Partial T cell defects and expanded CD56 NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene.

X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T B NK phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RG ) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4 T cell counts, a decreased frequency of naïve CD4 and CD8 T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4 CD45RO T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3 cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA terminally differentiated EM (EMRA) CD4 T cells. Of note, patient's NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56 cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation.