<i>NSD1</i>基因新发突变致Sotos综合征患儿1例临床分析并国内相关文献复习

doi:10.3877/cma.j.issn.1673-5250.2022.06.011

目的

探讨NSD1基因新发突变致Sotos综合征患儿的临床特征，并对国内相关研究文献进行复习。

方法

选择2019年9月18日青岛大学附属医院收治的1例Sotos综合征男性患儿(患儿1)为研究对象。回顾性分析其临床资料，采取全外显子组测序及Sanger测序对其致病突变基因位点进行分析，并进行家系验证。本例患儿检出突变位点，于千人基因组数据库、美国国家心肺和血液研究所外显子组测序数据库(ESP6500SI)、外显子组整合数据库(ExAC)进行检索，确定其是否为已报道突变位点。根据美国医学遗传学与基因组学学会(ACMG)制定的《序列变异解释的标准和指南》(以下简称为ACMG指南)，对检出突变致病性进行评级。以"Sotos综合征""脑性巨人症""儿童"为关键词，在万方数据知识服务平台、中国知网等数据库进行文献检索，并对检索文献进行复习。本研究遵循的程序符合青岛大学附属医院伦理委员会规定，并通过该伦理委员会审查、批准(审批文号：QYFYWZLL25663)。

结果

患儿1为3岁10个月男童，由于"生长过快3⁺年"就诊，有过度生长、特殊面容和神经精神发育迟缓等Sotos综合征典型症状；患儿1的男性生殖系统超声结果提示双侧隐睾，骨龄为3.5岁，头颅MRI提示脑实质内未见明显异常信号影，幕上脑白质较少，胼胝体较薄，双侧侧脑室扩张，枕大池增大；患儿1心脏超声、全脊柱正位X射线摄片均未见异常；患儿1 NSD1基因发生c.6007_6009+1delAAAG杂合突变，经Sanger测序验证显示，患儿父母未携带该杂合突变，患儿为新发突变，该突变尚未被千人基因组数据库、ESP6500SI、ExAC等数据库收录。根据ACMG指南，判断该突变为可能致病性突变。文献检索结果：共计检索到20篇国内Sotos综合征患儿相关病例报告，涉及26例Sotos综合征患儿(患儿2~27)。对包括患儿1及患儿2~27的27例该病患儿的分析结果如下。这27例患儿中，①男、女性患儿分别为22、5例。②中位确诊年龄为11个月。③22例患儿报道就诊主诉分别为神经精神发育落后(14例，63.6%)，生长过快(2例，9.1%)，抽搐或其他症状(6例，27.3%)，其余5例患儿未报道就诊主诉；查体发现过度生长为16例(59.3%)，特殊面容为23例(85.2%)，神经精神发育迟缓为27例(100.0%)。④骨龄较实际年龄偏大者为8例，心血管系统发育异常为11例，泌尿生殖系统发育异常为5例，颅脑影像学异常为24例。⑤23例患儿进行基因检测发现，5q35微缺失为10例(43.5%)，NSD1基因突变为12例(52.2%)，NFIX基因突变1例(4.3%)，均为散发病例。

结论

国内报道的Sotos综合征均为散发病例，以NSD1基因突变和5q35微缺失为主；男性患儿居多；均有神经精神发育落后表现，绝大多数有特殊面容和过度生长表现，患儿基因型与表型有较明显相关性。本研究首次报道的NSD1基因c.6007_6009+1delAAAG新发杂合突变丰富了人类NSD1基因突变类型。

关键词: Sotos综合征, NSD1基因, 基因突变, 过度生长, 特殊面容, 发育障碍, 儿童

Objective

To explore the clinical features of children with Sotos syndrome caused by a novel mutation in NSD1 gene and review relevant domestic literature.

