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.
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.
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.
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.
