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Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis Authors Sergio D Rosenzweig, MD Steven M Holland, MD Section Editor E Richard Stiehm, MD Deputy Editor Elizabeth TePas, MD, MS Disclosures Last literature review version 19.2: mayo 2011 | This topic last updated: junio 15, 2011 (More) INTRODUCTION — Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in the phagocyte NADPH oxidase (phox). These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes. The diagnosis is made by neutrophil function testing and then the exact defect is determined by genotyping. Infections are generally caused by catalase-positive microorganisms (most bacterial and all fungal pathogens are catalase-positive). The frequent sites of infection are lung, skin, lymph nodes, and liver. The formation of granulomata is especially problematic in the gastrointestinal and genitourinary tracts. Other inflammatory manifestations are seen as well. This topic will review the pathogenesis, clinical manifestations, and diagnosis of CGD. The treatment and prognosis of CGD, as well as an overview of primary disorders of phagocyte function, are discussed separately. (See "Chronic granulomatous disease: Treatment and prognosis" and "Primary disorders of phagocytic function: An overview".) PATHOGENESIS — Phagocytes utilize NADPH oxidase to generate reactive species of oxygen. CGD arises from mutations that result in the loss or functional inactivation of one of the subunits of the NADPH oxidase complex. The fully assembled NADPH oxidase is a five-protein complex. In the basal state, it exists as two components [1]: The membrane-bound heterodimer, called cytochrome b-245 or cytochrome b588, that is composed of gp91phox and p22phox and is embedded in the walls of secondary granules Proteins in the cytosol (p47phox, p67phox, and p40phox) All of these proteins are necessary for the proper generation of superoxide. Activation and assembly of the functional oxidase also requires the participation of Rac2, a small GTP-binding protein, and Rap1, a small GTPase. Activation of NADPH oxidase — The cytosolic components p47phox and p67phox are phosphorylated and bind tightly together after cellular activation is initiated by phagocytosis of microbes. In association with p40phox and Rac2, these proteins combine with the cytochrome complex (gp91phox and p22phox) to form the intact NADPH oxidase. An electron is then taken from NADPH and donated to molecular oxygen, leading to the formation of superoxide. This is converted to hydrogen peroxide by superoxide dismutase. In the final step, hydrogen peroxide is converted to hypochlorous acid, or bleach, in the presence of myeloperoxidase and chlorine in the neutrophil phagosome (figure 1) [1]. Respiratory burst — The rapid consumption of oxygen and production of superoxide and its metabolites is referred to as the respiratory burst. Phagocyte production of reactive oxygen species leads to the activation of granule proteases, including elastase and cathepsin G. These proteases are responsible for the destruction of ingested (phagocytosed) microorganisms. Thus, superoxide acts as an intracellular activating molecule and not as a direct microbicidal molecule, as was previously thought [2]. Genetic defects — Mutations in all five genes (gp91phox, p47phox, p22phox, p67phox, and p40phox) that make up the NADPH oxidase complex account for all of the known cases of CGD. There are one X-linked and four autosomal recessive forms of CGD. The gene for gp91phox is encoded by CYBB, located at Xp21.1. Defects in this gene cause X-linked CGD (MIM 306400), which account for about 65 to 70 percent of cases. The second membrane component, p22phox, is encoded by CYBA, located at chromosome 16q24. Defects in this gene cause an autosomal recessive CGD (MIM 233690), which account for less than 5 percent of cases [3]. The cytosolic factor p47phox is encoded by NCF1, located at 7q11.23 (MIM 233700). Defects in this gene account for about 25 percent of cases. The cytosolic factor, p67phox, is encoded by NCF2, located at chromosome 1q25 (MIM 233710). Defects in NCF2 account for less than 5 percent of cases [4-8]. The cytosolic factor, p40phox, is encoded by NCF4, located at 22a13.1 (MIM 601488). Defects in NCF4 have been described causing severe inflammatory bowel disease in a single child with mildly impaired respiratory burst activity [9]. Neutrophil immunodeficiency syndrome, a syndrome similar to CGD, is caused by a mutation in the RAC2 gene. Two patients with dominant negative mutations in RAC2 have been identified, the first presented with severe bacterial infections and poor wound healing. This patient's neutrophils exhibited decreased superoxide production, as well as impaired chemotaxis and adhesion [10]. The second case was identified by newborn screening and transplanted before disease manifestations were seen [11]. The large majority of the identified mutations