Congenital defects of phagocytes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Anmol Pitliya, M.B.B.S. M.D.[3]

Overview[edit | edit source]

Phagocytes are crucial to the immune system as they have the ability to ingest and kill foreign pathogens encountered by the body. In congenital phagocyte cell defects, the ability of phagocytes to kill foreign pathogens is impaired, leading to widespread infections. Congenital defects of phagocytes can be divided into two types including defects of phagocyte number and defects of phagocyte function.

Classification[edit | edit source]

Congeital Defects of Phagocyte Number[edit | edit source]

Congenital defects of phagocyte function[edit | edit source]

Shwachman-Diamond Syndrome[edit | edit source]

• Autosomal recessive (AR) transmission.^[1]
• It is caused by compound heterozygous or homozygous mutations in the SBDS gene on chromosome 7.^[2]
• Patients present with exocrine pancreatic dysfunction, bony metaphyseal dysostosis, and pancytopenias.^[3]
• CT scan can be useful in the diagnosis.^[4]

For more information on Shwachman-Diamond syndrome, click here.

G6PC3 deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.^[5]
• G6PC3 stands for glucose-6-phosphatase catalytic 3.
• It is caused by homozygous mutation in the G6PC3 gene on chromosome 17.
• Patients present with congenital neutropenia, cardiac abnormalities, inner ear deafness, neonatal sepsis and a prominent superficial venous pattern.

Glycogen storage disease type 1b[edit | edit source]

• Autosomal recessive (AR) transmission.^[6]
• It is caused by homozygous or compound heterozygous mutation in the G6PT1 gene which encodes glucose-6-phosphate translocase, on chromosome 11.
• Patients present with short stature, hepatomegaly, hypertension, eruptive xanthoma and hyperlipidemia.^[7]

For more information on glycogen storage disease type 1b, click here.

Cohen Syndrome[edit | edit source]

• Autosomal recessive (AR) transmission.^[8]
• It is caused by homozygous or compound heterozygous mutations in the COH1 gene on chromosome 8.
• Patients present with non-progressive psychomotor retardation, motor clumsiness, microcephaly, high-arched eyelids, short philtrum, thick hair, low hairline, hypotonia, hyperextensibility of the joints, retinochoroidal dystrophy, myopia, and granulocytopenia.

For more information on Cohen Syndrome, click here.

Barth Syndrome[edit | edit source]

• X-linked recessive (XLR) transmission.^[9]
• It is caused by mutation in the tafazzin gene (TAZ) on chromosome X.
• Patients present with dilated cardiomyopathy, a predominantly proximal skeletal myopathy, growth retardation, organic aciduria, and neutropenia.

For more information on Barth Syndrome, click here.

Clericuzio syndrome (poikiloderma with neutropenia)[edit | edit source]

• Autosomal recessive (AR) transmission.^[10]
• It is caused by homozygous or compound heterozygous mutation in the USB1 gene on chromosome 16.
• Patients present with a gradual, centripetally spreading, papular erythematous rash on the limbs during the first year of life. Neutropenia may also be present.

VPS45 deficiency[edit | edit source]

• Also known as severe congenital neutropenia-5 (SCN5).
• Autosomal recessive (AR) transmission.^[11]
• It is caused by homozygous mutation in the VPS45 gene on chromosome 1.
• Patients present in childhood with poor weight gain, hepatosplenomegaly, severe infections, hypergammaglobulinemia, nephromegaly due to extramedullary hematopoiesis, and bone marrow fibrosis.

P14/LAMTOR2 deficiency[edit | edit source]

• LAMTOR2 stands for late endosomal/lysosomal adaptor, MAPK AND MTOR activator 2.
• Autosomal recessive (AR) transmission.^[12]
• Patients present with short stature, hypopigmented skin, coarse facial features and recurrent bronchopulmonary infections.

JAGN1 deficiency[edit | edit source]

• JAGN stands for jagunal drosophila homolog of 1.
• Autosomal recessive (AR) transmission.^[13]
• Patients present with aberrant myeloid cell homeostasis and congenital neutropenia.

3-Methylglutaconic aciduria[edit | edit source]

• Autosomal recessive (AR) transmission.^[14]
• It is caused by homozygous or compound heterozygous mutation in the CLPB gene on chromosome 11, which leads to by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia.
• Patients present with delayed psychomotor development, congenital neutropenia, brain atrophy, microcephaly, movement disorders and cataracts.

For more information on 3-methylglutaconic aciduria, click here.

SMARCD2 deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.^[15]
• SMARCD2 stands for SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2.
• It is caused by a mutation in the SMARCD2 gene on chromosome 17.^[16]
• Patients present with myelodysplasia, bone defects and developmental abnormalities.

WDR1 deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.
• WDR1 stands for WD repeat-containing protein 1.
• It is caused by mutation in the WDR1 gene on chromosome 4.^[17]
• Patients present with recurrent infections, mild neutropenia, impaired wound healing and severe stomatitis with oral stenosis.^[18]

HYOU1 deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.
• HYOU1 stands for hypoxia up-regulated 1.
• It is caused by mutation in the HYOU1 gene on chromosome 11.
• Patients present with hypoglycemia and infections.

