title: 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-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 b(558) 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.
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Lewis
authors.forename: Manav
authors.initials: M
authors.lastname: Singla
authors.forename: Susan
authors.initials: S
authors.lastname: Sergeant
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Koty
authors.forename: Linda C
authors.initials: LC
authors.lastname: McPhail
mesh_terms: D000293:Adolescent; D003573:Cytochrome b Group / Q000032:analysis; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006801:Humans; D007438:Introns; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000032:analysis / Q000235:genetics*; D009504:Neutrophils / Q000502:physiology; D049951:X Chromosome Inactivation
chemical_list: D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; C036888:cytochrome b558; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
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