in the phagocyte oxidase (phox) proteins result in complete or nearly complete absence of the protein. A normal amount of a nonfunctioning or hypofunctioning protein results from the other mutations. The superscripts +, -, and 0 are used to indicate normal, decreased, or absent protein levels, respectively [1]. A macrophage-specific defect in gp91phox appears to predispose more to mycobacterial disease than the other infections typically seen in CGD [12] (see "Mendelian susceptibility to mycobacterial diseases (MSMD)"). Innate immune receptors — Patients with CGD, compared to the general population of patients with bacterial pneumonia, express lower levels of several neutrophil receptors, including Toll-like receptors (TLR5 and TLR9), complement receptors (CD11b, CD18, and CD35), and a chemokine receptor (CXCR1). In contrast, patients with pneumonia who do not have CGD generally have higher than normal expression levels of these proteins. Decreased expression results in impaired neutrophil activation (TLR5), phagocytosis (CD11b/CD18), and chemotaxis (CXCR1). Levels of expression of TLR5 and CD18 may correlate with CGD disease severity [13]. Enhanced inflammation — Several different mechanisms may be involved in the enhanced inflammation seen in patients with CGD. Tryptophan catabolism — A hyperinflammatory phenotype is associated with dysfunction of a superoxide-dependent step in tryptophan catabolism along the kynurenine pathway in a mouse model of CGD [14]. However, this abnormality is not present in human CGD patients [15]. Inflammatory mediators — Defective production of reactive oxygen species leads to increased expression of NF-kappaB-regulated inflammatory genes [16]. Higher levels of inflammatory mediators are expressed in monocytes from patients with Xlinked CGD without acute infection compared with controls. A similar increase in transcription of anti-inflammatory mediators is not seen. Efferocytosis — Efferocytosis is the process by which apoptotic inflammatory cells are recognized and removed by phagocytes. In a mouse model of CGD, efferocytosis by macrophages is suppressed [17]. EPIDEMIOLOGY — The frequency of CGD in the United States is approximately 1:200,000 live births [4]. The disease primarily affects males, as most mutations are X-linked. Rates are almost identical across ethnic and racial groups, with about one-third of the X-linked mutations occurring de novo. However, the autosomal recessive forms of CGD are more common and overall incidence rates may be higher in cultures in which consanguineous marriage is common [18]. CGD may present at any time from infancy to late adulthood, but the majority of patients are diagnosed as toddlers and children before the age of five. In several series, the median age at diagnosis was 2.5 to 3 years of age [19-22]. More recently, a growing number of patients are diagnosed in later childhood or adulthood. This is due in part to recognition of milder cases of autosomal recessive CGD, as well as delayed diagnosis in some patients. Diagnosis may be delayed because of potent antimicrobials that inadvertently treat many CGD-associated infections, postponing diagnosis until more severe infections indicate CGD as the underlying cause. X-linked CGD tends to have an earlier onset and be more severe than p47phox deficiency [4]. CLINICAL PRESENTATION — Patients with CGD may present with growth failure, abnormal wound healing, diarrhea, or infected dermatitis. They may have hepatomegaly, splenomegaly, or lymphadenitis on physical examination. A history of recurrent or unusually severe infections, particularly those caused by pathogens commonly associated with CGD, should prompt testing for this disorder. (See 'Infections' below.) X-linked carriers — The X-linked carrier state for gp91phox is not entirely silent. In affected women, lyonization (ie, the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes: one with normal respiratory burst function, the other with impaired respiratory burst activity [23]. Therefore, X-linked CGD carriers display a characteristic mosaic pattern on respiratory burst testing of individual peripheral blood cells microscopically or by flow cytometry. As few as 10 percent of cells having normal respiratory burst activity is sufficient to prevent most severe bacterial and fungal infections. Thus, most female carriers of X-linked gp91phox CGD mutations are not compromised in their ability to handle infectious challenges. However, carriers with less than 10 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD [24-27]. Females may have other manifestations of heterozygous carriage of X-linked CGD mutations, including discoid lupus erythematosus, aphthous ulcers, and photosensitivity [28,29]. INFECTIONS — Patients with CGD typically experience recurrent infections caused by bacterial and fungal pathogens. However, CGD patients may exhibit few clinical signs and symptoms, despite the presence of significant infection. Response to viral infections is normal in patients with CGD. Bacterial infections in CGD tend to be symptomatic and are associated with fever and mildly elevated leukocyte counts [30]. In contrast, fungal infections are associated with less fever and lower leukocytosis and are therefore more difficult to diagnose. Fungal infections are often detected either at asymptomatic stages on routine screening for infections [31] or at an advanced stage. As an example, patients with fungal osteomyelitis may not be diagnosed until later stages of disease, when they have multiorgan involvement [32]. Sites of infection — The most common sites of infection are lung, skin, lymph nodes, and liver [33]. The types of infections most often seen (in descending order of frequency) include: Pneumonia Abscesses (skin, tissue, organs) Suppurative adenitis Osteomyelitis Bacteremia/fungemia Superficial skin infections (cellulitis/impetigo) Pneumonia is the most common pulmonary infection, but patients may also have lung abscesses, empyema, and hilar lymphadenopathy. In contrast to what occurs in neutropenic patients, fungal pneumonias do not generally cavitate in CGD, whereas Nocardia infections do. The most common sites for abscesses are perianal/perirectal and the liver. Gingivitis, stomatitis, gastroenteritis, and otitis are also common [1,4,19-22]. Organisms — In general, the organisms that infect patients with CGD are catalase-producing and include Staphylococcus aureus and Aspergillus species. Catalase is an enzyme that inactivates the hydrogen peroxide normally produced by some bacteria and fungi during growth. Although most microorganisms produce hydrogen peroxide, some do not. It was thought that host phagocytes could use the hydrogen peroxide produced by catalase-negative microbes to generate reactive oxidants. However, the majority of pathogens are catalase-positive, and only a few cause infections in CGD, suggesting that catalase production alone is insufficient for pathogenicity. Furthermore, targeted deletion of the catalase gene in Aspergillus nidulans and Staphylococcus aureus did not affect virulence in animal models of CGD, indicating that microbial catalase is not a significant virulence factor for CGD infections. The overwhelming majority of infections in North America are due to five organisms: Staphylococcus aureus Burkholderia (Pseudomonas) cepacia Serratia marcescens Nocardia Aspergillus Outside of North America, Salmonella and BCG are frequent infections and should suggest the diagnosis. Other organisms isolated less frequently include Streptococcus species, Neisseria meningitidis, Acinetobacter junii, Candida species, Klebsiella pneumoniae, Mycobacterium tuberculosis, nontuberculous mycobacteria, Proteus species, and Leishmania species [19,21,22]. Bacterial infections — The frequency of bacterial infections in CGD has decreased since trimethoprim-sulfamethoxazole prophylaxis became routine in the 1980s. Most lung, skin, and bone infections were staphylococcal in the preprophylaxis era. On prophylaxis staphylococcal infections are essentially confined to the liver, lymph nodes, and skin [4]. Severe, resistant facial acne and painful inflammation of the nares are common infectious skin manifestations of S. aureus infection. Burkholderia cepacia complex, which is a common cause of pneumonia with primarily endobronchial disease in patients with cystic fibrosis (CF), can cause pneumonia with nodular infiltrates in patients with CGD [34-36]. Patients with CGD are prone to recurrent pulmonary infection with different strains of Burkholderia, unlike patients with CF who tend to have chronic infection with the same strain [36]. Infants often present with Serratia marcescens bone and soft tissue infections [32]. S. marcescens infections still occur in older children and adults with CGD, but the pattern of presentation is different [37]. Osteomyelitis is rare, but disseminated abscesses and skin infections with large, poorly healing ulcers are common. Mycobacterial infections accounted for almost 6 percent of pneumonias in American CGD surveys in 2000 and 2007 [4,38]. A high incidence of tuberculosis was observed in CGD patients living in areas endemic for TB [39,40]. Draining skin lesions at sites of BCG vaccination are seen in CGD patients, although these infections rarely disseminate. However, dissemination of BCG may be straindependent, since numerous cases of disseminated BCG have been reported in particular countries where different strains are found [41]. Granulibacter bethesdensis is an environmental organism that can cause fever, weight loss, and necrotizing pyogranulomatous lymphadenitis [42,43]. Fatal bacteremia has been reported as well [44]. Bacteremia is uncommon, but when it occurs, is usually due to the following organisms: Burkholderia cepacia complex [35,45-47] S. marcescens, which is also a common cause of bacterial osteomyelitis [32] Chromobacterium violaceum, a gram negative