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Chronic Granulomatous Disease

  • Author: Roman Janusz Nowicki, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Aug 21, 2015
 

Background

Chronic granulomatous disease (CGD) is a rare (∼1:250,000 births) disease caused by mutations in any one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.

CGD is a primary immunodeficiency that affects phagocytes of the innate immune system and leads to recurrent or persistent intracellular bacterial and fungal infections and to granuloma formation. In approximately two thirds of patients, the first symptoms of CGD appear during the first year of life in the form of infections, dermatitis (sometimes seen at birth), gastrointestinal complications (obstruction or intermittent bloody diarrhea due to colitis), and a failure to thrive. The clinical picture can be quite variable, with some infants having several of these complications and others appearing to be far less ill.[1] Cutaneous disease occurs in 60-70% of patients.

Also see Pediatric Chronic Granulomatous Disease.

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Pathophysiology

Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from the inability of phagocytes to kill microbes they have ingested. This impairment in killing is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In CGD, phagocytes ingest bacteria normally, but they cannot kill them.[2]

Patients with CGD are susceptible to severe and recurrent infections due to catalase-positive organisms and organisms resistant to nonoxidative killing. Catalase-negative bacteria, such as streptococci and pneumococci that have the capacity to generate hydrogen peroxide, are killed as they usually are. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.

CGD is usually inherited in an X-linked recessive fashion. Most patients (approximately 80%) are males, who have hemizygous mutations on the X-linked gene coding for gp91phox. The gene responsible for this form of the disease has been mapped to the p21.1 region of the X chromosome.[3] However, among chronic granulomatous disease subtypes, the autosomal recessive (AR) forms may be associated with milder disease. The extent to which environmental and secondary genetic factors influence phenotypic expression of disease is unknown. A wide variety of molecular defects have been described in the genes for the gp91phox component, the p22phox component,[4] and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations.[5, 6, 7]

In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency.[8] Another protein, p40phox, has been implicated in the regulation of the NADPH oxidase, but no individual with a mutation in the protein has been found to date. A new variant of CGD has been described; this form is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly.[9]

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Epidemiology

Frequency

United States

The exact incidence of chronic granulomatous disease (CGD) is unknown. CGD affects approximately 1 infant per 200,000-250,000 live births.

International

The prevalence of CGD varies among the populations investigated, with studies reporting variations from 1 case per 1 million individuals to 1 case per 160,000 individuals.[10, 11]

Race

Chronic granulomatous disease affects persons of all races.

Sex

Approximately 80% of patients with CGD are male, because the main cause of the disease is a mutation in an X-chromosome–linked gene. However, defects in autosomal genes may also underlie the disease and cause CGD in both males and females.[1]

Age

Symptom onset typically occurs at a young age, although the diagnosis has been at an older age in some patients.[12, 13, 14] Typically, patients with CGD have recurrent pyogenic infections that start in the first year of life. Occasionally, the onset may be delayed until the patient is aged 10-20 years.

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Contributor Information and Disclosures
Author

Roman Janusz Nowicki, MD, PhD Professor and Chairman, Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Poland

Roman Janusz Nowicki, MD, PhD is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, International Society for Human and Animal Mycology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

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