Immune Dysfunction and Hematologic Malignancies in Young Adults: A Two-Case Series Highlighting Germline Predisposition, DNA Repair Defects, and Primary Antibody Deficiency

Aim: This case series describes two young adults with aggressive hematologic malignancies and underlying immune dysfunction, in whom germline cancer predisposition syndromes were identified or strongly suspected. The study intends to highlight the diagnostic and interpretive challenges of tumor-oriented sequencing in this clinical context. Methods: We conducted a retrospective analysis of clinical, immunological, and genetic data from two patients referred to a tertiary hematology center for aggressive or recurrent hematologic malignancies associated with severe infectious complications and immune dysregulation. Targeted next-generation sequencing (NGS) panels were used in all cases, and confirmatory germline testing using non-hematopoietic tissue was performed when a hereditary predisposition syndrome was suspected. Results: Case 1 (M.E.G., 24 years) carried a heterozygous germline DDX41 variant and presented with peripheral T-cell lymphoma (Lennert variant), treatment-refractory disease, and a severe infectious burden. Case 2 (N.S.L., 24 years) had congenital IgG/IgA deficiency and was ultimately diagnosed with Nijmegen breakage syndrome due to a homozygous pathogenic NBN variant, and developed an aggressive Epstein–Barr virus (EBV)-associated B cell lymphoma against a background of primary immunodeficiency. Conclusions: Systematic germline evaluation should be considered for young patients with aggressive or multiple hematologic malignancies and unexplained immune dysfunction. Early identification of inherited cancer predisposition syndromes has major consequences for treatment strategies, donor selection for transplantation, family testing, and long-term oncologic surveillance.