rod found in brackish water, especially in the southeastern United States [48] Infection with catalase-negative organisms is uncommon, but severe chronic recurrent Actinomycosis has been reported [49]. All patients in one series presented with a prolonged history of fever and clinical signs of infection without an obvious focus. Sites of infection were cervicofacial, hepatic, and/or pulmonary. Fungal infections — Fungal infections were previously the leading causes of mortality in CGD [4], even though the rate of fungal infections is lower than bacterial infections. Fungal infections typically begin in the lung after inhalation of spores or hyphae. The resulting pneumonia may spread locally to ribs and spine or metastatically to brain. The frequency and mortality of fungal infections have been markedly reduced since the advent of itraconazole prophylaxis and the use of voriconazole and posaconazole for treatment of filamentous fungal infections (eg, Aspergillus). Bony involvement by fungi typically occurs by direct extension from the lung. Aspergillus nidulans, an organism that infects CGD patients almost exclusively, causes a significantly higher rate of osteomyelitis and mortality than other fungi [31,50]. Penicillium piceum is a relatively non-pathogenic fungus that can produce lung nodules and osteomyelitis in CGD [51]. In contrast, infections with Zygomycosis are rare in patients with CGD and are typically associated with iatrogenic immune suppression [52]. INFLAMMATORY AND OTHER MANIFESTATIONS — Patients with CGD are also prone to granulomata of various organs, growth retardation, chronic pulmonary disease, and autoimmune disorders. In contrast to many other immunodeficiencies, CGD is probably not associated with an increased incidence of neoplasia, although several cancers have been identified in patients with CGD [53]. Granulomata — Patients with CGD are prone to the formation of granulomata. These can affect any hollow viscus, but are especially problematic in the gastrointestinal and genitourinary tracts [33]. Other tissues and organs, such as the retina, liver, lungs, and bone, may also be affected by granulomata [54]. The reasons for granuloma formation in CGD are unknown. CGD cells fail to degrade chemotactic and inflammatory signals normally and this may lead to persistent and exuberant inflammation. Gastrointestinal — Gastrointestinal (GI) manifestations of CGD include abdominal pain, diarrhea, colitis, proctitis, strictures, fistulae, and obstruction. In a series of 140 CGD patients, 43 percent of X-linked and 11 percent of autosomal recessive CGD patients had GI manifestations [55]. All patients with confirmed inflammatory bowel disease complained of abdominal pain. Diarrhea was reported in 39 percent and nausea and vomiting in 24 percent. Thirty-five percent had GI obstruction (gastric, esophageal, duodenal, and other). Sixty-five percent of the patients in this series with GI involvement had either granulomatous or ulcerative colonic lesions [55]. Crohn's disease and ulcerative colitis were diagnosed in only 20 percent of those with inflammatory bowel lesions. The granulomata in CGD IBD were characterized by sharply defined histiocyte aggregates with surrounding lymphocytic inflammation, unlike the poorly formed granulomata seen in Crohn's disease. Hepatic — Liver abnormalities were frequently identified in a CGD cohort of 194 patients: liver enzymes were elevated in 73 percent, 25 percent had persistent elevations of alkaline phosphatase, and drug-induced hepatitis was reported in 15 percent [56]. In patients with abnormal liver enzymes who underwent liver biopsy, histology revealed granulomata in 75 percent and lobular hepatitis in 90 percent. Eighty percent of patients in the series above had a portal venopathy that was often associated with splenomegaly [56]. Liver abscesses and hepatomegaly were each seen in one-third of cases. Portal hypertension was an important risk factor for mortality and was strongly suggested by a decreasing platelet count over time [57]. Genitourinary — In a series of 60 CGD patients, approximately 40 percent of patients had urologic manifestations, including ureteral and urethral strictures, urinary tract infections, altered renal function, and bladder granulomata [58]. All patients with urologic strictures had defects of the membrane component of the NADPH oxidase (gp91phox or p22phox). Ophthalmic — Chorioretinal lesions are described in up to one quarter of X-linked CGD patients [59]. These lesions are mostly asymptomatic retinal scars associated with pigment clumping. These same lesions can be detected in gp91phox female carriers. Keratitis has also been reported [19]. Pulmonary — Chronic respiratory disease due to recurrent pulmonary infections is common. Findings on chest CT include bronchiectasis, obliterative bronchiolitis, and chronic fibrosis [19,33]. A clinical entity specific to CGD is mulch pneumonitis, so- called because