Methods

One case of a boy (child No.1) with Sotos syndrome admitted to the Affiliated Hospital of Qingdao University on September 18, 2019 was selected as research subject. The clinical data of this child were retrospectively analyzed, whole exome sequencing and Sanger sequencing were carried out to detect potential pathogenic mutation and family verification. The detected mutation was searched in databases of 1000 Genomes Project, NHLBI GO Exome Sequencing Project(ESP6500SI), and the Exome Aggregation Consortium (ExAC). According to the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the ACMG guideline), pathogenicity of detected gene mutation was comprehensively assessed. With the following key words of " Sotos syndrome" " cerebral gigantism" and "child", domestic literature related to Sotos syndrome was searched from Wanfang Data Knowledge Service Platform and China National Knowledge Infrastructure. The procedure followed in this study was in accordance with the regulations of the Ethics Committee of the Affiliated Hospital of Qingdao University, and was reviewed and approved by the Ethics Committee (Approval No. QYFYWZLL25663).

Results

The boy aged 3 years and 10 months, presented with " overgrowth for more than 3 years". His clinical characteristics were similar to the typical clinical manifestations of Sotos syndrome, including overgrowth, peculiar facial features and neuromental development retardation. Ultrasound of male reproductive system of child No.1 suggested bilateral cryptorchidism, bone age was 3.5 years, his skull MRI suggested no obvious abnormal signal shadow in brain intraparenchymal, less alba in supratentorial brain, thin corpus callosum, bilateral lateral ventricles dilatation, enlarged cisterna magna, without abnormalities in cardiac ultrasound and whole spine orthopantomograph. Child 1 had a heterozygous mutation in NSD1 gene c. 6007_6009+ 1delAAAG, and none of his parents carried this mutation verified by Sanger sequencing, this mutation was a novel mutation, which had not been reported in databases of 1000 Genomes Project, ESP6500SI and ExAC, and was probably pathogenic according to the ACMG guideline. Literature review results: a total of 20 pieces of literature of children with Sotos syndrome case reports were retrieved, involving 26 children with Sotos syndrome (child No.2 to 27), and the results of 27 children with Sotos syndrome (child No.1 to 27) were as follows. ①There were 22 males and 5 females. ②The median age at diagnosis of Sotos syndrome was 11 months. ③A total of 22 children were reported with chief complaint for consultation, including neuromental development retardation (14 cases, 63.6%), overgrowth (2 cases, 9.1%), and convulsions or other symptoms (6 cases, 27.3%), the remaining 5 children did not report a chief complaint for consultation. Physical examination revealed overgrowth in 16 cases (59.3%), peculiar facial features in 23 cases (85.2%), and neuromental development retardation in 27 cases (100.0%). ④The bone age was older than actual age in 8 cases, abnormal development of cardiovascular system in 11 cases, abnormal development of urogenital system in 5 cases, and abnormal cranial imaging in 24 cases. ⑤A total of 23 children accepted gene analysis, including 10 cases (43.5%) with 5q35 microdeletion, 12 cases (52.2%) with NSD1 gene mutation and 1 case (4.3%) with NFIX gene mutation. All of them were sporadic.

Conclusions

In China, all reported children with Sotos syndrome are sporadic, mainly with NSD1 gene mutation and 5q35 microdeletion. The majority of children are male. All children with Sotos syndrome have neuromental development retardation, and most of them have peculiar facial features and overgrowth. There is a significant correlation between genotype and phenotype. The novel heterozygous mutation in NSD1 gene c. 6007_6009+ 1delAAAG reported in this study for the first time enriches the spectrum of genotype in Sotos syndrome.

Key words: Sotos syndrome, NSD1 gene, Gene mutation, Overgrowth, Peculiar facial features, Developmental disabilities, Child

图1 Sotos综合征患儿1(男性，3岁10个月)的相关医学影像学检查结果[图1A：左腕部正位X射线摄片图(骨龄测定)；图1B、1C：分别为头颅MRI检查矢状面、横断面图，提示幕上脑白质较少，胼胝体较薄，双侧侧脑室扩张，枕大池增大]

图2 Sotos综合征患儿1(男性，3岁10个月)及其父母NSD1基因突变位点Sanger测序图(图2A：患儿1的NSD1基因发生c.6007_6009+1delAAAG杂合突变；图2B：患儿1父亲该位点无突变；图2C：患儿1母亲该位点无突变)

