Identification of a novel CCDC22 mutation in a patient with severe Epstein?Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia
Identification of a novel CCDC22 mutation in a patient with severe Epstein?Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia
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重度 Epstein?Barr 病毒相关噬血细胞性淋巴组织细胞增多症和侵袭性自然杀伤细胞白血病患者中新型 CCDC22 突变的鉴定
DOI：
10.1007/s12185-019-02595-0
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发表时间：
2019
影响因子：
2.1
通讯作者：
Tamura S
中科院分区：
文献类型：
--
作者：
Yamashita Y;Nishikawa A;Iwahashi Y;Fujimoto M;Sasaki I;Mishima H;Kinoshita A;Hemmi H;Kanazawa N;Ohshima K;Imadome KI;Murata SI、Yoshiura KI;Kaisho T;Sonoki T;Tamura S
侵袭性自然杀伤细胞白血病（ANKL）是一种罕见的肿瘤，其特征是EB病毒（EBV）相关的NK细胞的全身浸润，并迅速进行性的临床过程。我们报告了一例45岁的智力残疾男性患者发生ANKL，并描述了一种新的含卷曲螺旋结构域22（CCDC 22）基因突变的鉴定。他表现为持续发热、严重全血细胞减少和肝脾肿大。骨髓穿刺后，发现大量噬血细胞。通过qPCR在NK细胞分级分离中检测到高EBV病毒载量。初步诊断为EB病毒相关的噬血细胞性淋巴组织细胞增生症（EBV-HLH）。给予免疫抑制药物和化疗的联合治疗，但未能成功控制疾病。因此，他接受了HLA匹配的相关异基因造血干细胞移植治疗。然而，他的病情在30天内恶化，导致死亡结局。尸检显示许多EBV感染的NK细胞浸润主要器官，与ANKL一致。此外，全外显子组测序鉴定了CCDC 22基因的一个新的错义突变（c.112G>A，p.V38M），该突变导致X连锁智力残疾（XLID）。CCDC 22在NF-κB活化中起重要作用。我们的病例提示CCDC 22突变可能通过影响NF-κB信号通路参与EBV-HLH和NK细胞肿瘤以及XLID的发病机制。
Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein–Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation ofcoiled-coil domain-containing 22(CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified. High EBV viral load was detected in NK cells fractionation by qPCR. The initial diagnosis was EBV-related hemophagocytic lymphohistiocytosis (EBV–HLH). A combination of immunosuppressive drugs and chemotherapy was administered, but was unsuccessful in controlling the disease. Therefore, he was treated with HLA-matched related allogeneic hematopoietic stem cell transplantation. However, his condition deteriorated within 30 days, resulting in fatal outcome. Autopsy revealed many EBV-infected NK cells infiltrating major organs, consistent with ANKL. Furthermore, whole-exome sequencing identified a novel missense mutation of theCCDC22gene (c.112G>A, p.V38M), responsible for X-linked intellectual disability (XLID). CCDC22 has been shown to play a role in NF-κB activation. Our case suggests thatCCDC22mutation might be implicated in pathogenesis of EBV–HLH and NK-cell neoplasms as well as XLID via possibly affecting NF-κB signaling.