Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from defects in the multienzyme complex NADPH-oxidase (phagozyte oxidase, phox), which normally produces microbicidal reactive oxygen metabolites (ROM). The reason for our patient's CGD was unusual, as revealed by the following in vitro findings in neutrophils and EBV-transformed B-cells: lack of flavocytochrome b(558) expression, restoration of significant ROM production after transduction with gp91-phox cDNA by a retrovirus vector, an 879G-->A, Trp289-->Stop mutation in one X chromosomal gp91-phox allele, a one-sided paternal X chromosome inactivation, as shown by a lyonization assay at the HUMARA locus, and the result of a dihydrorhodamine 123 flow cytometry assay revealing consistently that 1 in 2500 neutrophils produced ROM at normal levels. Our conclusion: A presumed autosomal form of CGD has been excluded. Instead, a spontaneous mutation in gp91-phox coinciding with an extreme X chromosome inactivation ratio resulted in X-linked CGD in this young woman.