Table 4.

Genetic conditions associated with predisposition to HLH

	Selected mechanism(s) of HLH predisposition
Familial HLH
PRF1	Defective lymphocyte granule–mediated cytotoxicity
UNC13D	Defective lymphocyte granule–mediated cytotoxicity
STX11	Defective lymphocyte granule–mediated cytotoxicity
STXBP2	Defective lymphocyte granule–mediated cytotoxicity
Pigmentary disorders associated with HLH
RAB27A	Defective lymphocyte granule–mediated cytotoxicity
LYST	Defective lymphocyte granule–mediated cytotoxicity
AP3B1	Defective lymphocyte granule–mediated cytotoxicity
XLP-1 and XLP-2
SH2D1A	Defective 2B4-mediated cytotoxicity; defective T-cell restimulation–induced cell death; absent iNKT cells
XIAP	Dysregulated NLRP3 inflammasome function; increased effector cell susceptibility to cell death
NLRC4	Constitutively active NLRC4 inflammasome function
CDC42	Defective formation of actin-based structures; defective proliferation, migration, and cytotoxicity; increased IL-1β and Il-18 production
EBV susceptibility disorders
MAGT1	Defective Mg++ transporter; low NKG2D, defective cytotoxicity
ITK	Defective tyrosine kinase function; defective cytotoxic T-cell expansion and cytolytic capacity; decreased iNKT cells
CD27	CD27 expressed on T cells participates in costimulatory signaling, interacts with CD70; required for normal T-cell proliferation and triggering of cytotoxicity against EBV-infected B cells; decreased iNKT cells
CD70	CD70 expressed by EBV-infected B cells interacts with CD27 on T cells; required for normal expansion and cytotoxicity of the T cells; decreased NKG2D, 2B4; decreased iNKT cells
CTPS1	Enzyme involved in de novo synthesis of cytidine nucleotide triphosphate (CTP) (critical precursor of nucleic acid metabolism); deficiency leads to impaired proliferation; decreased iNKT cells
RASGRP1	Activates RAS, which leads to MAPK pathway activation; defects in T-cell activation, proliferation, and migration; decreased cytotoxicity; decreased iNKT cells