Study On Inner Ear Malformation For Its Classification And Relationship With SLC26A4 And GJB2 In Patient With Sensorineural Hearing Loss

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.