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. 2018 Jan;141(1):365-371.
doi: 10.1016/j.jaci.2017.04.035. Epub 2017 May 18.

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

Beatriz E Marciano  1 , Christa S Zerbe  1 , E Liana Falcone  1 , Li Ding  1 , Suk See DeRavin  2 , Janine Daub  1 , Samantha Kreuzburg  1 , Lynne Yockey  1 , Sally Hunsberger  3 , Ladan Foruraghi  1 , Lisa A Barnhart  1 , Kabir Matharu  2 , Victoria Anderson  1 , Dirk N Darnell  1 , Cathleen Frein  1 , Danielle L Fink  4 , Karen P Lau  4 , Debra A Long Priel  4 , John I Gallin  2 , Harry L Malech  2 , Gulbu Uzel  1 , Alexandra F Freeman  1 , Douglas B Kuhns  4 , Sergio D Rosenzweig  5 , Steven M Holland  6
Affiliations

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

Beatriz E Marciano et al. J Allergy Clin Immunol. 2018 Jan.

Abstract

Background: 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.

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

Methods: 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.

Results: 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.

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

Keywords: Superoxide; X inactivation; autoimmunity; dihydrorhodamine flow cytometry test; lyonization.

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