Prenatal Diagnosis of Chronic Granulomatous Disease in a Male Fetus

Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results

Genetic Characteristics, Infectious, and Noninfectious Manifestations of 32 Patients with Chronic Granulomatous Disease

Background:Chronic granulomatous disease (CGD) is a rare genetic disorder characterized by failure of phagocytic leukocytes to destroy certain microbes. We present a study on CGD patients enrolled at a single medical center concerning the infectious and noninfectious complications and genetic properties of the disease.Methods:Icotinamide adenine dinucleotide phosphate oxidase activity and the expression of flavocytochromeb(558) were measured by flow cytometry, and clinical outcomes of the patients were listed in relation to the genetic results.Results:The clinical and genetic findings of 32 pediatric cases with CGD from 23 families were enrolled. Pneumonia and anemia were the most common infectious and noninfectious symptoms. Genetic analysis showed that 10 families (43.5%) carriedCYBBvariants and 13 families (56.5%) have autosomal recessive (AR) CGD, in which 6 families (26%) carriedNCF1variants, 4 (17.4%) carriedCYBAvariants, and 3 (13%) carriedNCF2variants. The median age of clinical onset was 3.3 and 48 months for patients with X-linked CGD (X-CGD) and AR-CGD, respectively. The onset of symptoms before age 1 year was 94% in X-CGD, 28.5% in AR-CGD, and 12.5% in patients with oxidase residual activity. Moreover, a de novo germline mutation at c.1415delG inCYBB(OMIM#300481) and a novel c.251_263del13bp inCYBA(OMIM#608508) were also investigated.Conclusions:Ihydrorhodamine-1,2,3 assay could not detect carrier mother in de novo case withCYBBvariant. Most X-CGD patients have the onset of symptoms before age 1 year. Additionally, residual oxidase activity in AR-CGD causes a delay in onset, diagnosis, and prophylaxis. The protective role of residual activity is limited while the infection is ongoing and becoming serious

Chronic granutomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47(phox) component of the phagocyte NADPH oxidase

Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor I (NCF1) gene encoding the p47(phox) protein. Most (> 97%) CGD patients without p47(phox) (A47 degrees CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (psi NCF1) that contain this GT deletion. We have previously set up a gene,scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four psi NCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five psi NCF1 genes). All patients lacked p47(phox) protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the psi NCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis

Six different CYBA mutations including three novel mutations in ten families from Turkey, resulting in autosomal recessive chronic granulomatous disease

One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the CYBA gene, which encodes the alpha polypeptide of cytochrome b(558), (also known as p22-phox), a key transmembrane protein in the phagocyte NADPH oxidase system. This gene is localized on chromosome 16q24, encompasses 8.5 kb and contains six exons

Genetic Characteristics, Infectious, and Noninfectious Manifestations of 32 Patients with Chronic Granulomatous Disease.

Background:&nbsp;Chronic granulomatous disease (CGD) is a rare genetic disorder characterized by failure of phagocytic leukocytes to destroy certain microbes. We present a study on CGD patients enrolled at a single medical center concerning the infectious and noninfectious complications and genetic properties of the disease.Methods:&nbsp;Icotinamide adenine dinucleotide phosphate oxidase activity and the expression of flavocytochrome b558 were measured by flow cytometry, and clinical outcomes of the patients were listed in relation to the genetic results.Results:&nbsp;The clinical and genetic findings of 32 pediatric cases with CGD from 23 families were enrolled. Pneumonia and anemia were the most common infectious and noninfectious symptoms. Genetic analysis showed that 10 families (43.5%) carried CYBB variants and 13 families (56.5%) have autosomal recessive (AR) CGD, in which 6 families (26%) carried NCF1 variants, 4 (17.4%) carried CYBA variants, and 3 (13%) carried NCF2 variants. The median age of clinical onset was 3.3 and 48 months for patients with X-linked CGD (X-CGD) and AR-CGD, respectively. The onset of symptoms before age 1 year was 94% in X-CGD, 28.5% in AR-CGD, and 12.5% in patients with oxidase residual activity. Moreover, a de novo germline mutation at c.1415delG in CYBB (OMIM#300481) and a novel c.251_263del13bp in CYBA (OMIM#608508) were also investigated.Conclusions:&nbsp;Ihydrorhodamine-1,2,3 assay could not detect carrier mother in de novo case with CYBB variant. Most X-CGD patients have the onset of symptoms before age 1 year. Additionally, residual oxidase activity in AR-CGD causes a delay in onset, diagnosis, and prophylaxis. The protective role of residual activity is limited while the infection is ongoing and becoming serious.</h3

Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients

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. Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A&nbsp;mutation in one of the 4 genes encoding the components p22phox, p47phox, p67phox, and p40phox of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A&nbsp;mutation in the CYBB gene encoding gp91phox leads to X-linked recessive CGD. Objective The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. Methods We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. Results Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A220, A670 or X910 phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47phox-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index&nbsp;&ge; 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. Conclusion Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A220 and A670 subtypes manifests as severe as the X910 subtype.</p