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Войти в исследования Multicenter international cohort study of haploinsufficiency of A20 reveals novel genetic architecture and phenotypic evolution.
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He Tingyan, Wang Jun, Carpio Tumba Manuel, Wang Shihao, Luo Youyou, Chen Jie, Li Guomin, Shu Zhou, Zhang Song, Stone Deborah L, Huang Yanyan, Lv Qianying, Xiong Wen, Wang Jinbo, Yu Zhongxun, Cuff Charlotte Vera, Kairis Elizabeth, Kethri Akuti, Towheed Atif, Goyette Kyr, Karri Urekha, Wang Jiebiao, Liu Chen, Romeo Tina, Alsina Laia, Rosenberg Daniel L, Clemente Daniel, López-Robledillo Juan Carlos, Rong Zanhua, Zhao Xue, Jiang Lijun, Aldave-Becerra Juan Carlos, Muñoz-Urribarri Ana Beatriz, Oommen Prasad Thomas, Campbell-Stokes Priscilla, Zhu Meifang, Liu Peng, Guo Li, Xu Yiping, Yu Zihua, Tong Huajuan, Qiu Xiaojian, Zhang Yazhi, Chen Hongbo, Zhang Changming, Ou Junbin, Liu Congcong, Liu Jinxiang, Shen Yunyan, Cao Jianshe, Zhang Xinping, Yang Kangkang, Bao Ying, Li Zhijuan, Cao Jie, Duan Yuanhui, Liu Fujuan, Shi Buyun, Sun Min, Ma Li, Chen Yongxing, Yang Wei, Han Xu, Ma Shuangyue, Luo Jie, Gu Weiyue, Yu Guoliang, Shi Weina, Zhao Ruiqin, Sun Lei, Li Wenhui, An Yunfei, Tang Xuemei, Zhao Xiaodong, Han Tongxin, Ma Jing, Li Yan, Piao Yurong, Sun Fei, Zhang Dongfeng, Yin Meina, Zheng Shaoling, Li Tianwang, Niu Huizhong, Lin Li, Mei Shiyue, Zhou Fang, Yang Sirui, Li Danlu, Yan Mei, Zeng Huasong, Zeng Ping, Zheng Wenjie, Li Xiaozhong, Li Xiaolin, Liu Yuling, Huang Lijuan, Yu Haiguo, Fan Zhidan, Shen Min, Lu Meiping, Fang Zhihao, Rimland Casey Allison, Song Hongmei, Peterson Lance W, Yousuf Al-Nesf Maryam Ali, Aqel Sami, Mudawi Dalal Sideeg, Raje Nikita, Slowik Voytek, Harris Julia G, Snyder Brenda, Scheffler-Mendoza Selma, Yamazaki-Nakashimada Marco Antonio, Cooper Megan A, Lau Yu Lung, Cetin Gedik Kader, Wang Wenjie, Ying Wenjing, Hou Jia, Zhou Qinhua, Sun Bijun, Sun Jinqiao, Wang Xiaochuan, Ombrello Amanda K, Huang Ying, Wu Hai-Lin, Sun Li, Mao Huawei, Yu Xiaomin, Liu Zhihong, Aksentijevich Ivona, Kastner Daniel L, Schwartz Daniella M, Yang Jun, Zhou Qing
Аннотация
METHODS: A cross-sectional retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory, and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (<16 years vs ≥16 years), country of origin (China vs United States), and sex.
RESULTS: A total of 185 patients from 41 clinics across 7 countries were included (median age at onset, 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenia (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the US cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort (P = .002 and P < .0001, respectively), whereas uveitis was less common in these groups (P = .001 and P < .0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort (P = .033 and .003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay (P = .0054 and .0245, respectively); however, there were no clear associations between disruptions of specific functional A20 domains and age at onset or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors provided in refractory cases; 51.5% had obtained minimal disease activity at most recent follow-up.
CONCLUSIONS: HA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20.