title: Severe X-linked chronic granulomatous disease in two unrelated females.
abstract: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations of one of the subunits of phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to decreased or complete absence of neutrophil oxidative burst. We report the clinical and laboratory findings in two young unrelated females 14 and 9 years of age and natives of Tahiti and Reunion Islands, respectively, with severe X-linked granulomatous disease. In both cases, the infectious pattern was unusual, with convergent symptoms suggesting underlying mycobacterial infection. Functional analysis revealed low residual NADPH oxidase activity with about 5-10% of normal neutrophil population. De novo null mutations affecting the CYBB gene that encodes the gp91 protein were found in both cases in the heterozygous state (in patient 1, p.Arg130X in exon 5, and in patient 2, a novel insertion in exon 6, c.632_633insCATC). Methylation analysis confirmed that phenotype expression was linked to skewed X inactivation and showed that the de novo mutation arose on the maternally inherited chromosome in one case and on the paternally inherited chromosome in the other case. In conclusion, X-linked CGD carriers could therefore be at risk for severe infectious diseases depending on the skewed X inactivation pattern and the infectious context.
authors.affiliation: Service d'Immunologie Biologique, Hôpital Bichat-Claude Bernard, AP-HP, 46 rue Henri Huchard, 75018 Paris, France. sylvie.martin@bch.ap-hop-paris.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chollet-Martin
authors.forename: Anne
authors.initials: A
authors.lastname: Lopez
authors.forename: Catherine
authors.initials: C
authors.lastname: Gaud
authors.forename: Dominique
authors.initials: D
authors.lastname: Henry
authors.forename: Bertrand
authors.initials: B
authors.lastname: Stos
authors.forename: Jamel
authors.initials: J
authors.lastname: El Benna
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Chedevile
authors.forename: Dominique
authors.initials: D
authors.lastname: Gendrel
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Gougerot-Pocidalo
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D004247:DNA / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000097:blood / Q000235:genetics*; D009504:Neutrophils / Q000201:enzymology; D018384:Oxidative Stress / Q000235:genetics; D016133:Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: D008562:Membrane Glycoproteins; D004247:DNA; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases