Immunogenetic Screening Reveals Hidden Inborn Errors of Immunity in Pediatric Lymphoproliferative Disorders

Background and Aims Pediatric lymphoproliferative disorders (LPD), both malignant and nonmalignant, may conceal underlying inborn errors of immunity (IEI), yet systematic screening is rarely performed. We hypothesized that comprehensive immunogenetic evaluation would reveal a high prevalence of IEI in children with persistent LPD, providing actionable targets for precision therapy and surveillance. Methods We prospectively enrolled 38 patients (age <20 years) with polyclonal LPD (PL, n = 21) or malignant lymphoma (ML, n = 17) persisting >6 months off therapy. All underwent extended flow cytometry immunophenotyping and genomic analysis via panel/whole-exome sequencing filtered for International Union of Immunological Societies (IUIS) 2024 IEI genes. An IEI diagnosis required pathogenic variants and/or European Society for Immunodeficiencies (ESID) clinical criteria. Results were compared with age-matched healthy controls. Results We identified confirmed IEI in 42% of patients (16/38): 57% in PL and 24% in ML. Pathogenic variants included FAS, PIK3CD, STAT3, NFKB1/2, PRKCD, IKZF1, SH2D1A, and TACI. An additional 34% harbored variants of uncertain significance in IEI or lymphoma-associated genes (CTLA4, STAT5A, and ATM), yielding a total diagnostic yield of 66%. Remarkably, most patients lacked classic infection-related immunodeficiency signs. Immunophenotyping revealed distinctive IEI signatures: significantly elevated double-negative T cells (DNT; CD3+CD4-CD8-TCRαβ+, >2% of CD3+) and unswitched memory B cells (CD27+IgD+IgM+) compared to both non-IEI patients and controls (p < 0.01, p < 0.001). These patterns persisted across multiple IEI subtypes, suggesting potential screening biomarkers preceding genetic confirmation. Strikingly, all confirmed IEI in ML occurred exclusively in B cell lymphomas (Burkitt, diffuse large B cell lymphoma [DLBCL], and Hodgkin), reinforcing the critical role of B cell immune dysregulation in lymphomagenesis. Conclusions Over 60% of pediatric LPD patients harbor IEI-associated variants, even without classical immunodeficiency presentation. Our findings establish elevated DNT cells and altered B cell memory compartments as accessible screening biomarkers that could trigger genetic workup. This high diagnostic yield supports integrating routine immunogenetic screening into pediatric LPD diagnostic pathways, enabling gene-targeted interventions (sirolimus, abatacept), personalized surveillance protocols, and improved long-term outcomes. These data advocate for a paradigm shift toward precision immunology in pediatric oncohematology.