X-linked chronic granulomatous disease secondary to skewed X chromosome inactivation in a female with a novel CYBB mutation and late presentation

Abstract Chronic granulomatous disease (CGD) is characterized by defects in the superoxide producing enzyme NADPH oxidase causing phagocytes to improperly clear invading pathogens. Here we report findings of a late presenting 16-year-old female with X-linked CGD. The patient presented with community...

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Bibliographic Details
Published in:Clinical immunology (Orlando, Fla.) Fla.), 2008-11, Vol.129 (2), p.372-380
Main Authors: Lewis, Eric M, Singla, Manav, Sergeant, Susan, Koty, Patrick P, McPhail, Linda C
Format: Article
Language:English
Subjects:
Adolescent
Allergy and Immunology
Aspergillus fumigatus
Biological and medical sciences
Carrier
CGD
CYBB
Cytochrome b Group - analysis
Female
Flavocytochrome b558
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Genetic Diseases, X-Linked - genetics
gp91 phox
Granulomatous Disease, Chronic - genetics
Humans
Immunodeficiencies
Immunodeficiencies. Immunoglobulinopathies
Immunopathology
Introns
Medical sciences
Membrane Glycoproteins - genetics
Mutation
NADPH oxidase
NADPH Oxidase 2
NADPH Oxidases - analysis
NADPH Oxidases - genetics
Neutrophil
Neutrophils - physiology
Primary immunodeficiency
X Chromosome Inactivation
X-inactivation
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Summary:Abstract Chronic granulomatous disease (CGD) is characterized by defects in the superoxide producing enzyme NADPH oxidase causing phagocytes to improperly clear invading pathogens. Here we report findings of a late presenting 16-year-old female with X-linked CGD. The patient presented with community-acquired pneumonia, but symptoms persisted for 2 weeks during triple antimicrobial coverage. Cultures revealed Aspergillus fumigatus which was resolved through aggressive voriconazole treatment. Neutrophil studies revealed NADPH oxidase activity and flavocytochrome b558 levels that were 4–8% of controls and suggested carrier status of the mother. We found a null mutation in the CYBB gene (c.252insAG) predicting an aberrant gp91 phox protein (p.Cys85fsX23) in the heterozygous state. Methylation analysis demonstrated extremely skewed X chromosome inactivation favoring the maternally inherited defective gene. In conclusion, a novel mutation in the CYBB gene and an extremely skewed X-inactivation event resulted in the rare expression of the CGD phenotype in a carrier female.
ISSN:1521-6616
0090-1229
1521-7035
DOI:10.1016/j.clim.2008.07.022