patients with CGD can develop a characteristic syndrome of dyspnea, hypoxia, and fever leading to respiratory failure and death after inhalation of large burdens of fungal spores and hyphae, such as those found in mulch, hay, peat moss, or dirt [60]. This syndrome is important to recognize since it is best treated with simultaneous administration of glucocorticoids and antifungals. Oral disease — Oral manifestations of CGD include gingivitis, stomatitis, aphthous ulcerations, and gingival hypertrophy [19]. Skin — Non-infectious skin manifestations of CGD include photosensitivity, granulomatous lesions, and vasculitis [19]. Autoimmune disease — Autoimmune disorders are more common in CGD. Both discoid and systemic lupus erythematosus have been described, and occur with at least the same frequency in X-linked CGD female carriers [61,62]. Idiopathic thrombocytopenic purpura and juvenile idiopathic arthritis are also more frequent in CGD than in the general population [4]. Other reported autoimmune diseases in patients with CGD include autoimmune pulmonary disease, IgA nephropathy, antiphospholipid syndrome, and recurrent pericardial effusion [63]. Growth retardation — Patients with CGD commonly experience growth retardation. Failure to thrive is a frequent presenting symptom in young children. In one series of 94 patients, approximately 75 percent were below the population mean for height and weight at the time of diagnosis [19]. Thirty-five percent required nasogastric and/or parenteral nutritional supplementation. In another small series of 23 patients, approximately 20 percent were below the 10th percentile for height and weight [20]. Growth often improves in late adolescence [64]; many CGD patients attain their expected growth potential by adulthood. McLeod syndrome — The gene coding for the Kell blood cell antigen system (XK) maps to Xp21, immediately adjacent to CYBB, the gene for gp91phox. Patients with deletions in the X-chromosome may delete portions of both genes (contiguous gene disorder) and thereby present with X-linked CGD and McLeod syndrome. McLeod syndrome causes acanthocytosis and low or absent expression of the erythrocyte blood group Kell antigens, eg, Kell(-). This may result in anemia, elevated creatine phosphokinase, and late-onset peripheral and central nervous system manifestations. (See "A primer of red blood cell antigens and antibodies", section on 'McLeod phenotype' and "Spiculated cells (echinocytes and acanthocytes) and target cells", section on 'Blood group abnormalities'.) Special care has to be taken when transfusing X-linked CGD patients to avoid Kell(+) transfusions into these Kell(-) patients [65,66]. All X-linked CGD patients should be tested for Kell antigens. Those who test negative should have this noted on their medical record and wear medical identification jewelry stating that they must be given Kell(-) blood if they require a transfusion. DIAGNOSIS — Patients suspected of having CGD should initially undergo neutrophil function testing. Positive findings should be confirmed by additional testing, such as immunoblot, followed by genotyping. A history of recurrent and/or unusually severe infections, particularly abscesses and infections caused by the pathogens commonly associated with CGD, should prompt neutrophil function testing. Neonatal or early postnatal screening of potentially affected children is indicated if there is a family history of CGD. (See 'Infections' above.) Typical presenting clinical features include splenomegaly, hepatomegaly, growth retardation, diarrhea, and abnormal wound healing with dehiscence, but these are neither necessary nor sufficient for the diagnosis. Certain abnormalities in routine laboratory tests are associated with the disease, although these are not required for diagnosis: Hypergammaglobulinemia, possibly due to chronic inflammation Anemia of chronic disease Elevated erythrocyte sedimentation rate and C reactive protein, usually in the presence of infection Hypoalbuminemia, found in 70 percent of patients with GI involvement and 25 percent without GI manifestations [55] Neutrophil function tests — Diagnostic tests for CGD rely on various measures of neutrophil superoxide production. These include direct measurement of superoxide production, cytochrome c reduction assay, chemiluminescence, nitroblue tetrazolium (NBT) reduction test, and dihydrorhodamine 123 (DHR) oxidation test. We prefer the DHR test because of its objectivity, relative ease of use, ability to distinguish between X-linked and autosomal forms of CGD, and the ability to detect gp91phox carriers [67,68]. Other tests can provide reliable diagnosis of CGD, but either cannot distinguish carrier status or require significant operator experience. Dihydrorhodamine 123 (DHR) test — In this test, the non-fluorescent rhodamine derivative, DHR, is taken up by phagocytes and oxidized to a green fluorescent compound by products of the NADPH oxidase (figure 