图3 Sotos综合征患儿1(男性，3岁10个月)家系图注：Ⅰ表示第1代，Ⅱ表示子代。○表示女性，□表示男性。□1表示患儿1父亲，○2表示患儿1母亲，■1表示患儿1。为先证者

表1 27例Sotos综合征患儿临床表现、相关影像学检查及基因检测结果

患儿编号	年龄	主诉	出生体重(kg)/身长(cm)	就诊时头围(cm)/身高(cm)	心血管系统	骨龄	颅脑影像学	基因检测结果
患儿1	3岁10个月	生长过快3年余	4.3^b/53	50/117.5^c	未见异常	3岁	幕上脑白质较少，胼胝体较薄，双侧脑室扩张，枕大池增大	NSD1c.6007_6009+1delAAAG
患儿2^[6]	12岁	—^a	4.55^b/56	60/172^c	未见异常	14~17岁	右侧脑室扩大	—^a
患儿3^[7]	8岁11个月	口齿不清，学习困难	4.2^b/—^a	56/144^c	心尖区Ⅱ级收缩期杂音	10~14岁	未见异常	—^a
患儿4^[8]	4岁6个月	智力差	4.8^b/60	56/122^c	—^a	4岁6个月	脑室轻度扩大	—^a
患儿5^[9]	1岁2个月	抽搐	3.8/—^a	53/91^c	房间隔缺损或卵圆孔未闭	2~3岁	侧脑室旁白质软化，胼胝体薄	—^a
患儿6^[10]	1岁7个月	头大、智力发育落后	3.15/—^a	52/85	—^a	2~3岁	双侧脑白质血管周围间隙扩张，皮质下髓鞘化不良，胼胝体薄	5q部分缺失(含NSD1基因)
患儿7^[11]	6 h	低血糖6 h	4.03^b/50	38/50	动脉导管及卵圆孔未闭	—^a	脑实质异常信号	5q35.2-35.3(缺失长度为1.97 Mb)
患儿8^[11]	3 d	间断呕吐1 d	4.10^b/49	34/49	卵圆孔未闭	—^a	双侧基底节区和额叶损伤，乳突异常信号	5q35片段缺失
患儿9^[12]	10个月	智力发育落后	3.70/50	50/78.5^c	—^a	—^a	脑室大，脑发育不良	NSD1c.5885T>C
患儿10^[12]	11个月	智力落后，皮肤黑	—^a/—^a	—^a/78.2^c	—^a	—^a	未见异常	NSD1c.5990A>G
患儿11^[12]	6个月	智力发育迟缓	4.80^b/53	47/74^c	—^a	—^a	脑室扩张	NSD1c.4118-4119 insTGACCT
患儿12^[13]	4岁2个月	—^a	—^a/—^a	—^a/—^c	—^a	—^a	未见异常	NFIXc.613C>T
患儿13^[14]	9 d	胎儿宫内窘迫	2.95/51	34/51^c	房间隔缺损，动脉导管未闭	—^a	脑室扩大、大脑萎缩、脑积水	基因突变，无具体结果
