Background . Morphological diagnosis of central nervous system (CNS) neoplasms is challenging due to significant inter- and intratumoral heterogeneity, as well as similarities in the histological features of different nosological forms. The resolving power of traditional methods (histological and immunohistochemical examination) is limited and does not always allow accurate identification of tumor molecular subtypes. The current World Health Organization (2021) classification of CNS tumors recommends complementing morphological diagnosis with molecular characterization, including DNA methylation profiling, which enables more precise diagnosis and optimizes subsequent therapy. The purpose of the study – to develop and validate a DNA methylation-based classifier for CNS tumors using machine learning methods that ensures high predictive accuracy, reproducibility, and the ability to integrate both publicly available research data and locally collected samples from the N.N. Burdenko National Medical Research Center for Neurosurgery. Materials and methods . Publicly available DNA methylation data generated on the Illumina 450K platform (2,801 samples), as well as locally collected data comprising 776 tumor and control brain tissue samples obtained using the Illumina EPIC platform at the N.N. Burdenko National Medical Research Center for Neurosurgery, were used for model development. To eliminate inter-platform variation (batch effect between 450K and EPIC), data normalization was performed. Training and test sets were prepared using stratified sampling. The model was built using a gradient boosting on decision trees algorithm for each tumor methylation class. Additional multiclass submodels were developed for specific tumor types, such as medulloblastoma and glioblastoma. Classifier performance was evaluated in terms of predictive accuracy and reproducibility. Results . The classifier demonstrated high accuracy (» 0.95) in identifying both common and rare molecular classes of CNS tumors, including high-grade astrocytoma with piloid features. Incorporation of locally collected samples increased the method’s flexibility, improved representation of rare tumor types, and reduced the proportion of uncertain predictions. Conclusions . The DNA methylation-based CNS tumor classifier developed at the N.N. Burdenko National Medical Research Center for Neurosurgery demonstrates high accuracy and is comparable to similar international models. The application of machine learning algorithms enhanced analytical reliability, while inclusion of in-house data enabled adaptation of the model to local sample characteristics. The presented approach is applicable for research, refining diagnoses in challenging cases, and implementing automated molecular diagnostic procedures for CNS tumors.
Pulmonary embolism (PE) is a life-threatening condition characterized by the blockage of one or more branches of the pulmonary artery by a thrombus. This condition can be asymptomatic or lead to rapid death. Making an accurate diagnosis can be difficult for a doctor because PE is a relatively rare condition in children. This review summarises the available data on PE in children. The article discusses epidemiology, etiology, risk factors, pathogenesis, clinical presentation, diagnosis and treatment.
Retinoblastoma (RB) is one of the most common malignant intraocular tumors in children. The incidence rate of RB in the world is 1 case per 16,000–18,000 live newborns. In the absence of access to genomic biomarkers, ophthalmologists strictly rely on clinical signs when making therapeutic decisions. Knowledge of the genetic nature and molecular features of RB can provide a more objective understanding of the disease as a whole, conducting early diagnosis, predicting the course of the disease, including assessing the therapeutic response of the tumor to treatment. This makes it possible to individualize patient management tactics aimed at preserving life, and, importantly, preserving the organ of vision and its function. Until recently, molecular and genomic profiling of RB was limited exclusively to enucleated eyes, which was explained by the prohibition of performing a direct tumor biopsy due to the risk of extraocular spread. An alternative to a direct biopsy is a liquid biopsy. Its diagnostic potential is based on the presence of extracellular DNA in body fluids, including those of tumor origin. For patients with RB, the main material used to search for germinal mutations is blood. However, for the analysis of somatic mutations in a tumor, in the case of RB, blood is not a reliable enough material. The article provides an overview of publications on the possibilities of genomic profiling of RB using liquid biopsy. The material of choice for liquid biopsy in the case of intraocular RB was the aqueous humor of the anterior chamber of the eye in order to study the molecular genetic nature of RB in vivo.
Diffuse infiltrative retinoblastoma (RB) is a rare form of RB, which is the most malignant, first described by N. Ashton in 1958. Its occurrence among all forms of RB according to previously published articles ranges from 2.0 to 4.6 %. The article presents a unique case of diffuse infiltrative RB with extensive damage to the central nervous system, which resulted in remission in a child with a primary diagnosis of the disease at the age of 11 years.
