Microtia-atresia is a rare craniofacial malformation primarily affecting the first and second pharyngeal arches, leading to the deformity of the auricle and atresia of the external ear canal. Its etiology is heterogenous and largely unknown, including both genetic and environmental factors. The HOXA4 gene has been identified as potentially pathogenetic for microtia-atresia in three twin families. A hoxa4a mosaic knockdown zebrafish model was constructed using CRISPR/Cas9. hoxa4a was expressed in the mandible during early development in zebrafish, while the F0 mosaic knockdowns exhibited craniofacial malformations with abnormal chondrocyte morphologies. Specifically, hoxa4a knockdown reduced cranial neural crest cell proliferation while increasing apoptosis, markedly downregulating chondrogenic markers sox9a and col2a1a. Consequently, pharyngeal arch chondrocytes exhibited disorganized arrangement and morphological abnormalities, resulting in mandibular hypoplasia. Our findings provide important insights into the role of hoxa4a in zebrafish mandibular development and the pathology of microtia-atresia caused by HOXA4 gene mutations in humans.

Treacher Collins syndrome (TCS; OMIM: 154,500) is a rare autosomal dominant craniofacial disorder. POLR1D mutations account for 5

王秋菊: 随着人口老龄化进程的加快,老年性听力损失与认知障碍的共病现象逐渐引起临床与科研领域的高度重视.大量研究提示,听力下降不仅影响老年人沟通能力与生活质量,还可能与认知功能减退呈显著相关,甚至在一定程度上加速痴呆的发生与发展.

Objective: To evaluate outcomes of cochlear implantation (CI) in patients with unilateral sensorineural hearing loss (USNHL) and explore effects and stimulation current in USNHL patients with bony cochlear nerve canal (BCNC) stenosis versus normal cochlear nerve canals. Methods: A prospective study was conducted on 23 USNHL patients who underwent CI (MED-EL) from May 2019 to March 2023. Preoperative CT and MRI scans were performed to measure BCNC width. Subjects were divided into BCNC stenosis (BCNC-S) and BCNC normal (BCNC-N) groups. Hearing thresholds, speech recognition scores (SRS), sound localization ability, and auditory/musical abilities were assessed before and two years after CI. Differences were determined using Stata statistical software, with significance defined as p < .05. Results: Eleven patients were diagnosed with BCNC stenosis. CI significantly improved SRS under noisy conditions (p = .027) and sound localization ability (p < .05), as well as auditory and musical quality (p < .05). No significant differences in outcomes were found between BCNC-S and BCNC-N groups. BCNC-S group had higher stimulation current than BCNC-N group. Conclusions: CI provides similar improvements for USNHL patients with or without BCNC stenosis. Significance: The findings will contribute to the understanding of cochlear implant outcomes in patients with USNHL and BCNC stenosis.

Multimodal remote sensing image registration aligns images from different sensors for data fusion and analysis. However, existing methods often struggle to extract modality-invariant features when faced with large nonlinear radiometric differences, such as those between SAR and optical images. To address these challenges, we propose OSDM-MReg, a novel multimodal image registration framework that bridges the modality gap through image-to-image translation. Specifically, we introduce a one-step unaligned target-guided conditional diffusion model (UTGOS-CDM) to translate source and target images into a unified representation domain. Unlike traditional conditional DDPM that require hundreds of iterative steps for inference, our model incorporates a novel inverse translation objective during training to enable direct prediction of the translated image in a single step at test time, significantly accelerating the registration process. After translation, we design a multimodal multiscale registration network (MM-Reg) that extracts and fuses both unimodal and translated multimodal images using the proposed multimodal fusion strategy, enhancing the robustness and precision of alignment across scales and modalities. Extensive experiments on the OSdataset demonstrate that OSDM-MReg achieves superior registration accuracy compared to state-of-the-art methods.

