Congenital defects of phagocytes

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Overview

Classification

Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

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

Congenital phagocyte defects

Classification

 
 
Congenital defects of Phagocyte
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Congenital defects of phagocyte number
 
Congenital defects of phagocyte function

Congeital Defects of Phagocyte Number

 
 
 
 
Congenital defects of phagocyte number
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Syndrome associated
 
 
 
No syndrome associated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shwachman-Diamond syndrome
 
 
 
 
Elastase deficiency (SCN1)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G6PC3 deficiency (SCN4)
 
 
 
 
HAX1 deficiency (Kostmann Disease) (SCN3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glycogen storage disease type 1b
 
 
 
 
GFI 1 deficiency (SCN2)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohen syndrome
 
 
 
 
X-linked neutropenia/myelodysplasia WAS GOF
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Barth Syndrome
 
 
 
 
G-CSF receptor deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clericuzio syndrome (poikiloderma with neutropenia)
 
 
 
 
Neutropenia with combined immune deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VPS45 deficiency(SCN5)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P14/LAMTOR2 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
JAGN1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
methylglutacoic aciduria
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SMARCD2 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WDR1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HYOU1 deficiency
 
 
 
 

Congenital defects of phagocyte function

 
 
 
 
 
Congenital defects of phagocyte function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Syndrome associated
 
 
 
 
 
No Syndrome associated;DHR assay(or NBT test)?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cystic Fibrosis
 
 
Normal
 
 
Abnormal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Papillion-Lefèvre
 
 
 
 
GATA2 def (MonoMac syndrome
 
 
 
CGD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Localized juvenile periodontitis
 
 
 
 
Specific granule deficiency
 
 
 
Rac 2 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-Actin
 
 
 
 
Pulmonary alveolar proteinosis
 
 
 
G6PD def Class 1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukocyte adhesion deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 


Shwachman-Diamond Syndrome

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

G6PC3 deficiency

  • Autosomal recessive(AR) transmission.
  • 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

  • Autosomal recessive(AR) transmission.
  • 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.

Cohen Syndrome

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

Barth Syndrome

  • X-linked recessive(XLR) transmission.
  • 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.

Clericuzio syndrome (poikiloderma with neutropenia)

  • Autosomal recessive(AR) transmission.
  • 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 (SCN5)

  • Autosomal recessive(AR) transmission.
  • 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

  • Autosomal recessive(AR) transmission.
  • Patients present with short stature, hypopigmeted skin, coarse facial features and recurrent bronchopulmonary infections.

JAGN1 deficiency

  • Autosomal recessive(AR) transmission.
  • Patients present with aberrant myeloid cell homeostasis and congenital neutropenia.

3-Methylglutaconic aciduria

  • Autosomal recessive(AR) transmission.
  • 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.

SMARCD2 deficiency

  • Autosomal recessive(AR) transmission.
  • It is caused by a mutation in the SMARCD2 gene on chromosome 17.
  • Patients present with myelodysplasia, bone defects and developmental abnormalities.

WDR1 deficiency

  • Autosomal recessive(AR) transmission.
  • It is caused by mutation in the WDR1 gene on chromosome 4.
  • Patients present with recurrent infections, mild neutropenia, impaired wound healing and severe stomatitis with oral stenosis.

HYOU1 deficiency

  • Autosomal recessive (AR) transmission.
  • It is caused by mutation in the HYOU1 gene on chromosome 11.
  • Patients present with hypoglycemia and infections.

Elastase deficiency (SCN1)

  • Autosomal dominant (AD) transmission.
  • 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.
  • The mainstay of treatment is giving granulocyte-colony stimulating factor (GCSF or CSF3)

HAX1 deficiency (Kostmann Disease) (SCN3)

  • Autosomal recessive (AR) transmission.
  • 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.

GFI 1 deficiency

  • Autosomal dominant (AD) transmission.
  • B and T cell lymphopenia is the major feature of this disease.

X-linked neutropenia/myelodysplasia WAS GOF

  • X-linked recessive transmission.
  • Patients present with myeloid maturation arrest and monocytopenia.

G-CSF receptor deficiency

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

Neutropenia with combined immune deficiency

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

Cystic fibrosis

  • Autosomal recessive (AR) transmission.
  • It is caused by homozygous or compound heterozygous mutation in the cystic fibrosis conductance regulator gene (CFTR) on chromosome 7.
  • Patients can have pancreatic insufficiency, lung infections and increased levels of sweat chloride.
  • For detailed information about cystic fibrosis, click here Cystic fibrosis

Papillion-Lefèvre

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

Localized juvenile periodontitis

  • It is cause by a mutation in the FPR1 gene.

B-actin

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

Leukocyte adhesion deficiency

  • Autosomal recessive transmission.
  • It results from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule, which results in poor neutrophil chemotaxis and phagocytosis.
  • Patients develop recurrent infections, delay in umbilical cord seperation, and impaired pus formation.
  • The mainstay of treatment is HSCT and gene therapy.
  • For detailed information about leukocyte adhesion deficiency, click here leukocyte adhesion deficiency

GATA2 def (MonoMac syndrome)

  • Autosomal dominant (AD) transmission.
  • 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 nontuberculous mycobacterial (NTM) infections, although opportunistic fungal infections and disseminated human papillomavirus (HPV) infections also occur.
  • Bone marrow transplant has shown success as the mode of treatment in some cases.

Specific granule deficiency

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

Pulmonary alveolar proteinosis

  • Autosomal recessive (AR) transmission.
  • 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.

Chronic granulomatous disease (CGD)

  • X-linked recessive transmission, however it can also have autosomal recessive transmission in few cases.
  • 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.
  • For detailed information about Chronic granulomatous disease, click here Chronic granulomatous disease

Rac 2 deficiency

  • It is caused by mutation in the RAC2 gene on chromosome 22.
  • Patients present with severe infections and impaired wound healing.

Glucose-6-phosphate dehydrogenase deficiency (G6PD) Class 1

  • X-linked dominant (XLD) transmission.
  • 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 Glucose-6-phosphate dehydrogenase deficiency

References

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