A non-coding variant in 5' untranslated region drove up-regulation of pseudo-kinase EPHA10 and caused non-syndromic hearing loss in humans.

Hereditary hearing loss has a genetic and phenotypic heterogeneity. However, it is still difficult to explain this heterogeneity perfectly with known deafness genes. Here, we report a novel causative gene EPHA10 as well as its non-coding variant in 5' untranslated region identified in a family with post-lingual autosomal dominant non-syndromic hearing loss from southern China. One affected member of this family had an ideal hearing restoration after cochlear implantation. We speculated that there were probable deafness-causing abnormalities in the cochlea according to clinical imaging and auditory evaluations. A heterozygous variant c.-81_-73delinsAGC was found co-segregating with hearing loss. Epha10 was expressed in mouse cochlea at both transcription and translation levels. The variant caused upregulation of EPHA10 which may result from promoter activity enhancement after sequence change. Overexpression of Eph (the homolog of human EPHA10) exerted effects on the structure and function of chordotonal organ in fly model. In summary, our study linked pseudo-kinase EPHA10 to hearing loss in humans for the first time.

A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder.

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.

Clinical characteristics and surgical strategy of glomus tympanicum tumors. / 鼓室体瘤的临床特征及手术策略.

OBJECTIVES: To summarize the clinical characteristics of glomus tympanicum tumors, and to explore the surgical methods and the strategy for auditory protection. METHODS: Ten cases (ears) of glomus tympanicum tumors were collected from the Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University from August 2014 to February 2022. All patients underwent endoscopic or microscopic surgery to achieve total removal of the tumor, followed up for 3 months to 8 years. We summarized and analyzed its clinical characteristics, compared the preoperative and postoperative hearing levels of patients, and made a retrospective summary of the surgical methods and the strategy for auditory protection. RESULTS: Ten patients were all female at (49.50±8.00) years old. Their medical history ranged from 15 days to 6 years. Seven patients complained of pulsatile tinnitus, and 80% (8/10) of the affected ears suffered different degrees of hearing loss. According to the modified Fisch & Mattox classification of glomus tympanicum tumors, 3 ears (30%) of 10 ears were A1, 2 ears (20%) were A2 and 5 ears (50%) were B1. In all 10 cases (ears), hearing was improved in 3 cases, bone gas conductance was maintained in 6 cases, and hearing was slightly decreased in 1 case. The difference of bone gas conductance was 0-10 dB in 7 cases (ears) after operation, and 10-20 dB in 3 cases (ears). There was no significant difference in the average air conduction hearing threshold, bone conduction hearing threshold and air-bone conduction difference between before and after operation (all P>0.05). All cases had no postoperative complications, and the external auditory canal and the incision behind the ear healed well. There was no recurrence after follow-up. CONCLUSIONS: Glomus tympanicum tumor is easy to bleed, so it is a challenge for total tumor resection and hearing function protection during operation. For type A and type B1 tumors, they can be completely removed under the condition of keeping the tympanic membrane and the ossicular chain. At the same time, the postoperative hearing function can be preserved, and even the hearing can be improved.

Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome.

Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss (HL), which accounts for approximately 2-5% of all patients with congenital hearing loss. WS is classified into four subtypes depending on the clinical phenotypes. Currently, pathogenic mutations of PAX3, MITF, SOX10, EDN3, EDNRB or SNAI2 are associated with different subtypes of WS. Although supportive techniques like hearing aids, cochlear implants, or other assistive listening devices can alleviate the HL symptom, there is no cure for WS to date. Recently major progress has been achieved in preclinical studies of genetic HL in animal models, including gene delivery and stem cell replacement therapies. This review focuses on the current understandings of pathogenic mechanisms and potential biological therapeutic approaches for HL in WS, providing strategies and directions for implementing WS biological therapies, as well as possible problems to be faced, in the future.

Establishment of a risk index for early complications after trans-canal endoscopic ear surgery.

PURPOSE: This study aimed to determine the risk factors associated with early postoperative complications of trans-canal endoscopic ear surgery (TEES), then to develop a risk index. MATERIALS AND METHODS: This single-institution retrospective study reviewed TEESs from January 1, 2017, to December 31, 2019 in a tertiary hospital. In the derivation cohort, univariable and multivariable logistic regression were performed to identify factors significantly associated with early postoperative complications of TEES. Then these parameters were integrated into a trans-canal endoscopic ear surgery risk index (TEESRI). The performance of TEESRI was compared with that of the American Society of Anesthesiologists (ASA) classification using the validation cohort. RESULTS: 932 TEESs were enrolled in total and 151 (16.2%) developed early postoperative complications. In the derivation set, 8 factors including state of the opposite ear and presence of nasal or pharyngeal diseases were found to be independently associated with the occurrence of early postoperative complications on multivariable regression analysis [area under the curve (AUC), 0.806; 95% confidence interval (CI), 0.765-0.848]. Using the validation cohort, the AUC of the TEESRI was 0.776 [95%CI, 0.711-0.842], with a sensitivity of 82.2% and specificity of 65.5%, while the AUC of the ASA classification was 0.512 (95%CI, 0.421-0.603). The TEESRI outperformed the ASA classification when evaluating the risk for early postoperative complications of TEES. CONCLUSIONS: Based on the 8 risk factors, the TEESRI was established with satisfactory predicting capacity. Surgeons should pay extra attention to the risk factors in the TEESRI, when treating patients.

Otological manifestations in branchiootorenal spectrum disorder: A systematic review and meta-analysis.

Branchiootorenal spectrum disorder (BORSD) is a group of rare autosomal dominant entities characterized by branchiogenic malformations, hearing loss (HL) and renal anomalies. It comprises branchiootorenal syndrome and branchiootic syndrome, distinguished by the presence or absence of renal abnormalities. Pathogenic variants have been discovered in the following genes: EYA1, SIX5, SIX1 and SALL1. As the otological phenotype in BORSD is inconsistently reported, we performed a systematic review to provide an up-to-date overview, correlated with the genotype. Forty publications were included, describing 295 individual patients. HL was diagnosed in 95%, usually bilateral and mixed-type, and differed among the different genes involved. Mixed moderate-to-severe HL was the predominant finding in patients with EYA1 involvement, regardless of the presence of renal abnormalities. The sensorineural HL of profound severity was more prevalent in patients with SIX1 mutations. No significant differences among different mutation types or location within the genes could be observed. Structural otological manifestations, ranging from periauricular to inner ear anomalies, were common in both genes. Especially periauricular anomalies were more common and more severe in EYA1. In summary, otological differences among the different genes involved in BORSD are observed, so the molecular analysis is strongly advised.

Identification and functional analysis of a novel missense mutation of PAX3 associated with Waardenburg syndrome type I.

PURPOSE: Waardenburg syndrome type 1 (WS1) is a rare genetic disorder characterized by dystopia canthorum, abnormal iris pigmentation, and congenital hearing loss with variable penetrance.WS1 is caused by mutations in paired box gene 3 (PAX3). The current study aimed to investigate the genetic cause of hearing loss in a four-generation Chinese WS1 family. METHODS: The phenotype of the study family was characterized using clinical evaluation and pedigree analysis. Target region high-throughput sequencing system was designed to screen the all coding exons and flanking intronic sequences of the six WS-associated genes. Sanger sequencing was used to identify the causative nucleotide changes and perform the co-segregating analysis. The expression, subcellular distribution, and transcriptional activity of the mutant PAX3 protein were analysis to reveal the functional consequences of the mutation. RESULTS: Based on diagnostic criteria, the proband of this pedigree classified as WS1. We identified a novel missense mutation (c.117 C > A, p. Asn39Lys) in exon 2 of the PAX3 gene. In vitro, the Asn39Lys PAX3 retained nuclear distribution ability. However, it failed to activate the melanocyte inducing transcription factor (MITF) promoter and impaired the function of WT PAX3. CONCLUSIONS: Our study reports a novel missense PAX3 mutation in a Chinese family and shows haploinsufficiency may be the underlying mechanism for the WS1 phenotype.

Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis.

PURPOSE: To determine the genetic etiology of deafness in a family (HN-SD01) with autosomal dominant nonsyndromic hearing loss (NSHL). METHODS: Stepwise genetic analysis was performed on family HN-SD01, including hotspot variant screening, exome sequencing, virtual hearing loss gene panel, and genome-wide linkage analysis. Targeted region sequencing was used to screen ABCC1 in additional cases. Cochlear expression of Abcc1 was evaluated by messenger RNA (mRNA) and protein levels. Computational prediction, immunofluorescence, real-time quantitative polymerase chain reaction, and flow cytometry were conducted to uncover functional consequences of candidate variants. RESULTS: Stepwise genetic analysis identified a heterozygous missense variant, ABCC1:c.1769A>G (p.Asn590Ser), cosegregating with phenotype in HN-SD01. Screening of ABCC1 in an additional 217 cases identified candidate pathogenic variants c.692G>A (p.Gly231Asp) in a sporadic case and c.887A>T (p.Glu296Val) in a familial proband. Abcc1 expressed in stria vascularis and auditory nerve of mouse cochlea. Immunofluorescence showed p.Asn590Ser distributed in cytomembrane and cytoplasm, while wild type was shown only in cytomembrane. Besides, it generated unstable mRNA and decreased efflux capacity of ABCC1. CONCLUSION: Stepwise genetic analysis is efficient to analyze the genetic etiology of NSHL. Variants in ABCC1 are linked with NSHL and suggest an important role of extruding pumps in maintaining cochlea function.

New Genotypes and Phenotypes in Patients with 3 Subtypes of Waardenburg Syndrome Identified by Diagnostic Next-Generation Sequencing.

Background: Waardenburg syndrome (WS) is one of the most common forms of syndromic deafness with heterogeneity of loci and alleles and variable expressivity of clinical features. Methods: The technology of single-nucleotide variants (SNV) and copy number variation (CNV) detection was developed to investigate the genotype spectrum of WS in a Chinese population. Results: Ninety WS patients and 24 additional family members were recruited for the study. Fourteen mutations had not been previously reported, including c.808C>G, c.117C>A, c.152T>G, c.803G>T, c.793-3T >G, and c.801delT on PAX3; c.642_650delAAG on MITF; c.122G>T and c.127C>T on SOX10; c.230C>G and c.365C>T on SNAI2; and c.481A>G, c.1018C>G, and c.1015C>T on EDNRB. Three CNVs were de novo and first reported in our study. Five EDNRB variants were associated with WS type 1 in the heterozygous state for the first time, with a detection rate of 22.2%. Freckles occur only in WS type 2. Yellow hair, amblyopia, congenital ptosis, narrow palpebral fissures, and pigmentation spots are rare and unique symptoms in WS patients from China. Conclusions: EDNRB should be considered as another prevalent pathogenic gene in WS type 1. Our study expanded the genotype and phenotype spectrum of WS, and diagnostic next-generation sequencing is promising for WS.

[Giant cell reparative granuloma of the temporal bone: A case report].

Giant cell reparative granuloma (GCRG) is a type of non-neoplastic lesion that can be rarely found in clinical practices. Due to the lack of specificity in symptoms, signs and auxiliary examinations, it is likely to be misdiagnosed, and thereby affecting the treatment and prognosis. In July 2018, a GCRG patient who was described with "4 years of hearing loss in the left ear, accompanied by 2 months of preauricular swelling" as the first symptom was admitted in our hospital. Both the HRCT and MRI scans for the temporal bone suggested the presence of tumor at the left lateral skull base, but the nature still needed further examination. Intraoperatively, the tumor was completely removed and repaired locally. Pathological examination confirmed the symptoms as GCRG. Immunohistochemistry showed the expression of CD68 and CD163 in the tumor cells. Postoperatively, the patient recovered well without complications, and had the stitches removed before being discharged on schedule.

A novel mutation in the SMPX gene associated with X-linked nonsyndromic sensorineural hearing loss in a Chinese family.

X-linked inheritance is very rare and is estimated to account for only 1-5% of all nonsyndromic hearing loss cases. We found a multiplex family from China segregating with X-linked nonsyndromic hearing loss. After exclusive analysis of 10 common variations of three hearing loss-related genes, GJB2, mtDNA12srRNA and SLC26A4, a novel truncated variant of SMPX, c.87dupA (p.Gly30Argfs*12) (NCBI ClinVar Submission ID: SUB3136126), was identified by whole-exome sequencing. This variant was co-segregated with hearing loss in the entire family and was absent in 576 unrelated ethnically and geographically matched controls. We also detected a single nucleotide variation in two male controls with normal hearing, SMPX c.55A>G (p.Asn19Asp), which has been annotated as a rare variant in the Single Nucleotide Polymorphism (dbSNP) (rs759552778) and Exome Aggregation Consortium (ExAC) databases. This study has enriched the mutation spectrum of the SMPX gene.

iTRAQ-Based Quantitative Proteomic Analysis of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a common disease in the southern provinces of China with a poor prognosis. To better understand the pathogenesis of NPC and identify proteins involved in NPC carcinogenesis, we applied iTRAQ coupled with two-dimensional LC-MS/MS to compare the proteome profiles of NPC tissues and the adjacent non-tumor tissues. We identified 54 proteins with differential expression in NPC and the adjacent non-tumor tissues. The differentially expressed proteins were further determined by RT-PCR and Western blot analysis. In addition, the up-regulation of HSPB1, NPM1 and NCL were determined by immunohistochemistry using tissue microarray. Functionally, we found that siRNA mediated knockdown of NPM1 inhibited the migration and invasion of human NPC CNE1 cell line. In summary, this is the first study on proteome analysis of NPC tissues using an iTRAQ method, and we identified many new differentially expressed proteins which are potential targets for the diagnosis and therapy of NPC.

New ZNF644 mutations identified in patients with high myopia.

PURPOSE: Myopia, or near-sightedness, is one of the most common human visual impairments worldwide, and high myopia is one of the leading causes of blindness. In this study, we investigated the mutation spectrum of ZNF644, a causative gene for autosomal dominant high myopia, in a high-myopia cohort from a Chinese population. METHODS: DNA was isolated with the standard proteinase K digestion and phenol-chloroform method from a case cohort of 186 subjects diagnosed with high myopia (spherical refractive error equal or less than -6.00 diopters). Sanger sequencing was performed to find potential mutations in all coding exons, flanking splicing sites, and untranslated regions (UTRs) of ZNF644 (NM_201269). Identified novel variants were further screened in 526 ethnically matched normal controls. Functional prediction and conservation analysis were performed using ANNOVAR. RESULTS: Five novel variants were identified. Three are missense (c.1201A>G:p.T401A, c.2867C>G:p.T956S, c.3833A>G:p.E1278G), one is synonymous (c.2565A>G:p.T855T), and one (c.-219C>A) is located in the 5' UTR. Functional prediction indicates that c.3833A>G:p.E1278G was predicted to be damaging by SIFT and Polyphen2. Conservation analysis using PhyloP and GERP++ indicate all of the missense variants are highly conserved. None of these novel mutations was identified in 526 normal controls. CONCLUSIONS: ZNF644 is associated with high myopia in a cohort from a Chinese population. ZNF644 mutations have a minor contribution to the genetic etiology of high myopia.

Identification of a family with van der Hoeve's syndrome harboring a novel COL1A1 mutation and generation of patient-derived iPSC lines and CRISPR/Cas9-corrected isogenic iPSCs.

Van der Hoeve's syndrome, also known as osteogenesis imperfecta (OI), is a genetic connective tissue disorder characterized by fragile, fracture-prone bone and hearing loss. The disease is caused by a gene mutation in one of the two type I collagen genes COL1A1 or COL1A2. In this study, we identified a novel frameshift mutation of the COL1A1 gene (c.1607delG) in a family with OI using whole-exome sequencing, bioinformatics analysis and Sanger sequencing. This mutation may lead to the deletion of a portion of exon 23 and the generation of a premature stop codon in the COL1A1 gene. To further investigate the impact of this mutation, we established two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of OI patients carrying a novel mutation in the COL1A1 gene. Osteoblasts (OB) derived from OI-iPSCs exhibited reduced production of type I collagen and diminished ability to differentiate into osteoblasts. Using a CRISPR-based homology-directed repair strategy, we corrected the OI disease-causing COL1A1 novel mutations in iPSCs generated from an affected individual. Our results demonstrated that the diminished expression of type I collagen and osteogenic potential were enhanced in OB induced from corrected OI-iPSCs compared to those from OI-iPSCs. Overall, our results provide new insights into the genetic basis of Van der Hoeve's syndrome and highlight the potential of iPSC technology for disease modeling and therapeutic development.

[Application and efficacy analysis of tympanic cartilage shaping device in endoscopic type â tympanoplasty].

