Cohen综合征并文献复习

doi:10.3877/cma.j.issn.1673-5250.2020.01.008

目的

探讨VPS13B基因突变所致Cohen综合征患儿的临床特征及诊断特点，并进行相关文献复习，为Cohen综合征遗传咨询和诊断提供参考。

方法

选择2019年1月，于中山大学孙逸仙纪念医院儿科确诊为Cohen综合征的2例患儿(患儿1、2)为研究对象。采用回顾性分析方法，收集2例患儿的临床病例资料，并对其病史采集、相关检查结果进行分析。以"Cohen综合征""Cohen syndrome"为关键词，检索在线人类孟德尔遗传数据库(OMIM)、PubMed数据库、中国生物医学文献服务系统(SinoMed)、中国知网(CNKI)、万方数据知识服务平台、维普中文科技期刊数据库中Cohen综合征相关文献，检索时间设定为1973年1月1日至2019年1月1日。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》要求，并且征得受试儿家属(父亲、母亲及表叔)知情同意。

结果

①患儿1病史采集：男性，4岁3个月，主要临床表现为精神运动发育落后、小头畸形和身材矮小。相关检查结果：血常规检查结果提示中性粒细胞计数减少；听性脑干反应(ABR)检查提示左侧听觉传导通路损伤，双侧听觉反应阈值可疑范围；双眼视觉诱发电位(VEP)检查未见异常；脑电图正常；头颅MRI平扫提示双侧额部脑外间隙稍增宽；全脊柱正侧位X射线摄片提示右侧轻度髋发育不良伴右髋关节半脱位可能；腰椎轻度左侧弯，疑为双髋关节不对称所致；心电图、心脏彩色多普勒超声检查和染色体核型分析均未见异常。②患儿2病史采集结果：患儿1胞弟，男性，1岁4个月，亦表现为精神运动发育落后，小头畸形和身材矮小。相关检查结果：双耳ABR正常；VEP检查提示右眼F-VEP P2波潜伏期稍延迟，振幅正常；脑电图正常；头颅MRI平扫未见异常；全脊柱正侧位X射线摄片、心电图、心脏彩色多普勒超声检查和染色体核型分析均未见异常。③患儿1、2遗传性疾病大家系全外显子组检测提示，2例患儿均携带VPS13B基因2个杂合病理性突变，即VPS13B[8q22 NM_017890.4 Intron50 c．9259-1G>C][8q22 NM_017890.4 Exon57 c．11104_11105de1]基因突变，这2个基因突变位点目前均尚未见文献报道。

结论

Cohen综合征为一种罕见常染色体隐性遗传性疾病。临床上对于特殊面容、生长发育落后、高度近视、弱视和色素性视网膜病变伴中性粒细胞减少症的患儿，应考虑到Cohen综合征的可能性，并进行基因检测，以及时确诊Cohen综合征。

关键词: Cohen综合征, VPS13B基因, 精神发育迟滞, 语言发展障碍, 基因测定, 儿童

Objective

To analyze the clinical features and diagnosis of Cohen syndrome caused by VPS13B gene mutation and review related literatures, so as to provide guidance for genetic counseling and diagnosis of Cohen syndrome.

Methods

Two children (case 1 and 2) who were diagnosed as Cohen syndrome in the Department of Pediatrics of Sun Yat-sen Memorial Hospital, Sun Yat-sen University in January 2019 were selected as research subjects. Clinical data of these two children were collected by retrospective method, and their history-taking and related examination results were analyzed retrospectively. Relevant literatures of Cohen syndrome were retrieved in Online Human Mendelian Genetic Database (OMIM) and PubMed databases, Chinese Knowledge Infrastructure Engineering (CNKI) database and Wanfang database by taking " Cohen syndrome" as the keyword both in Chinese and English. The retrieval time was set from January 1, 1973 to January 1, 2019. This study was in line with World Medical Association Declaration of Helsinki revised in 2013, with the informed consent of the guardians (father, mother and uncle) of both two children.

Results

①History-taking results of case 1: boy, 4 years and 3 months old, mainly manifested as psychomotor retardation, microcephaly and short stature. Related examination results: blood routine examination showed neutropenia. Auditory brain-stem response (ABR) suggested that the left auditory conduction pathway was damaged and the threshold of bilateral auditory response was suspicious. There was no abnormality in binocular visual evoked potential (VEP). Electroencephalogram was normal, cranial MRI plain scan showed bilateral frontal extracerebral space slightly widened, total spinal anterolateral radiographs showed mild developmental dysplasia of hip and might combined with right hip subluxation, mild left lumbar curvature which might by caused by asymmetry of double hip joints. Electrocardiogram, cardiac color Doppler ultrasound and karyotype analysis all were normal. ②History-taking results of case 2: boy, 1 year and 4 months old, also showed psychomotor retardation, microcephaly and short stature. Related examination results: normal binaural ABR, VEP examination showed that the latency period of F-VEP P2 wave in the right eye was slightly delayed but the amplitude was normal. Electroencephalogram was normal. No abnormalities were found on MRI plain scan of the head, total spinal anterolateral radiographs, electrocardiogram, cardiac color Doppler ultrasound and karyotype analysis. ③Whole exon group testing for family of genetic diseases of case 1 and 2 showed these two subjects carried two heterozygous pathological mutations of VPS13B gene which were VPS13B[8q22 NM_017890.4 Intron50 c. 9259-1G>C][8q22 NM_017890.4 Exon57 c. 11104_11105de1]. And these two mutation sites of this gene have not been reported in the literature.

Conclusions

Cohen syndrome is a rare autosomal recessive hereditary disease. Children with unusual facies, stunted growth, severe myopia, amblyopia and pigmentary retinopathy with neutropenia should be paid attention to the possibility of Cohen syndrome, and genetic testing is helpful for diagnosis of this disease.

Key words: Cohen syndrome, VPS13B gene, Mental retardation, Language development disorders, Genetic testing, Child

图1 患儿1(男性，4岁3个月)入院当天体格检查照片图(图1A：小头畸形和耳突出不良；图1B：上中切牙未见异常；图1C：手指较为纤细)

表1 患儿1、2遗传性疾病大家系全外显子组检测结果

基因	区带	参考序列	突变位点	cDNA水平改变	蛋白质水平改变	突变状态	突变分类	患儿父母基因突变检测结果
基因	区带	参考序列	突变位点	cDNA水平改变	蛋白质水平改变	突变状态	突变分类	父亲	母亲
VPS13B	8q22	NM_017890.4	Intron50	c.9259-1G>C	p.？	杂合	病理性	未检测到	杂合携带
VPS13B	8q22	NM_017890.4	Exon57	c.11104_11105del	p.(Lys3702fs)	杂合	病理性	杂合携带	未检测到

表1 患儿1、2遗传性疾病大家系全外显子组检测结果

基因	区带	参考序列	突变位点	cDNA水平改变	蛋白质水平改变	突变状态	突变分类	患儿父母基因突变检测结果
基因	区带	参考序列	突变位点	cDNA水平改变	蛋白质水平改变	突变状态	突变分类	父亲	母亲
VPS13B	8q22	NM_017890.4	Intron50	c.9259-1G>C	p.？	杂合	病理性	未检测到	杂合携带
VPS13B	8q22	NM_017890.4	Exon57	c.11104_11105del	p.(Lys3702fs)	杂合	病理性	杂合携带	未检测到

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Cohen syndrome: two cases report and literature review

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Cohen syndrome: two cases report and literature review