21例Aicardi-Goutières综合征的临床表现和遗传学分析

doi:10.12280/gjszjk.20230078

摘要/Abstract

摘要：

目的： 总结我国经基因测序诊断Aicardi-Goutières综合征（Aicardi-Goutières syndrome，AGS）患者的临床表现和遗传学特征。方法： 收集符合纳入标准的AGS患者的临床资料和基因测序结果并进行回顾性分析。结果： 本研究纳入21例我国AGS患者，临床表现为智力障碍（90.0%）、运动障碍（89.5%）、肌张力障碍（73.7%）和小头畸形（70.6%）等；头颅影像学多表现为基底节双侧对称钙化、进行性脑萎缩（95.2%）；皮肤表现以冻疮样皮疹为主（84.2%）。21例患者中，TREX1基因突变8例，RNASEH2C基因突变5例，IFIH1基因突变4例，ADAR基因突变2例，RNASEH2A和RNASEH2B基因突变各1例，未涉及SAMHD1基因突变。84.2%为家系遗传，父母携带者均无症状，15.8%为新发突变。结论： 建议产前加强对胎儿生长受限、小头畸形和侧脑室增宽等软指标异常胎儿的重视，加强产检管理，及时多学科讨论和产前诊断，减少AGS患儿的出生。

关键词: Aicardi-Goutières综合征, 中国, 基因, 突变, 表型, 诊断, 产前诊断

Abstract:

Objective: The clinical manifestation and genetic characteristics of Chinese patients with Aicardi-Goutières syndrome (AGS) diagnosed by gene sequencing were summarized. Methods: Clinical data including the gene sequencing results of AGS patients meeting the inclusion criteria were collected and analyzed. Results: 21 Chinese AGS cases were included in this study. The clinical manifestations were intellectual disability (90.0%), movement disorders (89.5%), dystonia (73.7%) and microcephaly (70.6%). Cranial imaging showed bilateral symmetrical calcification of basal segment, progressive brain atrophy (95.2%), and skin manifestations with frostbite-like rash (84.2%). Gene mutation analysis of 21 cases showed 8 cases with mutations in TREX1, 5 cases with RNASEH2C mutations, 4 cases with IFIH1, 2 cases with ADAR mutations, 1 case with RNASEH2A and 1 case with RNASEH2B mutations. The mutations of SAMHD1 gene were not involved. 84.2% cases were pedigree inherited, those parents who carry genetic mutations have no symptoms, and 15.8% cases were new variants. Conclusions: It is important to strengthen prenatal attention to those fetuses with abnormal soft indicators such as fetal growth restriction, microcephaly and lateral ventricle widening, and to strengthen prenatal management, timely multidisciplinary discussion and prenatal diagnosis, so as to reduce the birth of children with AGS.

Key words: Aicardi-Goutières syndrome, China, Genes, Mutation, Phenotype, Diagnosis, Prenatal diagnosis

曾兰, 王锦, 朱会, 王齐艳, 朱书瑶, 陈艾, 罗泽民, 庞英. 21例Aicardi-Goutières综合征的临床表现和遗传学分析[J]. 国际生殖健康/计划生育杂志, 2023, 42(5): 361-365.

ZENG Lan, WANG Jin, ZHU Hui, WANG Qi-yan, ZHU Shu-yao, CHEN Ai, LUO Ze-min, PANG Ying. Clinical Manifestations and Genetic Analysis of 21 Cases with Aicardi-Goutières Syndrome[J]. Journal of International Reproductive Health/Family Planning, 2023, 42(5): 361-365.

图/表 3

参考文献 25

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序号	性别	发病年龄	喂养困难	皮疹	肌张力障碍	癫痫	眼球震颤	小颌畸形	小头畸形	头部影像学异常	智力障碍	运动障碍	既往诊断	确诊年龄	突变基因	突变位点	基因诊断及分型	参考文献
1	女	3 y	NA	+	-	-	-	-	-	+	+	+	NA	13 y 4 m	TREX1	c.139G>A c.458dupA	AGS1	[2]
2	男	9 y	NA	+	-	-	-	-	-	+	-	+	NA	39 y	TREX1	c.45G>T c.139G>A	AGS1	[3]
3	女	2 d	+	-	+	-	-	+	+	+	+	NA	败血症	3 m	TREX1	c.457_458insA c.517C>G	AGS1	[4]
4	女	6 m	-	+	+	-	-	-	-	+	+	+	NA	6 m	TREX1	c.137_138insC c.292_293insA	AGS1	[5]
5	男	2 m	+	+	+	-	-	NA	+	+	+	+	手足口病	9 m	TREX1	c.294dupA c.868_885del	AGS1	[6]
6	男	3 m	+	+	+	-	-	-	+	+	+	+	NA	6 y 7 m	TREX1	c.294_295insA c.868_885del	AGS1	[7]
7	女	NA	-	+	-	-	-	-	-	+	-	-	NA	4 y	TREX1	c.294_295insA c.868_885del	AGS1	[7]
8	男	胎儿期	+	+	+	-	+	+	+	+	+	+	代谢病	1 y 3 m	TREX1	c.868_885del c.293dupA	AGS1	[18]
9	女	3 y	-	+	-	-	NA	-	-	-	+	-	幼年特发性关节炎	11 y	RNASEH2B	c.859G>T Hom c.269C>T	AGS2	[8]
10	女	新生儿期	NA	NA	+	+	NA	NA	+	+	+	+	宫内感染	7 y	RNASEH2C	c.434G>T c.194G>A	AGS3	[9]
11	男	新生儿期	NA	NA	+	+	NA	NA	+	+	+	+	脑瘫	4 y	RNASEH2C	c.434G>T c.194G>A	AGS3	[9]
12	男	NA	+	+	+	+	NA	NA	+	+	+	+	脑瘫	9 y	RNASEH2C	c.194G>A c.227C>T	AGS3	[9]
13	男	新生儿期	NA	+	NA	+	NA	NA	NA	+	+	NA	脑瘫	5 y 11 m	RNASEH2C	c.227C>T c.194G>A	AGS3	[10]
14	男	胎儿期	+	+	+	+	+	+	+	+	+	+	颅内感染	5 y 1 m	RNASEH2C	c.392T>A c.434G>T	AGS3	[18]
15	女	1 m	+	-	+	+	+	-	+	+	+	+	颅内感染	5 m	RNASEH2A	c.199G>C c.322C>T	AGS4	[11]
16	男	婴儿期	NA	+	+	+	NA	-	+	+	+	+	NA	11 y	ADAR	c.1A>G c.3124C>T	AGS6	[12]
17	男	6 y	NA	+	+	NA	NA	NA	NA	+	+	+	脑瘫	29 y	ADAR	p.Gly1007Arg	AGS6	[13]
18	女	1 y	-	-	+	-	+	+	+	+	+	+	脑瘫	4 y 4 m	IFIH1	c.2336G>T	AGS7	[14]
19	男	7 m	-	+	+	-	NA	+	NA	+	+	+	Fahr综合征	30 y	IFIH1	c.1465G >T	AGS7	[15]
20	男	11 y	NA	+	NA	NA	NA	NA	NA	+	NA	+	Fahr综合征	13 y	IFIH1	c.2336G>A	AGS7	[16]
21	男	6 m	NA	+	-	-	-	-	+	+	+	+	NA	3 y	IFIH1	c.1016C>A	AGS7	[17]

