D2.433 - Clinical and Oxidative Function Profiles in Heterozygous Female Carriers of X-Linked Chronic Granulomatous Disease

X-linked chronic granulomatous disease (XL-CGD) results from CYBB mutations impairing NADPH oxidase function. Female heterozygotes have historically been considered asymptomatic due to random X-chromosome inactivation, ensuring residual reactive oxygen species (ROS) production. However, increasing evidence indicates that skewed lyonization may lead to clinically significant infection and immune dysregulation in carriers. 

To evaluate oxidative burst capacity and clinical manifestations in carrier mothers of XL-CGD patients, with the aim of identifying correlations between dihydrorhodamine (DHR) activity and clinical phenotype. Our cohort includes relatives of five patients (two siblings among them).We retrospectively reviewed four heterozygous relatives of confirmed XL-CGD patients followed at our tertiary Immunoallergology unit: three mothers and one great-nephew. Demographic, clinical, and laboratory data were collected from clinical records. Neutrophil oxidative burst was assessed by flow cytometry using the dihydrorhodamine (DHR) assay, and %DHR+ neutrophils were interpreted in light of reported thresholds for infection risk in carriers (<20%).

The mean age of the carriers was 48 years (range 28-70). All carriers harbored the familial CYBB variants. DHR testing revealed heterogeneous oxidative capacity: 50% (mother 1), 35% (mother 2), 100% (mother 3), and 100% (great-nephew). The two carriers with preserved oxidative burst (100%) remained asymptomatic. The mother with 35% oxidative activity experienced recurrent urinary tract and otitis media and repeated tonsillitis. The mother with 50% presented with recurrent urinary tract infections. 

Our data supports recent observations that a subset of heterozygous females with XL-CGD may develop CGD-like disease, despite intermediate residual ROS activity. These findings illustrate marked intra-familial variability, with reduced oxidative function (≤50%) associated with clinical manifestations, while preserved activity (100%) correlated with an asymptomatic phenotype. Routine functional testing of carrier mothers, longitudinal monitoring, and anticipatory guidance are warranted. Larger multicenter studies are needed to define risk stratification and management strategies, including consideration of prophylaxis in selected carriers.