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At a glance

A genetically heterogenous, potentially fatal immunodeficiency syndrome of childhood secondary to dysfunctional oxidative metabolism in the phagocytic cells, leading to recurrent and life-threatening bacterial and fungal infections.

Synonyms

Fatal Granulomatosis of Childhood; Chronic Granulomatous Disease (CGD) of Childhood; Progressive Septic Granulomatosis; Cytochrome-b-Negative X-Linked Granulomatous Disease (see “Genetic inheritance” for subtypes).

Incidence

Approximately 1:200,000-500,000 live births.

Genetic inheritance

In two-thirds of the cases, inheritance is X-linked recessive, with the responsible CYBB (Cytochrome b(245), Beta Subunit) gene located on chromosome Xp21.1. In the remaining one-third of cases, transmission is autosomal recessive. Four types of CGD are distinguished.

NCF1 (Neutrophil Cytosolic Factor 1) gene has been mapped to chromosome 7q11.23 and mutations are responsible for Autosomal Recessive Cytochrome b-Positive CDG Type I (Synonyms: CDG due to NCF1 Deficiency; Neutrophil Cytosolic Factor 1 Deficiency; Soluble Oxidase Component II Deficiency; NOXO2 Deficiency; p47-PHOX Deficiency).

NCF2 (Neutrophil Cytosolic Factor 2) gene mutations on chromosome 1q25.3 are responsible for Autosomal Recessive Cytochrome b-Positive CDG Type II.

Autosomal Recessive Cytochrome b-Positive CDG Type III (CDG due to NCF4 Deficiency) is due to mutations in the NCF4 (Neutrophil Cytosolic Factor 4) gene found on chromosome 22q12.3.

Autosomal Recessive Cytochrome b-Negative CDG is caused by mutations in the CYBA (Cytochrome b(245), Alpha Subunit) gene located on chromosome 16q24.2.

Pathophysiology

CGD can be caused by mutations in any of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. The resulting defect in the NADPH oxidase subcomponents leads to decreased production of antimicrobial reactive oxygen intermediates (superoxide) in neutrophils, monocytes, macrophages, and eosinophils. The neutrophil phagocytic metabolic burst is impaired. Neutrophil chemotaxis and killing of organisms are defective. The disease is characterized by granulomas and recurrent infections by catalase-positive organisms. Typical organisms include Aspergillus (most common), Candida, Staphylococcus, Pseudomonas, Salmonella, Nocardia, Serratia, and Burkholderia (ceno)cepacia. CDG results in reduced production of superoxide ions and hydrogen peroxide and is responsible for the significantly impaired ability to kill intracellular microorganisms.

Diagnosis

CGD most frequently (75% of patients) presents as recurrent childhood infections. Granulocyte function can be assessed by the nitroblue tetrazolium test. Molecular diagnosis of CGD can be achieved by measurement of the NADPH oxidase activity in phagocytes or the protein expression of NADPH oxidase components and by mutation analysis of the genes responsible for defect.

Clinical aspects

The disease can manifest as skin infections, recurrent pneumonias, lung abscesses, lymphadenitis, diarrhea, perianal abscesses, hepatic, splenic, pancreatic, perinephritic, and subdiaphragmatic abscesses, osteomyelitis, and sepsis (in 15% of patients). An incidence of up to 3.7 severe infections requiring hospitalization per 100 patients and month has been reported. A number of inflammatory (noninfectious) diseases can ...

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