoglycaemia. The identification of inadequate insulin suppression with hypoketotic hypoglycaemia led to the diagnosis of hyperinsulinaemic hypoglycaemia (HH). In addition, the diagnosis of chronic renal dysfunction associated with atypical Fanconi renal tubulopathy syndrome (FRTS) was indicated on the basis of a decreased estimated glomerular filtration rate (eGFR), nephrocalcinosis, millimetric lithiasis, rickets and complex proximal tubulopathy, among other laboratory findings. The association of atypical FRTS with HH was an indication for molecular genetic testing. The patient was identified as a carrier of the c.187C>T (p.Arg63Trp) variant in the HNF4A gene, which is a heterozygous missense variant classified as pathogenic. This entity is rare, and the published literature reporting HNF4A gene variants associated with atypical FRTS and HH is limited. It is therefore important to report such cases to contribute to the growing body of evidence and help identify pathogenic HNF4A variants and their implications.

Aim of the study: to assess quantitative and qualitative indicators of HIV drug resistance to antiretroviral drugs in patients with virological failure of first-line ART. Materials and methods . Clinical and laboratory parameters and results of HIV molecular genetic testing were analyzed in 964 patients with virological failure of antiretroviral therapy (ART) in 2018–2022 at the St. Petersburg AIDS Center. Fragments of the pol gene encoding HIV enzymes were examined by PCR and Sanger sequencing. Identification of HIV drug resistance mutations to antiretroviral therapy was performed using the Stanford University HIVDB algorithm Version 9.4.1. The dynamics of HIV resistance prevalence among ART recipients were assessed by comparing the results of two studies: a retrospective study (2006–2011) and a current study (2018–2022) in St. Petersburg. Results and discussion . Virological failure was associated with the development of HIV resistance mutations in 76.5% of patients. HIV resistance mutations were found in the majority of cases (93.9%) in patients receiving first-line ART. Regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTI) + non-nucleoside reverse transcriptase inhibitors (NNRTI) combination were more frequently used (72.1%), the proportion of first-generation NNRTI class drugs was 58,7%. According to the results of HIV resistance testing, resistance to the NRTI (90.6%) and NNRTI (78.3%) classes was more common than to protease inhibitors (PI) (3.8%) and integrase strand transfer inhibitors (INSTI) (0.9%). HIV resistance to two drug classes was found in 74,2% of patients, most frequently to the NRTI+NNRTI classes (71.3%). Multidrug resistance to three drug classes (NRTI+NNRTI+PI) was rarely detected, only in 1.3% of patients. Analysis of HIV resistance to antiretroviral drugs in patients over time showed an increase in resistance to NRTIs (from 79.8% to 90.6%) and NNRTIs (from 60.4% to 78.3%), comparing the periods 2006–2011 and 2018–2022. There was also a decrease in the number of patients with resistance to PIs (from 19.9% to 3.8%). Conclusion . Our study shows that acquired HIV drug resistance was the leading cause of virological ineffectiveness of antiretroviral therapy between 2018 and 2022. Importantly, the majority of HIV drug resistance was observed in patients receiving first-line therapy. These findings highlight the need to modernize first-line ART regimens, including the wider introduction into clinical practice of drugs with a high genetic barrier to resistance. These include modern integrase inhibitors or protease inhibitors. The choice of ART regimen should be based on the patient’s previous drug history and HIV resistance indicators. When selecting a new regimen plan for patients with multidrug-resistant HIV, it is essential to use at least two or three medications (typically from different classes) that do not have any resistance mutations.

