Granulomatous Disease, Chronic, X-Linked

A number sign (#) is used with this entry because X-linked chronic granulomatous disease (CGD) is caused by mutation in the gene encoding p91-phox (CYBB; 300481).

Description

Chronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the phagocyte NADPH oxidase (phox) complex, which generates the microbicidal 'respiratory burst' (reviewed by Dinauer et al., 2001 and Johnston, 2001).

Genetic Heterogeneity of Chronic Granulomatous Disease

Chronic granulomatous disease can be caused by mutations in any 1 of 5 genes encoding structural or regulatory subunits of the phagocyte NADPH oxidase complex. See also autosomal recessive cytochrome b-negative CGD (233690), caused by mutation in the CYBA gene (608508); autosomal recessive cytochrome b-positive CGD type I (233700), caused by mutation in the NCF1 gene (608512); autosomal recessive cytochrome b-positive CGD II (608515), caused by mutation in the NCF2 gene (608515); and autosomal recessive cytochrome b-positive CGD type III (613960), caused by mutation in the NCF4 gene (601488).

A similar syndrome, termed neutrophil immunodeficiency syndrome (608203), is caused by mutation in another protein involved in the NADPH oxidase complex, RAC2 (602049).

Clinical Features

Dinauer et al. (2001) suggested that Janeway et al. (1954) first noted CGD in a patient with hypergammaglobulinemia associated with severe recurrent and chronic nonspecific infections, but did not distinguish the disorder as a distinct entity. Berendes et al. (1957) and Bridges et al. (1959) identified a new syndrome which they termed 'fatal granulomatosis of childhood.' Four boys had suppurative lymphadenitis, hepatosplenomegaly, pulmonary infiltrates, and eczematoid dermatitis, with findings of granulomas in biopsy and autopsy specimens. Landing and Shirkey (1957) described 2 boys with recurrent infection who had infiltration of visceral organs by pigmented lipid histiocytes. Carson et al. (1965) reported 16 males in 8 families with a syndrome of chronic suppurative lymphadenitis, chronic dermatitis, chronic pulmonary disease and hepatosplenomegaly with subsequent fatal outcome. Hypergammaglobulinemia was often present. Quie et al. (1967) observed a form of fatal granulomatous disease in males in an X-linked pedigree pattern. The leukocytes were able to phagocytize staphylococci normally, but were defective in their ability to digest the organism.

In a series of 6 males with CGD, aged 2 to 22 years, Lischner and Martyn (1975) described chorioretinal lesions, sea-blue histiocytes, and changes misconstrued as indicative of eosinophilic granuloma. Dilworth and Mandell (1977) reported 4 adult male sibs, aged 28, 30, 32, and 40, who had the onset at age 6 years of serious bacterial infections involving the lungs and lymph nodes followed by a marked decrease in the frequency of infections in their mid-twenties. Sequelae included pulmonary fibrosis, ill-defined polyarthritis and glomerulonephritis. Despite normal morphology and the ability to ingest microbes, postphagocytic polymorphonuclear leukocytes failed to reduce nitroblue tetrazolium (NBT), consume oxygen and produce hydrogen peroxide, and stimulate the hexose monophosphate shunt. G6PD (305900) levels were normal. An intermediate quantitative NBT in the mother of the brothers and in a daughter of each of 2 of them supported X-linked recessive inheritance.

Bohler et al. (1986) studied 25 patients with CGD. In 18 of 22 clinically typical cases, the complete inability of superoxide generation by granulocytes was associated with the absence of detectable cytochrome b. Mothers, but not fathers, of such male patients showed diminished content of cytochrome b, confirming that the affected gene is localized on the X chromosome. Flavoprotein deficiency found in the granulocytes of 4 male patients was always associated with absence of detectable cytochrome b. Three further patients had a mild form of X-linked CGD; the oxidative activity of their phagocytes and the cytochrome b were diminished but not absent. Southwick and van der Meer (1988) described recurrent episodes of severe cystitis in 2 unrelated men, aged 23 and 20 years, with X-linked CGD. Ultrasonography showed large, discrete bladder masses that mimicked bladder carcinoma in both patients. Prolonged antibiotic therapy was necessary for clearing of the inflammatory bladder masses.

