Case Report: Functional characterization of lymphocyte populations in a pediatric patient with WHIM syndrome

WHIM syndrome is a rare primary immunodeficiency disorder caused by gain-of-function mutations of the chemokine receptor CXCR4, leading to abnormal and exacerbated leukocyte trafficking. It is associated with severe neutropenia and lymphopenia, and recurrent infections. Few pediatric cases have been reported, but comprehensive analyses of the composition and function of peripheral lymphocyte populations in pediatric WHIM syndrome are lacking. Here we report the case of a 6-year-old male patient carrying a CXCR4 c.1000C>T gain-of-function mutation, presenting with characteristic manifestations such as abnormal orientation of the cerebellar folia, myelokathexis and severe neutropenia as well as lymphopenia. In-depth analysis of peripheral lymphocyte subpopulations revealed an elevated CD4/CD8 T-cell ratio while T-cell activation, expansion and cytokine production were normal. B lymphopenia was accompanied with a shift in circulating B-cell populations towards transitional stages, and increased apoptosis. Interestingly, despite normal serum immunoglobulin levels, vaccination responses and B-cell receptor dependent activation, the patient's B cells showed a reduced capacity for plasmablast differentiation in vitro. These findings warrant follow-up studies in larger patient cohorts, as longitudinal monitoring of B-cell function might reveal emerging humoral defects in WHIM pediatric patients reaching adolescence and adulthood.