Chronic granulomatous disease 640657 222913863 2008-07-01T18:43:30Z DOI bot 6652755 Citation maintenance. Formatted: title. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Infobox_Disease | Name = Chronic granulomatous disease | Image = Superoxide.svg | Caption = [[Superoxide]] | DiseasesDB = 2633 | ICD10 = {{ICD10|D|71||d|71}} | ICD9 = {{ICD9|758.0}} | ICDO = | OMIM = 306400 | OMIM_mult = {{OMIM2|233690}} {{OMIM2|233700}} | MedlinePlus = 001239 | eMedicineSubj = ped | eMedicineTopic = 1590 | eMedicine_mult = {{eMedicine2|derm|719}} | MeshID = D006105 | }} '''Chronic granulomatous disease''' (CGD) is a diverse group of [[genetic disorder|hereditary diseases]] in which certain cells of the [[immune system]] have difficulty forming the reactive [[oxygen]] compounds (most importantly, the [[superoxide]] radical) used to kill certain ingested [[pathogen]]s.<ref name="titleChronic Granulomatous Disease: Immunodeficiency Disorders: Merck Manual Professional">{{cite web |url=http://www.merck.com/mmpe/sec13/ch164/ch164e.html |title=Chronic Granulomatous Disease: Immunodeficiency Disorders: Merck Manual Professional |accessdate=2008-03-01 |format= |work=}}</ref> This leads to the formation of [[granuloma]]ta in many organs.<ref name=Heyworth>{{cite journal | author = Heyworth P, Cross A, Curnutte J | title = Chronic granulomatous disease | journal = Curr Opin Immunol | volume = 15 | issue = 5 | pages = 578–84 | year = 2003 | pmid=14499268 | doi=10.1016/S0952-7915(03)00109-2}}</ref> CGD affects about 1 in 200,000 people in the [[United States]], with at least 20 new cases diagnosed each year.<ref name=Maryland>{{cite journal | author = Maryland Pao, M.D. et al. | title = Cognitive Function in Patients With Chronic Granulomatous Disease: A Preliminary Report | journal = Psychosomatics | volume = 45 | issue = June 2004 | pages = 230–4 | year = 2004 | pmid=15123849 | doi = 10.1176/appi.psy.45.3.230}}</ref> This condition was first described in 1957 as "a fatal granulomatosus of childhood".<ref name=Berendes>{{cite journal |author=Berendes H, Bridges RA, Good RA |title=A fatal granulomatosus of childhood: the clinical study of a new syndrome |journal=Minn Med |volume=40 |issue=5 |pages=309–12 |year=1957 |pmid=13430573 |doi=}}</ref><ref name=Bridges>{{cite journal |author=Bridges RA, Berendes H, Good RA |title=A fatal granulomatous disease of childhood; the clinical, pathological, and laboratory features of a new syndrome |journal=AMA J Dis Child |volume=97 |issue=4 |pages=387–408 |year=1959 |pmid=13636694 |doi=}}</ref> The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease.<ref name=Baehner>{{cite journal |author=Baehner RL, Nathan DG |title=Leukocyte oxidase: defective activity in chronic granulomatous disease |journal=Science |volume=155 |issue=764 |pages=835–6 |year=1967 |pmid=6018195 |doi=10.1126/science.155.3764.835}}</ref> == Pathophysiology == [[Image:Segmented neutrophils.jpg|thumb|right|Two [[neutrophil]]s among many [[red blood cell]]s. Neutrophils are one type of cell affected by chronic granulomatous disease.]] Phagocytes (i.e., [[Neutrophil granulocyte|neutrophils]], [[monocyte]]s, and [[macrophage]]s) require an [[enzyme]] to produce [[reactive oxygen species]] to destroy [[bacterium|bacteria]] after they ingest the bacteria in a process called [[phagocytosis]]. This enzyme is termed "phagocyte NADPH oxidase" (''PHOX''). The initial step in this process involves the one-electron reduction of molecular oxygen to produce [[superoxide]] free radical. Superoxide then undergoes a further series of reactions to produce products such as peroxide, hydroxyl radical and hypochlorite. The [[reactive oxygen species]] this enzyme produces are toxic to bacteria and help the phagocyte kill them once they are ingested. Defects in one of the four essential subunits of this enzyme can all cause CGD of varying severity, dependent on the defect. There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease<ref name=Heyworth />. == Genetics == Most cases of chronic granulomatous disease are transmitted as a mutation on the [[X chromosome]] and are thus called an "X-linked trait".