Introduction . Clear cell sarcoma of the kidney (CCSK) is a rare primary renal tumor in children. It is characterized by an aggressive course, rapid tumor growth, and a high propensity for metastasis. Clinical interest in CCSK stems not only from its aggressiveness as a distinct entity but also from the diagnostic challenges in differentiating it from other pediatric renal neoplasms. Standardization of diagnosis and optimization of therapy require the identification of molecular markers to improve differential diagnosis with other rare renal tumors. A comprehensive approach – from early detection by pediatricians to precise molecular genetic testing – is essential to improve prognosis. The purpose of the study – to evaluate the clinical, morphological, and molecular genetic features of CCSK. Materials and methods . We conducted a retrospective single-center study of children with CCSK who received treatment at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, between September 2009 and December 2023. Results . Prognostic factors assessed included sex, age at diagnosis, primary tumor volume, and molecular genetic characteristics. The cohort was predominantly male (15/22, 68 %) compared with female (7/22, 32 %). Median age at diagnosis was 29 (17–44) months, and median primary tumor volume was 543 (368–748) cm3 . All tumors were unilateral (right-sided – 45 %, left-sided – 55 %). Localized disease was present in 21 (95.5 %) patients and metastatic disease in 1 (4.5 %); no pulmonary metastases were detected at diagnosis. No significant sex differences were observed in age or tumor volume (p > 0.05). At a median follow-up of 4.1 years, 6 events (27.3 %) and 2 deaths (9.1 %) occurred. Event-free survival (EFS) was 100 % at 1 year, 79.6 % (95 % confidence interval 63.4–99.9) at 3 years, and 72.4 % (95 % confidence interval 53.9–97.1 %) at 5 years. Overall survival (OS) was 100 %, 88.4 %, and 88.4 % (95 % confidence interval 74.3–100 %), respectively. Median EFS and OS were not reached; median time to event was 2.5 (1.7–5.6) years. Age < 2.7 years (cutoff – 32 months) showed a trend toward inferior EFS (p = 0.096, log-rank). No differences in EFS were found according to sex (p = 0.954), tumor volume (p = 0.446), or treatment protocol (Umbrella SIOP-RTSG 2016 (n = 12) vs. other regimens (SIOP-93-01, SIOP-2001; n = 10) (p = 0.6). Molecular genetic testing was performed in 7 patients (32 %); BCOR internal tandem duplication was identified in all 7 (100 %). Conclusions . Age younger than 2.7 years may represent a potentially unfavorable prognostic factor in CCSK. The median time to first event of 2.5 years indicates that most relapses occur in the medium-term period after therapy completion.
Background . According to international statistics tumors of the central nervous system take a leading position in the structure of childhood cancer morbidity. The use of a multimodal strategy of anticancer therapy today allows achieving a high level of long-term survival, but often with severe variants of long-term toxicity. The study of the health status of cured patients and assessment of their quality of life (QOL) in the aspects of searching for controllable factors to reduce treatment toxicity is a pressing problem in pediatric oncology and pediatrics. Materials and methods . The study included 76 patients with a confirmed diagnosis of medulloblastoma (93.4 %) or atypical teratoid rhabdoid tumor (6.6 %), established at the age of up to 18 years, for which antitumor therapy was carried out. For assess to QOL, the Health Utilities Index questionnaire of Mark 2 and 3 versions (HUI2 and HUI3) was used, consisting of 15 questions. The impact of disease burden (histological tumor type, stage and type (primary tumor/relapse) of the disease, inclusion of high-dose chemotherapy, volume of radiation therapy and surgery) on the health attribute scores was analyzed. Results . The median age of patients at the time of the survey was 11.7 years with a median interval after completion of specific treatment of 6.4 years. Respondents to the survey were patients’ parents (n = 37; 48.7 %) and/or the attending physician monitoring the child (n = 39; 51.3 %). The average time spent on filling out the questionnaire was 8.0 ± 3.0 min. The frequency of a decrease in the levels of health attributes according to the HUI2 and HUI3 systems were 47% and 53 %, corresponding to mild (66 % and 62 %), moderate (27 % and 26 %) and severe (7 % and 12 %) severity of disorders. Functional health disorders mostly concerned such QOL components as cognitive abilities, emotions, sensation, mobility, varying from moderate to severe. Metastatic stage of the tumor had statistically significant negative impact on mobility and ambulation (p = 0.02), self-care (p = 0.05) and dexterity (p = 0.01); patients with disease recurrence showed decreased cognition (p = 0.03) and emotional status (p = 0.002); the use of craniospinal irradiation was also associated with decreased cognitive abilities (p = 0.04). Conclusions . Assessment of patients’ QOL using the HUI2 and HUI3 questionnaire is a simple and accessible method for routine use in clinical practice. Statistically significant deviations in health attributes were registered in children who underwent antitumor therapy for medulloblastoma or atypical teratoid rhabdoid tumor, while unfavorable risk factors were disease recurrence, metastatic stage of the disease and radiation therapy in the CSI. It is important to note that despite the high percentage of recorded deviations in the assessed health attributes, more than half of them corresponded to mild to moderate impairments. The most vulnerable components were the motor sphere and cognitive abilities. Given the small sample size, it is impossible to speak about a high degree of significance of the obtained results, which requires continuation of research in the specified cohort of patients, however, they coincide with international literature data. It should also be noted that the questionnaire provides an assessment of the health status of patients in a specific period, while it can change significantly over time and against the background of numerous factors, thereby determining the need for dynamic monitoring.
