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 widespread development of granulomatous (tumor-like mass) lesions of the skin, lungs, bones, and lymph nodes. Excess gammaglobulin in the blood (hypergammaglobulinemia), low levels of circulating red blood cells (anemia), an increase in white blood cells (leukocytosis), and a susceptibility to repeated bacterial and fungal infections occurs. 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), enlargement of the liver and spleen (hepatosplenomegaly) 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.

The exact cause of chronic granulomatous disease is unknown. There is a genetic form (X-linked recessive) that primarily affects males. Some cases may be inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

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 usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". 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 can not 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.

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%.

The location of the defective gene involved in some cases of chronic granulomatous disease has been located in the middle of the short arm of the X-chromosome at Xp21.1. Mutations in one of four different genes can cause a defect in an enzyme called phagocyte NADPH oxidase or phox. Certain white blood cells use this enzyme to produce hydrogen peroxide, which these cells need in order to kill certain bacteria and fungi. There are variants of the disorder that may involve other genes in females.
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Chronic granulomatous disease affects males more often than females. Approximately, two-thirds of individuals have the X-linked recessive form of the disorder. It usually occurs during childhood but symptoms may be delayed into early teens. In a few cases, 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 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.

Treatment
Treatment of chronic granulomatous disease consists of intermittent or continuous antibiotic therapy, such as trimethoprim and sulfamethoxazole. 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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

As of Autumn 2004, the NIH listed five clinical trials to investigate possible treatments for chronic granulomatous disease (CGD). Four of the studies, sponsored by the National Institute of Allergy and Infectious Disease (NIAID), are still in the recruitment phase of their trials, and are as follows:

1. A study to determine the efficacy and safety of a modified stem cell transplant procedure in CGD patients with active infection.

2. A study regarding learning and behavior problems in children with CGD.

3. A phase III trial of the drug, posaconazole, for treating invasive fungal infections associated with CGD.

4. Studying and developing gene therapy for treating CGD.

A study sponsored by the Fred Hutchinson Cancer Research Center is investigating the safety of total body irradiation and fludarabine followed by treatment with allogeneic peripheral blood stem cell or bone marrow transplantation in combination with cyclosporine and mycophenolate mofetil. For information, see the ClinicalTrials.gov web site or call the study chair, Ann Woolfrey, at: (206) 667-4453.

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

John Curnutte, MD, PhD, of the DNAX Research Institute is investigating a new technology of transfusing bone marrow stem cells into a fetus with CGD to prevent onset of the disease. The stem cells are transfused fourteen weeks into pregnancy. For more information, interested persons may contact:

John T. Curnutte, MD, PhD
DNAX Research Institute
901 California Avenue
Palo Alto, CA 94304-1104
Tel: (650) 496-6400
Fax: (650)496-1200
Email: contact@dnax.org

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.

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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
Lakshman R, Finn A. Neutrophil disorders and their management. J Clin Pathol. 2001; 54:7-19.

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.

Cross AR, Noack D, Rae J, et al. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update). Blood Cells Mol Dis. 2000;26:561-65.

Goldblatt D, Thrasher AJ. Chronic granulomatous disease. Clin Exp Immunol. 2000;122:1-9.

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.

Kume A, Dinauer MC. Gene therapy for chronic granulomatous disease. J Lab Clin Med. 2000;135:122-28.

JOURNAL ARTICLES
Stasia MJ, et al. Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease. Hum Genet. 2005;116:72-82.

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.

Grez M, et al. Gene therapy of chronic granulomatous disease. Bone Marrow Transplant. 2000;25:S99-104.

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

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

Doepel LK. Chronic Granulomatous Disease Research Advances on Several Fronts. 1996:3pp.
www.nlm.nih.gov/medlineplus/ency/article/001239.htm