Elastase deficiency (Severe Congenital Neutropenia 1)[edit | edit source]

• Autosomal dominant (AD) transmission.^[19]
• It is caused by a mutation in the ELANE gene on chromosome 19.
• Patients present with cyclic neutropenia starting in childhood with a cycle of approximately 21 days. Recurrent infections with fever are also common features.^[20]
• The mainstay of treatment is giving granulocyte-colony stimulating factor (GCSF or CSF3)^[21]

HAX1 deficiency (Kostmann Disease) (Severe Congenital Neutropenia 3)[edit | edit source]

• Autosomal recessive (AR) transmission.^[22]
• HAX1 stands for HCLS1-associated protein X1.
• It is caused by homozygous or compound heterozygous mutation in the HAX1 gene on chromosome 1.
• Patients present with recurrent bacterial infections and neurologic abnormalities like psychomotor retardation and seizures. Patients are also at increased risk of developing leukemia and myelodysplastic syndrome.^[23]

GFI 1 deficiency[edit | edit source]

• Autosomal dominant (AD) transmission.
• GFI 1 stands for growth-factor independent 1.
• B and T cell lymphopenia is the major feature of this disease.

X-linked neutropenia/myelodysplasia WAS GOF[edit | edit source]

• X-linked recessive transmission.^[24]
• Patients present with myeloid maturation arrest and monocytopenia.

G-CSF (Growth-colony stimulating factor) receptor deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.^[25]
• It is caused by a mutation in CSF3R gene on chromosome 1.

Neutropenia with combined immune deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.^[26]
• It is caused by a mutation in MKL1 gene on chromosome 22.
• Patients present with lymphopenia and thrombocytopenia.

Cystic fibrosis[edit | edit source]

• Autosomal recessive (AR) transmission.^[27]
• It is caused by homozygous or compound heterozygous mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) on chromosome 7.^[28]
• Patients can have pancreatic insufficiency, lung infections and increased levels of sweat chloride.

For more information about cystic fibrosis, click here.

Papillion-Lefèvre[edit | edit source]

• Autosomal recessive (AR) transmission.
• It is caused by homozygous or compound heterozygous mutation in the cathepsin C gene (CTSC) on chromosome 11.^[29]
• Patients present with palmoplantar keratoderma, periodontitis, and premature loss of dentition.^[30]
• Acitretin if started at a early age can help patients have normal adult dentition.^[31]

Localized juvenile periodontitis[edit | edit source]

• It is cause by a mutation in the FPR1 gene.
• The fMLP receptor (FPR1) of phagocytic cells interacts with bacterial fMLP and mediates chemotaxis, degranulation, and superoxide production.

B-actin[edit | edit source]

• It is cause by a mutation in the ACTB gene.
• Patients usually develop mental retardation.

Leukocyte adhesion deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.^[32]
• It results from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule located on chromosome 21, which results in poor neutrophil chemotaxis and phagocytosis.
• Patients develop recurrent infections, delay in umbilical cord seperation, and impaired pus formation.^[33]
• The mainstay of treatment is HSCT and gene therapy.^[34][35]

For more information about leukocyte adhesion deficiency, click here.

GATA2 def (MonoMac syndrome)[edit | edit source]

• Autosomal dominant (AD) transmission.^[36]
• GATA2 stands for GATA-binding protein 2.
• This syndrome is characterized by decreased or absent circulating monocytes, dendritic cells, natural killer cells, and B cells. Patients are at increased risk of developing severe or recurrent non-tuberculous mycobacterial (NTM) infections, although opportunistic fungal infections and disseminated human papilloma virus (HPV) infections also occur.^[37]
• Bone marrow transplant has shown success as the mode of treatment in some cases. ^[38]

Specific granule deficiency[edit | edit source]

• Autosomal recessive (AR) transmission.^[39]
• It is cause by homozygous mutation in the CEBPE gene on chromosome 14.
• Neutrophils of these patients display atypical bilobed nuclei.

Pulmonary alveolar proteinosis[edit | edit source]

• Autosomal recessive (AR) transmission.^[40]
• It is caused by homozygous mutation in the CSF2RB gene on chromosome 22.
• It is a rare lung disease characterized by the ineffective clearance of surfactant by alveolar macrophages causing respiratory failure.^[41]

For more information about pulmonary alveolar proteinosis, click here.

Chronic granulomatous disease (CGD)[edit | edit source]

• X-linked recessive transmission. However, it can also have autosomal recessive transmission in a few cases.^[42]
• It results from an inability of the phagocytes to kill microbes that they have already ingested.
• Patients present with pneumonia, osteomyelitis and recurrent abscesses of the skin and organs.^[43]

For detailed information about chronic granulomatous disease, click here.

Rac 2 deficiency[edit | edit source]

• It is caused by mutation in the RAC2 gene on chromosome 22.
• Rac 2 stands for RAS-Related C3 Botulinum Toxin Substrate 2.
• Patients present with severe infections and impaired wound healing.^[44]

Glucose-6-phosphate dehydrogenase deficiency (G6PD) Class 1[edit | edit source]

• X-linked dominant (XLD) transmission.^[45]
• It is caused by mutation in the G6PD gene on chromosome X causing decreased G6PD enzyme levels.
• Patients typically present with acute hemolytic anemia and neonatal jaundice.

For detailed information about glucose-6-phosphate dehydrogenase deficiency, click here.

References[edit | edit source]