Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites
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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DOI：
10.1177/1093526616686890
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发表时间：
2017-11-01
影响因子：
1.9
通讯作者：
Picarsic, Jennifer
中科院分区：
文献类型：
--
作者：
Liang, Jiancong;Alfano, Danielle N.;Picarsic, Jennifer
自身炎症性疾病是由先天免疫系统的病理性激活引起的。原发性噬血细胞淋巴组织细胞增多症是一种侵袭性综合征，由单基因突变引起的免疫过度激活导致细胞毒性细胞缺陷，继而无法清除激活的巨噬细胞。继发性HLH通常在没有已知孟德尔遗传的病例中被诊断出来。然而，一些“继发性”HLH病例被证明含有突变，并伴有细胞毒系统的部分功能障碍。最近，由NLRC4炎症体突变引起的巨噬细胞内在异常被认为与自身炎症和类似于原发HLH的反复出现的巨噬细胞激活综合征有关。我们报告一例28周的早产儿，患有先天性贫血、腹水和重度水肿性胎盘合并胎儿血栓性血管病变，在出生后早期出现肝脾肿大和不明原因的全身性炎症，并伴有HLH的实验室特征，并在2个月大时死亡。尸检证实肝脾肿大伴有明显的血窦吞噬，同时骨髓和淋巴结也有显著的血细胞吞噬。有广泛的急、慢性缺血性肠病，表现为肠套叠、纤维粘连和片状坏死性小肠结肠炎。整个外显子组测序分析表明，一个新的嵌合型杂合NLRC4512C>；T(p.Ser171Phe)从头突变被预测导致一个显性的功能获得突变，导致一个结构性活性蛋白。含有NLRC4的炎性小体通过诱导的自我繁殖机制组装，可能使全身巨噬细胞激活的持续过程成为可能，该患者被认为是在子宫中启动的。
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.