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Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22phox, NCF1, encoding p47phox, NCF2, encoding p67phox and NCF4, encoding p40phox. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b558 chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91phox (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.

International audience; Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.

Objective: Our aim was to evaluate the contribution of flow cytometry (FC) analysis in patients with a histopathological diagnosis of mantle cell lymphoma (MCL) and to develop a reliable scoring system. Materials and Methods: We assessed the results of FC analysis in peripheral blood or bone marrow samples of 36 patients diagnosed with MCL by histopathological evaluation. Multivariate analysis identified 5 variables associated with MCL: CD23 negativity, CD5/19 common positivity, CD20/22 common bright positivity, FMC7 positivity, and clonal sIg bright positivity. A 5-point scoring system was devised using these parameters. Results: Twenty-five patients (69.4%) scored 5 points, 8 (22.2%) scored 4 points, and 3 (8.4%) scored 3 points. The diag- nosis of MCL was confirmed by FC immunophenotyping in 91.6% of the patients. Conclusion: Our results suggest that a quintet diagnostic scoring system, which is considered to be reliable in the diagnosis of MCL, could make a substantial contribution to diagnosis and should be more widely introduced in practice.

Chronic granulomatous disease (CGD) is an uncommon congenital phagocyte disorder characterized by recurrent life-threatening infections. CGD generally present with recurrent suppurative infections, however, intracranial fungal abscess complicating CGD may cause a diagnostic problem to anyone unfamiliar with its clinical and radiological features., BACKGROUND: Chronic granulomatous disease (CGD) is an uncommon congenital phagocyte disorder characterized by recurrent life-threatening infections. CGD generally present with recurrent suppurative infections, however, intracranial fungal abscess complicating CGD may cause a diagnostic problem to anyone unfamiliar with its clinical and radiological features.HISTORY: We report the case of a 16-year-old boy who was consulted with a differential diagnosis of an intracranial tumor. The clues of his medical history and physical examination made us consider the diagnosis of CGD. Cytometric dihydrorhodamine assay and genotyping confirmed an autosomal recessive CGD. He was successfully treated without any complication or sequel for 18 months follow-up period with surgery and interferon-gamma, in addition with, liposomal amphotericin B and voriconazole that were found to be sensitive to the Aspergillus fumigates, which had been grown from the culture of the abscess cavity.DISCUSSION: We discuss the pathogenesis, radiological techniques, and management of cerebral Aspergillus abscess in a patient with CGD.CONCLUSION: Presentation of CGD with a cerebral Aspergillus abscess, mimicking a brain tumor is extremely rare in children; clinicians and neurosurgeons must be aware. The best management modality for cerebral Aspergillus abscess is to be vigilant about the disease, whereas adjuvant surgical and medical therapy with a close follow-up must be warranted for all cases

Chronic granulomatous Disease (CGD) is a rare immunodeficiency caused by a defect in the leukocyte NADPH oxidase. This enzyme generates superoxide, which is needed for the killing of bacteria and fungi by phagocytic leukocytes. Most CGD patients have mutations inLeukocyte NADPH oxidase activity, expression of oxidase components and gene sequences were measured with standard methods. The mutation found in the patients'The exceptional feature of the A67 CGD patients reported here is that the p.Ala202Val mutation in the activation domain of p67The mutation found in

Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder. Patients should be closely monitored due to risk of malignancy development. Due to its wide clinical heterogeneity, it often leads physicians to an inaccurate or missed diagnosis, and insight into this rare disease is important. Pediatric patients may develop lymphomas and acute lymphoblastic leukemia (ALL). However, in adults, there are limited numbers of reports regarding association of AT and ALL. Rarely, ALL cases may present with pleural fluid involvement. In our study, we presented an adult case with AT, in which ALL involvement was detected in pleural fluid by flow cytometry (FC). A 20-years old male presented to emergency department with fever, shortness of breath and cough, as he had been followed with a diagnosis of AT. The following findings were detected in laboratory tests: Hb, 11.5 g/L; WBC, 36 x 10(9)/L; Plt: 140 x 10(9)/L. Blastic cells were observed in peripheral blood smear. On chest radiography, pleural fluid appearance was observed. On thorax CT, pleural fluid was detected in both hemithorax. Cytoplasmic CD3(+) and superficial CD3 (+), CD45 (+), CD5 (+), CD7 (+) and CD38 (+) was found in the flow cytometric evaluation of peripheral blood. Superficial CD3 (+), CD2 (+), CD5 (+) and CD7 (+) were found in flow cytometric evaluation of pleural fluid. These findings were considered as consistent with pleural involvement of T-ALL. FC is a potentially useful diagnostic tool for clinical practice and it is a convenience method which has an important role in detection of ALL in patients with pleural fluid.