ObjectiveTo evaluate the role of prenatal ultrasound and three-dimensional ultrasound in the diagnosis of fetal congenital auricular malformations.MethodsThe ultrasonographic features of 14 fetuses diagnosed with auricular malformations at Peking Union Medical College Hospital between May 2019 and May 2024 were retrospectively reviewed, and pregnancy outcomes were followed up.ResultsThe median gestational age at which congenital auricle deformities were detected by ultrasound was 24 weeks 5 days. Of the 14 cases, 5 had bilateral deformities, 5 had right-sided deformities, and 4 had left-sided deformities. The auricular abnormalities detected included microtia, low set ears, accessory auricles, abnormal ear helix and question mark ear, all of which were confirmed by postnatal follow-up or pathological examination after termination. Ten fetuses underwent three-dimensional ultrasound, which provided additional diagnostic details. Eight fetuses presented with other systemic deformities: three had facial deformities such as micrognathia, nasal bone absence, and facial cleft, while five had additional structure anomalies including diaphragmatic hernia, cardiac anomalies, and polydactyly. Genetic testing was performed in nine cases: one fetus had complete trisomy 18, one had Xp22.31 duplication, and seven had normal results. Six pregnancies were electively terminated, while eight fetuses were carried to term. Among the newborns, four had no significant hearing impairment, four others (three with microtia and one with a question mark ear) had hearing loss and required further reconstructive treatment.ConclusionCongenital auricular deformities exhibit characteristic ultrasound features, and in most cases, prenatal diagnosis and evaluation can be achieved through ultrasound. This provides valuable information to support clinical decision-making and prenatal counseling.

Hemifacial microsomia (HFM) is a rare congenital craniofacial deformity that significantly impacts the appearance and hearing. The genetic etiology of HFM remains largely unknown, although genetic factors are considered to be primary contributors. We previously identified CTDSP2 as a potential causative gene in HFM cases. Utilizing CRISPR/Cas9, we knocked out ctdsp2 in zebrafish and analyzed the spatiotemporal expression of ctdsp2 and neural crest cell (NCC) markers through in situ hybridization (ISH). Craniofacial cartilage and chondrocyte phenotypes were visualized using Alcian blue and wheat germ agglutinin (WGA) staining. Cell proliferation and apoptosis were assessed via immunofluorescence with PH3 and TUNEL. RNA sequencing was performed on ctdsp2−/− embryos and control siblings, followed by rescue experiments. Knockout of ctdsp2 in zebrafish resulted in craniofacial defects characteristic of HFM. We observed abnormalities in NCC apoptosis and proliferation in the pharyngeal arches, as well as impaired differentiation of chondrocytes in ctdsp2−/− embryos. RNA-Seq analysis revealed significantly higher expression of genes in the p53 signaling pathway in mutants. Furthermore, ctdsp2 mRNA injection and tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia. Our findings suggest that ctdsp2 knockout induces zebrafish craniofacial dysplasia, primarily by disrupting pharyngeal chondrocyte differentiation and inhibiting NCC proliferation through p53 signaling pathway activation.

Neurofibromatosis type 1(NF1)presents with a diverse range of symptoms that can affect the skin,bones,eyes,central nervous system,and other organs.This article reports the diagnosis and treatment process of a patient with NF1 complicated by bilateral severe-to-profound sensorineural hearing loss.Genetic testing revealed a heterozygous variant of NF1 NM＿000267.3:c.4054＿4058del(p.Ser1352LeufsTer20,sup-porting the diagnosis of NF1.After thorough evaluation,a right cochlear implantation was performed,yielding satisfactory postoperative results.This case suggests that NF1 patients may exhibit phenotypic heterogeneity and atypicality,providing a reference for clinicians in the diagnosis and treatment of such patients.

Zygotic genome activation (ZGA) is a critical biological step in mammalian early embryo development. However, ZGA initiation in sheep and the related sophisticated RNA metabolism remains largely unknown. Here, we observed extensive alterations in gene expression and DNA methylation patterns, along with elevated levels of RNA polymerase II (RNAPII) and its phosphorylation at serine 2 (RNAPII-Ser2P) at the 16-cell stage. Moreover, the embryos were blocked at the 16-cell stage embryo when treated with α-Amanitin, indicating that ZGA is initiated at the 16-cell stage in sheep in vitro fertilized embryos. To uncover the sophisticated RNA metabolism during ZGA, we conducted weighted gene co-expression network analysis and identified 1957 critical maternal genes, including TET3, UHRF1, and KIF2C. Using dapars analysis, we discovered 1058 and 933 lengthened alternative polyadenylation (APA) events during ZGA in sheep and mice. Specifically, genes exhibiting shorten APA were highly expressed at sheep 16-cell stage embryos and mouse 2-cell stage embryos. During ZGA in sheep and mice, 2675 and 1963 genes showed exon skipping, an alternative splicing (AS) events, which is related to RNA binding, translation, gamete generation, and reproduction. Of note, inhibition of AS led to 2-cell block in mice and 8/16-cell block in sheep. Moreover, 5-EU, RNAPII, and RNAPII-Ser2P signal were decreased in AS inhibited 2-cell embryos in mice, suggesting AS might regulate the ZGA process by crosstalk with RNAPII. In conclusion, our data confirmed ZGA initiation at the 16-cell stage embryos, and provides insights into the complex RNA metabolism during ZGA in mammals.

