New human combined immunodeficiency caused by interferon regulatory factor 4 (IRF4) deficiency inherited by uniparental isodisomy

Abstract Background Interferon regulatory factor4 ( IRF4) is a fundamental transcription factor in adaptive and innate immunity, due to its key role in the differentiation and functional specialization of lymphoid and myeloid lineage cells. In mouse models, IRF4participates in bone marrow central tolerance, naive B cellactivation, germinal centre formation, plasma cell differentiation, immunoglobulin secretion, T helper subset differentiation, macrophage polarization, and dendritic cell differentiation, among other processes. Objective To describe the first case of autosomal recessive human IRF4deficiency. Methods Clinical, histological, immunophenotypic and genotypic features of a patient with an autosomal recessive complete IRF4deficiency are described. Results We report the first case of autosomal recessive complete IRF4deficiency in a 5-month-old Spanish girl caused by an uncommon mechanism for monogenicdiseases, a maternal isodisomyof chromosome 6. The girl was homozygous for a maternal splicing mutation that abolished IRF4expression and exhibited severe immunological as well as non-immunological abnormalities. Major clinical manifestations were severe dermatitis, gastro-intestinal and respiratory infections, failureto thrive, feverof unknown origin, hyperthyrotropinaemia, and severe fast hypoglycaemia. The immunological findings recapitulate many of the features observed in mouse models, including combined immunodeficiencywith reduced total memory B and T cells, alteration of the κ/λ light chain ratio in immature B cells, absence of germinal centres in lymph nodes, absence of plasma cells and agammaglobulinaemia. Macrophage and T helper celldifferentiation were also impaired. The patient died at 20 months of age of acute multiorgan failureafter haematopoietic stem cell transplant. Conclusions This case demonstrates the relevance of IRF4in the human immune system previously only inferred from mouse and cell models and expands our knowledge of the complexity of genetic mechanisms that lead to the appearance of primary immunodeficiencies.