Objective:To study the feasibility and efficacy of using a tympanic cartilage shaping device in endoscopic type Ⅰ tympanoplasty. Methods:A tympanic cartilage shaper was designed and manufactured by measuring tympanic membrane dimensions with HRCT imaging for cutting and shaping cartilage to repair the tympanic membrane. From August 2019 to October 2021, 66 patients（72 ears） with chronic suppurative otitis media in Xiangya Hospital underwent endoscopic type Ⅰ tympanoplasty with this tympanic cartilage shaping device, and were observed the tympanic membrane healing and hearing recovery effect after surgery. Postoperative follow-up ranged from 3-24 months, with an average of 9 months. The data were analyzed by the SPSS 26.0 software. Results:According to the imaging measurements, tympanic pars tensa width（8.60±0.20） mm, height（8.64±0.19） mm, design and manufacture a cylindrical cartilage shaping device with inner diameter 8.60 mm. After tympanoplasty, the healing rate of tympanic membrane was 100%; The average air-bone gap before surgery was（23.10±7.33） dB, then（14.30±6.40） dB 1 month after surgery, which were significant reduced compared with those before surgery. The average air-bone gap was（14.30±6.40） dB 3 month after surgery compared with 1 month after surgery, the difference was also statistically significant（t=6.630, P<0.05）. Conclusion:The tympanic membrane cartilage shaper shaping cartilage in endoscopic tympanoplasty is simple, stable and reliable, which can reduce the time of graft cartilage processing, improve the efficiency of surgery, and restore the tympanic membrane morphology and function in the postoperative period.

[Analysis of therapeutic effect of tympanoplasty type â in elderly patients with chronic suppurative otitis media].

Objective:To summarize the clinical characteristics of elderly patients with chronic suppurative otitis media who underwent type Ⅰ tympanoplasty, and to analyze for the first time the efficacy of type Ⅰtympanoplasty in elderly patients from multiple perspectives of medical data and patient evaluation, so as to provide reference for doctors and patients to make rational decisions on treatment methods. Methods:Forty-four elderly patients（45 ears） who underwent type Ⅰtympanoplasty from May 2016 to February 2022 were retrospectively analyzed, and were followed up for 6 months to 3 years. To analyze the clinical characteristics of patients, summarize the success rate of graft, and compare the hearing level of patients before and after surgery. The patients' quality of life before and after operation was evaluated by Chronic Ear Survey, and the scores obtained were statistically analyzed. Results:Of the 44 patients（45 ears）, 22.22%（10/45） of the ears had predisposing factors. The percentage of hearing loss, ear pus and tinnitus were 91.11%（41/45）, 88.89%（40/45） and 42.22%（19/45）, respectively. Mixed deafness accounted for 55.56%（25/45）. 66.67%（30/45） patients were diagnosed as tympanosclerosis by operation. The graft success rate was 97.78%. There was no significant difference in bone conduction hearing threshold before and after surgery, but there was significant difference in air conduction hearing threshold and air bone conduction difference. The scores of "activity restriction", "symptom", "medical resource utilization" and their total scores of the preoperative and postoperative were statistically different. Hypertension or diabetes had no significant effect on the efficacy of type Ⅰ tympanoplasty in elderly patients. Conclusion:Type Ⅰtympanoplasty is safe and effective in elderly patients, and the quality of life of patients after surgery is significantly improved. It is necessary to increase the awareness of elderly patients to seek medical advice and use surgical methods reasonably to treat chronic suppurative otitis media.

Short-term effects of intravenous batroxobin in treatment of sudden sensorineural hearing loss: a propensity score-matched study.

Background: Sudden sensorineural hearing loss (SSNHL) can cause great panic in patients. Whether it is advantageous to add intravenous batroxobin in the treatment of SSNHL remains to be determined. This study aimed to compare the short-term efficacy of therapy combined with intravenous batroxobin and that without intravenous batroxobin in SSNHL patients. Methods: This retrospective study harvested the data of SSNHL patients hospitalized in our department from January 2008 to April 2021. The hearing levels on the admitted day (before treatment) and the discharge day were considered pre-treatment hearing and post-treatment hearing, respectively. The hearing gain was the difference value of pre-treatment hearing and post-treatment hearing. We used Siegel's criteria and the Chinese Medical Association of Otolaryngology (CMAO) criteria to evaluate hearing recovery. The complete recovery rate, overall effective rate, and hearing gain at each frequency were considered outcomes. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the batroxobin group and the non-batroxobin group. Sensitivity analysis was carried out in flat-type and total-deafness SSNHL patients. Results: During the study period, 657 patients with SSNHL were admitted to our department. Among them, a total of 274 patients met the enrolled criteria of our study. After PSM, 162 patients (81 in each group) were included in the analysis. Once the hospitalized treatment was completed, the patients would be discharged the next day. Logistic regression analysis of the propensity score-matched cohort indicated that both the complete recovery rates [Siegel's criteria, OR: 0.734, 95% CI: 0.368-1.466, p = 0.381; CMAO criteria, OR: 0.879, 95% CI: 0.435-1.777, p = 0.720] and the overall effective rates [Siegel's criteria and CMAO criteria, OR: 0.741, 95% CI: 0.399-1.378, p = 0.344] were not significantly different between the two treatment groups. Sensitivity analysis has shown similar results. For flat-type and total-deafness SSNHL patients, no significant difference was found in post-treatment hearing gain at each frequency between the two groups after PSM. Conclusion: There was no significant difference in short-term hearing outcomes between treatment with batroxobin and treatment without batroxobin in SSNHL patients by Siegel's and CMAO criteria after PSM. Future studies for better therapy regimens of SSNHL are still needed.

