The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the BRCA2 gene. The second case involves a child with alveolar rhabdomyosarcoma, Xanthogranuloma Juvenile, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the NF1 gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nefroblastoma in whom a pathogenic variant in the DICER1 gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play crucial roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are crucial for improving outcomes in these individuals.

The causes of pediatric cancers often remain unknown; however, due to the development of medicine and technology, genetic disorders may play a crucial role in the genesis of neoplasms. Over time, the number of cancer predisposition syndromes (CPS) and awareness of them are increasing, providing the possibility of cancer prevention and early detection. In this study, we presented data concerning the number and type of oncological cases and their correlation with CPS occurrence in a cohort of Central and Eastern European pediatric population. The data were collected between 2000 and 2019 at the Karol Jonscher Clinical Hospital of Poznan University of Medical Sciences, resulting in a cohort of 2,190 cases in total, of which 193 children (8.81%) were confirmed to have CPS. CPS occurred most frequently in infancy (22.90% of all children suffering from any diagnosed cancer during the first year of life, p < 0.0001), accounting for more than a quarter of all CPS cases in our cohort. CPS were least likely to be observed in patients aged 14 and 15 years (2.17% and 2.44% of children diagnosed with any of the listed cancers at the exact age, respectively, p < 0.05). Among CPS, the most common were neurofibromatosis type I (NF1), Li-Fraumeni syndrome (LFS), and Down syndrome (DS). To conclude, it is important to emphasize the need for personalized treatment for each patient affected by both CPS and subsequent cancer in order to reduce the toxicity of therapy and improve quality of life by reducing the risk of side effect.