Hemophagocytic lymphohistiocytosis (HLH) is one of the most severe manifestations of XLP1 with high mortality.<h4>Objective</h4>Present a clinical case of fatal HLH associated with a novel <i>SH2D1A</i> variant, highlighting the variability of clinical presentation and the potential role of co-infections.<h4>Methods</h4>We analyzed clinical and laboratory data of three brothers who died from HLH in early age. This evidence concerns the gene SH2D1A and hemophagocytic syndrome.