Information on the following diseases can be found in the Related Disorders section of this report:

• Wegener's Granulomatosis
• Sarcoidosis
• Churg-Strauss Syndrome
• Polyarteritis Nodosa

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.

Chronic granulomatous disease is a genetic disease. In CGD, mutations in any one of four 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 recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is turned off' and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females in CGD usually do not display symptoms of the disorder because typically, tone-half of cells have the X chromosome with the normal gene "turned on". Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. 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% to have a son affected with the disease, and a 25% chance to have an unaffected son.

Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait 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, therefore, 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%.

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.

Symptoms of the following disorders can be similar to those of chronic granulomatous disease. Comparisons may be useful for a differential diagnosis:

Wegener's Granulomatosis is an uncommon collagen vascular disorder affecting the blood vessels. It begins as a localized inflammation of the upper and lower respiratory tract mucous membranes, and usually progresses into generalized inflammation of the blood vessels (vasculitis) and kidney (glomerulonephritis). Initial symptoms usually appear as a severe cold progressing to sinusitis, ulcerations of the mucous membranes in the nose with secondary bacterial infection, middle ear infection (otitis media), cough, expectoration of blood (hemoptysis) and pleuritis. The nasal mucous membrane appears red with a raised granular appearance. There may also be fever, loss of appetite and generalized discomfort. (For more information on this disorder, choose "Wegener" as your search term in the Rare Disease Database.)

Sarcoidosis is a multisystem disorder that most often affects individuals between 20 and 40 years of age. It is characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The granulomas that are formed are thought to alter the normal structure of and, potentially, the normal functions of, the affected organ(s), causing symptoms associated with the particular body system(s) in question. In individuals with sarcoidosis, such granuloma formation most commonly affects the lungs. However, in many cases, the upper respiratory system, lymph nodes, skin, and/or eyes may be involved. In addition, in some cases, other organs may be affected, including the liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, and/or nervous system (i.e., central or peripheral nervous system). The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of such involvement. In some cases, the symptoms of sarcoidosis may begin suddenly (acute), sometimes severely, and subside in a relatively short period of time (self limited). Acute sarcoidosis is often characterized by fatigue, fever, generalized muscle aches, difficulty breathing (dyspnea), joint pain, swollen glands, skin eruptions, eye irregularities, and/or other symptoms. In the subacute form, affected individuals may experience no symptoms (asymptomatic), even with organ involvement. In the chronic form of sarcoidosis, symptoms may appear slowly and subtly, and may persist or recur over a long time span. Symptoms associated with other organ involvement may follow. The exact cause of sarcoidosis is not known. (For more information on this disorder, choose "Sarcoidosis" as your search term in the Rare Disease Database.)

Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, particularly the lungs. The disorder is characterized by the formation and accumulation of an unusually large number of antibodies, abnormal clustering of certain white blood cells (eosinophilia), inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions (granulomatosis). Many individuals with Churg-Strauss syndrome have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by one or more years. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs' airways, causing difficulties breathing (dyspnea), coughing, and/or other symptoms and findings. Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may be variable, depending upon the specific organ systems involved. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal immunologic and autoimmune factors play an important role. (For more information on this disorder, choose "Churg-Strauss" as your search term in the Rare Disease Database.)

Polyarteritis nodosa is characterized by an inflammation of the small and medium sized arteries causing narrowing of the vessels. This may result in a lack of blood supply to tissues, possible formation of blood clots (thrombosis), and weakening, ballooning (aneurysm) or possible rupture of the vessel walls. Joint, muscle, abdominal and testicular pain may occur. The patient may also have fever, weight loss and high blood pressure (hypertension). The kidney is the organ most involved. The lungs are rarely affected. Skin rash may be present and gastrointestinal symptoms such as abdominal pain, vomiting of blood (hematemesis) and tender abdomen may be present. (For more information on this disorder, choose "Polyarteritis Nodosa" as your search term in the Rare Disease Database.)

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.

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.

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, 2008, the NIH listed six 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.

3. A trial of the drug, Infliximab, to Treat Crohn's-Like Inflammatory Bowel Disease in Chronic Granulomatous Disease

4. Studying and developing gene therapy for treating CGD.

Bone marrow transplants have proven to be successful in some affected individuals with CGD.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Entry Number: 306400, Last Edit Date: 4/2/99.

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

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

Berkow R, ed. The Merck Manual-Home Edition. Whitehouse Station, NJ: Merck Research Laboratories; 1997:821.

Frank MM, et al. Santer's Immunologic Diseases, 5th ed. Boston, MA: Little, Brown and Company; 1995:537-41.

REVIEW ARTICLES

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

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

Holland SM. Treatment of infections in the patient with Mendelian susceptibility to mycobacterial infection. Microbes Infect. 2000;2:1579-90.

Ezekowitz RA. Update on chronic granulomatous disease: the concept of near-normal host. Curr Clin Top Infect Dis. 2000;20:325-34.

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

Ryser MF, Roesler J, Gentsch M, Brenner S. Gene therapy for chronic granulomatous disease. Expert Opin Biol Ther. 2007 Dec;7(12):1799-809. Review.

Rosenzweig SD. Inflammatory manifestations in chronic granulomatous disease (CGD). J Clin Immunol. 2008 May;28 Suppl 1:S67-72. Epub 2008 Jan 12. Review.

Dinauer, MC. Chronic Granulomatous Disease and Other Disorders of Phagocyte Function. Hematology, Jan 2005; 2005: 89 - 95. available at http://asheducationbook.hematologylibrary.org/

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

Dinauer MC, et al. Inherited neutrophil disorders: molecular basis and new therapies. Hematology (Am Soc Hematol Educ Program). 2000;303-18.

Baehner RL. Chronic granulomatous disease of childhood: clinical, pathological, biochemical, molecular, and genetic aspects of the disease. Pediatr Pathol. 1990;10(1-2):143-153.

INTERNET:
Chronic Granulomatous Disease. Jeffrey Modell Foundation. nd. 4pp.
www.jmfworld.com/html/chronic_granulomatous_disease.html

Chronic Granulomatous Disease. A Guide for CGD Patients and their Families. nd. 2pp.
www.magicbydesign.com/cgd/guide/cgd.html

The CGD Research Trust. http://www.cgd.org.uk/

Chronic Granulomatous Disease. In: IDF Patient/Family Handbook. Pp.31-34.
www.primaryimmune.org/library/handbook/ Chronic%20Granulomatous%20Disease.pdf

Koton C. Chronic granulomatous disease. In: MEDLine plus. Medical Encyclopedia. 09/01/01: 3pp. www.nlm.nih.gov/medlineplus/ency/article/001239.htm