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 |
| . | 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 |