Table 5.

Congenital defects of phagocyte number or function

DiseaseGenetic defectInheritanceOMIMAffected cellsAffected functionAssociated features
1. Congenital neutropenias 
Elastase deficiency (severe congenital neutropenia [SCN] 1) ELANE AD 130130 N Myeloid differentiation Susceptibility to MDS/leukemia
Severe congenital neutropenia or cyclic neutropenia 
GFI 1 deficiency (SCN2) GFI1 AD 600871 N Myeloid differentiation B/T lymphopenia 
HAX1 deficiency (Kostmann disease) (SCN3) HAX1 AR 605998 N Myeloid differentiation Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia 
G6PC3 deficiency (SCN4) G6PC3 AR 611045 N Myeloid differentiation, chemotaxis
O2− production 		Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasia of trunks and limbs 
VPS45 deficiency (SCN5) VPS45 AR 610035 N Myeloid differentiation, migration Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly 
Glycogen storage disease type 1b SLC37A4/G6PT1 AR 602671 N + M Myeloid differentiation, chemotaxis,
O2− production 		Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly 
X-linked neutropenia/myelodysplasia WAS XL GOF 300299 N Differentiation, mitosis. Results from GOF mutations in GTPase binding domain of WASP Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies 
P14/LAMTOR2 deficiency LAMTOR2 AR 610389 N + M Endosomal biogenesis Neutropenia
Hypogammaglobulinemia CD8− cytotoxicity, partial albinism, growth failure 
Barth syndrome (3-methylglutaconic aciduria type II) TAZ XL 300394 N+L
Mel 		Mitochondrial function Cardiomyopathy, myopathy, growth retardation, neutropenia 
Cohen syndrome VPS13B AR 607817 N Myeloid differentiation Dysmorphism, mental retardation, obesity, deafness, neutropenia 
Clericuzio syndrome (poikiloderma with neutropenia) USB1 AR 613276 N Myeloid differentiation Retinopathy, developmental delay, facial dysmorphisms, poikiloderma 
JAGN1 deficiency JAGN1 AR 616012 N Myeloid differentiation Myeloid maturation arrest, osteopenia 
3-Methylglutaconic aciduria CLPB AD/AR 616254 N Myeloid differentiation
Mitochondrial protein 		Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR 
G-CSF receptor deficiency CSF3R AR 138971 N Stress granulopoiesis disturbed  
SMARCD2 deficiency SMARCD2 AR 601736 N Chromatin remodeling, myeloid differentiation, and neutrophil functional defect Neutropenia, developmental aberrations, bones, hematopoietic stem cells, myelodysplasia 
CEBPE deficiency CEBPE AR 245480 N Terminal maturation and global dysfunction Neutropenia, neutrophils with bilobed nuclei, poor chemotaxis 
Shwachman–Diamond syndrome SBDS AR 607444 N Neutrophil maturation, chemotaxis, ribosomal biogenesis Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia 
DNAJC21 AR 617052 N + HSC Pancytopenia, exocrine pancreatic insufficiency 
EFL1 AR 617941 N + HSC 
HYOU1 deficiency HYOU1 AR 601746 N Unfolded protein response Hypoglycemia, inflammatory complications 
SRP54 deficiency SRP54 AD 604857 N Protein translocation to ER, myeloid differentiation, and neutrophil functional defect Neutropenia, exocrine pancreatic insufficiency 
CXCR2 deficiency CXCR2 AR 619407 N Reduced expression of CXCR2 on patient cells, impaired responses to CXCL8 Profound neutropenia, myelokathexis, recurrent gingivitis, oral ulcers, hypergammaglobulinemia 
DBF4 deficiency DBF4 AR NA N Disturbed cell cycle Neurocognitive developmental aberrations 
SRP19/SRPRA deficiency SRP19 AR NA N Alterations in neutrophil granulocyte development with reduction in electron-dense granules Exocrine pancreatic insufficiency, growth insufficiency, recurrent pulmonary infections with bronchiectasis, congenital neutropenia 
SRPRA 
2. Defects of motility 
Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065 N + M +
L + NK 		Adherence, chemotaxis, endocytosis, T/NK cytotoxicity Delayed cord separation, skin ulcers, periodontitis, leukocytosis 
Leukocyte adhesion deficiency type 2 (LAD2) SLC35C1 AR 605881 N + M Rolling, chemotaxis Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay 
