Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited

•We present updated diagnostic criteria for FHL including revised clinical criteria and guidelines on genetic and cellular diagnostic assays.•HLH-2004 criteria (without NK-cell function) have significant validity (accuracy 99%) tested against infections and systemic inflammation. [Display omitted] Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)–based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion–based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged