Atypical immune dysfunction in G6PD deficiency: a case of mosaic neutrophil oxidative burst

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked disorder typically causing hemolysis from oxidative damage, but severe variants can impair phagocyte function. While low levels of neutrophil activity are usually sufficient, the interplay of cis-acting regulatory elements and variable X-inactivation can lead to atypical clinical presentations. We present the case of a 50-year-old woman with recurrent infections including multiple pneumonias, a pertinent history that includes splenectomy, and genetic tests revealing c.202G > A and c.376A > G variants consistent with G6PD deficiency. G6PD activity in red blood cells was at 2.6 U/g Hb, corresponding to an enzyme activity level of 30% or less, previously classified as class III by the World Health Organization. Neutrophil oxidative burst assay showed a mosaic pattern, indicating both normal and abnormal granulocyte fluorescence. This case highlights that a dihydrorhodamine reduction in G6PD-mutated cells can be mosaic and can mimic X-linked chronic granulomatous disease patterns and that lyonization ratios can vary between hematopoietic lineages, with a potential for clinically relevant neutrophil dysfunction.