患儿14^[15]	7个月	—^a	4.20^b/51	47.5/71	未见异常	2岁	脑室扩大、脑发育不良	5q35.2(缺失长度为1.75 Mb)
患儿15^[15]	10个月	—^a	3.60/50	45.5/48	未见异常	—^a	脑室扩大	NSD1c.1157T>G
患儿16^[15]	1岁1个月	—^a	3.50/53	48/80	未见异常	2~3岁	脑室扩大	NSD1c.1177G>T
患儿17^[16]	8个月	智力发育落后	4.45^b/—^a	—^a/78^c	—^a	—^a	双侧脑室稍扩大	NSD1c.1806delT
患儿18^[17]	8个月	智力发育落后	4.10^b/—^a	48.5/—^a	动脉导管未闭	—^a	胼胝体发育不良，脑室偏大	5q35.2-35.3(缺失长度为1 907 kb)
患儿19^[17]	3岁	智力发育落后	—^a/—^a	52.8/101	动脉导管未闭	—^a	脑室扩张	NSD1c.1262G>A
患儿20^[18]	8个月	行为发育迟缓	4.35^b/—^a	46.5/76^c	室间隔膜部瘤并缺损(多孔型)；卵圆孔未闭	10.8个月	双侧脑室内、室管膜下出血；双侧脑室增宽	5q35.2-35.3(缺失长度为1.54 Mb)
患儿21^[19]	6个月	智力低下	3.24/37.5	—^a/—^a	房间隔缺损、动脉导管未闭	—^a	脑白质发育不良伴髓鞘化迟缓	5q35.2-35.3(缺失长度为5 077 kb)
患儿22^[20]	1岁8个月	行为发育迟缓	3.40/48	51/83	房间隔缺损	1岁	双侧额颞部脑外间隙及侧脑室增宽	5q35.2-35.3(缺失长度为1.96 Mb)
患儿23^[21]	6岁11个月	生长过快5年余	3.40/—^a	58/148.3^c	左心房、心室增大，二尖瓣轻中度反流	8~9岁	幕上脑室增宽，双颞极颅板下、左侧小脑、脑外间隙增宽	NSD1c.5854C>T
患儿24^[22]	2岁4个月	间断抽搐4个月余	—^a/—^a	54.5/100^c	—^a	—^a	胼胝体发育细小	5q35.2-35.3(缺失长度为1. 797 Mb)
患儿25^[23]	5个月	智力发育迟滞	3.99/—^a	49.2/71^c	未见异常	—^a	双侧脑室体部异常信号	NSD1c.5791T>C
患儿26^[24]	9 d	纳差9 d	4.2^a/53	37/53	—^a	—^a	左侧脑室体部旁软化灶、双侧脑室稍增宽	5q35.2-q35.3(缺失长度为2.02 Mb)
患儿27^[25]	1岁6个月	自幼智力发育落后	4.6^b/—^a	51/88^c	未见异常	—^a	双侧脑室明显扩张	NSD1c.4378+1_c.4378+4delGTGA

