Table 5.

Congenital defects of phagocyte number, function, or both.

Disease	Affected cells	Affected function	Associated features	Inheritance	Genetic defect/presumed pathogenesis	OMIM number
1. Defects of neutrophil differentiation
(a) Severe congenital neutropenia1 (ELANE deficiency)	N	Myeloid differentiation	Subgroup with myelodysplasia	AD	ELANE: misfolded protein response	202700
(b) SCN2* (GFI 1 deficiency)	N	Myeloid differentiation	B/T lymphopenia	AD	GFI1: loss of repression of ELANE	613107
(c) SCN3 (Kostmann disease)	N	Myeloid differentiation	Cognitive and neurological defects in some patients	AR	HAX1:control of apoptosis	610738
(d) SCN4 (G6PC3 deficiency)	N + F	Myeloid differentiation, chemotaxis, ${\text{O}}_{\text{2}}^{-}$ production	Structural heart defects, urogenital abnormalities, and venous angiectasis of trunks and limbs	AR	G6PC3: abolished enzymatic activity of glucose-6-phosphatase, aberrant glycosylation, and enhanced apoptosis of neutrophils and fibroblasts	612541
(e) Glycogen storage disease type 1b	N + M	Myeloid differentiation, chemotaxis, ${\text{O}}_{\text{2}}^{-}$ production	Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly	AR	G6PT1: glucose-6-phosphate transporter 1	232220
(f) Cyclic neutropenia	N	?	Oscillations in the number of other leukocytes and platelets	AD	ELANE: misfolded protein response	162800
(g) X-linked neutropenia/*myelodysplasia	N + M	Mitosis	Monocytopenia	XL	WAS: regulator of actin cytoskeleton (loss of autoinhibition)	300299
(h) P14 deficiency*	N + L Mel	Endosome biogenesis	Neutropenia Hypogammaglobulinemia ↓CD8 cytotoxicity partial albinism growth failure	AR	ROBLD3: endosomal adaptor protein 14	610389
(i) Barth syndrome	N	Myeloid differentiation	Cardiomyopathy, growth retardation	XL	Tafazzin (TAZ) gene: abnormal lipid structure of mitochondrial membrane	302060
(j) Cohen syndrome	N	Myeloid differentiation	Retinopathy, developmental delay, facial dysmorphisms	AR	COH1 gene: Pathogenesis unknown	216550
(k) Poikiloderma with neutropenia	N	Myeloid differentiation, ${\text{O}}_{\text{2}}^{-}$ production	Poikiloderma, MDS	AR	C16orf57 gene: Pg unknown	604173
2. Defects of motility
(a) Leukocyte adhesion deficiency type 1 (LAD1)	N + M + L + NK	Adherence, chemotaxis, endocytosis, T/NK cytotoxicity	Delayed cord separation, skin ulcers periodontitis leukocytosis	AR	INTGB2: adhesion protein (CD18)	116920
(b) Leukocyte adhesion deficiency type 2 (LAD2)*	N + M	Rolling, chemotaxis	Mild LAD type 1 features plus hh-blood group plus mental and growth retardation	AR	FUCT1: GDP-Fucose transporter	266265
(c) Leukocyte adhesion deficiency type 3 (LAD3)	N + M + L + NK	Adherence, chemotaxis	LAD type 1 plus bleeding tendency	AR	KINDLIN3: Rap1-activation of β1-3 integrins	612840
(d) Rac 2 deficiency*	N	Adherence, chemotaxis ${\text{O}}_{\text{2}}^{-}$ production	Poor wound healing, leukocytosis	AD	RAC2: Regulation of actin cytoskeleton	602049
(e) β-actin deficiency*	N + M	Motility	Mental retardation, short stature	AD	ACTB: cytoplasmic actin	102630
(f) Localized juvenile periodontitis	N	Formyl peptide induced chemotaxis	Periodontitis only	AR	FPR1: chemokine receptor	136537
(g) Papillon–Lefèvre syndrome	N + M	Chemotaxis	Periodontitis, palmoplantar hyperkeratosis in some patients	AR	CTSC: cathepsin C: abnormal activation of serine proteases	245000
(h) Specific granule deficiency*	N	Chemotaxis	Neutrophils with bilobed nuclei	AR	C/EBPE: myeloid transcription factor	245480
(i) Shwachman–Diamond syndrome	N	Chemotaxis	Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia	AR	SBDS: defective ribosome synthesis	260400
3. Defects of respiratory burst
(a) X-linked chronic granulomatous disease (CGD)	N + M	Killing (faulty ${\text{O}}_{\text{2}}^{-}$ production)	McLeod phenotype in patients with deletions extending into the contiguous Kell locus	XL	CYBB: electron transport protein (gp91phox)	306400
(b-e) Autosomal CGD’s	N + M	Killing (faulty ${\text{O}}_{\text{2}}^{-}$ production)		AR	CYBA: electron transport protein (p22phox) NCF1: adapter protein (p47phox) NCF2: activating protein (p67phox) NCF4: activating protein (p40 phox)	233690 233700233710 601488
4. MSMD
(a) IL12 and IL23 receptor β1 chain deficiency	L + NK	IFN-γ secretion	Susceptibility to Mycobacteria and Salmonella	AR	IL12RB1: IL12 and IL23 receptor β1 chain	601604
(b) IL12p40 deficiency	M	IFN-γ secretion	Susceptibility to Mycobacteria and Salmonella	AR	IL12B: subunit of IL12/IL23	161561
(c) IFN-γ receptor 1 deficiency	M + L	IFN-γ binding and signaling	Susceptibility to Mycobacteria and Salmonella	AR, AD	IFNGR1: IFN-γR ligand binding chain	107470
(d) IFN-γ receptor 2 deficiency	M + L	IFN-γsignaling	Susceptibility to Mycobacteria and Salmonella	AR	IFNGR2: IFN-γR accessory chain	147569
(e) STAT1 deficiency (AD form)*	M + L	IFN-γsignaling	Susceptibility to Mycobacteria, Salmonella	AD	STAT1	600555
(f) Macrophage gp91 phox deficiency*	MΦ only	Killing (faulty O2- production)	Isolated susceptibility to mycobacteria	XL	CYBB: electron transport protein (gp 91 phox)	306400
(g) IRF8 deficiency (AD form)*	CD1c+ MDC	Differentiation of CD1c+ MDC subgroup	Susceptibility to Mycobacteria	AD	IRF8: IL12 production by CD1c+ MDC	601565
5. Other defects
(a) IRF 8-deficiency (AR form)*	Monocytes peripheral DC	Cytopenias	Susceptibility to Mycobacteria, Candida, myeloproliferation	AR	IRF8: IL12 production
(b) GATA2 deficiency (Mono MAC Syndrome)	Monocytes peripheral DC + NK + B	Multilineage cytopenias	Susceptibility to Mycobacteria, Papilloma Viruses, Histoplasmosis, Alveolar proteinosis, MDS/AML/CMML	AD	GATA2: loss of stem cells	137295
(c) Pulmonary alveolar proteinosis*	Alveolar macrophages	GM-CSF signaling	Alveolar proteinosis	Biallelic mutations in pseudoautosomal gene	CSF2RA	306250