Aim. To study the phenotypic and molecular genetic characteristics of patients with Wolff-Parkinson-White (WPW) syndrome. Material and methods. The study group consisted of 200 patients with WPW syndrome, including 97 men (n=48,5%) and 103 women (n=51,5%). All patients underwent clinical and paraclinical examinations, including electrocardiography (ECG), Holter monitoring, echocardiography, somatometry according to the standard V. V. Bunak method, and molecular genetic testing. DNA was extracted using the phenol-chloroform method, and genotyping was performed using the polymerase chain reaction. Results. Multivariate regression analysis revealed significant associations between some factors and WPW syndrome. The strongest predictor was a delta wave on the ECG (odds ratio (OR) =21,3; p<0,0001). Genetic variants PRKAG3="CC" (OR =16,7; p=0,0009), PRKAG2="GA" (OR =6,3; p=0,0023) and TBX3="GG" (OR =6,1; p=0,0078) also demonstrated a significant association with an increased probability of WPW syndrome. An increase in the QRS duration (OR =1,1 per unit; p<0,0001) and heart rate (OR =1,1; p=0,0008) on the ECG were associated with a non-significant odds increase. In contrast, QT interval increase (OR =0,97; p<0,0001) and higher height (OR =0,96; p=0,0073) were associated with a low risk of WPW syndrome. Rees-Eysenck normosthenic body type significantly reduced the odds (OR =0,47; p=0,0367). Conclusion. Heredity is a key factor in the development of WPW syndrome, as confirmed by data from numerous studies. Phenotypic characteristics, in addition to genetic markers, can serve as a valuable tool for risk stratification and the development of preventive strategies aimed at preventing the manifestation of WPW syndrome.

Aim. To identify independent genetic and non-genetic predictors of hypertension (HTN) and rank their contribution to disease progression, as well as to identify potential new mechanisms that may influence the hypertension development. Material and methods. This cross-sectional observational study included 610 patients, including 142 with HTN. All participants completed a questionnaire, blood pressure (BP) measurements, biometric measurements, and molecular genetic testing. HTN predictors were identified using logistic regression models. Using singlefactor models, individual HTN predictors were determined. A multivariate logistic regression model was created using covariates with a significance level of p<0,3 in univariate models to rank the contribution of each trait to HTN development. Results. A mathematical model was constructed using non-genetic and genetic markers to assess the risk of HTN, better classifying individuals with a low genetic risk for HTN. Genetic predictors were more significant for optimal calculations of HTN probability in the logistic regression model, while non-genetic traits were not included in the final model. Possible mechanisms that may lead to HTN, based on the identified genetic predictors, are considered. In addition, the concept of the contribution of a protective combination of genetic variants is also explored. Conclusion. A logistic regression model based on molecular genetic testing results is optimal for identifying individuals with a low HTN risk. Thus, for patients with a low genetic risk, lifestyle factors are more significant, and lifestyle modification is especially important for them to prevent HTN.

Relevance: Molecular genetic testing to determine the patient's genotype and tumor molecular profile is a key component of a personalized approach to treatment and follow-up. Current research in genetic screening focuses on transitioning from phenotypic diagnostic panels and PCR testing of predisposition genes to large panels that include many identified genes or whole-genome sequencing. Multigene testing is widely used across colorectal cancer (CRC) diagnostics and therapy, where genetic components make a significant contribution. Currently, practical oncology requires a review of high-throughput sequencing systems for the genetic screening of hereditary and sporadic CRC variants and for the optimization of early diagnosis in relatives of patients. The study aimed to review the methodology and current results of next-generation sequencing (NGS) applications for genetic screening of hereditary and sporadic colorectal cancer. Methods: This analytical review included 70 original research and review articles available in open-access databases, including Google Scholar, Web of Science, SpringerLink, Scopus, ScienceDirect, PubMed, and BMJ. Results: NGS-based multigene testing enables the simultaneous analysis of multiple genes involved in carcinogenesis, the identification of germline pathogenic mutations associated with hereditary tumor syndromes, and the detection of genetic variants in less-studied regions of genes, such as introns and untranslated regions, which help identify previously unknown factors predisposing to colorectal cancer. Conclusion: Molecular genetic diagnostics facilitate personalized treatment of patients and individualized clinical examination of relatives from risk groups. However, although approximately 25% of CRC cases are familial, fewer than 5% of families are studied genetically. The analyzed data confirm the need to transition from phenotypic panels to comprehensive panels, encompassing all identified genes involved in hereditary tumor syndromes or whole-genome sequencing. In addition, identifying new variants with moderate and low penetrance, as well as those with uncertain functional significance, expands the phenotypic spectrum of CRC and necessitates further studies to determine their inclusion in diagnostic sequencing panels

Gorlin‑Goltz syndrome (GGS) is a rare autosomal dominant disorder caused by mutations in the PTCH1 and SUFU genes, key components of the Sonic Hedgehog signaling pathway. GGS is characterized by a high risk of developing tumors, primarily basal cell carcinoma (BCC) and medulloblastoma. The article presents a clinical case of an 11‑year‑old patient with PTCH1‑associated GGS, who was diagnosed with medulloblastoma at the age of 3 years, and by the age of 6 years, multiple basal cell skin cancer manifested. The clinical case highlights the importance of early diagnosis, timely molecular genetic testing and interdisciplinary monitoring to improve the prognosis and quality of life of patients with this syndrome.