Today, the problem of polypharmacy is extremely important for all medical specialties, however, in pediatric oncology, it is determined by the specific treatment characteristics of the underlying disease, including combination antitumor therapy regimens, as well as the need to correct associated multisystem complications using various classes of drugs. The key risks of polypharmacy include an increased likelihood of drug interactions, adverse drug reactions, cognitive impairment, and prolonged hospitalization, as well as decreased treatment effectiveness and patient quality of life. However, there is limited research on optimizing drug therapy prescriptions. This article outlines the basic concepts of polypharmacy and review existing practical strategies for managing drug therapy prescription skills in pediatric oncology.
Background. The introduction of molecular genetic studies has made it possible to more fully characterize the genetic events associated with an increased risk of developing nephroblastoma (NB). In recent years, new cancer predisposition genes have been identified, in particular, the REST gene, which acts as a tumor suppressor. The purpose of the study – assessment of clinical and genetic characteristics of patients with NB associated with germinal mutations in the REST gene. Materials and methods . The study included 3 patients with a histologically confirmed diagnosis of NB and with germinal pathogenic variants in the REST gene who received treatment or counseling at the N.N. Blokhin National Research Medical Center for Oncology from September 01, 2019 to June 01, 2024. Results. The median age at the time of diagnosis of NB was 42.9 months, while the median age at the time of detection of the REST gene mutation was 85.5 months. All patients (n = 3) had phenotypic features and concomitant pathology. In the first case, facial dysmorphic disorder, autism spectrum disorders, as well as radiologically confirmed multiple metaphysical cortical defects of both tibia and right femur were observed. In the second case, gum hypertrophy and cerebral palsy were noted. The third patient was diagnosed with cryptorchidism with the concomitant obesity. In 2 patients, NB developed on the background of perilobar nephroblastomatosis, no correlation with the histological type of tumor was found. All patients are alive without signs of recurrence of the underlying disease, the median duration of follow-up was 2.4 years. Conclusions. A mutation in the REST gene is a rare genetic event in the pathogenesis of NB. The analysis of the clinical and genetic characteristics of three patients with this mutation demonstrated a high variability of phenotypic manifestations, including facial dysmorphic disorder, neuropsychiatric disorders, skeletal abnormalities and malformations of the genitourinary system. It is noteworthy that in 2 out of 3 patients, the development of NB was noted against the background of perilobar nephroblastomatosis, which requires further study. Despite the heterogeneity of clinical manifestations, the presence of a mutation in the REST gene in patients with NB in this group is associated with a favorable prognosis, taking into account the duration of follow-up, which allows us to consider this genetic marker as a potential factor for a favorable prognosis. Given the rarity of this mutation, the presented observations make a significant contribution to understanding the clinical and genetic characteristics of this cohort of patients.
We would like to present a clinical case of an extremely rare gastric tumor in a 16-year-old adolescent – gastric neuroendocrine tumor. Only 17 cases of gastric neuroendocrine tumors have been described in foreign literature, and there are no domestic publications on this topic. Due to the rarity of this tumor in children and adolescents and the lack of clear criteria for treatment no specific therapy has been developed at the present time, and the optimal treatment is maximal surgical removal of the tumor.