<ref name=Winkelstein>{{cite journal | author = Winkelstein J, Marino M, Johnston R et al | title = Chronic granulomatous disease. Report on a national registry of 368 patients | journal = Medicine (Baltimore) | volume = 79 | issue = 3 | pages = 155–69 | year = 2000 | pmid=10844935 | doi = 10.1097/00005792-200005000-00003}}</ref> The affected gene on the X chromosome codes for the gp91 [[protein]] [[p91-PHOX]] (''p'' is the weight of the protein in [[kDa]]; the ''g'' means [[glycoprotein]]). CGD can also be transmitted in an [[autosomal recessive]] fashion (via [[Cytochrome b-245, alpha polypeptide|CYBA]] and [[NCF1]]) and affects other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense.<ref name=HeyworthPG>{{cite journal | author = Heyworth P, Curnutte J, Rae J, Noack D, Roos D, van Koppen E, Cross A | title = Hematologically important mutations: X-linked chronic granulomatous disease (second update) | journal = Blood Cells Mol Dis | volume = 27 | issue = 1 | pages = 16–26 | year = 2001 | pmid=11162142 | doi=10.1006/bcmd.2000.0347}}</ref><ref name=Cross>{{cite journal | author = Cross A, Noack D, Rae J, Curnutte J, Heyworth P | title = Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update) | journal = Blood Cells Mol Dis | volume = 26 | issue = 5 | pages = 561–5 | year = 2000 | pmid=11112388 | doi=10.1006/bcmd.2000.0333}}</ref> A low level of NADPH, the cofactor required for superoxide synthesis, can lead to CGD. This has been reported in women who are [[homozygous]] for the genetic defect causing [[glucose-6-phosphate dehydrogenase deficiency]] (G6PD), which is characterised by reduced NADPH levels. {| align="center" style="border: 1px solid {{{border|gray}}}; background-color: {{{color|#fdffe7}}};" |- |align="center"|[[Image:X-link dominant father.jpg|250px]] |align="center"|[[Image:XlinkRecessive.jpg|250px]] |align="center"|[[Image:Xlink dominant mother.jpg|250px]] |} ==Clinical manifestations== Classically, patients with chronic granulomatous disease will suffer from recurrent bouts of infection due to the decreased capacity of their immune system to fight off disease-causing organisms. The recurrent infections they acquire are specific and are, in decreasing order of frequency: * [[pneumonia]] * [[abscess]]es of the skin, tissues, and organs * [[suppurative arthritis]] * [[osteomyelitis]] * [[bacteremia]]/[[fungemia]] * superficial skin infections such as [[cellulitis]] or [[impetigo]] [[Image:Aspergillus fumigatus 01.jpg|thumb|right|Microscopic image of the fungus, ''[[Aspergillus fumigatus]]'', an organism that commonly causes disease in people with chronic granulomatous disease.]] People with CGD are sometimes infected with unique organisms that usually do not cause disease in people with normal immune systems. Some of the organisms that cause disease in CGD patients are ''[[Staphylococcus aureus]]'', ''[[Escheria coli]]'', ''[[Klebsiella]]'' species, ''[[Aspergillus]]'' species, and ''[[Candida (genus)|Candida]]'' species. Aspergillus has a unique propensity to cause infection in people with CGD. Of the Aspergillus species, ''[[Aspergillus fumigatus]]'' seems to be the one that most commonly causes disease. Most people with CGD are diagnosed in childhood, usually before age 5.<ref name=Winkelstein>{{cite journal | author = Winkelstein J, Marino M, Johnston R, Boyle J, Curnutte J, Gallin J, Malech H, Holland S, Ochs H, Quie P, Buckley R, Foster C, Chanock S, Dickler H | title = Chronic granulomatous disease. Report on a national registry of 368 patients | journal = Medicine (Baltimore) | volume = 79 | issue = 3 | pages = 155–69 | year = 2000 | doi = 10.1097/00005792-200005000-00003 | unused_data = |Ss pmid=10844935}}</ref> Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur. ==Laboratory findings== The [[Nitro blue tetrazolium chloride|nitroblue-tetrazolium]] (NBT) test is the original and most widely-known test for chronic granulomatous disease.<ref name=Kasper>Kasper, DL, Fauci, AS, Longo, DL, Braunwald, E, Hauser, SL, and Jameson, JL. Harrison's Principles of Internal Medicine, 16th edition 2005;357. ISBN 0-07-139140-1.</ref> It is negative in CGD, and positive in normal individuals. This test depends upon the direct reduction of NBT by [[superoxide]] free radical to form an insoluble formazan. This test is simple to perform and gives rapid results, but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected. An advanced test called the cytochrome C reduction assay tells physicians how much superoxide a patient's phagocytes can produce. Once the diagnosis of CGD is established, a genetic analysis may be used to determine exactly which mutation is the underlying cause. ==Treatment== Management of chronic granulomatous disease revolves around two goals: 1) diagnose the disease early so that [[antibiotic]]s can be given to keep an infection from occurring, and 2) educate the patient about his or her condition so that prompt treatment can be given if an infection occurs. Physicians often prescribe the antibiotic [[trimethoprim-sulfamethoxazole]] to prevent bacterial infections.