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Volume 15
Issue 11
10.3390/jcm15114291
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Case Report

A Comprehensive Literature Review and Case Report of Severe Lymphoproliferative Disease Secondary to CD137 Deficiency

by
Abeer S. Algrafi
1,*,
Turki Alwasaidi
2,
Mohammed Albalawi
1,
Mohsen Alzahrani
3,
Saad Almutairi
2 and
Haitham Osman
2
1
Department of Internal Medicine, College of Medicine, Taibah University, Madinah 42353, Saudi Arabia
2
Department of Medicine, Prince Mohammed Bin Abdulaziz Hospital, Ministry of National Guard Health Affairs, Madinah 42324, Saudi Arabia
3
Department of Oncology, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2026, 15(11), 4291; https://doi.org/10.3390/jcm15114291
Submission received: 13 April 2026 / Revised: 15 May 2026 / Accepted: 26 May 2026 / Published: 1 June 2026
(This article belongs to the Section Immunology & Rheumatology)
Versions Notes

Abstract

Inborn errors of immunity, including primary immunodeficiency disorders (PIDs), comprise a heterogeneous group of genetic conditions characterized by immune system dysfunction. One such rare PID is CD137 deficiency, which results from TNFRSF9 mutations. CD137, also known as 4-1BB, plays a pivotal role in immune system regulation and co-stimulation. This literature review explores CD137 deficiency and its implications, emphasizing its association with EBV-associated lymphoproliferative disease and potential therapeutic targets. We present the case of a 21-year-old female patient with CD137 deficiency who experienced recurrent infections, autoimmunity, and lymphoma. Genetic analysis revealed that the patient had a homozygous TNFRSF9 variant. The patient subsequently developed severe Epstein–Barr virus (EBV)-associated lymphoproliferative disease, which is one of the clinical manifestations associated with CD137 deficiency. Additionally, this review discusses similar cases in the literature and details the clinical manifestations and immune abnormalities associated with CD137 deficiency. Understanding the genetic complexity of CD137 deficiency and the immune system dysregulation it causes provides insights into potential therapeutic interventions for affected individuals. This review highlights the role of CD137 as a crucial regulator of immune homeostasis and a potential target for immunotherapy in autoimmune diseases and malignancies.
Keywords: primary immunodeficiency disorders; CD137 deficiency; TNFRSF9 mutations; Epstein–Barr virus (EBV); lymphoproliferative disease primary immunodeficiency disorders; CD137 deficiency; TNFRSF9 mutations; Epstein–Barr virus (EBV); lymphoproliferative disease

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MDPI and ACS Style

Algrafi, A.S.; Alwasaidi, T.; Albalawi, M.; Alzahrani, M.; Almutairi, S.; Osman, H. A Comprehensive Literature Review and Case Report of Severe Lymphoproliferative Disease Secondary to CD137 Deficiency. J. Clin. Med. 2026, 15, 4291. https://doi.org/10.3390/jcm15114291

AMA Style

Algrafi AS, Alwasaidi T, Albalawi M, Alzahrani M, Almutairi S, Osman H. A Comprehensive Literature Review and Case Report of Severe Lymphoproliferative Disease Secondary to CD137 Deficiency. Journal of Clinical Medicine. 2026; 15(11):4291. https://doi.org/10.3390/jcm15114291

Chicago/Turabian Style

Algrafi, Abeer S., Turki Alwasaidi, Mohammed Albalawi, Mohsen Alzahrani, Saad Almutairi, and Haitham Osman. 2026. "A Comprehensive Literature Review and Case Report of Severe Lymphoproliferative Disease Secondary to CD137 Deficiency" Journal of Clinical Medicine 15, no. 11: 4291. https://doi.org/10.3390/jcm15114291

APA Style

Algrafi, A. S., Alwasaidi, T., Albalawi, M., Alzahrani, M., Almutairi, S., & Osman, H. (2026). A Comprehensive Literature Review and Case Report of Severe Lymphoproliferative Disease Secondary to CD137 Deficiency. Journal of Clinical Medicine, 15(11), 4291. https://doi.org/10.3390/jcm15114291

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