Objective: To investigate clinicopathological and molecular genetic characteristics of CD117-positive eosinophilic renal cell tumors (ERCTs) with unusual morphological and immunophenotypic features. Methods: Formalin-fixed, paraffin-embedded tissues from 10 cases (9 cases from Xiangya Hospital, Central South University and 1 case from Bishan Hospital of Chongqing Medical University) of diagnostically challenging CD117-positive ERCTs between January 2017 and October 2024 were collected. Histological reviews were performed on HE-stained sections, followed by immunostaining and whole-exome sequencing (WES). Results: The 10 patients were composed of 4 males and 6 females, with ages ranging from 29 to 57 years, median 49.5 (36.8, 51.8) years. The sizes of tumors ranged from 2.5 to 6.0 cm, median 4.8(2.9,5.2) cm. All 10 ERCTs were composed of variably eosinophilic cells and characterized by prominent morphological features including exclusively eosinophilic (2 cases), focal chromophobe-like (3 cases), prominent nested (2 cases), prominent flocculent cytoplasm (1 case), a collision of renal oncocytoma (RO)/chromophobe renal cell carcinoma (ChRCC) (1 case), and diffusely degenerative atypia (1 case). Immunohistochemically, a subset of 10 tumors variably expressed CK7 (7/10) and vimentin (3/10), while they were all positive for CD117 (10/10), PAX8 (10/10), SDHB (10/10), and FH (10/10) and negative for CAⅨ (10/10) and 2SC (10/10). The Ki-67 proliferation index ranged from 1% to 5%. WES identified a GNAS mutation in one case of the RO/ChRCC collision tumor, while no characteristic mutations of other renal cell tumor types were detected in the remaining 9 cases. The analysis of copy number variations revealed complex karyotypic alterations in 4 tumors, harboring various gain of chromosomes 4, 5, 7, 12, 13, 15, 16, 18, and 22, with 3 cases showing variable loss of chromosomes 1, 2, 6, 10, 13, and 17. These 4 cases were molecularly classified as eosinophilic ChRCC. The remaining 6 cases, including 2 cases with a normal diploid karyotype and 4 cases with slight karyotypic alterations, were molecularly classified as 5 ROs and 1 RO-dominant RO/ChRCC collision tumor. Finally, the original diagnosis was retained in 4 cases and revised in 6 cases. Conclusions: CD117-positive ERCTs with uncertain classification may exhibit various morphological overlaps, non-classic histological features, and aberrant immunophenotypes. Combined immunostaining of CK7, CD117, vimentin, SDHB, FH, and 2SC can greatly help discriminate among these tumors and their mimics. When the diagnosis is challenging based only on morphology and immunohistochemistry, molecular genetic tests may be useful.

Introduction: Tooth agenesis is one of the most frequent congenital abnormalities found in the maxillofacial region. Oligodontia, a severe form of tooth agenesis, occurs as an isolated anomaly or as a syndromic feature. Objectives: To identify the molecular genetic etiology of multiple missing permanent teeth (oligodontia). Discussion: Disruptions in tooth development arise from mutations in genes like WNT10A and PAX9, where PAX9 plays a crucial role in dental epithelial cell differentiation. Additional genes, such as MSX1, AXIN2, EDA, EDAR, and EDARADD, play diverse roles in tooth agenesis. The WNT pathway, particularly the WNT/β-catenin signaling, is crucial in tooth development. Mutations in LRP6 compromise the activation of this pathway, indicating its functional significance in tooth development. Biallelic variants in POLR3GL have been associated with oligodontia, expanding the spectrum of POLR3-related disorders. Disruption of Pol III function may affect the transcription of essential RNAs involved in tooth development. Conclusions: Oligodontia is a genetically heterogeneous condition with a complex genetic basis involving multiple genes and pathways. Molecular analysis and genetic testing are essential for accurate diagnosis and management, contributing to our evolving understanding of the genetic causes of oligodontia.