Johnston (2001) reviewed the clinical aspects of CGD. The disorder presents most often with pneumonia, infectious dermatitis, osteomyelitis, and recurrent or severe abscess formation beneath the skin and in the organs of the mononuclear phagocyte system. Tissue examination typically shows microscopic granulomas. The estimated incidence of CGD in the U.S. is 1/200,000 births per year. Of 368 patients with CGD, approximately 76% had the X-linked recessive form, 18% had disease due to p47-phox (NCF1; 608512) deficiency, 4% due to p67-phox (233710) deficiency, and 3% due to p22-phox (608508) deficiency. Johnston (2001) found that the organisms infecting CGD patients in the 1990's changed markedly from those reported from 1957 to 1976. Initially, Staphylococcus, Klebsiella, and E. coli were the most common organisms, whereas Aspergillus nidulans, Candida, Burkholderia cepacia (formerly Pseudomonas cepacia), and Serratia marcescens had become more prominent since then. Secondary complications in patients with CGD include enteritis/colitis, obstruction of the urinary tract, discoid lupus, and chorioretinitis.

Variant or Atypical CGD

Lew et al. (1981) described a man with what the authors termed a 'variant' form of CGD. The disorder resembled CGD in some respects, but differed by showing normal activation of phagocyte membrane oxidase. However, the oxidase showed reduced activity under physiologic conditions because of an apparent altered affinity for reduced NADP. Granulocytes from the patient's mother, but not those of the father, exhibited defective superoxide production, supporting X-linked inheritance. The proband had only mild infections limited to the skin and no history of the usual systemic or visceral infections. At age 16, he developed thrombocytopenia which responded to steroids, and, at age 19, splenectomy. The mother had discoid lupus erythematosus, a disease reported to be associated with the CGD carrier state (Schaller, 1972). The maternal grandfather had a lifelong history of skin infections and was said to have died of tuberculosis at age 62.

In general, X-linked CGD is cytochrome b-negative. However, Borregaard et al. (1983) reported a family with X-linked, cytochrome b-positive CGD. Curnutte (1988) suggested the existence of a fourth type of CGD, CGD type IV, which is exceedingly rare and is characterized by X-linked inheritance but normal levels of cytochrome b. He reported 2 brothers with this disorder, referred to 4 other cases with a similar clinical picture, and suggested that these cases are allelic variants.

Clark et al. (1989) concluded that the X-linked cytochrome b-negative type of CGD due to deficiency of the beta subunit of cytochrome b represents about 51% of cases of CGD. Another 5% of cases of CGD have an X-linked cytochrome b-positive form, which is allelic to the X-linked cytochrome b-negative form, in which a mutation preserves a functionally defective but detectable cytochrome (see 300481.0001 and Dinauer et al., 1989). Patients with this rare cytochrome b-positive X-linked form of CGD were reported by Ament and Ochs (1973) and Okamura et al. (1988).

Bolscher et al. (1991) classified CGD cases as 'classic' if there was no respiratory burst activity demonstrable in a patient's neutrophils and cytochrome b(558) was absent as determined by absorption spectroscopy; they classified cases as 'variant' when a patient's neutrophils had residual burst activity and residual amounts of cytochrome b(558). These patients may also be referred to as having cytochrome b-positive X-linked CGD.

Female Carriers

The mother of the affected boy described by MacFarlane et al. (1967) had a chronic dermatitis of the neck (Jessner benign lymphocytic infiltration) and a partial defect in phagocytosis demonstrable in vitro that was qualitatively identical to that in her son.

Thompson and Soothill (1970) and Kragballe et al. (1981) described an increased incidence of cutaneous lupus erythematosus (discoid lupus erythematosus) and recurrent mouth ulcers in female carriers of X-linked CGD. The degree in reduction of superoxide production was closely related to the manifestations of clinical disease.

Finlay et al. (1983) suggested that a persistent eruption in light-exposed areas is a manifestation of the CGD heterozygous state. They observed the changes in the mother and sister of an affected boy. Similarities to cutaneous SLE and to Jessner benign lymphocytic infiltration were noted in earlier reports that have emphasized the significance of this finding (Brandrup et al., 1981; Nelson et al., 1977; Schaller, 1972). Finlay et al. (1983) called this CGDCGD (carrier genodermatosis of chronic granulomatous disease) and suggested that the skin disorder can be a useful guide in genetic counseling and prenatal diagnosis.

Inheritance

Windhorst et al. (1967) did family studies establishing X-linked recessive inheritance of CGD, and demonstrating 2 populations of leukocytes in heterozygous females. Controversy over whether the inheritance is X-linked or autosomal was illustrated by the letter of Windhorst (1969) and accompanying reply.