Study background: Chronic granulomatous Disease (CGD) is a rare immunodeficiency caused by a defect in the leukocyte NADPH oxidase. This enzyme generates superoxide, which is needed for the killing of bacteria and fungi by phagocytic leukocytes. Most CGD patients have mutations in CYBB, the X-linked gene that encodes gp91phox, the catalytic subunit of the leukocyte NADPH oxidase. We report here three autosomal recessive CGD patients from two families with a homozygous mutation in NCF2, the gene that encodes p67phox, the activator subunit of the NADPH oxidase. Methods: Leukocyte NADPH oxidase activity, expression of oxidase components and gene sequences were measured with standard methods. The mutation found in the patients’ NCF2 gene was expressed as Ala202Valp67phox in K562 cells to measure its effect on NADPH oxidase activity. Translocation of the mutated p67phox from the cytosol of the patients’ neutrophils to the plasma membrane was measured by confocal microscopy and by Western blotting after membrane purification. Results: The exceptional feature of the A67 CGD patients reported here is that the p.Ala202Val mutation in the activation domain of p67phox was clearly hypomorphic: substantial expression of p67phox protein was noted and the NADPH oxidase activity in the neutrophils of the patients was 20-70% of normal, dependent on the stimulus used to activate the cells. The extent of Ala202Val-p67phox translocation to the plasma membrane during cell activation was also stimulus dependent. Ala202Val-p67phox in K562 cells mediated only about 3% of normal oxidase activity compared to cells transfected with the wild-type p67phox. Conclusion: The mutation found in NCF2 is the cause of the decreased NADPH oxidase activity and the (mild) clinical problems of the patients. We propose that the p.Ala202Val mutation has changed the conformation of the activation domain of p67phox, resulting in reduced activation of gp91phox.

The NLRP3 inflammasome can be activated by pathogen-associated molecular patterns or endogenous danger-associated molecular patterns. The activation of the NLRP3 inflammasome results in proteolytic activation and secretion of cytokines of the interleukin-1 (IL-1) family. The precise mode of activation of the NLRP3 inflammasome is still elusive, but has been postulated to be mediated by reactive oxygen species (ROS) generated by an NADPH oxidase. Using primary cells from chronic granulomatous disease (CGD) patients lacking expression of p22(phox), a protein that is required for the function of Nox1-4, we show that cells lacking NADPH oxidase activity are capable of secreting normal amounts of IL-1 beta. Thus, we provide evidence that activation of the NLRP3 inflammasome does not depend on ROS generated from an NADPH oxidase. (Blood. 2010; 115(26):5398-5400), The NLRP3 inflammasome can be activated by pathogen-associated molecular patterns or endogenous danger-associated molecular patterns. The activation of the NLRP3 inflammasome results in proteolytic activation and secretion of cytokines of the interleukin-1 (IL-1) family. The precise mode of activation of the NLRP3 inflammasome is still elusive, but has been postulated to be mediated by reactive oxygen species (ROS) generated by an NADPH oxidase. Using primary cells from chronic granulomatous disease (CGD) patients lacking expression of p22phox, a protein that is required for the function of Nox1-4, we show that cells lacking NADPH oxidase activity are capable of secreting normal amounts of IL-1ß. Thus, we provide evidence that activation of the NLRP3 inflammasome does not depend on ROS generated from an NADPH oxidase.

Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by impairment of intracellular microbicidal activity of phagocytes. Mutations in one of four known nicotinamide adenine dinucleotide phosphate (NADPH) -oxidase components preclude generation of superoxide and related antimicrobial oxidants, leading to the phenotype of CGD. Defects in gp91-phox, encoded by CYBB gene, lead to X-linked CGD and have been reported to be responsible for approximately 65% of all CGD cases. The autosomal gene in CGD are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47-phox, and NCF4, encoding p40-phox (figure 1) (1,2). The mutation in these genes, respectively, abolishes the activity of the oxidase and leads to autosomal recessive chronic granulomatous disease (AR-CGD) which is approximately 35% of all CGD cases (table 1).

Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, mutations are found in ITGB2, the gene that encodes the beta subunit of the beta(2) integrins. This syndrome is characterized directly after birth by delayed separation of the umbilical cord. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Le(a) and Le(b) blood group antigens. Finally, in LAD-III (also called LAD-I/variant) the conformational activation of the hematopoietically expressed beta integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of beta integrin conformation. (C) 2011 Elsevier Inc. All rights reserved., Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, mutations are found in ITGB2, the gene that encodes the ß subunit of the ß(2) integrins. This syndrome is characterized directly after birth by delayed separation of the umbilical cord. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Le(a) and Le(b) blood group antigens. Finally, in LAD-III (also called LAD-I/variant) the conformational activation of the hematopoietically expressed ß integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of ß integrin conformation.PMID:22134107[PubMed - indexed for MEDLINE]

A 43-year-old male patient was diagnosed with chronic myelogenous leukemia (CML), and hydroxyurea treatment was begun 3 months before consultation. Physical examination revealed the spleen 2 cm below the costal margin. The Philadelphia chromosome was positive. After hydroxyurea treatment, imatinib (Gleevec) was started. On the 15th day of imatinib treatment, the patient was admitted because of fever, diarrhea, and generalized rash. Informed consent was obtained. Whole blood count showed a hemoglobin concentration of 10.5 g/L, white cell count of 23,000/mm3, and platelet count of 240,000/mm3. Imatinib treatment was stopped to see if these symptoms were related to the drug. After cessation of imatinib, the fever resolved and the skin lesions disappeared. Imatinib was changed to dasatinib. The patient takes dasatinib at 100 mg and the treatment is on-going. A wide spectrum of dermatologic toxicities has been associated with imatinib, among which a maculopapular rash is the most common event. Imatinib-induced skin rash is believed to be due to the blockade of the c-kit protein, which is present in skin. Severe toxicity of skin rash, fever, and diarrhea associated with imatinib has been reported. The initial dose for chronic-phase disease, 400 mg/day, is very well tolerated. A higher risk for developing rash will occur with imatinib doses higher than 600 mg/day, advanced age, and female sex. In many patients who experience unacceptable adverse effects, transient dose reduction or treatment interruption allows for patients to resolve the adverse effects.

Chronic granulomatous disease is a genetically determined immunodeficiency disorder affecting phagocytic cells rendering them unable to kill certain bacteria and fungi. The present study is a single-center retrospective study that aimed to document the clinical course of 26 children, with a median age of 2.5 years, from 21 families diagnosed as chronic granulomatous disease from 1989-2008. A median delay of 39 months was observed between the onset of infections and age at diagnosis. Pneumonia was the most common initial manifestation of the disease followed by lymphadenitis, skin abscess and diarrhea. An AR inheritance was predominant in the study group. All patients received antibacterial and antifungal prophylaxis, resulting in a marked decrease in the incidence of infections. Overall mortality was 19.2%. These results showed that all features in our group (clinical, progression and outcome) were similar to the literature except for the predominance of autosomal recessive form.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations. (C) 2010 Elsevier Inc. All rights reserved., Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations.

Background Despite major advances in the management of newborn infants, neonatal sepsis (NS) remain important causes of neonatal morbidity and mortality in the newborn, mainly among preterm and low birth weight infants. Objective: The aim of this study was to investigate the usefulness of neutrophil CD64 expression alone and together with other infection markers in NS. Methods: Peripheral blood samples were taken from 109 neonates, who were categorized into three groups: proven or clinical sepsis (n = 35); disease without infection (n = 42); and healthy controls (n = 32). Complete blood count with differential, interleukin-6 (IL-6), C-reactive protein (CRP), and cell surface expression of CD64 on neutrophils have been evaluated in a prospective manner as a diagnostic aid for NS. Results: Expression of CD64 was significantly enhanced in neonates with sepsis compared with newborns with disease without infection and healthy controls (P = 0.001 and P = 0.001, respectively). Cutoff values of IL-6, CRP, CD64(MFI), and CD64(i) were 24.9 pg/ml, 4.05 mg/l, 87.7, and 4.39, respectively. Sensitivity-negative predictive values of IL-6, CRP, and CD64(MFI)/CD64(i) were 80.0-90.6%, 80.0-88.8%, and 88.6-94.0%, respectively. Combining all three tests increased the sensitivity to 100%; however, specificity and positive predictive value decreased to 62.1 and 55.5%, respectively. Conclusions: CD64 might be used either alone or combined with IL-6 and CRP for early diagnosis of NS. The advantages of CD64 when compared with IL-6 and CRP are rapid quantitation, very small blood volume required, and easy handling. J. Clin. Lab. Anal. 24:363-370, 2010. (C) 2010 Wiley-Liss, Inc.