Diagnosis of chronic myeloid neoplasms and approach to germline predisposition in children

Abstract

Chronic myeloid disorders in the pediatric population include myelodysplastic syndrome/neoplasm (MDS), juvenile myelomonocytic leukemia (JMML) and similar disorders, such as Noonan syndrome-associated myeloproliferations, and myeloproliferative neoplasms (MPNs) including chronic myeloid leukemia, mastocytosis, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. These disorders pose significant diagnostic complexities due to their rarity and overlap with reactive conditions. This review examines the distinctive clinicopathologic features of chronic myeloid neoplasms occurring in childhood, emphasizing the importance of a comprehensive diagnostic approach that integrates clinical assessment, morphologic analysis, immunophenotyping, and genetic studies. Special attention is given to germline predisposition syndromes and their implications for diagnosis and management, including GATA2 deficiency, SAMD9/SAMD9L disorders, severe congenital neutropenia, Fanconi anemia, telomere biology disorders, familial platelet disorders, and germline variants in ERCC6L2, CEBPA, DDX41, and TP53, among others. MDS occurring in the setting of insertional mutagenesis after gene therapy is discussed. Emphasis is placed on the description of reactive non-neoplastic conditions that may mimic myeloid neoplasia in the pediatric setting. The pathologist's role is crucial in recognizing subtle morphologic clues and integrating them with molecular findings to distinguish these entities from germline disorders and benign processes.