Diagnosis

Prenatal Diagnosis

Matthay et al. (1984) described a luminol enhanced chemiluminescence micromethod used for prenatal diagnosis of CGD. Fetal blood was useful, whereas amniocytes were not.

De Boer et al. (1992) reported successful prenatal diagnosis of CGD using PCR.

Pathogenesis

During phagocytosis, neutrophils undergo the 'respiratory burst,' an oxidative response in which highly reactive bactericidal oxidative metabolites, including superoxide, hydrogen peroxide, hydroxyl radicals, and perhaps singlet oxygen, are formed within the intact phagocyte. The NADPH oxidase complex is responsible for the respiratory burst. Segal (1985) gave a useful review of the molecular basis of CGD, viewed as a syndrome caused by any defect in the function of the electron transport chain essential to the microbicidal activity of white cells.

In patients with CGD, Baehner and Nathan (1967) demonstrated a defect in a leukocyte oxidase; the intact leukocytes failed to reduce the redox dye nitroblue tetrazolium or to show increased oxygen consumption during phagocytosis. Baehner and Karnovsky (1968) found deficiency of reduced nicotinamide-adenine dinucleotide oxidase of polymorphonuclear leukocytes in 5 patients with CGD. In cells from patients with CGD, Quie et al. (1967) found diminished activity of the bacterial capacity of polymorphonuclear leukocytes.

In 2 patients with CGD, Curnutte et al. (1974) found low levels of superoxide production; both patients were male (Babior, 1974). In granulocyte samples from 3 patients with X-linked CGD, Curnutte et al. (1975) found that the cells produced no detectable superoxide. The failure was not due to an inhibitor. Samples from the mothers of 2 of the patients produced superoxide at diminished rate, whereas samples from the third mother had normal superoxide production. Hohn and Lehrer (1974) found deficiency of NADPH oxidase as the presumed basic defect in X-linked CGD. In neutrophils from a patient with CGD, Segal and Peters (1976) demonstrated a defect in an NADH-dependent enzyme located in the plasma membrane that reduces NBT. McPhail et al. (1977) also presented evidence that NADPH oxidase activity is deficient in CGD and suggested that a failure of activation of the enzyme underlies the deficiency. Of the 9 patients studied, 7 were considered to have the autosomal recessive and 2 the X-linked type. No physiologic difference between the types was detected.

In neutrophils of patients with CGD, Segal et al. (1978) demonstrated absence of a newly described heme-containing cytochrome b(-245). Obligatory CGD heterozygotes showed intermediate levels of the cytochrome b. The authors noted that the burst of oxygen metabolism associated with phagocytosis is not to provide energy for the cells, but rather is involved in the bacterial killing process. Due to the defect in the oxygen-dependent microbicidal system in CGD, neutrophils are unable to kill certain bacteria, particularly those that contain catalase and can catabolize hydrogen peroxide. The cytochrome b deficient in CGD is independent of cytochrome P450 of the endoplasmic reticulum and of mitochondrial cytochrome oxidase. Segal et al. (1983) found that cytochrome b(-245) was undetectable in 19 males with presumed X-linked CGD; heterozygous female relatives had reduced concentrations of the cytochrome and variable proportions of cells that were unable to generate superoxide, these 2 characteristics being closely correlated. Of the 19 cases, 3 were sporadic with no carrier females in the family. In all 8 patients, including 7 women, with a probable autosomal recessive form of CGD, the cytochrome was present but nonfunctional. Segal et al. (1983) reported an Asian family with affected females with depressed levels and function of cytochrome b(-245).

Segal (1987) determined that cytochrome b is composed of 2 closely linked subunits with approximate molecular masses of 23 kD and 91 kD. In 5 patients with X-linked CGD, neither protein was detected. Parkos et al. (1989) found that neither cytochrome b subunit, p22-phox or p91-phox, could be detected in neutrophils from 3 patients with X-linked cytochrome b-negative CGD or in 4 patients with autosomal cytochrome b-negative CGD. The authors concluded that the stable expression of either of the 2 subunits is dependent upon the other.

In an editorial, Karnovsky (1983) noted that genetic defects in CGD may occur at many levels, since it is an enzyme system rather than a single enzyme involved in the transmission of electrons during the respiratory burst. Potential affected steps include stimulation of the cell membrane; apposition of membrane-bound components of the machinery of the respiratory burst; the cytoskeleton which may control movement of membrane or cytoplasmic components; one or more enzymes that reduced cytochrome b(-245); the amount of the cytochrome present; the intimate nature of the cytochrome itself.

