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. Published by Elsevier Inc.
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. Published by Elsevier Inc.
Entities:
Keywords:
Superoxide; X inactivation; autoimmunity; dihydrorhodamine flow cytometry test; lyonization
Authors: Rebecca A Marsh; Jennifer W Leiding; Brent R Logan; Linda M Griffith; Danielle E Arnold; Elie Haddad; E Liana Falcone; Ziyan Yin; Kadam Patel; Erin Arbuckle; Jack J Bleesing; Kathleen E Sullivan; Jennifer Heimall; Lauri M Burroughs; Suzanne Skoda-Smith; Shanmuganathan Chandrakasan; Lolie C Yu; Benjamin R Oshrine; Geoffrey D E Cuvelier; Monica S Thakar; Karin Chen; Pierre Teira; Shalini Shenoy; Rachel Phelan; Lisa R Forbes; Deepak Chellapandian; Blachy J Dávila Saldaña; Ami J Shah; Katja G Weinacht; Avni Joshi; Farid Boulad; Troy C Quigg; Christopher C Dvorak; Debi Grossman; Troy Torgerson; Pamela Graham; Vinod Prasad; Alan Knutsen; Hey Chong; Holly Miller; M Teresa de la Morena; Kenneth DeSantes; Morton J Cowan; Luigi D Notarangelo; Donald B Kohn; Elizabeth Stenger; Sung-Yun Pai; John M Routes; Jennifer M Puck; Neena Kapoor; Michael A Pulsipher; Harry L Malech; Suhag Parikh; Elizabeth M Kang Journal: J Clin Immunol Date: 2019-08-02 Impact factor: 8.317