Heterozygous TCF3-related disease presenting as X-linked agammaglobulinemia mimicry in a male toddler with B-cell aplasia, agammaglobulinemia, and severe neutropenia

Disease associated with TCF3 variants are rare and associated with autosomal dominant inheritance agammaglobulinemia. Patients present with profound reduction in CD19+ cells and a block in B cell development at the common lymphoid precursor to pro–B cell phase of differentiation. Severe neutropenia is frequently described in X-linked agammaglobulinemia (XLA) patients but not yet described as a presenting finding in TCF3-related disease. This case describes a 13-month-old full term male with a history of reactive airway disease and recurrent infections including multiple bouts of acute otitis media, hand -foot-mouth, and viral upper respiratory illnesses who presented with fever and persistent severe neutropenia (absolute neutrophil count <100 cell/uL) necessitating hospital admission. Given his infectious history and severe neutropenia, he underwent evaluation for an underlying inborn error of immunity with the following pertinent findings: undetectable IgG (<16 mg/dL), IgM (<10 mg/dL), IgA (<2 mg/dL) and IgE (<2 kU/L), negative pneumococcal, tetanus and diphtheria vaccine titers despite vaccination, lymphocyte subsets with normal CD3, CD4, CD8, and CD16/56 absolute values but extremely low CD19 level (38 cells/cmm), and negative anti-neutrophil antibodies. Patient Bruton tyrosine kinase (Btk) protein flow cytometry results in monocytes were similar to an experimental control, while B-cell subset analysis was unable to be obtained given low B-cell numbers. Comprehensive genetic testing subsequently identified a heterozygous pathogenic TCF3 variant, c.1663G>A, p. (Glu555Lys). Following initiation of intravenous immunoglobulin (IVIG) replacement, our patient's neutropenia resolved quickly and completely. He continues to receive monthly IVIG with goal IgG troughs >800 mg/dL and resultant significant improvement in infections. As in XLA, our patient's severe neutropenia rapidly resolved with initiation of immunoglobulin replacement. While it has been shown that neutrophil development is somewhat dependent on the Btk protein, further study into the importance of the TCF3 protein and additionally adequate immunoglobulin levels in neutrophil expansion is needed. Finally, germline inborn errors of immunity, including TCF3 variants, should be considered in children with a history of recurrent infections and persistent neutropenia.