Molecular diagnosis of chronic granulomatous disease

Published on Feb 1, 2014in Clinical and Experimental Immunology3.532
· DOI :10.1111/CEI.12202
Dirk Roos114
Estimated H-index: 114
(UvA: University of Amsterdam),
M de Boer31
Estimated H-index: 31
(UvA: University of Amsterdam)
Patients with chronic granulomatous disease (CGD) suffer from recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, liver, brain and bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia and Salmonella species. CGD is a rare (approximate to 1:250000 births) disease caused by mutations in any one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes. Molecular diagnosis of CGD involves measuring NADPH oxidase activity in phagocytes, measuring protein expression of NADPH oxidase components and mutation analysis of genes encoding these components. Residual oxidase activity is important to know for estimation of the clinical course and the chance of survival of the patient. Mutation analysis is mandatory for genetic counselling and prenatal diagnosis. This review summarizes the different assays available for the diagnosis of CGD, the precautions to be taken for correct measurements, the flow diagram to be followed, the assays for confirmation of the diagnosis and the determinations for carrier detection and prenatal diagnosis
📖 Papers frequently viewed together
1,408 Citations
488 Citations
371 Citations
#1Houda Elloumi (NIH: National Institutes of Health)H-Index: 8
#2Steven M. Holland (NIH: National Institutes of Health)H-Index: 114
Inasmuch as neutrophils are the primary cellular defense against bacterial and fungal infections, disorders that affect these white cells typically predispose individuals to severe and recurrent infections. Therefore, diagnosis of such disorders is an important first step in directing long-term treatment/care for the patient. Herein, we describe methods to identify chronic granulomatous disease, leukocyte adhesion deficiency, and neutropenia. The assays are relatively simple to perform and cost ...
28 CitationsSource
#1Anders Åhlin (Boston Children's Hospital)H-Index: 17
#2Jakob Fugeläng (Boston Children's Hospital)H-Index: 1
Last. Jacek Winiarski (Karolinska University Hospital)H-Index: 47
view all 6 authors...
Aim Chronic granulomatous disease (CGD) is a rare X-linked or autosomal recessive primary immune deficiency characterized by recurrent, life-threatening bacterial and fungal infections. Mortality rates are high with conventional treatment. However, haematopoietic stem cell transplantation (HSCT) offers cure. Here, we compare the outcome of HSCT in 14 Swedish patients with CGD to that in 27 patients with CGD who were given conventional treatment. Methods Forty-one patients in Sweden were diagnose...
33 CitationsSource
#2Yildiz Camcioglu (Istanbul University)H-Index: 25
Last. Dirk Roos (UvA: University of Amsterdam)H-Index: 114
view all 15 authors...
Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22 phox , p47 phox , p67 phox , and p40 phox of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91 phox leads to X-linked recessive CGD. Objective The aim of this study is to show ...
104 CitationsSource
Chronic granulomatous disease (CGD) was first described in the 1950s and has become a paradigm for genetic neutrophil diseases. It is characterized by recurrent infections with a narrow spectrum of bacteria and fungi as well as a common set of inflammatory complications most notably including inflammatory bowel disease. Over the last half century major advances in management have profoundly altered the major clinical issues and the life expectancy of CGD. With X-linked and autosomal recessive fo...
260 CitationsSource
#1Marie J StasiaH-Index: 1
#2Michele MollinH-Index: 2
Last. Dirk Roos (UvA: University of Amsterdam)H-Index: 114
view all 14 authors...
Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder with multi-systemic manifestations, caused by a heterozygous segmental deletion of 1.55-1.83 Mb at chromosomal band 7q11.23. The deletion can include the NCF1 gene that encodes the p47(phox) protein, a component of the leukocyte NADPH oxidase enzyme, which is essential for the defense against microbial pathogens. It has been postulated that WBS patients with two functional NCF1 genes are more susceptible to occurrence of hypertensio...
12 CitationsSource
#1Marie José Stasia (CNRS: Centre national de la recherche scientifique)H-Index: 23
#2Karin van Leeuwen (UvA: University of Amsterdam)H-Index: 12
Last. Dirk Roos (UvA: University of Amsterdam)H-Index: 114
view all 14 authors...
Chronic granulomatous disease (CGD) is a rare congenital disorder in which phagocytes cannot generate superoxide (O(2)(-)) and other microbicidal oxidants due to mutations in one of the five components of the O(2)(-)-generating NADPH oxidase complex. The most common form is caused by mutations in CYBB on the X chromosome, encoding gp91phox, the enzymatic subunit of the phagocyte NADPH oxidase. Here, we report two rare cases of male X-linked CGD patients, one caused by a 5.7-kb duplication of a r...
2 CitationsSource
#1Douglas B. Kuhns (SAIC: Science Applications International Corporation)H-Index: 50
#2W. Gregory AlvordH-Index: 45
Last. John I. Gallin (NIH: National Institutes of Health)H-Index: 105
view all 14 authors...
Background Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22phox, p40phox, p47phox, p67phox (autosomal chronic granulomatous disease), or gp91phox (X-linked chronic granulomatous disease), which result in varia...
371 CitationsSource
#1Harry R. HillH-Index: 74
#2Nancy H. Augustine (UofU: University of Utah)H-Index: 25
Last. Carl T. Wittwer (ARUP Laboratories)H-Index: 75
view all 13 authors...
High-resolution melting analysis was applied to X-linked chronic granulomatous disease, a rare disorder resulting from mutations in CYBB. Melting curves of the 13 PCR products bracketing CYBB exons were predicted by Poland's algorithm and compared with observed curves from 96 normal individuals. Primer plates were prepared robotically in batches and dried, greatly simplifying the 3- to 6-hour workflow that included DNA isolation, PCR, melting, and cycle sequencing of any positive products. Small...
