【作者】 孙宝春；

【导师】 戴朴；

【作者基本信息】 中国人民解放军军医进修学院 ， 耳鼻咽喉科学， 2011， 博士

【摘要】 目的研究感音神经性耳聋病例的流行病学资料,通过高分辨率螺旋CT检查探讨中国人感音神经性耳聋患者群体中内耳畸形的发病率情况；在Sennaroglu分类的基础上分析各类内耳畸形的影像学特征,从形态学、组织胚胎学及听力学方面探讨内耳畸形分类的依据；研究感音神经性耳聋中CT表型与SLC26A4、GJB2基因致病性突变类型之间的关系,初步探讨SLC26A4、GJB2基因检测在部分感音神经性耳聋患者中辅助或替代CT成为诊断工具的可行性。方法在第一部分中,对我院门诊近10年来2747例感音神经性耳聋病例进行回顾性分析,采用流行病学方法对感音神经性耳聋病例的一般情况、听力学情况进行调查,通过对大宗病例CT资料的研究,了解中国人感音神经性耳聋患者群体中内耳畸形的发病情况。以Sennaroglu分类为标准,对以上病例中通过CT检查发现存在内耳畸形的843例患者,按以下部位进行详细观察：耳蜗、前庭、半规管、前庭导水管及内听道；对其中的441例耳蜗畸形按以下分类：Michel畸形、耳蜗未发育、共同腔畸形、耳蜗发育不全、不完全分隔-Ⅰ型、不完全分隔-Ⅱ型(Mondini畸形)进行研究,在大宗病例中统计各类畸形的详细情况,同时结合影像学及听力学方法对上述分类结果进行分析。在第二部分中,对2598例感音神经性耳聋患者按DNA测序的方法检测SLC26A4基因和GJB2基因,统计这两种基因在以上各类CT表型中对应的致病性突变情况,研究SLC26A4、GJB2基因致病性突变在以上各类CT表型中的分布特点,分析SLC26A4、GJB2基因型与CT表型之间的关系。结果1、通过CT检查在2747例感音神经性耳聋患者中发现843例内耳畸形病例,内耳畸形的发病率为30.69%(843/2747)2、843例内耳畸形患者的调查分析结果：(1)一般情况：性别比例男女之比为1.33：1；种族分布汉族为96.68%(815/843),然后依次为满族、蒙古族、回族以及其他族；发病年龄平均2.89±0.92,1～3岁比例最高为34.68%(292/843)；单、双侧均可发病,其中双侧占93.36%(787/843)；存在家族史的占2.37%(20/843)。(2)听力学情况：平均听阈为89.71±6.30dB HL,以重度、极重度聋为主,占84.25%；声导抗A型为主,占74.43%。3、按照Sennaroglu分类方法,843例内耳畸形的CT检查详细结果：(1)各部位畸形构成情况：耳蜗畸形为52.31%(441/843)、单纯大前庭导水管为40.33%(340/843)、单纯前庭/半规管/内听道畸形为7.36%(62/843)。(2)内耳畸形中441例耳蜗畸形分类情况：Michel畸形为1.13%(5/441)、耳蜗未发育为1.81%(8/441)、共同腔畸形为3.17%(14/441)、IP-Ⅰ畸形为8.62%(38/441)、耳蜗发育不全为9.07%(40/441)、Mondini畸形(伴大前庭导水管)为76.19%(336/441)。(3)CT检查出与大前庭导水管相关畸形(单纯大前庭导水管340例、大前庭导水管伴Mondini畸形336例)676例,占全部内耳畸形的比例为80.19%(676/843)；严重内耳畸形(Michel畸形、耳蜗未发育、共同腔畸形、IP-Ⅰ畸形、耳蜗发育不全)105例,占全部畸形的比例为12.46%(105/843)。(4)与前庭导水管扩大相关内耳畸形在感音神经性耳聋患者中的发病率为24.61%(676/2747)；严重内耳畸形在感音神经性耳聋中的发病率为3.82%(105/2747)。4、2598例感音神经耳聋病例中SLC26A4、GJB2基因突变检测结果：(1)共检出SLC26A4基因致病性突变(双等位基因突变)517例,全部在前庭导水管扩大相关内耳畸形中检出。共检出GJB2基因致病性突变(双等位基因突变)414例,其中在CT正常组中检出411例,占全部检出例数的99.28%(411/414)；在单纯前庭/半规管/内听道畸形中检出2例；在单纯大前庭导水管中检出1例(SLC26A4、GJB2基因双突变)(2)517例SLC26A4基因致病性突变中,双等位基因纯合突变164例、复合杂合突变353例。(3)414例GJB2基因致病性突变中,双等位基因纯合突变213例、复合杂合突变199例、单等位基因显性突变(R184Q)2例。5、感音神经性耳聋中内耳CT表型与SLC26A4、GJB2基因突变之间的关系：(1)CT表型为严重内耳畸形的病例中均未检测出SLC26A4、GJB2基因致病性突变(双等位基因突变)(2)SLC26A4基因致病性突变(双等位基因突变)全部在CT表型为前庭导水管扩大相关内耳畸形病例中检出。(3)GJB2基因致病性突变(双等位基因突变)99.28%在内耳CT表型为正常的耳聋病例中检出。结论通过CT检查发现感音神经性耳聋患者群体中内耳畸形发病率为30.69%,内耳畸形中与前庭导水管扩大相关内耳畸形的病例占80.19%。通过DNA测序发现,SLC26A4基因致病性突变(双等位基因突变)100%在前庭导水管扩大相关内耳畸形的病例中检出,GJB2基因致病性突变(双等位基因突变)99.28%在内耳CT正常的耳聋病例中检出,二者与CT表型密切相关；SLC26A4、GJB2基因联合检测,有望在部分感音神经性耳聋患者中辅助甚至替代CT成为诊断工具。更多还原

【Abstract】 Objective1. Analyze the data of the patients with sensorineural hearing loss in China and investigate the status of inner ear malformations based on reading the image of high-resolution computed tomography.2. Analyze the characteristic feature of inner ear malformation according to Sennaroglu’classification and discuss the results based on the evidence provided by radiological, histological and embryological, and audiological examinations.3. Explore the relationship between the CT phenotypes of inner ear and pathogenic mutations of SLC26A4 gene and GJB2 gene, and analyze the feasibility of using the method of gene sequence analysis to help or replace CT examination in diagnosing part of patients with sensorineural