表1 27例Sotos综合征患儿临床表现、相关影像学检查及基因检测结果

患儿编号	年龄	主诉	出生体重(kg)/身长(cm)	就诊时头围(cm)/身高(cm)	心血管系统	骨龄	颅脑影像学	基因检测结果
患儿1	3岁10个月	生长过快3年余	4.3^b/53	50/117.5^c	未见异常	3岁	幕上脑白质较少，胼胝体较薄，双侧脑室扩张，枕大池增大	NSD1c.6007_6009+1delAAAG
患儿2^[6]	12岁	—^a	4.55^b/56	60/172^c	未见异常	14~17岁	右侧脑室扩大	—^a
患儿3^[7]	8岁11个月	口齿不清，学习困难	4.2^b/—^a	56/144^c	心尖区Ⅱ级收缩期杂音	10~14岁	未见异常	—^a
患儿4^[8]	4岁6个月	智力差	4.8^b/60	56/122^c	—^a	4岁6个月	脑室轻度扩大	—^a
患儿5^[9]	1岁2个月	抽搐	3.8/—^a	53/91^c	房间隔缺损或卵圆孔未闭	2~3岁	侧脑室旁白质软化，胼胝体薄	—^a
患儿6^[10]	1岁7个月	头大、智力发育落后	3.15/—^a	52/85	—^a	2~3岁	双侧脑白质血管周围间隙扩张，皮质下髓鞘化不良，胼胝体薄	5q部分缺失(含NSD1基因)
患儿7^[11]	6 h	低血糖6 h	4.03^b/50	38/50	动脉导管及卵圆孔未闭	—^a	脑实质异常信号	5q35.2-35.3(缺失长度为1.97 Mb)
患儿8^[11]	3 d	间断呕吐1 d	4.10^b/49	34/49	卵圆孔未闭	—^a	双侧基底节区和额叶损伤，乳突异常信号	5q35片段缺失
患儿9^[12]	10个月	智力发育落后	3.70/50	50/78.5^c	—^a	—^a	脑室大，脑发育不良	NSD1c.5885T>C
患儿10^[12]	11个月	智力落后，皮肤黑	—^a/—^a	—^a/78.2^c	—^a	—^a	未见异常	NSD1c.5990A>G
患儿11^[12]	6个月	智力发育迟缓	4.80^b/53	47/74^c	—^a	—^a	脑室扩张	NSD1c.4118-4119 insTGACCT
患儿12^[13]	4岁2个月	—^a	—^a/—^a	—^a/—^c	—^a	—^a	未见异常	NFIXc.613C>T
患儿13^[14]	9 d	胎儿宫内窘迫	2.95/51	34/51^c	房间隔缺损，动脉导管未闭	—^a	脑室扩大、大脑萎缩、脑积水	基因突变，无具体结果
患儿14^[15]	7个月	—^a	4.20^b/51	47.5/71	未见异常	2岁	脑室扩大、脑发育不良	5q35.2(缺失长度为1.75 Mb)
患儿15^[15]	10个月	—^a	3.60/50	45.5/48	未见异常	—^a	脑室扩大	NSD1c.1157T>G
患儿16^[15]	1岁1个月	—^a	3.50/53	48/80	未见异常	2~3岁	脑室扩大	NSD1c.1177G>T
患儿17^[16]	8个月	智力发育落后	4.45^b/—^a	—^a/78^c	—^a	—^a	双侧脑室稍扩大	NSD1c.1806delT
患儿18^[17]	8个月	智力发育落后	4.10^b/—^a	48.5/—^a	动脉导管未闭	—^a	胼胝体发育不良，脑室偏大	5q35.2-35.3(缺失长度为1 907 kb)
患儿19^[17]	3岁	智力发育落后	—^a/—^a	52.8/101	动脉导管未闭	—^a	脑室扩张	NSD1c.1262G>A
患儿20^[18]	8个月	行为发育迟缓	4.35^b/—^a	46.5/76^c	室间隔膜部瘤并缺损(多孔型)；卵圆孔未闭	10.8个月	双侧脑室内、室管膜下出血；双侧脑室增宽	5q35.2-35.3(缺失长度为1.54 Mb)
患儿21^[19]	6个月	智力低下	3.24/37.5	—^a/—^a	房间隔缺损、动脉导管未闭	—^a	脑白质发育不良伴髓鞘化迟缓	5q35.2-35.3(缺失长度为5 077 kb)
患儿22^[20]	1岁8个月	行为发育迟缓	3.40/48	51/83	房间隔缺损	1岁	双侧额颞部脑外间隙及侧脑室增宽	5q35.2-35.3(缺失长度为1.96 Mb)
患儿23^[21]	6岁11个月	生长过快5年余	3.40/—^a	58/148.3^c	左心房、心室增大，二尖瓣轻中度反流	8~9岁	幕上脑室增宽，双颞极颅板下、左侧小脑、脑外间隙增宽	NSD1c.5854C>T
患儿24^[22]	2岁4个月	间断抽搐4个月余	—^a/—^a	54.5/100^c	—^a	—^a	胼胝体发育细小	5q35.2-35.3(缺失长度为1. 797 Mb)
患儿25^[23]	5个月	智力发育迟滞	3.99/—^a	49.2/71^c	未见异常	—^a	双侧脑室体部异常信号	NSD1c.5791T>C
患儿26^[24]	9 d	纳差9 d	4.2^a/53	37/53	—^a	—^a	左侧脑室体部旁软化灶、双侧脑室稍增宽	5q35.2-q35.3(缺失长度为2.02 Mb)
患儿27^[25]	1岁6个月	自幼智力发育落后	4.6^b/—^a	51/88^c	未见异常	—^a	双侧脑室明显扩张	NSD1c.4378+1_c.4378+4delGTGA

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Sotos syndeome with a novel mutation in NSD1 gene: a case report and domestic literature review

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Sotos syndeome with a novel mutation in NSD1 gene: a case report and domestic literature review