Introduction. Anaplastic thyroid cancer (ATC) accounts for less than 1 % of thyroid neoplasms, but is characterized by high aggressiveness and death in the vast majority of cases. The median survival in this pathology is <6 months. Despite development of multimodal approaches to treatment of ATC (surgery, chemotherapy, radiation therapy), local and systemic control of the disease remains unsatisfactory in most patients. The use of targeted drugs and immunotherapy opens up new possibilities for increasing the survival rate of patients with ATC, but the effectiveness of their combination with surgery and also long-term results remain poorly understood. The role of surgical treatment of primary tumor is subject of discussion: on the one hand, radical resection can improve local control of the disease and reduce symptoms of compression, and on the other, aggressive operations often involve a high risk of complications and do not always lead to increase in life expectancy. Of particular difficulty is definition of criteria for selecting patients who could actually benefit from surgical treatment. Aim. To evaluate the effectiveness of surgical treatment with various options for combined treatment and determine criteria for its feasibility in ATC. Materials and methods. The multicenter prospective study included 65 patients with morphologically confirmed stage IVA–C ATC treated in 2016–2022 at the Pirogov High Medical Technology Clinic of St. Petersburg State University, the National Medical Research Center of Radiology and the National Medical Research Center of Endocrinology. Patients are divided into 4 groups: 1) surgical treatment ( n = 23); 2) surgical treatment and chemotherapy ( n = 26); 3) surgical treatment, chemotherapy and radiation therapy ( n = 5); 4) surgical treatment, chemotherapy and targeted therapy ( n = 9). Patient survival was assessed using the Kaplan–Meier method. Comparison of clinical-anamnestic data from 3 independent groups was performed using the Kruskal–Wallis test with further post-hoc analysis; comparison of the study groups – using Cox regression. Results. median of overall survival in the surgical treatment, chemotherapy, and targeted therapy group was 20 months (95 % confidence interval 12–24), in the surgical treatment group was 2 months (hazard ratio, 0.075; p <0.001). Partial response was recorded in 56 % of patients receiving targeted therapy, in other groups it was not observed ( p <0.001). Comparison of data from patients who underwent R0 / R1- and R2 resection was not possible due to small number of patients who underwent conditionally radical surgery ( n = 12) Conclusion. Surgical intervention in ATC can be justified only as part of an integrated approach using agnostic targeted therapy. The results of the study highlight the need for molecular genetic testing and interdisciplinary consultation in each case. In the future, it is necessary to study new combinations of targeted drugs and immunotherapy in neoadjuvant regimen.

Hereditary vitreoretinopathies (HVRs) are genetically based disorders affecting the vitreous and retina, potentially leading to severe vision loss. This review focuses on two major subtypes of HVRs: Stickler syndrome (SS) and VCAN-related vitreoretinopathies (primarily Wagner syndrome and erosive vitreoretinopathy [ERVR]). Stickler syndrome is a multisystemic collagenopathy typically caused by mutations in collagen genes such as COL2A1 and COL11A1. It is characterized by distinctive ocular findings (notable vitreous anomalies, high myopia, and an increased risk of retinal detachment), along with craniofacial, auditory, and skeletal manifestations. VCAN-related vitreoretinopathies result from mutations in the VCAN gene, which encodes the extracellular matrix proteoglycan versican. These conditions are typically characterized by specific ocular features, such as an ‘optically empty vitreous’ (as seen in Wagner syndrome), and generally lack prominent systemic manifestations. This review discusses the molecular genetic basis, detailed clinical phenotypes, and key elements for differential diagnosis of both disease groups, along with current ophthalmologic management strategies. Furthermore, genetic diagnostic methods used in these complex disorders, their diagnostic yields, genotype-phenotype correlations, diagnostic challenges, and future research directions are explored. Early and accurate diagnosis—especially when supported by molecular genetic testing—is vital for appropriate patient monitoring, prophylactic treatment planning to prevent complications such as retinal detachment, and genetic counseling for affected family members. A deeper understanding of these disorders will be achievable through ongoing research in ocular genetics and multidisciplinary approaches.

