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首页> 外文期刊>Pediatric and developmental pathology: the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society >Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites
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Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites

机译：新型NLRC4突变导致血管活性淋巴管激菌，肝肺肿大，胎儿血栓性血管病变和先天性贫血和腹水的围产期自身炎症综合征

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Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of “secondary” HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.
机译：自身炎性疾病是由先天免疫系统的病理活化引起的。初级血小杂性淋巴管吞咽症（HLH）是由单体突变引起的过度免疫激活的激进综合征，导致细胞毒性细胞缺陷和随后未能消除活化的巨噬细胞。在没有已知的孟德尔遗传的情况下，次要HLH经常被诊断出来。然而，已经显示出一些“二次”HLH的病例，以含有细胞毒性体系的部分功能障碍的突变。最近，NlRC4炎症组突变引起的巨噬细胞内在异常与自身炎症和复发性巨噬细胞激活综合征类似于原发性HLH。我们举报了一个前28周的早产儿，患有先天性贫血，腹水和胎儿血栓性血管病变的案例，其血栓形成血管病变，他在早期产后疗程中开发了Hlh的实验室特征，并在2个月内脱颖而出年龄。后期检测证实了肝脾肿大，具有显着的正弦血管增生，以及骨髓和淋巴结中醒目的血液吞咽病。具有广泛的急性和慢性缺血性肠蠕动，具有乱蓬蓬的肠环，纤维粘连和斑驳的坏死性小肠结肠炎特征。整体exome测序分析证明了一种新的马赛克杂合子NLRC4 512c> T（p.SER171phe）De Novo突变，其预先引起占主导地位的功能突变，导致组成型活性蛋白质。通过诱导的自我繁殖机构组装含NlRC4的炎性炎症的组装可能能够使系统巨噬细胞活化的延长过程能够在本患者中的子宫内启动。

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