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Granulomatous disease, chronic, X-linked(CGDX)

MedGen UID:
336165
Concept ID:
C1844376
Disease or Syndrome
Synonyms: CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED; GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC
 
Gene (location): CYBB (Xp21.1-11.4)
 
Monarch Initiative: MONDO:0010600
OMIM®: 306400

Disease characteristics

Excerpted from the GeneReview: Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival. [from GeneReviews]
Authors:
Jennifer W Leiding  |  Steven M Holland   view full author information

Additional descriptions

From OMIM
X-linked chronic granulomatous disease (CGDX) is a primary immunodeficiency characterized by onset of symptoms in the first months or years of life. Patients present with recurrent infections, lymphadenopathy, inflammatory bowel disease, granulomatous colitis, fever, skin infections, osteomyelitis, and/or abscesses. Infectious organisms usually include Staphylococcus aureus, Burkholderia cepacia, Serrata, Salmonella, mycobacteria, and fungi. The disorder results from impaired function of the phagocytic NADPH oxidase complex, which generates the microbiocidal respiratory burst. Laboratory studies using the DHR assay show impaired phagocytic production of reactive oxygen species in response to PMA stimulation (reviews by Dinauer et al., 2001 and Johnston, 2001; summary by Song et al., 2014). Genetic Heterogeneity of Chronic Granulomatous Disease Chronic granulomatous disease can be caused by mutation in several genes encoding structural or regulatory subunits of the phagocyte NADPH oxidase complex. See also CGD1 (233700), caused by mutation in the NCF1 gene (608512) on chromosome 7q11; CGD2 (233710), caused by mutation in the NCF2 gene (608515) on chromosome 1q25; CGD3 (613960), caused by mutation in the NCF4 gene (601488) on chromosome 22q13; CGD4 (233690), caused by mutation in the CYBA gene (608508) on chromosome 16q24; and CGD5 (618935) caused by mutation in the CYBC1 gene (618334) on chromosome 17q25. A similar syndrome, termed neutrophil immunodeficiency syndrome (608203), is caused by mutation in another protein involved in the NADPH oxidase complex, RAC2 (602049). Roos et al. (2021) provided a review of autosomal forms of chronic granulomatous disease.  http://www.omim.org/entry/306400
From MedlinePlus Genetics
Chronic granulomatous disease is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body from foreign invaders such as bacteria and fungi. Individuals with chronic granulomatous disease may have recurrent bacterial and fungal infections. People with this condition may also have areas of inflammation (granulomas) in various tissues that can result in damage to those tissues. The features of chronic granulomatous disease usually first appear in childhood, although some individuals do not show symptoms until later in life.

People with chronic granulomatous disease typically have at least one serious bacterial or fungal infection every 3 to 4 years. The lungs are the most frequent area of infection; pneumonia is a common feature of this condition. Individuals with chronic granulomatous disease may develop a type of fungal pneumonia, called mulch pneumonitis, which causes fever and shortness of breath after exposure to decaying organic materials such as mulch, hay, or dead leaves. Exposure to these organic materials and the numerous fungi involved in their decomposition causes people with chronic granulomatous disease to develop fungal infections in their lungs. Other common areas of infection in people with chronic granulomatous disease include the skin, liver, and lymph nodes.

Inflammation can occur in many different areas of the body in people with chronic granulomatous disease. Most commonly, granulomas occur in the gastrointestinal tract and the genitourinary tract. In many cases the intestinal wall is inflamed, causing a form of inflammatory bowel disease that varies in severity but can lead to stomach pain, diarrhea, bloody stool, nausea, and vomiting. Other common areas of inflammation in people with chronic granulomatous disease include the stomach, colon, and rectum, as well as the mouth, throat, and skin. Additionally, granulomas within the gastrointestinal tract can lead to tissue breakdown and pus production (abscesses). Inflammation in the stomach can prevent food from passing through to the intestines (gastric outlet obstruction), leading to an inability to digest food. These digestive problems cause vomiting after eating and weight loss. In the genitourinary tract, inflammation can occur in the kidneys and bladder. Inflammation of the lymph nodes (lymphadenitis) and bone marrow (osteomyelitis), which both produce immune cells, can lead to further impairment of the immune system.

Rarely, people with chronic granulomatous disease develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs.