A comprehensive genotype-phenotype evaluation of eight Chinese probands with Waardenburg syndrome.

BACKGROUND: Waardenburg syndrome (WS) is the most common form of syndromic deafness with phenotypic and genetic heterogeneity in the Chinese population. This study aimed to clarify the clinical characteristics and the genetic cause in eight Chinese WS families (including three familial and five sporadic cases). Further genotype-phenotype relationships were also investigated. METHODS: All probands underwent screening for the known WS-related genes including PAX3, SOX10, MITF, EDNRB, EDN3, and SNAI2 using next-generation sequencing to identify disease-causing genes. Further validation using Sanger sequencing was performed. Relevant findings for the associated genotype-phenotype from previous literature were retrospectively analyzed. RESULT: Disease-causing variants were detected in all eight probands by molecular genetic analysis of the WS genes (SOX10(NM_006941.4): c.544_557del, c.553 C > T, c.762delA, c.336G > A; MITF(NM_000248.3): c.626 A > T; PAX3(NM_181459.4): c.838delG, c.452-2 A > G, c.214 A > G). Six mutations (SOX10:c.553 C > T, c.544_557del, c.762delA; PAX3: c.838delG, c.214 A > G; MITF:c.626 A > T) were first reported. Clinical evaluation revealed prominent phenotypic variability in these WS patients. Twelve WS1 cases and five WS2 cases were diagnosed in total. Two probands with SOX10 mutations developed progressive changes in iris color with age, returning from pale blue at birth to normal tan. Additionally, one proband had a renal malformation (horseshoe kidneys).All cases were first described as WS cases. Congenital inner ear malformations were more common, and semicircular malformations were exclusively observed in probands with SOX10 mutations. Unilateral hearing loss occurred more often in cases with PAX3 mutations. CONCLUSION: Our findings helped illuminate the phenotypic and genotypic spectrum of WS in Chinese populations and could contribute to better genetic counseling of WS.

[Progress in diagnosis and treatment of cerebrospinal fluid otorrhea caused by inner ear malformation].

Cerebrospinal fluid otorrhea caused by inner ear malformation is rare, and its clinical manifestations are atypical. Therefore, it can easy be misdiagnosed or missed. Recurrent meningitis caused by inner ear malformation can lead to serious complications. This article reviews the classification of inner ear malformation, the etiology the common fistula locations, clinical features, imaging features, surgical approaches, postoperative complications and influencing factors of surgical efficacy of cerebrospinal fluid otorrhea due to inner ear malformation.

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development.

Waardenburg syndrome (WS) is an autosomal dominant inherited disorder that is characterized by sensorineural hearing loss and abnormal pigmentation. SOX10 is one of its main pathogenicity genes. The generation of patient-specific induced pluripotent stem cells (iPSCs) is an efficient means to investigate the mechanisms of inherited human disease. In our work, we set up an iPSC line derived from a WS patient with SOX10 mutation and differentiated into neural crest cells (NCCs), a key cell type involved in inner ear development. Compared with control-derived iPSCs, the SOX10 mutant iPSCs showed significantly decreased efficiency of development and differentiation potential at the stage of NCCs. After that, we carried out high-throughput RNA-seq and evaluated the transcriptional misregulation at every stage. Transcriptome analysis of differentiated NCCs showed widespread gene expression alterations, and the differentially expressed genes (DEGs) were enriched in gene ontology terms of neuron migration, skeletal system development, and multicellular organism development, indicating that SOX10 has a pivotal part in the differentiation of NCCs. It's worth noting that, a significant enrichment among the nominal DEGs for genes implicated in inner ear development was found, as well as several genes connected to the inner ear morphogenesis. Based on the protein-protein interaction network, we chose four candidate genes that could be regulated by SOX10 in inner ear development, namely, BMP2, LGR5, GBX2, and GATA3. In conclusion, SOX10 deficiency in this WS subject had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. The DEGs most significantly enriched in inner ear development and morphogenesis may assist in identifying the underlying basis for the inner ear malformation in subjects with WS.