Chronic Granulomatous Disease 

  • Author: Roman Janusz Nowicki, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 4, 2012
 

Background

Chronic granulomatous disease (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. Chronic granulomatous disease is a syndrome that typically manifests as pneumonia, infectious dermatitis, and recurrent or severe subcutaneous abscess formation. In addition to increased susceptibility to infections, patients have a higher prevalence of mucosal inflammatory disorders such as colitis, enteritis, and gastric outlet obstruction. Cutaneous disease occurs in 60-70% of patients.

eMedicine's Pediatrics article Chronic Granulomatous Disease may be of interest.

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Pathophysiology

Chronic granulomatous disease 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 chronic granulomatous disease, phagocytes ingest bacteria normally, but they cannot kill them.[1]

Patients with chronic granulomatous disease 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.

Chronic granulomatous disease is usually inherited in an X-linked recessive fashion. Most patients (approximately 90%) 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.[2] 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,[3] and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations.[4, 5, 6]

In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency.[7] 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 chronic granulomatous disease has been described; this form is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly.[8]

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Epidemiology

Frequency

United States

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

International

The prevalence of chronic granulomatous disease varies among the populations investigated, with studies reporting variations from 1 case per 1 million individuals to 1 case per 160,000 individuals.[9, 10]

Mortality/Morbidity

The long-term survival of patients who develop symptoms after the end of the first year of life is significantly better than that of patients whose illness starts in infancy.

Morbidity secondary to infection or granulomatous complications remains significant for many patients, particularly those with the X-linked form. Currently, the annual mortality rate is 1.5% per year for persons with autosomal recessive chronic granulomatous disease and 5% for those with X-linked chronic granulomatous disease.

Since the advent of prophylactic antibiotics, antifungals, and interferon-gamma (INF-gamma), the prognosis for patients with chronic granulomatous disease has improved. Patients living to their 30s and 40s is now common.

Patients with chronic granulomatous disease and modest residual production of reactive oxygen intermediates (ROIs) have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and is a predictor of survival in patients with chronic granulomatous disease.[11]

Race

Chronic granulomatous disease affects persons of all races.

Sex

Approximately 90% of patients with chronic granulomatous disease are male.

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 chronic granulomatous disease 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, 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, and International Society for Human and Animal Mycology

Disclosure: Nothing to disclose.

Specialty Editor Board

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: Stiefel GSK Company Salary Employment; Orfagen Consulting fee Consulting; Maruho Consulting fee Consulting; Astellas Consulting fee Consulting; Abbott Consulting fee Consulting; Leo Pharma Consulting fee Consulting

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

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

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

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

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

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

Disclosure: Nothing to disclose.

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