Background: To investigate the characteristics of mismatch negativity (MMN) in terms of latency and amplitude in children with bilateral congenital microtia using a Bone conduction implant (Bonebridge), and to explore the relationship between cortical level auditory discrimination, speech perception, and psychosocial well-being. Methods: This descriptive, observational, cross-sectional study compared three groups: eight children with bilateral congenital microtia and Bonebridge implants (bilateral group), eight children with unilateral congenital microtia and no hearing aids (unilateral group), and eight children with normal hearing (NH group). Participants underwent MMN evaluation using a classic oddball paradigm with a pure tone burst stimulus, featuring a 1000 Hz standard stimulus and a 1200 Hz deviant stimulus, presented in a sound field at 65 dBHL. Additionally, speech perception tests, the Meaningful Use of Speech Scale (MUSS), and psychosocial status questionnaires, including the Social Anxiety Scale for Children (SASC) and the Children's Loneliness Scale (CLS), were administered to all subjects. Results: The bilateral group's average MMN latency was 241.23 f 29.47 ms, and the unilateral group's was 209.96 f 54.32 ms, both significantly longer than the NH group's 146.05 f 15.73 ms (p p < 0.0001, F=3.509, 95 % CI 68.09 to 122.3 and p = 0.0097, F=11.92, 95 % CI 18.07 to 109.8, respectively). However, no significant difference was found in MMN latency between the bilateral and unilateral groups (p p = 0.202, F=3.397, 95 % CI-18.84 to 81.36). The unilateral group scored significantly higher on the MUSS (38.63 f 1.41 vs. 30.75 f 3.80, p = 0.0001, F=7.276, 95 % CI-11.16 to-4.590), had lower CLS scores (47.13 f 8.13 vs. 58.25 f 8.39, p = 0.024, F=1.065, 95 % CI 1.652 to 20.60), and lower SASC scores (4.13 f 2.09 vs. 6.50 f 2.25, p = 0.062, F=1.204, 95 % CI-0.138 to 4.89) compared to the bilateral group. MMN latency in the bilateral group correlated with SASC scores. Conclusion: The MMN latency in congenital microtia patients may serve as an indicator of central auditory discrimination capabilities. In children with bilateral congenital microtia and Bonebridge implants, MMN latency can reflect social anxiety conditions to a certain degree.

Hearing is one of the most vital sensory functions in human beings and a crucial means of perceiving and acquiring information from the natural environment. The advancement of human society is closely linked to the development of language, with hearing serving as the foundation for verbal communication. As individuals age, the deterioration of the auditory system becomes a significant factor contributing to sensory impairments in the elderly. In addition to hearing loss, the aging of the auditory system is also associated with cognitive decline and psychosocial disorders, which severely impact the quality of life for older adults. Currently, there are no effective treatments or interventions available for addressing the aging of the auditory system. Therefore, identifying biomarkers of the auditory system aging is of great significance. The Aging Biomarker Consortium of China has conducted a comprehensive evaluation of aging biomarkers in the auditory system, focusing on three dimensions: morphological, functional, and humoral biomarkers. This initiative aims to establish a foundation for assessing the degree of aging in the auditory system and to promote the management of auditory health in an aging society, ultimately enhancing the auditory health of the elderly population both in China and globally.

Microtia-atresia is a rare type of congenital craniofacial malformation causing severe damage to the appearance and hearing ability of affected individuals. The genetic factors associated with microtia-atresia have not yet been determined. The AMER1 gene has been identified as potentially pathogenic for microtia-atresia in two twin families. An amer1 mosaic knockdown zebrafish model was constructed using CRISPR/Cas9. The phenotype and the development process of cranial neural crest cells of the knockdown zebrafish were examined. Components of the Wnt/β-catenin pathway were examined by qPCR, Western blotting, and immunofluorescence assay. IWR-1-endo, a reversible inhibitor of the Wnt/β-catenin pathway, was applied to rescue the abnormal phenotype. The present study showed that the development of mandibular cartilage in zebrafish was severely compromised by amer1 knockdown using CRISPR/Cas9. Specifically, amer1 knockdown was found to affect the proliferation and apoptosis of cranial neural crest cells, as well as their differentiation to chondrocytes. Mechanistically, amer1 exerted an antagonistic effect on the Wnt/β-catenin pathway. The application of IWR-1-endo could partially rescue the abnormal phenotype. We demonstrated that amer1 was essential for the craniofacial development of zebrafish by interacting with the Wnt/β-catenin pathway. These findings provide important insight into the role of amer1 in zebrafish mandibular development and the pathology of microtia-atresia caused by AMER1 gene mutations in humans.

