Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

作者全名："Zhang, Wenjing; Chen, Xuemei; Gao, Guodong; Xing, Shubin; Zhou, Lina; Tang, Xuemei; Zhao, Xiaodong; An, Yunfei"

作者地址："[Zhang, Wenjing; Chen, Xuemei; Xing, Shubin; Tang, Xuemei; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Childrens Hosp, Dept Rheumatol & Immunol, Chongqing, Peoples R China; [Gao, Guodong] Southwest Univ, Coll Comp & Informat Sci, Chongqing, Peoples R China; [Zhou, Lina; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China; [Zhou, Lina; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing, Peoples R China; [Zhou, Lina; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Childrens Hosp, China Int Sci & Technol Cooperat Base Child Dev &, Chongqing, Peoples R China; [Zhou, Lina; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China"

通信作者："An, YF (corresponding author), Chongqing Med Univ, Childrens Hosp, Dept Rheumatol & Immunol, Chongqing, Peoples R China.; An, YF (corresponding author), Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China.; An, YF (corresponding author), Chongqing Med Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing, Peoples R China.; An, YF (corresponding author), Chongqing Med Univ, Childrens Hosp, China Int Sci & Technol Cooperat Base Child Dev &, Chongqing, Peoples R China.; An, YF (corresponding author), Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China."

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000632428400001

JCR分区：Q1

影响因子：7.3

年份：2021

卷号：12

期号：　

开始页：　

结束页：　

文献类型：Review

关键词：signal transducer and activator of transcription 1; chronic mucocutaneous candidiasis; Mendelian susceptibility to mycobacterial diseases; GoF; LOF; hypothyroidism

摘要："Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled. Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions. Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed. Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection. Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT."

基金机构：Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [82070135]; Chongqing Technology Innovation and Application Demonstration [cstc2018jscx-msybX0005]

基金资助正文："We are grateful for the support, cooperation, and trust of the patients, donors, and their families. This work was supported by the Natural Science Foundation of China (Grant Number 82070135); Chongqing Technology Innovation and Application Demonstration (Grant Number cstc2018jscx-msybX0005)."