CD137 deficiency patients: two new patients and review of the literature

CD137 (4-1BB, TNFRSF9) plays a crucial role in T-cell activation, proliferation, and antiviral immunity. Biallelic TNFRSF9 variants cause CD137 deficiency, a rare inborn error of immunity characterized by Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis (HLH) and lymphoproliferation/malignancy. In this study, we aimed to characterize the clinical, immunological, and genetic spectrum of CD137 deficiency to provide insights into patient management. We recruited two patients carrying the same homozygous large deletion encompassing exons 1-6 of the TNFRSF9 gene and reviewed previously reported cases. The genetic defect was identified by whole-exome sequencing and confirmed by multiplex ligation-dependent probe amplification. Reported variants included missense, splice-site, and frameshift variants, large deletions, and compound heterozygous variants. A total of 14 patients, including the two newly reported cases, exhibited recurrent sinopulmonary infections and EBV viremia. HLH occurred in four patients (28.5%), including both newly reported patients, while lymphoma developed in seven patients (50%). Most patients were of Middle Eastern origin, and parental consanguinity was documented in 12 of 14 patients (85%). Hematopoietic stem cell transplantation (HSCT) was performed in 35.7% (5/14) of patients, with a median age of 9 years (range, 7-17 years) among four reported cases. All transplanted patients were alive at the last follow-up, whereas mortality occurred exclusively among non-transplanted patients, including EBV-positive cases. These findings expand the phenotypic and mutational spectrum of CD137 deficiency and highlight the importance of incorporating copy number variant analysis into exome-based diagnostic pipelines when conventional single-nucleotide variant analysis is inconclusive. HSCT remains the only potentially curative treatment, and early molecular diagnosis is essential to enable timely consideration of HSCT and to mitigate life-threatening EBV-driven immunopathology.