<ref name=Weening>{{cite journal | author = Weening R, Kabel P, Pijman P, Roos D | title = Continuous therapy with sulfamethoxazole-trimethoprim in patients with chronic granulomatous disease | journal = J Pediatr | volume = 103 | issue = 1 | pages = 127–30 | year = 1983 | pmid=6408232 | doi = 10.1016/S0022-3476(83)80798-7}}</ref> This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with [[itraconazole]],<ref name=Cale>{{cite journal | author = Cale C, Jones A, Goldblatt D | title = Follow up of patients with chronic granulomatous disease diagnosed since 1990 | journal = Clin Exp Immunol | volume = 120 | issue = 2 | pages = 351–5 | year = 2000 | pmid=10792387 | doi=10.1046/j.1365-2249.2000.01234.x}}</ref> although a newer drug of the same type called [[voriconazole]] may be more effective.<ref name=Sabo>{{cite journal | author = Sabo J, Abdel-Rahman S | title = Voriconazole: a new triazole antifungal | journal = Ann Pharmacother | volume = 34 | issue = 9 | pages = 1032–43 | year = 2000 | pmid=10981251 | doi=10.1345/aph.19237}}</ref> The use of this drug for this purpose is still under scientific investigation. [[Interferon]], in the form of [[interferon gamma-1b]] (Actimmune) is approved by the [[Food and Drug Administration]] for the prevention of infection in CGD. It has been shown to prevent infections in CGD patients by 70% and to reduce their severity. Although its exact mechanism is still not entirely understood, it has the ability to give CGD patients more immune function and therefore, greater ability to fight off infections. This therapy has been standard treatment for CGD for several years.<ref>{{cite journal | author = | title = A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group | journal = N Engl J Med | volume = 324 | issue = 8 | pages = 509–16 | year = 1991 | pmid=1846940}}</ref> Gene therapy is currently being studied as a possible treatment for chronic granulomatous disease. CGD is well-suited for gene therapy since it is caused by a mutation in single gene which only affects one body system (the [[hematopoietic system]]). Viruses have been used to deliver a normal gp91 gene to rats with a mutation in this gene, and subsequently the phagocytes in these rats were able to produce [[oxygen radical]]s.<ref name=Dinauer>{{cite journal | author = Dinauer M, Gifford M, Pech N, Li L, Emshwiller P | title = Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease | journal = Blood | volume = 97 | issue = 12 | pages = 3738–45 | year = 2001 | pmid=11389011 | doi = 10.1182/blood.V97.12.3738}}</ref> In 2006, two human patients with X-linked chronic granulomatous disease underwent gene therapy and blood cell precursor [[stem cell]] transplantation to their [[bone marrow]]. Both patients recovered from their CGD, clearing pre-existing infections and demonstrating increased oxidase activity in their neutrophils. However, long-term complications of this therapy are unknown.<ref name=Ott>{{cite journal | author = Ott M, Schmidt M, Schwarzwaelder K, et al. | title = Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 | journal = Nat Med | volume = 12 | issue = 4 | pages = 401–9 | year = 2006 | pmid=16582916 | doi=10.1038/nm1393}}</ref> ==Prognosis== The prognosis of chronic granulomatous disease is guarded, with long-term outcomes closely tied to early diagnosis and early therapeutic intervention. With increasing treatment options for CGD the life-span for these patients is expected to also increase.{{Fact|date=September 2007}} == References == {{reflist|2}} ==External links== * [http://www.cgdassociation.org/ The Chronic Granulomatous Disease Association] * [http://www.cgd.org.uk/ Chronic Granulomatous Disorder Research Trust] {{Immune disorders}} [[Category:Immune system disorders]] [[Category:Genetic disorders]] [[de:Septische Granulomatose]] [[it:Malattia granulomatosa cronica]] [[nl:Chronische granulomateuze ziekte]]