Background. The juxtaglomerular cell tumor (JCT) of the kidney, or reninoma, is a rare benign renal neoplasm that occurs exceptionally rarely in pediatric patients. In contrast to other renal tumors, JCT pathogenesis is driven by renin-angiotensin system activation, clinically manifesting as refractory hypertension due to excessive tumor-derived renin secretion. We present a clinical case of an 11-year-old patient with JCT. Materials and methods . From January 2012 to January 2025 in the Pathology Department of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology only one case of JCT was identified. Results. An 11-year-old girl had headaches and developed arterial hypertension (blood pressure 170/90 mmHg) during 3 months. Abdominal ultrasound revealed a tumor in the left kidney. Further evaluation at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology showed contrast-enhanced abdominal computed tomography demonstrated a solid, heterogeneous mass (3.2 × 2.9 × 3.0 cm, V = 14.5 cm3) in the midsegment of the left kidney. There were no metastatic lung lesions on contrast-enhanced chest computed tomography. According to the clinical-radiological findings, patient's age (11 years), and tumor characteristics (size < 200 cm3), nephron-sparing surgery was performed. The patient underwent initial laparoscopic left kidney resection with lymph node sampling. Histopathological examination confirmed the diagnosis of JCT and radical tumor resection. Arterial hypertension was relieved in the postoperative period. Conclusions. The diagnosis and management of JCT require a multidisciplinary approach integrating clinical presentation, laboratory parameters, and expertise from pediatric oncologists, radiologists, surgeons, and pathologists. Given the tumor's typically small dimensions and benign biological behavior nephron-sparing surgery should be discussed with curative intent.
Malignant diseases in children remain one of the most difficult areas of modern oncology, where even significant progress in diagnosis and standard treatment methods does not always allow for stable disease control. Over the past decade, cellular immune technologies have attracted special attention, primarily CAR-T and CAR-NK therapies, which have opened up the possibilities of targeted effects on tumors and demonstrated unprecedented effectiveness in recurrent B-cell leukemias. CAR-T cells made it possible to change the prognosis for patients who have lost sensitivity to traditional therapy regimens, and CAR-NK presented the prospect of a safer, potentially universal platform. However, the successful results in hematological diseases contrast sharply with the difficulties of using these technologies in solid tumors and rare childhood oncopathologies. Heterogeneity of antigens, features of the tumor microenvironment, low infiltration and insufficient cell persistence remain the main barriers limiting the expansion of indications. Additional challenges include immunotoxicity, variability in clinical outcomes, and complexity in the production of cellular products, especially in pediatrics. The review examines the key mechanisms of action of CAR-therapies, the specifics of their effectiveness and safety in children, as well as modern strategies for improving effectiveness, from multiantigenic and tandem designs to combined approaches and methods of personalized monitoring. Particular attention is being paid to areas of future research, including response biomarkers, monitoring of minimal residual disease, and integration of cellular technologies with other therapies.
Hemolytic anemia due to pyruvate kinase deficiency is a rare congenital disease caused by a defect in the glycolytic pathway. This anemia is the most common among all enzymopathies. There are various treatment methods for this disease. This article presents a clinical case of a successful allogeneic hematopoietic stem cell transplantation in a patient with pyruvate kinase deficiency.
Background. Antitumor therapy using various different classes chemotherapy drugs in childhood has a negative impact on prepubertal and pubertal gonads. One of the groups dealing with the problems of pediatric oncofertility was the St. Petersburg Group for the Preservation of Oncofertility in Children with Cancer. The primary goal of the “Snowflake” program (N.N. Petrov National Medical Research Center of Oncology, leader A.P. Karitsky) is to preserve fertility in patients under 17 years old with tumors, the end point is the creation of a cryobank of biological material. The purpose of the work is to present the first results of targeted recruitment of patients to the “Snowflake” program, as well as to analyze the speed of this recruitment. Materials and methods . The N.N. Petrov National Medical Research Center of Oncology initiated clinical study protocols for preserving fertility in prepubescent and puberty girls and boys. The planned number of study participants is 125 people. The recruitment forecast is 5 patients per month, or 60 patients per year. Results. During the program, 28 primary children aged one to 17 years were screened for the risk of developing gonadotoxicity after anticancer treatment. Fourteen patients did not meet the inclusion criterias, 14 children were included in the final report. The reasons for exclusion were low risk of gonadotoxicity (n = 9), refusal of invasive intervention (n = 5), genetic paternity was not a priority for the family of one boy. In 6 cases, germ cell tumors were diagnosed, 3 cases were patients with soft tissue sarcomas and 2 were patients with lymphomas, one each with osteosarcoma, Wilms tumor and medulloblastoma. Cryopreservation of ovarian tissue was performed for 6 girls, testicular tissue for 4 boys, 4 more teenagers performed sperm extraction using masturbation. There was no delay in initiating anticancer treatment in either case. Conclusions. Further studies of gonadotoxicity are needed as the number of survivors with childhood cancer will increase in the coming years.