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; ACTB, actin beta; B, B-lymphocytes; CEBPE, CCAAT/enhancer-binding protein epsilon; CMML, chronic myelomonocytic leukaemia; CTSC, cathepsin C; CYBA, cytochrome b alpha subunit; CYBB, cytochrome b beta subunit; DC, dendritic cells; ELANE, elastase neutrophil-expressed; GATA2, GATA binding protein 2; IFN, interferon; IFNGR1, interferon-gamma receptor subunit 1; IFNGR2, interferon-gamma receptor subunit 2; IL12B, interleukin-12 beta subunit; IL12RB1, interleukin-12 receptor beta 1; IFR8, interferon regulatory factor 8; F, fibroblasts; FPR1, formyl peptide receptor 1; FUCT1, fucose transporter 1; GFI1, growth factor independent 1; HAX1, HLCS1-associated protein X1; ITGB2, integrin beta-2; L, lymphocytes; M, monocytes–macrophages; MDC, myeloid dendritic cells; MDS, myelodysplasia; Mel, melanocytes; MΦ, macrophages; MSMD, Mendelian susceptibility to mycobacterial disease; N, neutrophils; NCF1, neutrophil cytosolic factor 1; NCF2, neutrophil cytosolic factor 2; NCF4, neutrophil cytosolic factor 4; NK, natural killer cells; ROBLD3, roadblock domain containing 3; SBDS, Shwachman–Bodian–Diamond syndrome; STAT, signal transducer and activator of transcription.

*Ten or fewer unrelated cases reported in the literature.

Table 5 includes seven newly described genetic defects of phagocyte number and/or function including Barth syndrome, Cohen syndrome and Poikiloderma with neutropenia. In these three clinically well-known diseases the genetic defects have been elucidated, although their molecular pathogenesis remains ill-defined. A new cause of autosomal recessive chronic granulomatous disease, namely a deficiency of the cytosolic activating protein p40 phox, has now been found in two CGD patients and is included under defects of respiratory burst. Under the heading of Mendelian susceptibility of mycobacterial disease (MSMD) two new entities were added: a) a subgroup of X-linked gp91 phox deficiency with isolated susceptibility to mycobacteria and a defect of the respiratory burst in macrophages only; b) an autosomal dominant form of IRF8 deficiency, resulting from a lack of CD1c⁺ myeloid dendritic cells that would normally secrete IL12. The clinical phenotype of MSMD may vary, depending on the nature of the genetic defect. Finally GATA2 deficiency was recently identified as the cause of the Mono MAC syndrome, with multilineage cytopenias (of monocytes, peripheral dendritic cells, NK- and B-lymphocytes) resulting in opportunistic infections (including mycobacteria), alveolar proteinosis and malignancy.