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Chronic granulomatous disease.
Medical expert of the article
Last reviewed: 12.07.2025
Chronic granulomatous disease is a hereditary disorder caused by a defect in the superoxide anion formation system in neutrophils in response to stimulation by microorganisms. This disorder is based on genetically programmed changes in the structure or deficiency of the enzyme NADPH oxidase, which catalyzes the reduction of oxygen to its active form, superoxide. Superoxide is the main component of the respiratory burst, which destroys microorganisms. Due to the genetic defect, intracellular death of bacteria and fungi capable of producing their own catalase (catalase-positive ones - Staphylococcus aureus, Burkholderia cepacia, Aspergillus spp.) is blocked. Depending on the severity of the defect, there are 4 main types of chronic granulomatous disease: complete absence of formation (X-linked form - 75% of cases), partial deficiency, structural defect leading to dysfunction or regulation of NADPH oxidase formation. The localization and nature of the gene rearrangements underlying the disease, and the clinical features of the variants are known.
The incidence of chronic granulomatous disease is from 1:1,000,000 to 1:250,000 of the population (1 in 200,000-250,000 live births). Mostly boys are affected, much less often girls.
History of chronic granulomatous disease
Two years after Bruton's description of aammaglobulinemia in 1952, Janeway et al. (1954) described 5 children with severe, recurrent, life-threatening infections caused by Staphylococcus aureus, Proteus, or Pseudomonas aeruginosa. An increase in serum immunoglobulin levels was noted. In 1957, two independent reports (Landing and Shirkey and Good et al.), and then Berendes and Bridges in 1957, described several boys with purulent lymphadenitis, hepatosplenomegaly, severe pulmonary disease, purulent skin lesions, and hypergammaglobulinemia. The specific antibody response was normal, and the increase in gamma globulin concentration corresponded to the severity of the infectious process. Early mortality of all children, despite intensive treatment, provided the basis for Bridges et al. In 1959, this syndrome was named "fatal granulomatosis of childhood". In 1967, Jonston and McMurry described 5 boys and summarized 23 previously described patients with a clinical syndrome of hepatosplenomegaly, recurrent purulent infections, and hypergammaglobulinemia. All patients were boys, 16 of whom had a brother or brothers with similar clinical symptoms, indicating X-linked inheritance of the disease. Jonston and McMurry proposed to name this syndrome "chronic fatal granulomatosis". In the same year, Quie et al. described abnormalities in intracellular bacterial killing in neutrophils, and since then the term "chronic granulomatous disease" has been used. Interestingly, in French this disease is called "granulomatose septique chronique", which means "chronic septic granulomatosis".
Pathogenesis of chronic granulomatous disease
Chronic granulomatous disease develops as a result of a defect in the enzyme NADPH oxidase, which catalyzes the "respiratory burst" that normally accompanies phagocytosis in all cells of the myeloid series. The "respiratory burst" leads to the formation of free oxygen radicals, which play a critical role in the intracellular killing of pathogenic bacteria and fungi. Due to the disruption of microorganism digestion with preserved phagocytosis, hematogenous dissemination of infection by neutrophils occurs. As a result, patients with chronic granulomatous disease suffer from severe recurrent infections caused by intracellular pathogens. In addition, against this background, patients with chronic granulomatous disease develop diffuse granulomatosis of internal organs (esophagus, stomach, biliary system, ureter, bladder), which is quite often the cause of obstructive or painful symptoms.
The enzyme NADPH oxidase consists of 4 subunits: gp91-phox and p22-phox, which make up cytochrome b558, and 2 cytosolic components - p47-phox and p67-phox. Chronic granulomatous disease can be caused by a defect in any of these components. A mutation in the gp91-phox gene, which is localized on the short arm of the X chromosome (Xp21.1), leads to the development of an X-linked variant of the disease and is found in 65% of all patients with chronic granulomatous disease. The remaining 35% of cases of chronic granulomatous disease are inherited in an autosomal recessive (AR) manner. The gene encoding the p47-phox subunit is localized on chromosome 7 till.23 (25% of CGD AR), p67-phox is localized on chromosome lq25 (5% of CGD AR), and p22-phox is localized on chromosome 16q24 (5% of CGD AR).
Symptoms of Chronic Granulomatous Disease
Clinical manifestations of chronic kidney disease - as a rule, during the first 2 years of life, children develop severe recurrent bacterial or fungal infections. The frequency and severity vary depending on the variant of chronic granulomatous disease. Girls get sick at an older age, the course of the disease is moderate to mild. The main clinical sign is the formation of granulomas. The lungs, skin, mucous membranes, and lymph nodes are mainly affected. Liver and subhepatic abscesses, osteomyelitis, perianal abscesses and fistulas are characteristic. Meningitis, stomatitis, and sepsis may occur. Pneumonia caused by B. cepatia is acute, with a high probability of death if treated incorrectly with antibiotics; Fungal infections, especially aspergillosis, are also extremely dangerous and have a long-term chronic course with lymphadenitis, hepatosplenomegaly, colitis, damage to the kidneys, bladder, and esophagus.
Diagnosis of chronic granulomatous disease
The main diagnostic criterion for chronic granulomatous disease is the NBT (NitroBlue Tetrazolium) test or neutrophil chemiluminescence testing. The methods are highly sensitive, but require careful testing and interpretation of results to avoid diagnostic errors. In rarer variants of the disease, neutrophil extracts are tested for cytochrome b 558 content using immunoblotting or spectral analysis. The most accurate, but less accessible, are molecular biological methods for diagnosing chronic granulomatous disease with the determination of structural defects in the corresponding genes.
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Treatment of chronic granulomatous disease
With timely diagnosis, adequate prevention and proper treatment, children with chronic granulomatous disease can be provided with a satisfactory quality of life. In severe cases and the risk of disability, a radical treatment method is allogeneic hematopoietic stem cell transplantation, the decision to perform which depends on many factors and is made collectively; such treatment is carried out in highly specialized clinics. Approaches to gene therapy are being developed, but so far this is a purely experimental method.