2). The sensitivity and quantitative nature of this assay make it possible to differentiate oxidase positive from oxidase negative phagocyte subpopulations in CGD carriers and identify deficiencies in gp91phox and p47phox. DHR testing can also be quantitated to allow for allocation of cellular response into more and less impaired subgroups. The degree of residual superoxide production as measured by DHR testing provides important prognostic information that dovetails with genetic information [69]. (See 'Genetic testing' below.) Other conditions that affect the neutrophil respiratory burst include myeloperoxidase deficiency and SAPHO (the syndrome of synovitis, acne, pustulosis, hyperostosis, as osteitis), giving abnormal DHR test results but normal measures of extracellular superoxide production (eg, cytochrome c reduction or NBT tests) [70,71]. Several reference laboratories in the United States and around the world offer these assays. Nitroblue tetrazolium (NBT) test — The oldest and best-known laboratory test for CGD is the nitroblue tetrazolium (NBT) test. This provides a simple and rapid (but largely qualitative) determination of phagocyte NADPH oxidase activity. Superoxide produced by normal peripheral blood neutrophils stimulated in vitro reduces yellow NBT to dark blue/black formazan, which forms a precipitate in the cells. Normal phagocyte oxidase activity will result in at least 95 percent positive cells in this assay. X-linked carriers can be identified with this test. Test limitations include a higher rate of false negative results and operator subjectivity. Confirmatory tests — Techniques such as immunoblot can be used to confirm the diagnosis of CGD. Failure to detect p47phox or p67phox proteins indicates autosomal recessive mutations in the corresponding genes. The limitation of this technique is that it cannot distinguish between the X-linked gp91phox defect and the p22phox autosomal recessive defect, since expression of these two proteins on the cell membrane is mutually dependent. If there is a deficiency of either one of them, the other is also absent in immunoblot analysis [1]. Genetic testing — The clinical history usually suggests autosomal recessive or Xlinked disease, based on sex, consanguinity, age at presentation, and severity. A diagnosis of CGD based on abnormal neutrophil function should be followed by a confirmatory test to verify that the patient really does have CGD before genetic counseling is provided. Sequencing of the patient's phagocyte oxidase (phox) genes to determine the exact molecular defect is recommended but not necessary. Genetic testing is available through specialized commercial laboratories and selected tertiary referral centers (commercial laboratories in the United States include: GeneDx in Maryland, Correlagen Diagnostics in Massachusetts, and ARUP Laboratories in Utah; tertiary centers include: NIH in Bethesda, Great Ormand Street Hospital in London, Necker Hospital in Paris, and Garrahan Hospital in Buenos Aires). Genetic testing is increasingly important in the risk profiling of X-linked CGD. Mutations in the gene encoding gp91phox (CYBB) are usually either missense (replacement of the correct amino acid with an incorrect one but preserving protein synthesis) or nonsense (replacement of an amino acid with a stop codon leading to protein truncation and usually abrogating protein synthesis). Nonsense mutations generally lead to more severe CGD with diminished survival. Missense mutations that are in amino acids 1 to 309 are associated with residual superoxide formation, slight DHR positivity, and better survival. In contrast, mutations at amino acids 310 and beyond affect critical protein functional domains and lead to complete loss of DHR activity, more severe CGD, and diminished survival [69]. Prenatal diagnosis — If the precise mutation of a family member with CGD is known, then chorionic villus sampling can be performed to obtain a sample for genotyping of the fetus. Another testing option is to sample fetal blood and perform a DHR or NBT test. DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CGD mainly involves disorders associated with recurrent and/or unusually severe infections, particularly those caused by the pathogens commonly associated with the disease. (See 'Infections' above.) However, it is usually possible to differentiate between these diseases and CGD when the entire clinical picture is examined. The differential diagnosis may consider: Cystic fibrosis Hyper IgE syndrome Glucose 6-phosphate dehydrogenase (G6PD) deficiency Glutathione synthetase (GS) deficiency Crohn's disease (in patients with inflammation limited to the rectum) Cystic fibrosis patients may develop Burkholderia cepacia complex infections. However, the infections in patients with cystic fibrosis are limited to the lung and typically occur in the setting of significant bronchiectasis, which is not as common in patients with CGD. (See "Cystic