Retinal diseases constitute a clinically and genetically heterogeneous group of disorders characterized by progressive dysfunction or degeneration of the neural retina and/or retinal pigment epithelium. In recent years, molecular genetic testing methods have become indispensable tools for the diagnosis, subclassification, and management of these conditions. Techniques based on next-generation sequencing (NGS), including targeted gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS), have significantly expanded our understanding of pathogenic variants and facilitated the discovery of novel gene-disease associations. In addition to their diagnostic utility, these tests play a critical role in genetic counseling, carrier detection, assessment of therapeutic eligibility, and recruitment into clinical trials. Despite their growing clinical relevance, genetic tests raise complex ethical challenges. Predictive and prenatal testing—especially in disorders for which no effective treatment currently exists—pose dilemmas related to autonomy, confidentiality, informed consent, and distributive justice. Furthermore, disparities in access to emerging gene-based therapies, the application of testing in minors and unborn individuals, concerns surrounding the privacy of genetic data, and the obligation to recontact patients when new clinically significant information becomes available represent key areas of ethical concern. These issues underscore the need for well-defined policies and multidisciplinary approaches to ensure ethically responsible integration of genetic testing into ophthalmic care.

More than 60 lysosomal disorders have been described to date, and continued advancements in molecular (i.e., next generation sequencing) and biochemical (i.e., mass spectrometry) genetic testing will increase this number. In parallel, the same advancements have improved laboratory efficiency by allowing the simultaneous measurement of multiple enzyme activities and/or biomarker concentrations, as well as the rapid generation of genomic information with fewer tests. Here, we provide an overview of currently available biochemical and molecular genetic tests, and how they and their correlation to each other can support screening, diagnosis, and monitoring of patients with lysosomal disorders.

5α-reductase deficiency is a rare autosomal recessive disorder of sex development resulting from mutations in the SRD5A2 gene, which impairs the conversion of testosterone to dihydrotestosterone (DHT). We report a case of a 3-year-old child, firstborn of consanguineous parents, who presented with severe pallor, growth failure, and ambiguous genitalia since birth. He was born preterm with low birth weight and required NICU admission for delayed crying. Initially reared as female due to apparently female genitalia, parental concern arose at 6 months when progressive phallic enlargement and bilateral inguinal swellings were noted. Cytogenetic analysis confirmed a normal 46, XY male karyotype. Bilateral orchidopexy was performed at 1.5 years. Despite three intramuscular testosterone injections, microphallus persisted. Examination revealed moderate anemia, growth retardation, bifid scrotum with pea-sized testes, phallus length 2.5 cm, and penoscrotal hypospadias (EMS 3). Hematological evaluation suggested iron deficiency anemia, necessitating four blood transfusions. The β-hCG stimulation test showed elevated testosterone (250.34 ng/dl) with disproportionately low dihydrotestosterone (2.88 ng/dl) and raised T/DHT ratio(86.92:1), indicating 5α-reductase deficiency as the likely etiology of 46,XY DSD. Molecular genetic testing has been advised. This case highlights the complexity of managing 46,XY DSD with suspected 5α-reductase deficiency, particularly when compounded by systemic comorbidities such as chronic anemia and growth failure. Early diagnosis is crucial for gender assignment decisions, counselling of parents, and planning future surgical and hormonal interventions. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S63]

Abstract Background Allergic rhinosinusitis is a complex IgE-mediated inflammatory disorder affecting millions globally, with significant epidemiological, immunological, and clinical heterogeneity. Recent advances in molecular profiling, biologic therapies, and diagnostic technologies have driven a paradigm shift in understanding and managing this disease. Purpose This review synthesizes contemporary knowledge on the pathophysiology, traditional and innovative treatment modalities, diagnostic innovations, and future directions in allergic rhinosinusitis management, emphasizing precision medicine and integrated therapeutic approaches. Main body The immunopathogenesis involves intricate Type 2 immune responses modulated by genetic polymorphisms such as ZNF608, environmental allergens, and immune dysregulation. Traditional therapies, including antihistamines and intranasal corticosteroids, remain foundational but are limited by adherence and side effects. Emerging biologics targeting IgE and cytokines (omalizumab, dupilumab, mepolizumab) and novel small molecule inhibitors demonstrate enhanced efficacy in severe and refractory cases. Advances in immunotherapy, including sublingual and subcutaneous approaches with novel delivery systems, offer personalized treatment options. Cutting-edge diagnostic technologies—molecular genetic testing, high-resolution imaging, AI-driven tools, and wearable biosensors—enable precise allergen identification and real-time monitoring. Non-pharmacological adjuncts such as laser and ozone therapies, nutraceuticals, and physical therapies provide complementary benefits. Surgical interventions, enhanced by navigation and minimally invasive techniques, optimize outcomes for refractory disease. Conclusion Integrating multi-omics, biologic therapies, and digital health tools heralds a new era of precision medicine in allergic rhinosinusitis. Future research should focus on gene therapy, nanomedicine, and AI-enabled personalized protocols to overcome current therapeutic limitations and improve long-term patient outcomes. Graphical Abstract

