A novel IL2RG transmembrane mutation resulting in severe combined immunodeficiency and maternal T cell engraftment

Abstract

IntroductionX-linked severe combined immunodeficiency (SCID) is commonly associated with mutations in IL2RG, an integral part of several receptors essential for lymphocyte development. In this case, our patient has a novel IL2RG missense mutation in the transmembrane domain leading to a T-B+NK+ phenotype. Case PresentationA 2-week-old boy born full-term from an uncomplicated, non-consanguineous pregnancy presents for absent T-cell receptor excision circles (TREC) on newborn screen. He had been growing well, no thrush/diarrhea/infections. Patient had an uncle who died at 1-year-old from pneumonia but had no other family history. On exam he was healthy appearing, no dysmorphic features, rash, or hepatosplenomegaly.CBC was notable for absolute lymphocyte count of 530. TBNK flow cytometry at 2-weeks-old revealed < 1% CD3+ cells/CD4+ helper cells/CD8+ cytotoxic T cells, B cells were normal at 410, NK cells were mildly low 148, CD45Ra was < 1%, and CD45Ro was 100% (Table 1). Mitogen stimulation was markedly decreased. Microarray was normal, without 22q11.2 deletion. Primary immunodeficiency panel revealed hemizygous variance at the IL2RG gene c.811G>A (p.Gly 271Arg) that is not seen in the general population.Patient was diagnosed with T-B+NK+ SCID. Mom was CMV+ and stopped breastfeeding. Patient was started on IVIG and prophylactic therapy: fluconazole, acyclovir, and bactrim. He was referred to BMTand enrolled in a gene therapy trial as he has no matched sibling donors. At 2-months-old, repeat TBNK was notable for increased CD3 and CD4 cells, raising the concern for maternal engraftment (Table 1). Subsequent HLA chimerism study of T cells demonstrated HLA from mother(CD3) 91% and HLA from patient(CD3) 9% indicating engraftment of maternal cells. Patient was asymptomatic, no diarrhea or rash.Table 1Labs2-weeks-old2-months-oldTBNKAbsolute CD3+ (%)1 (<1%)49 (3%)Absolute CD3+4+ (%)1 (<1%)47 (3%)Absolute CD3+CD8+(%)1 (<1%)1 (<1%)CD4CD8 Ratio233.67Absolute CD19+ (%)410 (72%)1611 (92%)Absolute CD56+16+ (%)148 (26%)79 (5%)CD45 Ra<1%CD45 Ro100%Mitogen StimulationPHA2988 cpmCon A3774 cpmPWM1654 cpm DiscussionThe IL2RG gene G271A mutation results in a missense mutation that changes the charge of the amino acid glycine(uncharged) to arginine(positively charged) at the transmembrane region of the gamma chain, which likely interferes with the receptor's localization on the cell surface. Interestingly, NK cells are preserved in this patient indicating some preservation of signaling by IL15. This case illustrates a novel mutation in the IL2RG transmembrane domain that results in T-B+NK+ phenotype with maternal engraftment.