20 CitationsSource
#1Juan D. Matute (IU: Indiana University)H-Index: 3
#1Juan D. Matute (IU: Indiana University)H-Index: 11
Last. Mary C. Dinauer (IU: Indiana University)H-Index: 84
view all 15 authors...
Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91phox and p22phox, which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47phox and p67phox. A fifth subunit, p40phox, plays an important role in phagocytosis-induced superoxide production ...
332 CitationsSource
#2Ozden Sanal (Hacettepe University)H-Index: 50
Last. Dirk Roos (UvA: University of Amsterdam)H-Index: 114
view all 9 authors...
Background One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the NCF2 gene, which encodes the polypeptide p67phox, a key cytoplasmic protein in the phagocyte NADPH oxidase system. NCF2 is localized on chromosome 1q25, encompasses 40 kb and contains 16 exons. Materials and methods We report here the clinical and molecular characterization of six patients with CGD from six consanguineous Turkish families. The ages of the five fema...
25 CitationsSource
Cited By108
#1Hsin-Hui Yu (NTU: National Taiwan University)H-Index: 21
#2Yao-Hsu Yang (NTU: National Taiwan University)H-Index: 41
Last. Bor-Luen Chiang (NTU: National Taiwan University)H-Index: 73
view all 3 authors...
Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocyte function due to defective NADPH oxidase (phox). Compared with the common types of CYBB/gp91phox, NCF1/p47phox, and CYBA/p22phox deficiency, NCF4/p40phox deficiency is a mild and atypical form of CGD without invasive bacterial or fungal infections. It can be diagnosed using serum-opsonized E.coli as a stimulus in dihydrorhodamine (DHR) assay. Patients with CYBC1/Eros deficiency, a new and rare form of CGD, present as l...
11 CitationsSource
Clinical disease caused by the agent of tuberculosis, Mycobacterium tuberculosis, and by less virulent mycobacteria, such as bacillus Calmette-Guerin (BCG) vaccines and environmental mycobacteria, can result from inborn errors of immunity (IEIs). IEIs underlie more than 450 conditions, each associated with an impairment of the development and/or function of hematopoietic and/or non-hematopoietic cells involved in host defense. Only a minority of IEIs confer predisposition to mycobacterial diseas...
#1Dirk RoosH-Index: 114
#2Karin van LeeuwenH-Index: 12
Last. Marie José StasiaH-Index: 23
view all 36 authors...
Chronic granulomatous disease is a primary immunodeficiency due to a defect in one of six subunits that make up the nicotinamide adenine dinucleotide phosphate oxidase complex. The most commonly defective protein, gp91phox , is inherited in an X-linked fashion; other defects have autosomal recessive inheritance. Bacterial and fungal infections are common presentations, although inflammatory complications are increasingly recognized as a significant cause of morbidity and are challenging to treat...
1 CitationsSource
#1Agnes Ulfig (RUB: Ruhr University Bochum)H-Index: 2
#2Lars I. Leichert (RUB: Ruhr University Bochum)H-Index: 21
Neutrophils are predominant immune cells that protect the human body against infections by deploying sophisticated antimicrobial strategies including phagocytosis of bacteria and neutrophil extracellular trap (NET) formation. Here, we provide an overview of the mechanisms by which neutrophils kill exogenous pathogens before we focus on one particular weapon in their arsenal: the generation of the oxidizing hypohalous acids HOCl, HOBr and HOSCN during the so-called oxidative burst by the enzyme m...
16 CitationsSource
#1Hatice Ezgi Baris (Marmara University)H-Index: 3
#2Ismail Ogulur (Marmara University)H-Index: 10
Last. Safa Baris (Marmara University)H-Index: 22
view all 21 authors...
Abstract Background Chronic granulomatous disease (CGD) is characterized by defective microbial killing due to mutations affecting subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Definitive genetic identification of disease subtypes may be delayed or not readily available. Objective We sought to investigate the role of intracellular staining of NADPH oxidase enzyme subunits in predicting the respective genetic defects in CGD patients and carriers. Methods Thi...
3 CitationsSource
#1Takashi Ishikawa (Jikei University School of Medicine)H-Index: 2
#2Masashi Okai (Jikei University School of Medicine)
Last. Toshinao Kawai (Jikei University School of Medicine)H-Index: 12
view all 6 authors...
BACKGROUND Patients with chronic granulomatous disease (CGD) develop severe infections, including Bacillus Calmette-Guerin (BCG). Although the autosomal recessive CGD (AR-CGD) patients should hypothetically develop relatively fewer infections compared to the X-linked CGD (X-CGD) patients due to more residual reactive oxygen intermediates, the impacts of BCG vaccination on AR-CGD and X-CGD patients are unclear. Herein, we demonstrated the clinical features of BCG infections, treatments, and genet...
1 CitationsSource
#1Benjamin T Prince (OSU: Ohio State University)H-Index: 5
#2Beth K Thielen (UMN: University of Minnesota)H-Index: 9
Last. Steven M. Holland (NIH: National Institutes of Health)H-Index: 114
view all 10 authors...
Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their ...
#1Idit Lachover Roth (Meir Medical Center)H-Index: 1
#2Pazit Salamon (Meir Medical Center)H-Index: 4
Last. David Hagin (Tel Aviv Sourasky Medical Center)H-Index: 10
view all 11 authors...
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defects in the NADPH oxidase complex. Mutations in NCF2 encoding the cytosolic factor p67phox result in autosomal recessive CGD. We describe three patients with a novel c.855G>C NCF2 mutation presenting with diverse clinical phenotype. Two siblings were heterozygous for the novel mutation and for a previously described exon 8-9 duplication, while a third unrelated patient was homozygous for the novel mutati...
3 CitationsSource