X-linked Carriers of Chronic Granulomatous Disease: Illness, Lyonization and Stability

Publication date: Available online 18 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Beatriz E. Marciano, Christa S. Zerbe, E. Liana Falcone, Li Ding, Suk See DeRavin, Janine Daub, Samantha Kreuzburg, Lynne Yockey, Sally Hunsberger, Ladan Foruraghi, Lisa A. Barnhart, Kabir Matharu, Victoria Anderson, Dirk N. Darnell, Cathleen Frein, Danielle L. Fink, Karen P. Lau, Debra A. Long Priel, John I. Gallin, Harry L. Malech, Gulbu Uzel, Alexandra F. Freeman, Douglas B. Kuhns, Sergio D. Rosenzweig, Steven M. Holland
BackgroundChronic 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.ObjectiveTo understand the clinical manifestations associated with the X-linked CGD carrier state.MethodsWe 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.ResultsClinical 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.ConclusionsA low %DHR+ strongly predicts infection risk in X-linked CGD carriers, while the carrier state itself is associated with autoimmunity.

Teaser

Comprehensive long term follow up of X-CGD carriers identifies low %DHR as a critical predictor of infection susceptibility, whereas the %DHR is unrelated to autoimmune or inflammatory manifestations.


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