Table 1.
Genetic conditions associated with predisposition to HLH.
| Form | Gene (locus) | Protein | Function | Associated immunological and clinical features |
|---|---|---|---|---|
| Familial HLH | ||||
| FHL1 | Unknown (9q21.3–q22?) |
Unknown | Unknown | – |
| FHL2 | PRF1 (10q21–22) |
Perforin | Pore formation | – |
| FHL3 | UNC13D (17q25) |
Munc13-4 | Cytolytic granule priming and fusion | – |
| FHL4 | STX11 (6q24) |
Syntaxin-11 | Cytolytic granule fusion | – |
| FHL5 | STXBP2 (19p13) |
Munc18-2 | Cytolytic granule fusion | Chronic enteropathy, sensorineural hearing deficit, abnormal bleeding |
| Degranulation defect syndromes | ||||
| Griscelli syndrome type 2 | RAB27A (15q21) |
Rab27α | Cytolytic granule docking | Partial albinism, silver-grey hair |
| Chediak-Higashi syndrome | LYST (1q42–43) |
LYST | Cytolytic granule trafficking | Partial albinism, recurrent pyogenic infections |
| Hermansky-Pudlak syndrome type 2 |
AP3B1 (5q14.1) |
AP3B1 | Cytolytic granule trafficking | Partial albinism, bleeding tendency |
| X-linked lymphoproliferative syndromes and EBV-susceptibility disorders | ||||
| XLP-1 | SH2D1A (Xq24–25) |
SAP | Signaling in T and NK cells | Defective killing of EBV-infected B cells; May present with HLH, EBV-driven lymphoma, hypogammaglobulinemia |
| XLP-2 | BIRC4 (Xq25) |
XIAP | Inhibition of apoptosis, inflammasome control, NOD1/NOD2 signaling | Elevated IL-18, colitis, hypogammaglobulinemia |
| X-linked immunodeficiency with magnesium defect (XMEN) | MAGT1 (Xq21.1) |
MAGT1 | Mg transport, NKG2D-dependent cytotoxicity | CD4 lymphopenia, EBV-driven lymphoproliferation/lymphoma |
| IL-2-inducible T cell kinase deficiency |
ITK (5q34) |
ITK | TCR signaling | Absence of iNKT-cells, EBV-driven lymphoproliferation/lymphoma |
| CD27 deficiency | CD27 (12p13) |
CD27 | T-cell costimulatory signaling | Combined immunodeficiency, EBV-driven lymphoproliferation/lymphoma |
| Autoinflammatory syndromes | ||||
| NLRC4 gain-of-function | NLRC4 (2p22.3) |
NLRC4 | Inflammasome assembly | Constitutive inflammasome activation, elevated IL-1β/IL-18, recurrent fever, enteropathy |
| NOCARH syndrome | CDC42 (1p36.12) |
CDC42 | Actin assembly | Neonatal cytopenias, dyshematopoiesis, recurrent febrile episodes, urticaria-like rash |