hearing loss.Material and Methods1. The investigation took the form of a retrospective review of CT findings relating to the 2747 cases of outpatients in our hospital in recent 10 years. We obtained data of the outpatients with epidemio logical methods based on analyzing the status of general information and audiological evaluation, and then analyzed the data of inner ear malformation based on CT examination. Those 843 cases of inner ear malformations diagnosed by CT were classified according to the methods proposed by Sennaroglu. The CT images were thoroughly reviewed for malformations under the following subgroups:cochlear, vestibular, semicircular canal, internal auditory canal, and vestibular aqueduct malformations. Cochlear malformations were classified as Michel deformity, cochlear aplasia, commoncavity deformity, incomplete partition typesⅠ(IP-Ⅰ), hypoplastic cochlea, and incomplete partition typesⅡ(IP-Ⅱ) (Mondini deformity). Summarized the statistic data of each inner ear malformation and analyzed the results based on the evidence provided by radiological, histological and embryological, and audiological examinations.2. The DNA sequence of SLC26A4 gene and GJB2 gene were analyzed in 2598 cases of patients with sensorineural hearing loss to explore the relationship between the CT phenotypes and the pathogenic mutations of SLC26A4 gene and GJB2 gene.Results1.843 cases of inner ear malformations were found in 2747 cases of patients with sensorineural healring loss by CT examination. The incidence of inner ear malformation was 30.69%(843/2747).2. The epidemiological informations of 843 cases of inner ear malformation:(1) General information:The ratio of male and female was 1.33:1. Han nationality consists of 96.68%(815/843) of the whole group, followed by Man, Mongolia, Hui and other nationalities. The average onset age was 2.89±0.92 years old, mostly ranged from 1 to 3 years old, which consists of 34.68%(292/843) of the group. The malformed ear could be either unilateral or bilateral, and 93.36%(787/843) cases were unilateral. 2.37%(20/843) patients of the group have family history.(2) Audiological evaluations:The average auditory threshold was 89.71±6.30 dB HL and most patients were profound or extremely profound sensineural hearing loss, which consist 84.25% of the group, and 74.30% of tympanogram was type A.3. The detailed information of 843 cases of inner ear malformation according to Sennaroglu’s classification was as follows:(1) Each component of the inner ear with malformation consisted of the group as:cochlea was 52.31%(441/843), simple vestibular aquaduct was 40.33%(340/843), vestibular/semicircular cannal/internal auditory cannal were 7.35%(62/843) of the group.(2) 441 cases of cochlea malformation were consisted of these types of malformation:Michel deformity was 1.13%(5/441), cochlear aplasia was 1.81%(8/441), common cavity deformity was 3.17%(14/441), incomplete partition typeⅠ(IP-Ⅰ) was 8.62%(38/441), hypoplastic cochlea was 9.07%(40/441) and incomplete partition typeⅡ(IP-Ⅱ) (Mondini malformation) was 76.19%(336/441) of the group.