Chronic Granulomatous Disease

Chronic Granulomatous Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Chronic Granulomatous Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • CGD
  • chronic dysphagocytosis
  • chronic granulomatous disease
  • congenital dysphagocytosis
  • fatal granulomatous disease of childhood
  • granulomatosis, chronic, familial
  • granulomatosis, septic, progressive
  • impotent neutrophil syndrome

Disorder Subdivisions

  • None

General Discussion

Chronic granulomatous disease (CGD) is a rare inherited primary immune deficiency disorder that affects certain white blood corpuscles (neutrophils, monocytes, macrophages, eosinophils). The disorder is characterized by an inability to resist repeated infectious diseases and a tendency to develop chronic inflammation. Life-threatening recurrent fungal and bacterial infections affecting the skin, lungs, and bones may occur along with swollen areas of inflamed tissues known as granulomas that can be widely distributed. Symptoms usually begin in infancy or childhood. Individuals with mild forms of the disorder may not develop symptoms until the teens or adulthood. Chronic granulomatous disease is a genetic disorder and is caused by inherited defects in an important enzyme in white blood cells that manufactures oxidants for microbial killing.

Symptoms

Chronic granulomatous disease is characterized by a susceptibility to repeated bacterial and fungal infections. CGD can also be associated with the development of granulomatous lesions of the skin, lungs, bones, and lymph nodes formed by collections of inflammatory white blood cells. Excess gammaglobulin in the blood (hypergammaglobulinemia), low levels of circulating red blood cells (anemia), an increase in white blood cells (leukocytosis) can occur as a result of repeated infections or chronic inflammation. Evidence of chronic infections may be seen in the liver, gastrointestinal tract, brain and eyes.



There is usually a history of repeated infections, including inflammation of the lymph glands (suppurative lymphadenitis), skin infections, and pneumonia. Blood studies often show evidence of chronic infection. There may also be a persistent runny nose (rhinitis), inflammation of the skin (dermatitis), diarrhea, perianal abscesses, and an inflammation of the mucous membranes of the mouth (stomatitis).



Infection of the bones (osteomyelitis), brain abscesses, obstruction of the genitourinary tract and/or gastrointestinal tract due to the formation of granulomatous tissue, and delayed growth are also symptomatic of chronic granulomatous disease. Abnormal enlargement of the liver and spleen (hepatosplenomegaly) may also occur.

Causes

Chronic granulomatous disease is a genetic disease. In CGD, mutations in any one of five different genes can cause a defect in an enzyme called phagocyte NADPH oxidase. Certain white blood cells use this enzyme to produce hydrogen peroxide, which these cells need in order to kill certain bacteria and fungi.



Genetic diseases are determined by two genes, one received from the father and one from the mother. There is a genetic form (X-linked recessive) of CGD that primarily affects males. The remaining cases of CGD are inherited as autosomal recessive traits, which can affect both males and females.



X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.



Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.



If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.



Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Chronic granulomatous disease affects males more often than females. Approximately, two-thirds of individuals have the X-linked recessive form of the disorder. Because it is a genetic disease, CGD is present at birth. Symptoms from CGD usually first occur during infancy or childhood, but sometimes may be delayed until the early teens. In a few cases, the first symptoms have been known to occur in adulthood.



It is estimated that about four to five in every million people worldwide has chronic granulomatous disease.

Standard Therapies

Diagnosis

A diagnosis of chronic granulomatous disease is made based upon a thorough clinical evaluation, a detailed patient history, and a specialized procedure called nitroblue tetrazolium (NBT) slide test. During this procedure, a blood sample is taken to obtain white blood cells. NBT is then mixed with the white blood cells. In healthy individuals, the white blood cells produce a chemical oxidant that destroys bacteria. This chemical also reacts with NBT turning it a deep blue color. If this reaction does not occur, then this important chemical is not being produced by an individual's white blood cells. Another similar test for diagnosis of CGD uses a molecule called dihydrorhodamine 123 (DHR) to determine whether or not white blood cells are making oxidants normally.



Treatment

Treatment of chronic granulomatous disease consists of continuous antibiotic therapy to help prevent infections, such as trimethoprim and sulfamethoxazole to protect against bacterial infections, and itraconazole for anti-fungal protection. Infections usually require additional antibiotics. Corticosteroid drugs are also of benefit for treating granulomatous complications. Bone marrow transplants have proven to be successful in some affected individuals with CGD.



The orphan drug, Actimmune (interferon gamma-1b), has been approved by the Food and Drug Administration (FDA) for the treatment of chronic granulomatous disease. For information on this drug, contact the manufacturer:



InterMune, Inc.

3280 Bayshore Blvd.

Brisband, CA 94005

Tel.: (415) 466-2200

Fax: (415) 466-2300



Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Clinical trials related to CGD can also be found by searching the web site at http://clinicaltrials.gov/.



