A NEW X-LINKED VARIANT OF CHRONIC GRANULOMATOUS-DISEASE CHARACTERIZED BY THE EXISTENCE OF A NORMAL CLONE OF RESPIRATORY BURST-COMPETENT PHAGOCYTIC-CELLS

Chronic granulomatous disease (CGD) is characterized by recurrent infections, and is usually associated with a complete inability of phagocytic cells to generate superoxide anion (O-2(-)). Rarely, variant forms of CGD have been reported in which there is reduced, but detectable, O-2(-) production by phagocytic cells. We describe three adult males in two kindreds with a unique form of X-linked cytochrome b(558)-deficient (X91(-)) CGD not previously reported. All three patients had two distinct populations of phagocytic cells, with one subset capable of normal respiratory burst activity and the other larger subset inactive, as in classic CGD (X91 degrees). The respiratory burst activity in neutrophils purified from each patient was approximate to 10% of normal as determined by O-2(-) production, O-2 consumption, cytochrome b(558) spectroscopy, and membrane oxidase activity using a cell-free activation system. In contrast with other patients with X91(-)-variant CGD, the unique feature of these patients is the presence of a small but significant population (5% to 15%) of circulating neutrophils and monocytes with completely normal respiratory burst activity as assessed by nitroblue tetrazolium (NBT) reduction and flow-cytometric measurement of dihydrorhodamine oxidation. NBT reduction of peripheral blood granulocyte-macrophage progenitor cells also showed the presence of a subset of colonies derived from myeloid progenitor cells that had normal respiratory burst capabilities. A mosaic XX chromosome karyotype and an unstable oxidase complex that might occur during myeloid maturation were both excluded as possible explanations. In these families, the molecular defect in the gp91-phox gene, which is currently under investigation, appears to prevent expression of the gene in the majority of neutrophils, but not in a small subset. Our studies suggest that commitment to either a respiratory burst-competent or -incompetent phagocytic cell occurs at the level of the myeloid progenitor cell. (C) 1995 by The American Society of Hematology.