Leukocyte adhesion deficiency type 3 (LAD3) FERMT3 AR 607901 N + M +
L + NK 		Adherence, chemotaxis LAD type 1 plus bleeding tendency 
Rac2 deficiency RAC2 AD LOF 608203 N Adherence, chemotaxis
O2− production 		Poor wound healing, leukocytosis 
β-Actin deficiency ACTB AD 102630 N + M Motility Mental retardation, short stature 
Localized juvenile periodontitis FPR1 AR 136537 N Formyl peptide–induced chemotaxis Periodontitis only 
Papillon–Lefèvre syndrome CTSC AR 602365 N + M Chemotaxis Periodontitis, palmoplantar hyperkeratosis in some patients 
WDR1 deficiency WDR1 AR 604734 N Spreading, survival, chemotaxis Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nucleus herniate 
Cystic fibrosis CFTR AR 602421 M only Chemotaxis Respiratory infections, pancreatic insufficiency, elevated sweat chloride 
Neutropenia with combined immune deficiency due to MKL1 deficiency MAP3K9/MKL1 AR 606078 N + M +L + NK Impaired expression of cytoskeletal genes Mild thrombocytopenia 
CCR2 CCR2 AR 219600 M Impaired CCL2-dependent monocyte migration to the lungs and infected tissues Pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including BCG disease 
3. Defects of respiratory burst 
X-linked chronic granulomatous disease (CGD), gp91phox CYBB XL 306400 N + M Killing (faulty O2− production) Infections, autoinflammatory phenotype, IBD
McLeod phenotype in patients with deletions extending into the contiguous Kell locus 
AR CGD CYBA AR 608508 Infections, autoinflammatory phenotype 
CYBC1 618334 
NCF1 608512 
NCF2 608515 
NCF4 613960 
G6PD deficiency class I G6PD XL 305900 N Reduced O2− production Infections 
4. Other nonlymphoid defects 
Pulmonary alveolar proteinosis CSF2RA XL (biallelic mutations in pseudoautosomal gene) 300770 Alveolar macrophages GM-CSF signaling Alveolar proteinosis 
CSF2RB AR 614370 
DiseaseGenetic defectInheritanceOMIMAffected cellsAffected functionAssociated features
1. Congenital neutropenias 
Elastase deficiency (severe congenital neutropenia [SCN] 1) ELANE AD 130130 N Myeloid differentiation Susceptibility to MDS/leukemia
Severe congenital neutropenia or cyclic neutropenia 
GFI 1 deficiency (SCN2) GFI1 AD 600871 N Myeloid differentiation B/T lymphopenia 
HAX1 deficiency (Kostmann disease) (SCN3) HAX1 AR 605998 N Myeloid differentiation Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia 
G6PC3 deficiency (SCN4) G6PC3 AR 611045 N Myeloid differentiation, chemotaxis
O2− production 		Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasia of trunks and limbs 
VPS45 deficiency (SCN5) VPS45 AR 610035 N Myeloid differentiation, migration Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly 
Glycogen storage disease type 1b SLC37A4/G6PT1 AR 602671 N + M Myeloid differentiation, chemotaxis,
O2− production 		Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly 
X-linked neutropenia/myelodysplasia WAS XL GOF 300299 N Differentiation, mitosis. Results from GOF mutations in GTPase binding domain of WASP Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies 
P14/LAMTOR2 deficiency LAMTOR2 AR 610389 N + M Endosomal biogenesis Neutropenia
Hypogammaglobulinemia CD8− cytotoxicity, partial albinism, growth failure 
Barth syndrome (3-methylglutaconic aciduria type II) TAZ XL 300394 N+L
Mel 		Mitochondrial function Cardiomyopathy, myopathy, growth retardation, neutropenia 
Cohen syndrome VPS13B AR 607817 N Myeloid differentiation Dysmorphism, mental retardation, obesity, deafness, neutropenia 
Clericuzio syndrome (poikiloderma with neutropenia) USB1 AR 613276 N Myeloid differentiation Retinopathy, developmental delay, facial dysmorphisms, poikiloderma 
JAGN1 deficiency JAGN1 AR 616012 N Myeloid differentiation Myeloid maturation arrest, osteopenia 
3-Methylglutaconic aciduria CLPB AD/AR 616254 N Myeloid differentiation
Mitochondrial protein 		Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR 
G-CSF receptor deficiency CSF3R AR 138971 N Stress granulopoiesis disturbed  
SMARCD2 deficiency SMARCD2 AR 601736 N Chromatin remodeling, myeloid differentiation, and neutrophil functional defect Neutropenia, developmental aberrations, bones, hematopoietic stem cells, myelodysplasia 
CEBPE deficiency CEBPE AR 245480 N Terminal maturation and global dysfunction Neutropenia, neutrophils with bilobed nuclei, poor chemotaxis 
Shwachman–Diamond syndrome SBDS AR 607444 N Neutrophil maturation, chemotaxis, ribosomal biogenesis Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia 
DNAJC21 AR 617052 N + HSC Pancytopenia, exocrine pancreatic insufficiency 
EFL1 AR 617941 N + HSC 
HYOU1 deficiency HYOU1 AR 601746 N Unfolded protein response Hypoglycemia, inflammatory complications 
SRP54 deficiency SRP54 AD 604857 N Protein translocation to ER, myeloid differentiation, and neutrophil functional defect Neutropenia, exocrine pancreatic insufficiency 
CXCR2 deficiency CXCR2 AR 619407 N Reduced expression of CXCR2 on patient cells, impaired responses to CXCL8 Profound neutropenia, myelokathexis, recurrent gingivitis, oral ulcers, hypergammaglobulinemia 
DBF4 deficiency DBF4 AR NA N Disturbed cell cycle Neurocognitive developmental aberrations 
SRP19/SRPRA deficiency SRP19 AR NA N Alterations in neutrophil granulocyte development with reduction in electron-dense granules Exocrine pancreatic insufficiency, growth insufficiency, recurrent pulmonary infections with bronchiectasis, congenital neutropenia 
SRPRA 
2. Defects of motility 
Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065 N + M +
L + NK 		Adherence, chemotaxis, endocytosis, T/NK cytotoxicity Delayed cord separation, skin ulcers, periodontitis, leukocytosis 
Leukocyte adhesion deficiency type 2 (LAD2) SLC35C1 AR 605881 N + M Rolling, chemotaxis Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay 
Leukocyte adhesion deficiency type 3 (LAD3) FERMT3 AR 607901 N + M +
L + NK 		Adherence, chemotaxis LAD type 1 plus bleeding tendency 
Rac2 deficiency RAC2 AD LOF 608203 N Adherence, chemotaxis
O2− production 		Poor wound healing, leukocytosis 
β-Actin deficiency ACTB AD 102630 N + M Motility Mental retardation, short stature 
Localized juvenile periodontitis FPR1 AR 136537 N Formyl peptide–induced chemotaxis Periodontitis only 
Papillon–Lefèvre syndrome CTSC AR 602365 N + M Chemotaxis Periodontitis, palmoplantar hyperkeratosis in some patients 
WDR1 deficiency WDR1 AR 604734 N Spreading, survival, chemotaxis Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nucleus herniate 
Cystic fibrosis CFTR AR 602421 M only Chemotaxis Respiratory infections, pancreatic insufficiency, elevated sweat chloride 
Neutropenia with combined immune deficiency due to MKL1 deficiency MAP3K9/MKL1 AR 606078 N + M +L + NK Impaired expression of cytoskeletal genes Mild thrombocytopenia 
CCR2 CCR2 AR 219600 M Impaired CCL2-dependent monocyte migration to the lungs and infected tissues Pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including BCG disease 
3. Defects of respiratory burst 
X-linked chronic granulomatous disease (CGD), gp91phox CYBB XL 306400 N + M Killing (faulty O2− production) Infections, autoinflammatory phenotype, IBD
McLeod phenotype in patients with deletions extending into the contiguous Kell locus 
AR CGD CYBA AR 608508 Infections, autoinflammatory phenotype 
CYBC1 618334 
NCF1 608512 
NCF2 608515 
NCF4 613960 
G6PD deficiency class I G6PD XL 305900 N Reduced O2− production Infections 
4. Other nonlymphoid defects 
Pulmonary alveolar proteinosis CSF2RA XL (biallelic mutations in pseudoautosomal gene) 300770 Alveolar macrophages GM-CSF signaling Alveolar proteinosis 
CSF2RB AR 614370 

MDS, myelodysplastic syndrome; IUGR, intrauterine growth retardation; LAD, leukocyte adhesion deficiency; AML, acute myelogenous leukemia; N, neutrophil; M, monocyte; MEL, melanocyte; L, lymphocyte; NK, natural killer; BCG, bacillus Calmette–Guérin; IBD, inflammatory bowel disease.

Total number of defects in Table 5: 45.

New IEIs: 4, DBF4, SRP19, SRPRA, and CCR2 (73, 74, 75).

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