Repeated episodes of infection and inflammation reduce the life expectancy of individuals with chronic granulomatous disease; however, with treatment, most affected individuals live into mid- to late adulthood.  https://medlineplus.gov/genetics/condition/chronic-granulomatous-disease

Clinical features

From HPO
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Liver abscess
MedGen UID:
6124
Concept ID:
C0023885
Disease or Syndrome
A circumscribed area of pus or necrotic debris in the liver.
Cellulitis
MedGen UID:
40174
Concept ID:
C0007642
Disease or Syndrome
A bacterial infection and inflammation of the skin und subcutaneous tissues.
Atelectasis
MedGen UID:
13946
Concept ID:
C0004144
Pathologic Function
Collapse of part of a lung associated with absence of inflation (air) of that part.
Cough
MedGen UID:
41325
Concept ID:
C0010200
Sign or Symptom
A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation.
Pleural effusion
MedGen UID:
10805
Concept ID:
C0032227
Disease or Syndrome
The presence of an excessive amount of fluid in the pleural cavity.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Air bronchogram
MedGen UID:
1720690
Concept ID:
C3669021
Finding
An air bronchogram is a pattern of air-filled (low-attenuation) bronchi on a background of opaque (high-attenuation) airless lung. The sign implies (a) patency of proximal airways and (b) evacuation of alveolar air by means of absorption (atelectasis) or replacement (eg, pneumonia) or a combination of these processes. In rare cases, the displacement of air is the result of marked interstitial expansion (eg, lymphoma).
Eczematoid dermatitis
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Recurrent E. coli infections
MedGen UID:
4543
Concept ID:
C0014836
Disease or Syndrome
Increased susceptibility to infections with Escherichia coli, as manifested by recurrent episodes of infection with this agent.
Granuloma
MedGen UID:
5376
Concept ID:
C0018188
Pathologic Function
A compact, organized collection of mature mononuclear phagocytes, which may be but is not necessarily accompanied by accessory features such as necrosis.
Immunodeficiency
MedGen UID:
7034
Concept ID:
C0021051
Disease or Syndrome
Failure of the immune system to protect the body adequately from infection, due to the absence or insufficiency of some component process or substance.
Lymphadenitis
MedGen UID:
7410
Concept ID:
C0024205
Disease or Syndrome
Inflammation of a lymph node.
Osteomyelitis
MedGen UID:
10497
Concept ID:
C0029443
Disease or Syndrome
Osteomyelitis is an inflammatory process accompanied by bone destruction and caused by an infecting microorganism.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Rectal abscess
MedGen UID:
57700
Concept ID:
C0149770
Pathologic Function
A collection of pus in the area of the rectum.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargement (swelling) of a lymph node.
Granulomatosis
MedGen UID:
488910
Concept ID:
C0521173
Disease or Syndrome
A granulomatous inflammation leading to multiple granuloma formation, which is a specific type of inflammation. A granuloma is a focal compact collection of inflammatory cells, mononuclear cells predominating, usually as a result of the persistence of a non-degradable product and of active cell mediated hypersensitivity.
Recurrent bacterial skin infections
MedGen UID:
322727
Concept ID:
C1835686
Finding
Increased susceptibility to bacterial infections of the skin, as manifested by recurrent episodes of infectious dermatitis.
Absence of bactericidal oxidative respiratory burst in phagocytes
MedGen UID:
375405
Concept ID:
C1844385
Finding
An absence of the phase of elevated metabolic activity, during which oxygen consumption increases, that occurs in neutrophils, monocytes, and macrophages shortly after phagocytosing material. An enhanced uptake of oxygen leads to the production, by an NADH dependent system, of hydrogen peroxide (H2O2), superoxide anions and hydroxyl radicals, which play a part in microbiocidal activity.
Recurrent Staphylococcus aureus infections
MedGen UID:
392925
Concept ID:
C2673462
Finding
Increased susceptibility to Staphylococcus aureus infections, as manifested by recurrent episodes of Staphylococcus aureus infection.
Recurrent Klebsiella infections
MedGen UID:
867386
Concept ID:
C4021751
Finding
Increased susceptibility to Klebsiella infections, as manifested by recurrent episodes of Klebsiella infection.
Recurrent Aspergillus infections
MedGen UID:
867387
Concept ID:
C4021752
Finding
An increased susceptibility to Aspergillus infections, as manifested by a history of recurrent episodes of Aspergillus infections.
Recurrent Burkholderia cepacia infections
MedGen UID:
871196
Concept ID:
C4025673
Finding
Increased susceptibility to infections with Burkholderia cepacia, as manifested by recurrent episodes of infection with this agent.
Recurrent Serratia marcescens infections
MedGen UID:
871204
Concept ID:
C4025682
Finding
Increased susceptibility to Serratia marcescens infections, as manifested by recurrent episodes of Serratia marcescens infection.
Impaired oxidative burst
MedGen UID:
898272
Concept ID:
C4280805
Laboratory or Test Result
In the NBT test, neutrophils change the colorless compound NBT into a compound with a deep blue color. If this test is negative (i.e., no blue color is produced), then this indicates a defect in superoxide-generating NADPH oxidase activity with inability to efficiently kill phagocytized bacteria.
Discoid lupus erythematosus
MedGen UID:
1811126
Concept ID:
C5574816
Disease or Syndrome
Cutaneous lesion that develops as a dry, scaly, red patch that evolves to an indurated and hyperpigmented plaque with adherent scale. Scarring may result in central white patches (loss of pigmentation) and skin atrophy.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Decreased activity of NADPH oxidase
MedGen UID:
336679
Concept ID:
C1844394
Finding
Deficiency or absence of cytochrome b(-245)
MedGen UID:
375407
Concept ID:
C1844390
Finding

