Schematic representation of the spectrum of HLH-predisposing genetic conditions, representing different pathogenic mechanisms. Genes are grouped by pathogenic mechanisms and radially organized by their associated risk of HLH, where genes at the center are fully penetrant. Mutations in genes required for lymphocyte cytotoxicity invariably lead to HLH in infancy. Mutations in other genes that impair control of common viruses via impaired lymphocyte signaling (eg, SH2D1A,ITK, and CD27) are often associated with HLH, whereas impaired lymphocyte development and function (genes causative of severe combined immunodeficiency or combined immunodeficiency) may also predispose patients to HLH. Moreover, patients with more general defects in interferon signaling (eg, genes causative of Mendelian susceptibility to mycobacterial diseases) may develop HLH. Constitutive activation or dysregulation of the inflammasome, as observed in patients with activating NLRC4 mutations or loss-of-function XIAP mutations, can cause HLH through primary macrophage activation. This might also be the case for genetic variants in other DIAP genes, as revealed by Chinn et al. Similarly, even in metabolic diseases such as Wolman disease (LIPA), primary macrophage activation resulting from accumulation of metabolites might constitute the initial trigger for HLH development. In chronic granulomatous disease, impaired autophagy may represent a mechanism for HLH susceptibility.