Diffuse astrocytoma with MYB or MYBL1 alteration is a newly defined molecular subtype of pediatric-type low-grade diffuse gliomas. This tumor type was first included in the 2021 World Health Organization classification of tumors of the central nervous system. To date, only a limited number of cases with a similar histo-molecular profile have been reported in the literature. The tumor is characterized by a favorable clinical course and prognosis. This report presents a clinical case of a brain astrocytoma with MYB/MYBL1 alteration in a 2-year-old girl. A distinctive feature of this case is the absence of any specific antitumor treatment – the patient did not undergo chemotherapy or radiotherapy. Only stereotactic biopsy was performed, followed by histological and molecular verification of the diagnosis. Eight years after the initial diagnosis, the disease remains stable, with some reduction in tumor size observed over time. According to our data, the presented case of MYB/MYBL1-altered astrocytoma is unique within the Russian medical literature.
Introduction. Malignant tumors of the parameningeal region are neoplasms with varying morphologies. The most common malignant tumors of this location are rhabdomyosarcoma, esthesioneuroblastoma, and undifferentiated carcinoma. Rhabdomyosarcoma is the most common soft tissue sarcoma. The incidence rate of rhabdomyosarcoma is 0.9 per 100,000 children. According to the Children's Oncology Group, comprehensive, intensive antitumor treatment, including multiagent chemotherapy, radiation therapy, and modern surgical technologies, has increased overall 5-year survival rates to 70 %. Developing in these anatomical structures, rhabdomyosarcoma involves several adjacent anatomical areas, including the visual system and the brain. Treatment of children with parameningeal rhabdomyosarcoma requires not only achieving oncological radicality but also minimizing the long-term consequences of therapy that impact quality of life. In this context, the choice of surgical approach – between traditional open surgeries and transnasal endoscopic surgery – takes on particular importance. Open approaches, despite their effectiveness, carry the risk of damaging the facial growth plates and causing significant cosmetic defects. However, transnasal endoscopic surgery avoids these drawbacks while ensuring adequate oncologic control, making it an increasingly preferred method in pediatric practice. The aim of the study – demonstratation of the capabilities and advantages of transnasal endoscopic surgery in the treatment of children with parameningeal rhabdomyosarcoma. Materials and methods . The study included 36 patients aged 9 months to 14 years diagnosed with parameningeal rhabdomyosarcoma who underwent specialized treatment between 2017 and 2022. Boys predominated – 20 (56 %). All patients underwent surgical treatment at the Research Institute of Preschool Education and Gynecology, N.N. Blokhin National Medical Research Center, Ministry of Health, Russia. Results. After a median follow-up of 60 months, 25 patients (68 %) in the study group are alive. Deaths occurred in 10 patients (29 %), of which 9 (26 %) were due to disease progression, and 1 (3 %) was due to complications of the treatment. One patient (3 %) was lost to follow-up. Conclusions. The expanded use of transnasal endoscopic surgery in the treatment of children with parameningeal rhabdomyosarcoma is driven by a unique combination of advantages: excellent intraoperative visualization, ensuring radical intervention, and minimal trauma, preserving intact anatomical structures. Further development of this technique, in turn, is stimulated by technological innovations and close interdisciplinary collaboration.
Introduction. Chronic graft-versus-host disease (cGVHD) remains a serious complication of allogeneic hematopoietic stem cell transplantation in children. In steroid-refractory cases, the prognosis is still unfavorable, and data on the use of the selective ROCK2 inhibitor belumosudil in the pediatric population, particularly in children under 12 years of age, are limited. Materials and methods . A retrospective multicenter analysis was conducted on 43 patients aged ≤ 18 years with steroid-refractory or steroiddependent cGVHD (2014 NIH criteria) who received belumosudil in 9 transplant centers across the Russian Federation between 2023 and 2025. The dose of the drug was determined by the patient's body weight, ranging from 50 to 200 mg/day. The evaluation included the rate and speed of achieving an overall response (complete and partial responses), organ-specific efficacy, safety profile, as well as the frequency of dose reduction, temporary interruptions, and treatment discontinuation. Results. The median age of patients at the start of therapy was 12 years (range: 2–18 years). The median number of prior lines of therapy was 3. An overall response was achieved in 65 % of patients (28/43): a complete response in 5 % (2/43) and a partial response in 60 % (26/43). The highest rates of organ-specific responses were observed in lung involvement (79.5 %), gastrointestinal tract (64 %), oral mucosa, and eyes (65.5 % and 68.5 %, respectively). The median time to response was 35 days. Adverse events of any grade were reported in 70 % of patients, with serious events occurring in 37 %. The most frequent were infectious complications (56 %), hematological toxicity (37 %), and hepatotoxicity (21 %). Dose reduction was required in 35 % of patients, a temporary interruption in 21 %, and treatment discontinuation in 19 %. Conclusion . Belumosudil demonstrated clinically significant efficacy and a manageable safety profile in pediatric patients with severe steroid-refractory cGVHD, including children under 12 years of age. The data obtained add to the limited global publications on the use of belumosudil in pediatrics and support the feasibility of conducting prospective studies.
Introduction. Li–Fraumeni syndrome (LFS) is associated with a pathogenic variant in the TP53 gene and the development of malignant tumors (MT) in various locations. Moreover, the spectrum of MT is characterized by wide heterogeneity even within a single family. The distribution, type, and position of mutations in the TP53 gene are also variable, and the gene penetrance is incomplete, leading to the presence of healthy carriers of pathogenic variants. Genetic diagnosis of LFS is crucial for the early detection of neoplasms, as well as for the selection of treatment for the primary tumor. The aim of the study was to search for clinical and genetic correlations between pathogenic variants of TP53 and the characteristics of the associated malignant neoplasms (severity of clinical manifestations) for the subsequent classification of patients based on the individual risk of developing MT and the formation of a dynamic observation strategy. Materials and methods . The study included 25 children with confirmed LFS between 2003 and 2025. All patients received treatment at the Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov. Molecular genetic testing was performed using the next-generation sequencing method using a panel of onco-associated genes. Gene rearrangement analysis was performed using multiplex ligation-dependent probe amplification. Segregation analysis for 30 relatives from 16 families was performed using the Sanger sequencing method. Results. Genetic testing revealed 13 mutations within exons 3–8, as well as the I332Pfs*14 deletion in exon 10 of the TP53 gene. Familial LFS was identified in 13 of 16 families. Penetrance was 75.7 %, with primary multiple tumors identified in 5 (20 %) children and 7 (58 %) patients over 18 years of age. Analysis of pediatric LFS patients allowed us to identify two clinical and genetic groups. The first group of children with highly penetrant pathogenic variants Q165*, R175H, R248W, R273C, R306*, exon 10 deletion, and exon 3 splice site mutation was associated with mesenchymal neoplasms of earlier onset and a high risk of developing second tumors. The second group includes lowpenetrance variants R110C, R196Q, R196P, and S215I, identified in children with aggressive, late-onset, low-risk nervous system tumors. The high-penetrance variant P47R*fs76 was found in one family in children who could be classified into the two aforementioned clinical and genetic groups. Among adult patients, six out of eight women carrying mutations in the TP53 gene were diagnosed with breast cancer, four of them had bilateral tumors. Three patients with bilateral breast cancer and variants G108_F109 del, R175H, and R306* were later diagnosed with MT of other localizations. In men, LFS was manifested by the development of sarcomas after 18 years (P47R*fs76 and R306*), as well as rarer neoplasms such as rectal cancer, lymphoma, and brain tumor (R248W). Conclusion . A genetic study allows not only to confirm the diagnosis of LFS, but also to stratify patients into risk groups for developing certain diseases, which can be used to draw up an individual follow-up plan. Preventive mastectomy may also be considered for women with LFS. Incomplete penetrance and a variety of clinical manifestations indicate the possible influence of modifying factors, which necessitates further investigation of this phenomenon and minimization of contact with carcinogenic factors for carriers of pathogenic variants in the TP53 gene.
