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

• Published in: Clinical immunology (Orlando, Fla.) Vol. 129; no. 2; pp. 372 - 380
• Main Authors: Lewis, Eric M, Singla, Manav, Sergeant, Susan, Koty, Patrick P, McPhail, Linda C
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01-11-2008; Elsevier
• Subjects: Adolescent; Allergy and Immunology; 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; CGD; X-inactivation; gp91 phox; Flavocytochrome b 558; NADPH oxidase; CYBB; Neutrophil; Carrier; Primary immunodeficiency; Sex linked character; Granulocyte; Hemopathy; Inactivation; NAD(P)H oxidase; Immunology; Primary; Female; Genetics; X-Chromosome; gp91phox; Immunopathology; Chronic granulomatous disease; Secondary; Late; Flavocytochrome b558; Immune deficiency; Genetic disease; Mutation; Leukocyte disease
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2008.07.022

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.