Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
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DOI：
10.1182/blood-2015-11-679902
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发表时间：
2016-06-23
期刊：
影响因子：
20.3
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
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作者：
Toubiana, Julie;Okada, Satoshi;Netea, Mihai G.
自2011年在常染色体显性遗传（AD）慢性粘膜皮肤念珠菌病（CMC）患者中发现以来，杂合STAT 1功能获得性（GOF）突变在全球范围内越来越多地被发现。需要划定与它们相关的临床范围。我们招募了来自5大洲40个国家的167名患者的274名患者。记录人口统计学数据、临床特征、免疫学参数、治疗和结局。274例患者的中位年龄为22岁（范围：1-71岁）; 98%的患者患有CMC，发病时的中位年龄为1岁（范围：0-24岁）。患者经常表现出细菌感染（74%），主要是因为金黄色葡萄球菌（36%），包括呼吸道和皮肤，分别为47%和28%的患者，和病毒感染（38%），主要是因为疱疹病毒科（83%），并影响32%的患者的皮肤。侵袭性真菌感染（10%），主要由念珠菌属引起。(29由结核分枝杆菌、环境分枝杆菌或卡介苗引起的分枝杆菌病（6%）较不常见。许多患者有自身免疫表现（37%），包括甲状腺功能减退症（22%），1型糖尿病（4%），血细胞减少症（4%）和系统性红斑狼疮（2%）。侵袭性感染（25%）、脑动脉瘤（6%）和癌症（6%）是预后不良的最强预测因子。在接受长期抗真菌治疗的202例患者中，39%的患者CMC持续存在。大多数（82%）但不是所有受试患者的循环白细胞介素-17A产生T细胞计数较低。STAT 1 GOF突变是AD CMC的基础，以及出乎意料的广泛的其他临床特征，不仅包括各种感染性和自身免疫性疾病，还包括预后不良的脑动脉瘤和癌症。
Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism(22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms(6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.