Chronic Granulomatous Disease

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DESCRIPTION

Chronic granulomatous disease (CGD) is a rare, primary immunodeficiency caused by a genetic defect that results in an inability of phagocytes to generate superoxide, which is important in microbial killing. Affected individuals are susceptible to recurrent, life-threatening bacterial and fungal infections.

EPIDEMIOLOGY

Incidence

1:200,000 to 1:250,000 live births in the United States and Europe; rates in other countries vary depending on ethnic practices and degree of consanguinity.

ETIOLOGY

CGD is the result of a spontaneous or inherited genetic mutation that is present at birth.

RISK FACTORS

Genetics

  • Mutations in any of the five genes that code for the five subunits of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex (phox) can result in CGD.
  • Mutations in the gp91phox subunit (CYBB) are responsible for 65% of cases and are inherited in an X-linked manner (1/3 of these cases are the result of a de novo mutation).
  • Mutations in p47phox, p22phox, p67phox, and p40phox subunits account for the remaining cases and have an autosomal recessive inheritance.
  • Mutations in the p47phox subunit are the most common cause of autosomal recessive CGD (25% of all cases).

PATHOPHYSIOLOGY

  • Phagocytes (neutrophils, monocytes, and macrophages) require NADPH oxidase to generate reactive oxygen species (ROS) in a process called the respiratory burst.
  • During this process, the NADPH oxidase complex transfers an electron to molecular oxygen forming superoxide, which is eventually converted to hydrogen peroxide.
  • Superoxide plays a significant role in killing bacterial and fungal pathogens both directly and through the activation of more important intraphagosomal proteases.
  • The clinical phenotype of CGD is related to the level of residual superoxide production; patients who have higher levels of superoxide production have better long-term survival rates.
  • Only the X-linked subunit gp91phox is phagocyte-specific, and patients with defects in the autosomal subunits may also have other abnormalities such as vascular disease, diabetes, and inflammatory bowel disease.

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