X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability

Chronic granulomatous disease (CGD) is characterized by recurrent life-threatening bacterial and fungal infections and aberrant inflammation. Mutations in CYBB cause X-linked CGD and account for 65% to 70% of cases in Western countries.

We sought to understand the clinical manifestations associated with the X-linked CGD carrier state.

We undertook a comprehensive retrospective study of 162 affected female subjects. We examined dihydrorhodamine 123 (DHR) oxidation data for percentage of X-chromosome inactivation. We correlated lyonization (%DHR⁺) with clinical features. Where possible, we followed %DHR⁺ values over time.

Clinical data were available for 93 female subjects: %DHR⁺ values were 46% (mean) and 47% (median; SD, 24). Using the %DHR⁺ value as the criterion for X inactivation, 78% of patients had levels of inactivation of 20% to 80%, suggesting random inactivation that was independent of age. In contrast, carriers with CGD-type infections had median %DHR⁺ values of 8% (n = 14; range, 0.06% to 48%), and those with only autoimmune or inflammatory manifestations had median %DHR⁺ values of 39% (n = 31; range, 7.4% to 74%). Those with both infections and autoimmunity had low %DHR⁺ values (n = 6; range, 3% to 14%). A %DHR⁺ value of less than 10% was strongly associated with infections (odds ratio, 99). Strong association persisted when %DHR⁺ values were less than 20% (odds ratio, 12). Autoimmunity was not associated with %DHR⁺ values. In 2 sets of identical twins, the %DHR⁺ populations tracked closely over time. Although the %DHR⁺ populations were very similar between sisters, those between mothers and daughters were unrelated.

A low %DHR⁺ value strongly predicts infection risk in X-linked CGD carriers, and the carrier state itself is associated with autoimmunity.