PDF(Pubmed)
Abstract：
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood-transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant-independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1-mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases.
摘要：
严重再生障碍性贫血（SAA）是一种危及生命的骨髓衰竭综合征，其发展可由环境引发，自身免疫，和/或遗传因素。后者包括基因中的种系致病性变体，这些变体会导致习惯性易感综合征以及仅偶尔发生的免疫缺陷。这些疾病之一是慢性粘膜皮肤念珠菌病（CMC）的常染色体显性形式，其由种系STAT1功能获得(GOF)致病变体定义。STAT1的过度表达和组成型激活导致Janus激酶/信号转导子和转录激活因子1（STAT）信号通路失调，它通常组织免疫和造血系统不同成分的发育和适当的相互作用。尽管SAA是这种疾病中极为罕见的并发症，当很明显潜在的致病机制可能，以类似的方式，也有助于至少一些特发性SAA病例。基于这些前提,我们在此介绍的是CMC家族中历史上最可能的首例脐带血移植SAA病例,该家族有STAT1GOF致病变异.此外,我们概述了迄今为止报道的6例CMCSAA病例的特征,并讨论了STAT1GOF致病变异和其他STAT1信号紊乱在这些特定类型的骨髓衰竭综合征中的意义.因为一个组成型激活的STAT1信号，无论是由STAT1GOF种系致病变异或任何其他致病变异独立事件驱动，显然对于启动和维持SAA疾病过程很重要，我们建议承认SAA是STAT1突变的CMC病例中明确的疾病表现之一.出于同样的原因,我们认为有必要将STAT1的分子和功能分析纳入SAA病例的诊断工作.