序号	性别	发病年龄	喂养困难	皮疹	肌张力障碍	癫痫	眼球震颤	小颌畸形	小头畸形	头部影像学异常	智力障碍	运动障碍	既往诊断	确诊年龄	突变基因	突变位点	基因诊断及分型	参考文献
1	女	3 y	NA	+	-	-	-	-	-	+	+	+	NA	13 y 4 m	TREX1	c.139G>A c.458dupA	AGS1	[2]
2	男	9 y	NA	+	-	-	-	-	-	+	-	+	NA	39 y	TREX1	c.45G>T c.139G>A	AGS1	[3]
3	女	2 d	+	-	+	-	-	+	+	+	+	NA	败血症	3 m	TREX1	c.457_458insA c.517C>G	AGS1	[4]
4	女	6 m	-	+	+	-	-	-	-	+	+	+	NA	6 m	TREX1	c.137_138insC c.292_293insA	AGS1	[5]
5	男	2 m	+	+	+	-	-	NA	+	+	+	+	手足口病	9 m	TREX1	c.294dupA c.868_885del	AGS1	[6]
6	男	3 m	+	+	+	-	-	-	+	+	+	+	NA	6 y 7 m	TREX1	c.294_295insA c.868_885del	AGS1	[7]
7	女	NA	-	+	-	-	-	-	-	+	-	-	NA	4 y	TREX1	c.294_295insA c.868_885del	AGS1	[7]
8	男	胎儿期	+	+	+	-	+	+	+	+	+	+	代谢病	1 y 3 m	TREX1	c.868_885del c.293dupA	AGS1	[18]
9	女	3 y	-	+	-	-	NA	-	-	-	+	-	幼年特发性关节炎	11 y	RNASEH2B	c.859G>T Hom c.269C>T	AGS2	[8]
10	女	新生儿期	NA	NA	+	+	NA	NA	+	+	+	+	宫内感染	7 y	RNASEH2C	c.434G>T c.194G>A	AGS3	[9]
11	男	新生儿期	NA	NA	+	+	NA	NA	+	+	+	+	脑瘫	4 y	RNASEH2C	c.434G>T c.194G>A	AGS3	[9]
12	男	NA	+	+	+	+	NA	NA	+	+	+	+	脑瘫	9 y	RNASEH2C	c.194G>A c.227C>T	AGS3	[9]
13	男	新生儿期	NA	+	NA	+	NA	NA	NA	+	+	NA	脑瘫	5 y 11 m	RNASEH2C	c.227C>T c.194G>A	AGS3	[10]
14	男	胎儿期	+	+	+	+	+	+	+	+	+	+	颅内感染	5 y 1 m	RNASEH2C	c.392T>A c.434G>T	AGS3	[18]
15	女	1 m	+	-	+	+	+	-	+	+	+	+	颅内感染	5 m	RNASEH2A	c.199G>C c.322C>T	AGS4	[11]
16	男	婴儿期	NA	+	+	+	NA	-	+	+	+	+	NA	11 y	ADAR	c.1A>G c.3124C>T	AGS6	[12]
17	男	6 y	NA	+	+	NA	NA	NA	NA	+	+	+	脑瘫	29 y	ADAR	p.Gly1007Arg	AGS6	[13]
18	女	1 y	-	-	+	-	+	+	+	+	+	+	脑瘫	4 y 4 m	IFIH1	c.2336G>T	AGS7	[14]
19	男	7 m	-	+	+	-	NA	+	NA	+	+	+	Fahr综合征	30 y	IFIH1	c.1465G >T	AGS7	[15]
20	男	11 y	NA	+	NA	NA	NA	NA	NA	+	NA	+	Fahr综合征	13 y	IFIH1	c.2336G>A	AGS7	[16]
21	男	6 m	NA	+	-	-	-	-	+	+	+	+	NA	3 y	IFIH1	c.1016C>A	AGS7	[17]