Variant forms of CGD, both X-linked and autosomal, have been described in which the patients' phagocytes respond to some but not to all stimuli of the oxidase system (Tauber et al., 1983). Defects in the activation system may lead to CGD, as well as absence or defect in a component of the complex oxidase system that generates superoxide and hydrogen peroxide. When monocytes from the X-linked and autosomal forms of CGD were fused, Hamers et al. (1984) showed that the hybrid cells were cytochrome-b-positive and expressed NBT-reductase activity in the presence of phorbol myristate acetate (PMA).

Buescher et al. (1985) used the ability or lack of ability to reduce NBT dye to identify 2 populations of white cells in females heterozygous for CGD. The findings in 11 heterozygotes were consistent with lyonization at a stage when 8 embryonic founder cells for the hematopoietic system were present. Individuals showed little variation, most of it attributable to experimental error among serial determinations. The variation remaining after accounting for experimental error suggests the existence of more than 400 pluripotent stem cells supporting hematopoiesis. Similar studies have been done using G6PD.

Mapping

Francke et al. (1985) studied a male patient with 3 X-linked disorders: chronic granulomatous disease with cytochrome b(-245) deficiency and McLeod red cell phenotype (300842), Duchenne muscular dystrophy (310200), and retinitis pigmentosa (see RP3, 300029). A subtle interstitial deletion of part of Xp21 was demonstrated as the presumed basis of this 'contiguous gene syndrome.' The close clustering of CGD, DMD and RP suggested by these findings was inconsistent with separate linkage data (see HISTORY and Densen et al., 1981), which indicated that McLeod and CGD are close to Xg and that DMD and RP are far from Xg. Francke et al. (1985) suggested that the deletion may contain a single defect affecting perhaps a cell membrane component which underlies all 3 disorders. Using a method for cloning the specific DNA fragment absent in patients homozygous or hemizygous for chromosomal deletions, Kunkel et al. (1985) confirmed a minute interstitial deletion of Xp21 in the patient reported by Francke et al. (1985); see 300679.

Using cloned, polymorphic DNA probes, Baehner et al. (1986) mapped CGD to Xp21.2-p21.1, proximal to DMD. CGD lies in a region of Xp that appears to have more recombination than anticipated on the basis of physical distance between markers. This linkage assignment is inconsistent with the linkage to Xg, but entirely consistent with the findings in the boy reported by Francke et al. (1985) with an interstitial deletion of Xp21, The earlier data on linkage to Xg were apparently in error.

Clinical Management

Ezekowitz et al. (1988) attempted a therapeutic trial using interferon-gamma (IFNG; 147570), an activator of phagocytes, in CGD. They observed a 5- to 10-fold increase in superoxide production by granulocytes and monocytes, a proportionate rise in granulocyte bactericidal activity, and an increase in the cellular contents of phagocyte cytochrome b and immunoreactive cytochrome b heavy chain. The findings of Ezekowitz et al. (1988) motivated multicenter groups to perform double-blinded clinical studies of IFN-gamma as a prophylactic agent in CGD, which demonstrated its clinical benefit in most patients. In these group studies, however, no apparent increases in phagocyte superoxide generation were observed. For that reason, the patient studied by Ezekowitz et al. (1988) was considered to be an exceptional case. Rae et al. (1998) showed that the patient of Ezekowitz et al. (1988) had a single-base substitution in the sixth position of the first intron of the CYBB gene (300481.0020). Condino-Neto and Newburger (2000) proposed that IFN-gamma improved the splicing efficiency of CYBB gene transcripts in that patient and corrected a nuclear processing defect due to the intronic mutation by augmenting nuclear export of normal transcripts.

Ishibashi et al. (2001) demonstrated an IFN-gamma-dependent increase of superoxide production associated with a change in the mRNA splicing pattern of CYBB gene transcripts in neutrophils from 3 patients in 1 family who had a silent mutation adjacent to intron 3 of the CYBB gene (300481.0015). They found significant differences in the splicing pattern of CYBB gene transcripts in patient neutrophils between days 1 and 25 after administration of IFN-gamma. Furthermore, a complete transcript containing the missing exons was detected in all specimens after the treatment. The changes in the splicing pattern of the transcripts and the prolonged effect on superoxide-generating ability of the patients' neutrophils indicated that IFN-gamma induced a partial correction of the abnormal splicing of CYBB gene transcripts in myeloid progenitor cells.