Introduction. The article presents a case of a child with long QT syndrome, skeletal and facial abnormalities, and mental deficiency. This symptom complex was a manifestation of an Ogden syndrome, previously undescribed in Russia X-linked disease associated with a NAA10 gene mutation. Brief description . Molecular genetic testing confirmed a mutation (p.Tyr43Ser) in this gene, which was also found in the child’s sister and mother. During anesthesia, the boy suffered cardiac arrest due to severe bradycardia and asystole, due to which a cardioverter-defibrillator was implanted. Discussion. Ogden syndrome is a disease associated with NAA10 gene mutations, which may remain unrecognized. Severe psychoneurological symptoms can mask the cardiac manifestations of the disease for a long time, including long QT syndrome and arrhythmias, which can manifest as dangerous life-threatening arrhythmias and sudden death.

Primary distal renal tubular acidosis (dRTA) is a rare inherited renal tubular disorder having a significant impact on growth and kidney function. Data on molecular genetics and long-term outcomes of primary dRTA, especially for newer genotypes, are limited. 63 probands with a clinical diagnosis of dRTA underwent molecular genetic testing, specifically including SLC4A1, ATP6V1B1, ATP6V0A4, WDR72, and FOXI1. Genotype-phenotype characteristics and long-term outcomes were studied in this observational cohort study. Diagnostic yield of genetic testing was 58.7%. Genotype positivity was associated with severe clinical and biochemical disease. SLC4A1 (38.5%) was the most common genotype, followed by WDR72 (13.5%) and ATP6V1B1 (11.5%). SLC4A1: p.Ala858Asp (32.7%) was the exclusive biallelic variant detected (likely founder variant in the region). Five (9.6%) had variants of unknown significance. Notable features at initial presentation were delayed diagnosis (median 17 months), frequent failure to thrive [44 (78.6%)], rickets [40 (71.4%)], and hypokalaemic paralysis [11 (19.6%)]. Mean [(standard deviation (SD)] follow-up duration was 14.8 (11.7) years. 30 (53.6%) were>18 years of age at last clinical visit. Long-term follow-up was characterised by poor final height [mean (SD score): -3.0 (2.2)], persistent bone deformities [19 (33.9%)], and decreased eGFR [mean (SD): 89.4 (26.1) ml/min/1.73m2]. The biallelic SLC4A1: p.Ala858Asp variant was characteristically associated with increased osmotic fragility of red blood cells, manifesting as haemolytic anaemia. ATP6V1B1, ATP6V0A4 and FOXI1 variants were associated with sensorineural hearing deficit. All probands with WDR72 variants manifested amelogenesis imperfecta. We report 13 novel genetic variants in primary dRTA and the fourth proband with a rare FOXI1 variant. Primary dRTA in Asian Indians is a genetically diverse disease, and is characterised by delayed diagnosis, severe growth failure, bone deformities, and decreased kidney function in the long term. Findings from this study highlight the regional diversity and expand genotype-phenotype correlations in primary dRTA.