Professional guidelines

PubMed

Collins CJ, Yi F, Dayuha R, Whiteaker JR, Ochs HD, Freeman A, Su HC, Paulovich AG, Segundo GRS, Torgerson T, Hahn SH
Front Immunol 2020;11:464. Epub 2020 Apr 1 doi: 10.3389/fimmu.2020.00464. PMID: 32296420Free PMC Article
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Scand J Immunol 2012 Nov;76(5):512-8. doi: 10.1111/j.1365-3083.2012.02772.x. PMID: 22924737

Recent clinical studies

Etiology

Chiesa R, Wang J, Blok HJ, Hazelaar S, Neven B, Moshous D, Schulz A, Hoenig M, Hauck F, Al Seraihy A, Gozdzik J, Ljungman P, Lindemans CA, Fernandes JF, Kalwak K, Strahm B, Schanz U, Sedlacek P, Sykora KW, Aksoylar S, Locatelli F, Stepensky P, Wynn R, Lum SH, Zecca M, Porta F, Taskinen M, Gibson B, Matthes S, Karakukcu M, Hauri-Hohl M, Veys P, Gennery AR, Lucchini G, Felber M, Albert MH, Balashov D, Lankester A, Güngör T, Slatter MA
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J Clin Immunol 2019 Oct;39(7):653-667. Epub 2019 Aug 2 doi: 10.1007/s10875-019-00659-8. PMID: 31376032Free PMC Article
Arnold DE, Heimall JR
Adv Ther 2017 Dec;34(12):2543-2557. Epub 2017 Nov 22 doi: 10.1007/s12325-017-0636-2. PMID: 29168144Free PMC Article
Rawat A, Bhattad S, Singh S
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Cale CM, Morton L, Goldblatt D
Clin Exp Immunol 2007 Apr;148(1):79-84. doi: 10.1111/j.1365-2249.2007.03321.x. PMID: 17286762Free PMC Article

Diagnosis

Yu HH, Yang YH, Chiang BL
Clin Rev Allergy Immunol 2021 Oct;61(2):101-113. doi: 10.1007/s12016-020-08800-x. PMID: 32524254
Roos D
Methods Mol Biol 2019;1982:531-542. doi: 10.1007/978-1-4939-9424-3_32. PMID: 31172494
Arnold DE, Heimall JR
Adv Ther 2017 Dec;34(12):2543-2557. Epub 2017 Nov 22 doi: 10.1007/s12325-017-0636-2. PMID: 29168144Free PMC Article
Roos D
Br Med Bull 2016 Jun;118(1):50-63. Epub 2016 Mar 16 doi: 10.1093/bmb/ldw009. PMID: 26983962Free PMC Article
Larsen LR, Raffensperger J
J Pediatr Surg 1979 Jun;14(3):329-31. doi: 10.1016/s0022-3468(79)80493-5. PMID: 480097