Ho et al. (1996) reported successful bone marrow transplantation (BMT) in a 16-month-old Australian Aboriginal boy. His HLA-identical brother was the donor. The authors reviewed 5 previous reports on BMT in patients with X-linked CGD.

Horwitz et al. (2001) treated 10 male patients with CGD by transplantation of peripheral blood stem cells from an HLA-identical sib after undergoing a nonmyeloablative conditioning regimen consisting of cyclophosphamide, fludarabine, and antithymocyte globulin. The allograft was depleted of T cells to reduce the risk of severe graft-versus-host disease (GVHD; see 614395). To reduce the risk of graft rejection, donor lymphocytes were infused at intervals after transplantation, according to a predetermined regimen. After a median follow-up of 17 months, the proportion of donor neutrophils in the circulation in 8 of 10 patients was 33 to 100%, a level that could be expected to provide normal host defense; in 6 patients the proportion was 100%. In 2 patients, graft rejection occurred. Preexisting granulomatous lesions resolved in the patients in whom transplantation was successful. Eight of the patients had the p91-phox founder disease; 1 patient each had the p22-phox form and the p47-phox form.

Liese et al. (2000) evaluated the effect of antibiotic and antifungal long-term prophylaxis on the prognosis of CGD in 39 patients with different subtypes, both X-linked and autosomal recessive. Antibiotic prophylaxis with TMP-SMX significantly decreased the incidence of severe infections in patients with complete loss of cytochrome b activity but had no significant effect in patients with the other subtypes. Eight of the patients with complete absence of cytochrome b activity were also given itraconazole, and none developed fungal infections over 15.5 patient-years, whereas patients of all subtypes who received only antibiotics showed an increase in severe fungal infections. The different subtypes were also analyzed for age at diagnosis, age at first infection, and long-term survival.

In a placebo-controlled study, Gallin et al. (2003) found that itraconazole is an effective and well-tolerated prophylaxis for fungal infections in chronic granulomatous disease. Lagakos (2003) commented on the fact that the trial required 10 years to enroll just 39 patients, thus illustrating some of the problems and options that arise in the design of clinical trials for new therapies for rare diseases.

Gene Therapy

Porter et al. (1993) used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from 3 unrelated patients with X-linked CGD. The protein was glycosylated and membrane-associated, and the reconstituted oxidase was appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells was similar to that of normal B-cell lines.

Ezekowitz (2001) raised the possibility that the ability to purify and manipulate stem cells from bone marrow (Orkin, 2000) may provide new approaches to somatic gene therapy. The possibility that single-gene defects could be repaired in autologous stem cells ex vivo and, on return to the patient, home selectively to the organ of choice seemed within reach.

Ott et al. (2006) reported successful treatment of X-linked CGD in 2 unrelated patients with myelosuppression followed by gene therapy using a monocistronic gammaretroviral vector expressing the p91-phox gene to transform peripheral blood cells. Gene-modified cells predominantly in the myeloid fraction were detected as early as 21 days post-reinfusion and persisted over a year later accompanied by clinical improvement in both patients. Analysis of retroviral integration sites showed clustering of activating insertions in or near the PR domain-containing zinc finger genes MDS1 (600049)-EVI1 (165215) or PRDM16 (605557), or the SETBP1 gene that influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis 3- to 4-fold in both individuals.

Molecular Genetics

In a patient with cytochrome b-positive X-linked CGD, Dinauer et al. (1989) identified a mutation in the gene encoding the cytochrome b heavy chain (CYBB; 300481.0001). In 6 patients with X-linked CGD, both cytochrome b-negative and cytochrome b-positive forms, Bolscher et al. (1991) identified 6 different point mutations in the CYBB gene (300481.0002-300481.0007).

Roos (1994) reviewed all 4 genetic forms of chronic granulomatous disease. Cross et al. (1996) tabulated 123 mutations in the CYBB gene known to cause chronic granulomatous disease. Heyworth et al. (1997) presented updated tables containing 64 newly identified mutations.

Ariga et al. (1998) concluded that the proportion of sporadic cases of CGD, i.e., patients in whom the mother is not a carrier, is very low, and that the proportion of sporadic carriers, i.e., mothers who inherited a new mutation, is high. These results suggested that the mutation for the disease originates mainly in male gametes.

Patino et al. (1999) reported the molecular characterization of 7 unrelated kindreds with CGD from Colombia and Brazil. In 6 of these kindreds, all mothers were carriers; in the seventh, the mutation was de novo.

