感音神经性耳聋中内耳畸形的分类以及与SLC26A4、GJB2基因关系的研究

发布时间：2018-07-03 07:58

本文选题：感音神经性耳聋 + 内耳崎形　；参考：《中国人民解放军军医进修学院》2011年博士论文

【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。
[Abstract]:objective
The epidemiological data of sensorineural deafness were studied and the incidence of internal ear malformation in Chinese people with sensorineural deafness was examined by high resolution spiral CT. The imaging features of various internal ear deformities were analyzed on the basis of Sennaroglu classification, and the study of morphology, histology, embryology and audiology were discussed. The basis of the classification of the malformation of the inner ear; the relationship between the CT phenotype and the pathogenicity of the GJB2 gene in sensorineural deafness, and the feasibility of the SLC26A4, GJB2 gene detection in partially sensorineural deafness to assist or replace CT as a diagnostic tool.
Method
In the first part, a retrospective analysis of 2747 cases of sensorineural deafness in our hospital over the past 10 years was conducted. The general situation and audiology of sensorineural deafness cases were investigated by epidemiological methods. Through the study of the CT data of large cases, the internal ear distortion in Chinese people with sensorineural deafness was understood. 843 cases of internal ear malformation were found in the above cases by Sennaroglu classification. The following sites were observed in detail: cochlea, vestibule, semicircular canal, vestibular aqueduct and internal auditory canal; 441 Cases of cochlear malformation were classified as follows: Michel malformation, cochlear undeveloped, common cavity malformation. Shape, cochlear dysplasia, incomplete separation - type I, incomplete separation - type II (Mondini malformation), and the detailed analysis of various deformities in a large number of cases, and the analysis of the above classification results combined with imaging and audiology methods. In the second part, 2598 cases of sensorineural deafness were sequenced by DNA sequencing. The SLC26A4 gene and GJB2 gene were detected, and the corresponding pathogenic mutation of these two genes in all kinds of CT phenotypes was analyzed. The distribution characteristics of SLC26A4, GJB2 gene mutations in all kinds of CT phenotypes were studied, and the relationship between the SLC26A4, GJB2 genotypes and CT phenotypes was analyzed.
Result
1, 843 cases of inner ear malformation were found in 2747 patients with sensorineural hearing loss by CT examination. The incidence of inner ear malformation was 30.69% (843/2747).
2843 cases of internal ear malformation were investigated and analyzed.
(1) the general situation: the ratio of gender to male and female is 1.33:1; the ethnic Han nationality is 96.68% (815/843), and then in turn is Manchu, Mongolian, Hui and other ethnic groups; the average age of age 2.89 + 0.92,1 to 3 years is 34.68% (292/843). 7% (20/843).
(2) audiology: the average hearing threshold was 89.71 + 6.30dB HL, which was mainly severe, very severe deafness, accounting for 84.25%, and acoustic impedance A was the main type, accounting for 74.43%.
3, according to the Sennaroglu classification method, 843 cases of inner ear malformation were examined by CT in detail.
(1) the malformation of each part: the cochlear malformation was 52.31% (441/843), the simple large vestibular aqueduct was 40.33% (340/843), and the vestibule / semicircular canal / inner auditory malformation was 7.36% (62/843).
(2) the classification of 441 Cases of cochlear malformation in the inner ear malformation: Michel malformation was 1.13% (5/441), cochlea was 1.81% (8/441), cochlear malformation was 3.17% (14/441), IP- I malformation was 8.62% (38/441), cochlear development was 9.07% (40/441), Mondini malformation (vestibular aqueduct) was 76.19% (336/441).
(3) CT detected 676 cases of large vestibular aqueduct associated malformation (340 cases of large vestibular aqueduct and 336 cases of large vestibular aqueduct accompanied by Mondini malformation), which accounted for 80.19% (676/843) of all inner ear malformations, and 105 cases of severe inner ear malformation (Michel malformation, cochlear undeveloped, common cavity malformation, IP- I malformation and cochlear dysplasia), accounting for all malformations. The proportion was 12.46% (105/843).
(4) the incidence of internal ear malformation associated with vestibular aqueduct in sensorineural deafness was 24.61% (676/2747), and the incidence of severe inner ear deformities in sensorineural deafness was 3.82% (105/2747).
Detection of SLC26A4 and GJB2 gene mutations in 42598 cases of sensorineural hearing loss:
(1) a total of 517 cases of SLC26A4 gene mutation (double allele mutation) were detected, all of which were detected in the vestibular aqueduct related inner ear malformation. A total of 414 cases of GJB2 gene mutation (double allele mutation) were detected, of which 411 cases were detected in the normal CT group, accounting for 99.28% (411/414) of the total number of cases, and in the simple vestibule / semicircular canal / within. 2 cases were found in the auditory canal deformity, and 1 cases (SLC26A4, GJB2 gene double mutation) were found in the large vestibular aqueduct.
(2) in 517 cases of SLC26A4 gene mutation, 164 cases of homozygous alleles and 353 cases of compound heterozygous mutations.
(3) in 414 cases of GJB2 gene mutation, 213 alleles of homozygous alleles, 199 cases of compound heterozygous mutations, and 2 cases of single allele dominant mutation (R184Q).
5, the relationship between the CT phenotype of inner ear and the mutation of SLC26A4 and GJB2 gene in sensorineural hearing loss:
(1) SLC26A4 and GJB2 gene mutations (double alleles mutation) were not detected in CT phenotype with severe inner ear malformations.
(2) the SLC26A4 gene mutation (double allele mutation) was detected in the CT phenotype with enlarged vestibular aqueduct associated inner ear malformations.
(3) the GJB2 gene mutation (double allele mutation) 99.28% was detected in the inner ear CT phenotype in normal deafness cases.
conclusion
The incidence of inner ear malformation in the group of sensorineural deafness was 30.69% through CT examination, and the cases of inner ear malformation associated with the enlarged vestibular aqueduct associated inner ear malformation were found to be 80.19%. through DNA sequencing, and the pathogenicity of the SLC26A4 gene (double allele mutation) 100% was detected in the cases of the enlargement of the vestibular aqueduct related internal ear malformation. The GJB2 gene pathogenicity mutation (double allele mutation) 99.28% was detected in the CT normal deafness cases in the inner ear, and the two was closely related to the CT phenotype; SLC26A4, GJB2 gene combined detection, could be used to assist and even replace CT in some sensorineural deafness patients.
【学位授予单位】：中国人民解放军军医进修学院
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R764.43

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