Therapy

Kohn DB, Booth C, Kang EM, Pai SY, Shaw KL, Santilli G, Armant M, Buckland KF, Choi U, De Ravin SS, Dorsey MJ, Kuo CY, Leon-Rico D, Rivat C, Izotova N, Gilmour K, Snell K, Dip JX, Darwish J, Morris EC, Terrazas D, Wang LD, Bauser CA, Paprotka T, Kuhns DB, Gregg J, Raymond HE, Everett JK, Honnet G, Biasco L, Newburger PE, Bushman FD, Grez M, Gaspar HB, Williams DA, Malech HL, Galy A, Thrasher AJ; Net4CGD consortium
Nat Med 2020 Feb;26(2):200-206. Epub 2020 Jan 27 doi: 10.1038/s41591-019-0735-5. PMID: 31988463Free PMC Article
Marsh RA, Leiding JW, Logan BR, Griffith LM, Arnold DE, Haddad E, Falcone EL, Yin Z, Patel K, Arbuckle E, Bleesing JJ, Sullivan KE, Heimall J, Burroughs LM, Skoda-Smith S, Chandrakasan S, Yu LC, Oshrine BR, Cuvelier GDE, Thakar MS, Chen K, Teira P, Shenoy S, Phelan R, Forbes LR, Chellapandian D, Dávila Saldaña BJ, Shah AJ, Weinacht KG, Joshi A, Boulad F, Quigg TC, Dvorak CC, Grossman D, Torgerson T, Graham P, Prasad V, Knutsen A, Chong H, Miller H, de la Morena MT, DeSantes K, Cowan MJ, Notarangelo LD, Kohn DB, Stenger E, Pai SY, Routes JM, Puck JM, Kapoor N, Pulsipher MA, Malech HL, Parikh S, Kang EM; submitted on behalf of the Primary Immune Deficiency Treatment Consortium
J Clin Immunol 2019 Oct;39(7):653-667. Epub 2019 Aug 2 doi: 10.1007/s10875-019-00659-8. PMID: 31376032Free PMC Article
Martín-Nalda A, Roca I, Fontecha CG, Fernández-Polo A, Barber I, Martinez-Gallo M, Soler-Palacin P
Pediatrics 2016 Aug;138(2) Epub 2016 Jul 19 doi: 10.1542/peds.2015-4017. PMID: 27436506
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Mol Ther 2014 Aug;22(8):1472-1483. Epub 2014 May 29 doi: 10.1038/mt.2014.87. PMID: 24869932Free PMC Article
Aiuti A, Roncarolo MG
Hematology Am Soc Hematol Educ Program 2009:682-9. doi: 10.1182/asheducation-2009.1.682. PMID: 20008254

Prognosis

Blanc PD, Annesi-Maesano I, Balmes JR, Cummings KJ, Fishwick D, Miedinger D, Murgia N, Naidoo RN, Reynolds CJ, Sigsgaard T, Torén K, Vinnikov D, Redlich CA
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Gajendran M, Loganathan P, Catinella AP, Hashash JG
Dis Mon 2018 Feb;64(2):20-57. Epub 2017 Aug 18 doi: 10.1016/j.disamonth.2017.07.001. PMID: 28826742
Tsirouki T, Dastiridou A, Symeonidis C, Tounakaki O, Brazitikou I, Kalogeropoulos C, Androudi S
Ocul Immunol Inflamm 2018;26(1):2-16. Epub 2016 Jul 28 doi: 10.1080/09273948.2016.1196713. PMID: 27467180
Ostheimer TA, Burkholder BM, Leung TG, Butler NJ, Dunn JP, Thorne JE
Am J Ophthalmol 2014 Sep;158(3):637-43.e1. Epub 2014 May 27 doi: 10.1016/j.ajo.2014.05.019. PMID: 24875002
Roos D, de Boer M
Clin Exp Immunol 2014 Feb;175(2):139-49. doi: 10.1111/cei.12202. PMID: 24016250Free PMC Article

Clinical prediction guides

Danne C, Skerniskyte J, Marteyn B, Sokol H
Nat Rev Gastroenterol Hepatol 2024 Mar;21(3):184-197. Epub 2023 Dec 18 doi: 10.1038/s41575-023-00871-3. PMID: 38110547
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Nat Med 2016 Feb;22(2):146-53. Epub 2016 Jan 18 doi: 10.1038/nm.4027. PMID: 26779811Free PMC Article
Cachat J, Deffert C, Hugues S, Krause KH
Clin Sci (Lond) 2015 May 1;128(10):635-48. doi: 10.1042/CS20140635. PMID: 25760962
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Circulation 2014 Dec 2;130(23):2031-9. Epub 2014 Sep 19 doi: 10.1161/CIRCULATIONAHA.113.006824. PMID: 25239440Free PMC Article
Armstrong-James D, Harrison TS
Curr Opin Microbiol 2012 Aug;15(4):434-9. Epub 2012 Aug 10 doi: 10.1016/j.mib.2012.06.001. PMID: 22884572

Recent systematic reviews

Cheng CY, Baritussio A, Giordani AS, Iliceto S, Marcolongo R, Caforio ALP
Autoimmun Rev 2022 Apr;21(4):103037. Epub 2022 Jan 5 doi: 10.1016/j.autrev.2022.103037. PMID: 34995763
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Mills SC, von Roon AC, Tekkis PP, Orchard TR
BMJ Clin Evid 2011 Apr 27;2011 PMID: 21524318Free PMC Article
Mills SC, von Roon AC, Tekkis PP, Orchard TR
BMJ Clin Evid 2010 Nov 30;2010 PMID: 21406129
von Roon AC, Reese GE, Orchard TR, Tekkis PP
BMJ Clin Evid 2007 Nov 7;2007 PMID: 19450352Free PMC Article

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