Ishibashi et al. (2000) reported a statistical analysis of 229 patients from 195 families with chronic granulomatous disease in Japan and described the findings of mutation analysis of 28 and 5 unrelated patients, respectively, with gp91- and p22-phox deficiency. The ratio of male to female patients was 6.6/1, the incidence was calculated to be about 1 in 220,000 births, and the life expectancy of the patients born in the 1970s was estimated to be about 25 to 30 years. A total of 9 patients from 8 families had been found in Japan with CGD in combination with retinitis pigmentosa. Three families had a large deletion involving the CYBB gene. One patient had X-CDG in combination with McLeod syndrome (300842).

Cytogenetics

Kumatori et al. (1998) concluded that nonhomologous recombination between the CYBB gene and a LINE-1 element lies 5-kb upstream of CYBB in normal persons. They reported a patient with chronic granulomatous disease who had a 25-kb deletion extending to the 5-prime two-thirds of CYBB. The 3-prime breakpoint of the deletion was located in exon 7 of CYBB; the 5-prime breakpoint was in the LINE-1 element. There were no significant homologies between corresponding normal 5-prime and 3-prime regions flanking the breakpoint of the patient, so a nonhomologous recombination was considered the most likely mechanism for the 25-kb deletion. The analysis also showed that the patient had a novel 30-bp duplication in the 5-prime flanking region of the deletion point, which was transmitted by his mother with the deletion. The study suggested that the deletion occurred in his grandfather.

Animal Model

Pollock et al. (1995) created an animal model of X-linked CGD. They used gene targeting to generate mice with a null allele of the gene that encodes the 91-kD subunit of the oxidase cytochrome b. Affected hemizygous male mice lacked phagocyte superoxide production, manifested an increased susceptibility to infection with Staphylococcus aureus and Aspergillus fumigatus, and had an altered inflammatory response to thioglycollate peritonitis. They suggested that the animal model would be helpful in developing new treatments for CGD and in evaluating the role of phagocyte-derived oxidants in inflammation.

Deffert et al. (2014) conducted a literature search that found nearly 300 cases of mycobacterial infection in CGD, principally caused by M. bovis bacillus Calmette-Guerin (BCG). The authors then investigated BCG infection in 3 different mouse models of CGD: 2 strains of mice lacking Ncf1 and mice lacking Cybb. All 3 CGD mouse strains were highly susceptible to intravenous BCG infection, manifest as severe weight loss, hemorrhagic pneumonia with high numbers of neutrophils, and 50% mortality. These mice had only moderately increased bacterial load. Macrophage-specific rescue of Cybb restored BCG resistance. ROS was generated in granulomas of wildtype mice, but not CGD mice. Massive increases in the release of the cytokines Tnf (191160), Ifng, Il17 (603149), and Il12 (161561), as well as Cxcl1 (155730), a neutrophil chemoattractant, occurred early after infection in CGD mice, possibly explaining disease severity. Macrophages clustered in granulomas in wildtype mice, whereas macrophages were diffusely distributed in lungs of CGD mice. Deffert et al. (2014) concluded that lack of NADPH oxidase leads to markedly increased severity of BCG infection through increased cytokine production and reduced granuloma formation.

History

No abnormality of red cell Kell phenotype (see 110900) was found in 15 Japanese cases of CGD (Ito et al., 1979). It had been suggested that a defect of blood group precursor in the white cell membrane leads to deficient activation of NADH dehydrogenase in 1 form of CGD. It turned out that the cases of CGD with the McLeod phenotype, resulting from deletion of the Xk locus, represented a contiguous gene syndrome, as defined by Schmickel (1986), due to deletion of the closely linked CYBB and Xk loci in Xp21.

Densen et al. (1981) reported a highly informative family in which 4 of 8 brothers had CGD by clinical history and tests of neutrophil function. All 4 affected brothers had Kell (Kx)-negative neutrophils. The remaining 4 unaffected brothers were in good health and had normal NBT tests. However, 1 of the unaffected brothers had Kx-negative neutrophils that functioned normally. Densen et al. (1981) concluded that closely linked but distinct genes code for CGD and Kx. In addition, close linkage of the Xk and Xg loci was demonstrated; no recombinant was found in this sibship. Although it appears that the coexistence of CGD and the McLeod syndrome in some patients is due to the deletion of 2 very closely linked genes, Xk and CGD, Branch et al. (1986) showed that granulocytes lack red cell Kx antigen. The previous finding of Kx on white cells was presumably due to contamination of the testing serum by anti-WBC antibodies of non-Kx specificity.