(3) Large vestibular aqueduct and Mondini accompanied with large vestibular aqueduct were related to the vestibular aqueduct malformation, which consisted of 80.19%(676/843) cases of the whole malformation group. Michel deformity, cochlear aplasia, common cavity deformity, incomplete partitionⅠ(IP-Ⅰ) and hypoplastic cochlea were related to severe deformity of inner ear and consisted of 12.46% (105/843) of the whole malformation group.(4) Vestibular aqueduct related malformation was consisted 24.61% (676/2747) of the sensorineural hearing loss entity group and severe deformity of inner ear were consisted 3.82%(105/2747) of the entity group.4. Results of the DNA sequence analysis of SLC26A4 gene and GJB2 gene in 2598 cases of patients with sensorineural hearing loss:(1) The sequence results revealed that 517 cases carried pathogenic mutations (Bi-allelic mutations) of SLC26A4 gene and detected without exceptionally in the group related to vestibular aqueduct malformation. There were 414 cases carried pathogenic mutation (Bi-allelic mutations) of GJB2 gene, among which 411 (99.28%) cases were found in the normal group,2 cases were found in the simple vestibular/semicircular cannal/internal auditory cannal malformation group and 1 case was found in vestibular aqueduct malformation (this case was particularly carried pathogenic mutation of SLC26A4 and GJB2 gene simultaneously).(2) 517 cases carried pathogenic mutations of SLC26A4 gene, among which 164 cases were homozygous,353 cases were compound heterozygous.(3) 414 cases carried pathogenic mutation of GJB2, among which 213 cases were homozygous,199 cases were compound heterozygous and 2 case carried dominant mutation of GJB2 gene.5. The relationship between the CT phenotypes and the pathogenic mutations of SLC26A4 gene and GJB2 gene in patients with sensorineural hearing loss:(1) None of the pathogenic mutation (Bi-allelic mutations) in SLC26A4 gene or GJB2 gene was detected in group of severe CT phenotypes.(2) Pathogenic mutations (Bi-allelic mutations) of SLC26A4 gene were detected in all cases in the group of vestibular aqueduct related CT phenotype.(3) Pathogenic mutations (Bi-allelic mutations) of GJB2 gene were detected in 99.28% cases in the group of normal CT phenotype.ConclusionThe results suggested that 30.69% cases of inner ear malformation can be found in patients with sensorineural hearing loss by CT examination, among which 80.19% cases related to vestibular aqueduct malformation. Pathogenic mutations (Bi-allelic mutations) of SLC26A4 gene were detected in 100% in the group of vestibular aqueduct related CT phenotype, while pathogenic mutations (Bi-allelic mutations) of GJB2 were detected in 99.28% cases in the group of normal CT phenotype. These two kinds of gene types may be closely related to CT phenotype of patients with sensorineural hearing loss. Associated analysis of SLC26A4 gene and GJB2 gene can help or replace CT examination to diagnose part of patients with sensorineural hearing loss.更多还原