Here we describe 5 patients from 2 unrelated kindreds with bi-allelic mutations in IRAK4, where one of which was a missense mutation, resulting in a severe autoinflammatory phenotype without overt immune deficiency, presenting with fever without infection, increased inflammatory markers, massive splenomegaly, transfusion dependent anemia; and severe neuroinflammation in 3/5 cases. This evidence concerns the gene IRAK4 and Immunodeficiency.