ORIGINAL RESEARCH article
Front. Immunol.
Sec. Primary Immunodeficiencies
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1653662
This article is part of the Research TopicThe expanding spectrum of Hemophagocytic lymphohistiocytosis: pathogenic mechanisms and therapeutic implicationsView all articles
Two Cases of Combined Immunodeficiency with ITPR3 Mutations Presenting with Life-Threatening Severe EBV-Associated Hemophagocytic Lymphohistiocytosis
Provisionally accepted
- 1Children‘s Hospital of Chongqing Medical University, Chongqing, China
- 2Huazhong University of Science and Technology, Wuhan, China
- 3The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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ITPR3 encodes a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca²⁺ channel on the endoplasmic reticulum (ER) membrane responsible for ER Ca²+ release. Recently, both autosomal dominant and recessive ITPR3 mutations have been reported in association with combined immunodeficiency (CID), accompanied by multisystem manifestations including neurological involvement. We herein report two CID patients with multisystem disorders harboring germline heterozygous ITPR3 mutations (c.7570C>G, p.Arg2524Gly and c.7570C>T, p.Arg2524Cys). Both patients developed severe Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), and one patient succumbed to disease-related complications. Our study demonstrates that ITPR3-associated CID confers a susceptibility to EBV-driven pathologies, particularly HLH, which warrants heightened clinical vigilance. Therefore, early hematopoietic stem cell transplantation (HSCT) should be considered to improve survival outcomes in these patients.
Keywords: hemophagocytic lymphohistiocytosis, HLH, ITPR3, ebv, Combined immunodeficiency
Received: 25 Jun 2025; Accepted: 03 Sep 2025.
Copyright: © 2025 Yu, Li, Zhang, Li, Sun, An, Xiong, Jin and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hao Xiong, Huazhong University of Science and Technology, Wuhan, China
Peina Jin, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Xiaodong Zhao, Children‘s Hospital of Chongqing Medical University, Chongqing, China
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