As of Autumn, 2012, the NIH listed multiple clinical trials to investigate possible treatments for chronic granulomatous disease (CGD), and include as follows:



1. Several different studies to determine the efficacy and safety of stem cell transplant procedures in CGD patients.



2. Studying and developing gene therapy for treating CGD.



3. Studying the response of white blood cells from CGD patients to interferon-gamma treatment.



Contact for additional information about chronic granulomatous disease:



Mary C. Dinauer, MD, PhD

Fred M. Saigh Distinguished Chair of Pediatric Research

Professor of Pediatrics and of Pathology & Immunology

Washington University School of Medicine

St. Louis Children's Hospital

660 S. Euclid Ave.

Campus Box 8208

St. Louis, MO 63110

Office: 314-286-0542

Fax: 314-286-2893

Website: http://peds.wustl.edu

References

TEXTBOOKS

Dinauer M. Chronic Granulomatous Disease. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins;. 2003:386-87.



Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1039.



JOURNAL ARTICLES

Kang EM, Marciano BE, DeRavin S, Zarember KA, Holland SM, Malech HL. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011;127(6):1319-26.



Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363(27):2600-10.



Matute JD, Arias AA, Wright NA, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114(15):3309-15.



Rosenzweig SD. Inflammatory manifestations in chronic granulomatous disease (CGD). J Clin Immunol. 2008;28 Suppl 1:S67-72.



Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008;140(3):255-66.



Dinauer MC. Chronic Granulomatous Disease and Other Disorders of Phagocyte Function. Hematology. Hematology Am Soc Hematol Educ Program. 2005:89-95.



Gallin JL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003;348:2416-22.



Johnson RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001;8:17-22.



Segal BH, Leto TL, Gallin JI, et al. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). 2000;79:170-200.



INTERNET

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome b-Positive, Type II. Entry No: 233710. Last Edited March 23, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 10, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Granulomatous Disease, Chronic, X-Linked; CGD. No: 306400. Last Edited December 16, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 10, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Atypical mycobacteriosis, familial, X-linked 2; AMCBX2. Entry No: 300645. Last Edited August 18, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 10, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome b-Positive, Type I. Entry No: 233700. Last Edited August 12, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 10, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome b-Negative. Entry No: 233690. Last Edited June 3, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 10, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome b-Positive, Type III. No: 613960. Last Edited May 31, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 10, 2012.



Chronic granulomatous disease. MedlinePlus. http://www.nlm.nih.gov/medlineplus/ency/article/001239.htm. Updated September 15, 2010. Accessed September 10, 2012.



Chronic granulomatous disease. PubMed Health. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002219/. Last Updated September 15, 2010. Accessed September 10, 2012. Chronic Granulomatous Disease. In: IDF Patient & Family Handbook For Primary Immunodeficiency Diseases, 4th ed. 2007:30-35. http://primaryimmune.org/wp-content/uploads/2011/04/Patient-Family-Handbook-4th.pdf. Accessed September 10, 2012.

Resources

Chronic Granulomatous Disease Association, Inc.

2616 Monterey Road

San Marino, CA 91108

Tel: (626)441-4118

Email: cgda@socal.rr.com

Internet: http://www.cgdassociation.org



Immune Deficiency Foundation

40 W. Chesapeake Avenue

Suite 308

Towson, MD 21204

Tel: (410)321-6647

Fax: (410)321-9165

Tel: (800)296-4433

Email: idf@primaryimmune.org

Internet: http://www.primaryimmune.org



Chronic Granulomatous Disease Registry

c/o Immune Deficiency Foundation

25 West Chesapeake Avenue

Room 206

Towson, MD 21204

Tel: (410)321-6647

Fax: (410)321-9165

Tel: (800)296-4433

Email: idf@primaryimmune.org

Internet: http://www.primaryimmune.org



NIH/National Institute of Allergy and Infectious Diseases

Office of Communications and Government Relations

6610 Rockledge Drive, MSC 6612

Bethesda, MD 20892-6612

Tel: (301)496-5717

Fax: (301)402-3573

Tel: (866)284-4107

TDD: (800)877-8339

Email: ocpostoffice@niaid.nih.gov

Internet: http://www.niaid.nih.gov/



International Patient Organization for Primary Immunodeficiencies

Firside Main Road

Downderry

Cornwall, PL11 3LE

United Kingdom

Tel: 441503250668

Fax: 441503250961

Email: info@ipopi.org

Internet: http://www.ipopi.org/



Jeffrey Modell Foundation

780 Third Avenue

New York, NY 10017

USA

Tel: (212)819-0200

Fax: (212)764-4180

Tel: (866)469-6474

Email: info@jmfworld.org

Internet: http://www.info4pi.org



CGD Society

199A Victoria Street

London, SW1E 5NE

United Kingdom

Tel: 08009878988

Email: hello@cgdsociety.org

Internet: http://www.cgdsociety.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



European Society for Immunodeficiencies

1-3 rue de Chantepoulet

Geneva, CH 1211

Switzerland

Tel: 410229080484

Fax: 41229069140

Email: esid@kenes.com

Internet: http://www.esid.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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