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%-70% of cases in western countries. To understand the clinical manifestations associated with the X-linked CGD carrier state. We undertook a comprehensive retrospective study of 162 affected females. We examined dihydrorhodamine oxidation (DHR) data for percent (%) X chromosome inactivation. We correlated lyonization (%DHR+) with clinical features. Where possible, we followed %DHR+ levels over time. Clinical data were available for 93 females: The %DHR+ was 46% (mean) and 47% (median)(SD=24). Using %DHR+ as the criterion for X inactivation, 78% of patients had levels of inactivation 20-80%, suggesting random inactivation that was independent of age. In contrast, carriers with CGD-type infections had median %DHR+ of 8% (n=14, range 0.06-48 %); those with only autoimmune or inflammatory manifestations (AIM) had median %DHR+ of 39% (n=31, range 7.4-74%). Those with both infections and autoimmunity had low %DHR+ (n=6, range=3-14%). A %DHR+ < 10 % was strongly associated with infections (OR:99). Strong association persisted when the %DHR+ was < 20% (OR=12) Autoimmunity was not associated with %DHR+. In two sets of identical twins the %DHR+ populations tracked closely over time. While the %DHR+ populations were very similar between sisters, those between mothers and daughters were unrelated. A low %DHR+ strongly predicts infection risk in X-linked CGD carriers, while the carrier state itself is associated with autoimmunity. Copyright © 2017. Published by Elsevier Inc.

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