Abstract
INTRODUCTION: ITPR3 encodes a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca(2+) channel on the endoplasmic reticulum (ER) membrane responsible for ER Ca(2+) 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. METHODS: We retrospectively analyzed the clinical characteristics of two patients with ITPR3 deficiency accompanied by hemophagocytic lymphohistiocytosis (HLH) at our center. Through a literature review, we further compared their clinical manifestations with those of combined immunodeficiency (CID) patients who presented with HLH. RESULTS AND DISCUSSIONS: Our 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 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.