TABLE 1.

Genetically determined forms of hemophagocytotic lymphohistiocytosis (HLH).

Primary HLH	Gene	Protein	Pathophysiology	Functional testing
Familial HLH (FHL)
FHL-1	Unknown	Unknown
FHL-2	PFR1	Perforin	Lack of perforin expression in lytic granules	Perforin expression
FHL-3	UNC13D	Munc13-4	Deficiency in fusion of lytic granule with plasma membrane	Degranulation
FHL-4	STX11	Syntaxin11	Deficiency in fusion of lytic granule with plasma membrane	Degranulation
FHL-5	STXBP2	Munc18-2	Deficiency in fusion of lytic granule with plasma membrane	Degranulation
Other immunodeficiency syndromes with defect in degranulation
GS-II	RAB27A	Rab27a	Deficiency in docking of lytic granule to the plasma membrane	Degranulation hair microscopy
CHS	LYST	Lyst	Defect in maturation of vesicles into secretory cytotoxic granules	Degranulation hair microscopy
—
Other inborn errors of immunity	Gene	Protein	Pathophysiology	Functional testing
Immunodeficiency syndromes with HLH as a frequent manifestation
XLP-1	SH2D1A	SAP	Defective killing of EBV infected B-cells by CD8 and NK cells	SAP expression
XLP-2	BIRC4	XIAP	Impaired inhibition of inflammasome activity	XIAP expression L18MDP assay
TIM3 deficiency	HAVCR2	TIM3	Persistent T cell activation and increased production of inflammatory cytokines	TIM3 expression
Immunodeficiency syndromes with HLH as an occasional manifestation
Chronic granulomatous disease (CGD)	CYBB, CYBA, NCF1, NCF2, NCF4	Components of NADPH oxidase	Excessive inflammatory responses due to altered inflammasome regulation by NADPH oxidase?	Oxidative Burst
(S)CID	>50 genes	various	Lack of pathogen control	Lymphocyte phenotyping
Wiskott-Aldrich syndrome	WAS	WASP	Lack of pathogen control Impaired cytoskeleton-inflammasome interaction?	WASP expression (FACS)
CD27 deficiency	CD27	CD27	Impaired co-stimulation of T cells Lack of EBV control	CD27 expression
ITK deficiency	ITK	ITK	Impaired TCR mediated signaling Lack of EBV control	ITK expression
IFNγ receptor deficiency	IFNGR1 IFNGR2	IFN-gamma receptor	Lack of pathogen control (mycobacteria, salmonella)	STAT1 phosphorylation
ALPS	FAS (het) FASLG	FAS FASLG	Defects in Fas ligand-mediated elimination of activated lymphocytes	TCR DNT Vitamin B12, soluble FasL
Autoinflammatory diseases with HLH as a frequent manifestation
NLRC4 gain of function	NLRC4 (het)	NLRC4	Constitutive inflammasome activation IL-1β/IL-18 production	Genetic testing
CDC42 mutations	CDC42 (het)	CDC42	Impaired cytoskeleton-inflammasome interaction?	Genetic testing