A rare co-occurrence of Crohn’s disease (CD) and familial Mediterranean fever (FMF) is a complex comorbidity with similarities in their immune pathophysiology and clinical manifestations. This case highlights the challenges in differential diagnosis and therapeutic dilemmas arising from the need to simultaneously manage two immune-mediated diseases. We report a clinical case of an Armenian man with recurrent abdominal pain, chronic diarrhea, episodes of dynamic intestinal obstruction and weight loss. His examination at the age of 39 years revealed signs of systemic inflammation, such as increased erythrocyte sedimentation rate to 62 mm/h, C-reactive protein level to 63 mg/l, and fecal calprotectin to 1039 micrograms/g. Endoscopic examination showed gastric ulcers (0.7 × 0.5 cm), an ileum stricture impenetrable with an endoscope, as well as multiple ulcers of the terminal ileum (SES-CD 9 points). The histological report concluded on chronic ulcerative ileitis with high activity. After one year, the results of molecular genetic testing showed a homozygous pathogenic variant of the MEFV c.2177TC gene (p.Val726Ala) was identified, confirming FMF with persistent activity (serum amyloid A was increased to 32.3 micrograms/ml). The patient was diagnosed with stricturing CD with severe progressive course (A2L1L4B2p) and colchicine-resistant FMF. For CD, the patient consecutively treated with adalimumab, upadacitinib, and ustekinumab with partial response and subsequent ileocecal resection. For FMF, he received colchicine without an effect and canakinumab with complete cessation of attacks. Administration of two targeted agents for two diseases was discussed, but no final decision was taken. By the time of writing this manuscript (January 2025), the patient retained the endoscopic activity of CD with no attacks FMF under treatment with ustekinumab and colchicine. In patients with Crohn’s disease, particularly those of Armenian descent, presenting with atypical abdominal pain and treatment resistance, FMF should be excluded. Molecular genetic testing for MEFV mutations should be included into the diagnostic workup, as their presence should be regarded as a CD modifying factor associated with the disease severity and complication risks. FMF-effective drugs (e. g., canakinumab) may not control CD progression, while CD-targeted therapies (adalimumab, ustekinumab) may not fully resolve FMF manifestations. The safety and efficacy of combining biologics remain unresolved. This case underscores the need for a multidisciplinary approach, development of clear criteria to assessing the activity of combined disease, and further research to optimize treatment strategies.

IntroductionBreast cancer remains the leading cause of cancer-related mortality among women worldwide, including Kazakhstan. Germline mutations in the BRCA1 and BRCA2 genes play pivotal roles in the pathogenesis of breast cancer, particularly in its aggressive subtypes. Despite the well-established impact of BRCA1-associated tumors on clinical outcomes, their specific characteristics within the Kazakhstani population remain insufficiently studied. This knowledge gap underscores the necessity for further research, including the present study.ObjectiveTo analyze the clinical, morphological, and molecular-biological features of BRCA1-associated breast carcinomas in Kazakhstani patients, with the aim of identifying more effective strategies for diagnosis and treatment.Materials and methodsThis study included 86 female patients diagnosed with primary invasive breast cancer who received treatment at the Oncology Center in Astana between December 2023 and June 2024. This retrospective study was conducted at a single center. Molecular genetic testing was performed via next-generation sequencing to identify pathogenic variants in the BRCA1 gene. Clinical and pathological data were retrospectively extracted from patients’ medical records.ResultsThe mean age at diagnosis for patients with BRCA1-associated breast cancer was 44 years, which is 6 years younger than that of patients without BRCA1 mutations (50 years). BRCA1 mutation carriers more frequently presented with advanced-stage disease, higher histological grade, and elevated proliferative activity. The incidence of metastasis was significantly greater among BRCA1-positive patients (41.7% vs. 5.4%, p = 0.002). Compared with BRCA1-negative tumors, BRCA1-positive carcinomas exhibit markedly lower expression of estrogen and progesterone receptors, a molecular signature characteristic of triple-negative breast cancer.DiscussionThe findings of this study confirm that BRCA1-associated breast carcinomas are distinguished by distinct clinicopathological features, including early onset, aggressive biological behavior, and high-grade histology. These characteristics highlight the importance of personalized treatment and diagnostic strategies and underscore the need for tailored clinical risk assessments for Kazakhstani patients.ConclusionThis study revealed significant differences in the clinical and morphological characteristics of BRCA1-associated breast carcinomas among Kazakhstani women. These results provide a foundation for improving diagnostic and therapeutic approaches in Kazakhstan and for developing population-specific clinical guidelines.

Lung cancer is the most common malignant neoplasm and ranks first in the structure of cancer mortality. Lung cancer has long been thought to be a smoker’s disease and largely preventable by limiting tobacco use, but recent studies have shown an alarming increase in the incidence of the disease among non-smokers of both sexes. Personalized medicine, including careful molecular genetic testing, optimizes treatment for each patient and improves their quality of life during therapy.The subject of this article is a specific clinical case of the effective use of Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been widely used as first-line therapy in patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC), and currently shows excellent results in the adjuvant mode. The aim of the work is to analyze the effectiveness of the use of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in lung adenocarcinoma using an example from clinical practice. During the discussion of the specifics of treatment of a patient with NSCLC, the results of laboratory tests, data from various diagnostic and treatment methods are used.