A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
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DOI：
10.1084/jem.20190147
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发表时间：
2019-12-01
影响因子：
15.3
通讯作者：
Tartaglia, Marco
中科院分区：
文献类型：
--
作者：
Lam, Michael T.;Coppola, Simona;Tartaglia, Marco
噬血细胞性淋巴组织细胞增生症（HLH）的特征是由于过度活化的免疫细胞的抑制不足而导致的免疫失调，并且与可变的临床谱相关，该临床谱与更常见的病理生理学重叠。HLH很难诊断，可能是炎症综合征的一部分。在这里，我们确定了一种新的血液学/自身炎症条件（NOCARH综合征）在4个不相关的患者具有重叠的功能，包括造血功能障碍，自身炎症，皮疹，HLH发病的血细胞减少症。患者具有相同的从头CDC 42突变（Chr 1：22417990 C>T，p.R186C）和改变的造血区室、免疫失调和炎症。CDC 42突变与综合征性神经发育障碍相关。在体外和体内测定记录了独特的影响p.R186C对CDC 42的定位和功能，与性状的独特性。Emapalumab对一名成功进行骨髓移植的患者的生存至关重要。早期识别疾病和建立治疗，然后进行骨髓移植对生存很重要。
Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.