fibrosis: Clinical manifestations and diagnosis".) Hyper IgE syndrome patients develop staphylococcal infections and may develop Aspergillus in the lung. However, the Aspergillus infections occur only in the setting of preexisting lung cysts, which are not common in patients with CGD. Also, hyper IgE patients have characteristic facies and markedly elevated IgE levels, whereas CGD patients do not. (See "Hyperimmunoglobulin E syndrome".) G6PD deficiency and GS deficiency affect the neutrophil respiratory burst and increase susceptibility to bacterial infections [72-74]. G6PD deficiency is most often associated with some degree of hemolytic anemia, whereas CGD is not. Severe GS deficiency is also associated with hemolytic anemia, in addition to 5-oxoprolinuria, acidosis, and mental retardation. These disorders are reviewed separately. (See "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency".) In vitro the respiratory burst may also be inhibited by diverse pathogens, including Legionella pneumophila, Toxoplasma gondii, Chlamydia, Entamoeba histolytica, and Ehrlichia risticii. Human granulocytic ehrlichiosis infection depresses the respiratory burst by downregulating gp91phox [75]. This effect is not diagnostically significant. SUMMARY AND RECOMMENDATIONS Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent life-threatening bacterial and fungal infections and granuloma formation. Most patients are diagnosed before the age of five. (See 'Introduction' above.) CGD is caused by defects in phagocyte NADPH oxidase (phox), the enzyme complex responsible for the phagocyte respiratory burst. (See 'Pathogenesis' above.) Mutations in all five genes (gp91phox, p47phox, p22phox, p67phox, and p40phox) that make up the NADPH oxidase complex account for all of the known cases of CGD. Most mutations are X-linked (gp91phox). (See 'Genetic defects' above.) Female carriers generally do not have an increased rate of infections, but they are more predisposed to certain inflammatory manifestations associated with CGD. However, highly lyonized females can develop typical CGD infections. (See 'X-linked carriers' above.) Patients with CGD typically experience recurrent infections caused by bacterial and fungal pathogens. The frequent sites of infection are lung, skin, lymph nodes, and liver. (See 'Infections' above.) The overwhelming majority of infections in patients with CGD living in North America are due to five organisms: Staphylococcus aureus, Burkholderia (Pseudomonas) cepacia complex, Serratia marcescens, Nocardia, and Aspergillus. (See 'Organisms' above.) Patients with CGD are prone to the formation of granulomata that are especially problematic in the gastrointestinal and genitourinary tracts. Colitis is a common gastrointestinal manifestation. (See 'Inflammatory and other manifestations' above.) 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Roos D, van Zwieten R, Wijnen JT, et al. Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 1999; 94:2955. 73. Whitin JC, Cohen HJ. Disorders of respiratory burst termination. Hematol Oncol Clin North Am 1988; 2:289. 74. Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 2001; 139:79. 75. Banerjee R, Anguita J, Roos D, Fikrig E. Cutting edge: infection by the agent of human granulocytic ehrlichiosis prevents the respiratory burst by downregulating gp91phox. J Immunol 2000; 164:3946. GRAPHICS NADPH oxidase activation Glucose-6-phosphate dehydrogenase is required for the production of nicotinamide adenine dinucleotide phosphate (NADPH), an essential component of the NADPH oxidase system (1). The phagocyte NADPH oxidase system generates superoxide anion (O- 2) by transferring electrons from NADPH to molecular oxygen (O2) (2). Superoxide is metabolized to hydrogen peroxide (H2O2) by superoxide dismutase (3). Hydrogen peroxide can follow different metabolic pathways: myeloperoxidase can convert it into hypochlorus acid (HOCl) (4), which in combination with other reactive oxygen species is involved in the oxygen-dependent killing of microorganisms (5). Hydrogen peroxide can also be degraded to H2O and O2, thereby avoiding deleterious effect on the cell (6, 7, dashed lines). DHR test Dihydrorhodamine assay for CGD diagnosis. Unstimulated (left) and phorbol myristate acetate stimulated (right) neutrophils are shown. Y axis is number of events, X axis is fluorescence intensity shown on a log scale. In the normal (top panels) there is a rightward shift seen with stimulation. In the X-linked CGD carrier state (second row), there are 2 populations seen: one is normally fluorescent, while the other is essentially the same as the unstimulated population. In the patient with X-linked CGD (third row) there is no shift in fluorescence with stimulation. In the patient with the autosomal recessive p47phox deficiency (fourth row), the rightward shift seen with stimulation is abnormally broad and not very bright. Tracings courtesy of Dr. Douglas B. Kuhns, SAIC Frederick.