This study presents a case of a girl of three year and 4 month old with ataxia and severe sensorineural hearing loss for 2 years. In order to improve hearing, she was hospitalized in the PUMC Hospital. Genetic testing performed found compound heterozygous variants of c.1186C > T(p.P396S) and c.1357C > T(p.R453W) in TWNK gene. After a multidisciplinary discussion of the case, the team suspected mitochondrial DNA depletion syndrome type 7(hepatocerebral type). The patient has shown nervous system impairment involvement but no evidence of liver dysfunction. The efficacy of cochlear implantation is uncertain and general anesthesia if applied will accelerate the progress of encephalopathy and might lead to multiple organ failure. Unsure of the perioperative safety, the parents of the girl did not chose the option of hearing intervention temporarily, but chose oral symptomatic supportive treatment with coenzyme Q10, folate, levocarnitine, and complex vitamins as recommended.

HYPOTHESIS:The current study employed a skull-simulator verification method to assess whether the output of softband bone conduction hearing devices (BCHDs) at the manufacturer's default settings deviated widely from the target determined by the fitting formula. BACKGROUND:Real ear analysis is utilized for the verification of the fitting of air conduction hearing devices (ACHDs) in a variety of institutions. This procedure, however, has not been used in the fitting of BCHDs, largely due to the difficulty of testing the output of these devices to temporal bones. Despite the availability of skull simulators, they have not been utilized clinically to measure BCHD output. MATERIALS AND METHODS:This prospective, single-center study enrolled 42 subjects, aged 3 months to 10 years, with microtia-atresia-associated mild-to-severe bilateral conductive hearing loss. Hearing sensitivity was evaluated behaviorally by pure tone audiometry (PTA) in 22 subjects 4 years or older (the PTA group), and by auditory brainstem response (ABR) in 20 subjects younger than 4 years (the ABR group). Following 6 months of subjects wearing the prescribed softband BCHDs, their dial level (DL) thresholds were reassessed while using their own BCHDs, configured with zero gain across all frequencies, functioning solely as a bone vibrator. These DL thresholds were inputted into the fitting formula, desired sensation level-bone conduction devices (DSL-BCD) for children, to obtain the target values of BCHD output. The simulator output of the BCHD programmed at the manufacturer's default setting was measured in response to speech presented at 55, 65, and 80 dB SPL, followed by gain adjustment based on the differences between the simulator output and the target. Aided speech intelligibility index (SII) was measured before and after the gain adjustment. RESULTS:The softband BCHDs at the manufacturer's settings generally had lower output than the prescribed target values. This difference was larger at low frequencies and low levels. Across the 12 points tested (four frequencies from 500 to 4000 Hz multiplied by three levels), 22 (52.3%) and 42 (100%) BCHDs had deviations of +7 and +5 dB, respectively, at one point or more. The gain adjustments reduced the deviation and improved the SII values at the two lower levels of speech presented. CONCLUSION:The simulator output of softband bone conduction hearing devices (BCHDs) with the manufacturer's settings may exhibit significant deviations from the formula. Objective output verification should be considered a beneficial step in BCHD fitting and is recommended when applicable.

Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. CDC27 was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of CDC27. cdc27 knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in cdc27−/− mutants. cdc27 mRNA injections and cdkn1a or tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia, while sox9a mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between CDC27 and HFM, primarily through the inhibition of CNCC proliferation and disruption of pharyngeal chondrocyte differentiation.

Goldenhar syndrome, a rare craniofacial malformation, is characterized by developmental anomalies in the first and second pharyngeal arches. Its etiology is considered to be heterogenous, including both genetic and environmental factors that remain largely unknown. To further elucidate the genetic cause in a five-generation Goldenhar syndrome pedigree and exploit the whole-exome sequencing (WES) data of this pedigree, we generated collapsed haplotype pattern markers based on WES and employed rare variant nonparametric linkage analysis. FBLN2 was identified as a candidate gene via analysis of WES data across the significant linkage region. A fbln2 knockout zebrafish line was established by CRISPR/Cas9 to examine the gene's role in craniofacial cartilage development. fbln2 was expressed specifically in the mandible during the zebrafish early development, while fbln2 knockout zebrafish exhibited craniofacial malformations with abnormal chondrocyte morphologies. Functional studies revealed that fbln2 knockout caused abnormal chondrogenic differentiation, apoptosis, and proliferation of cranial neural crest cells (CNCCs), and downregulated the bone morphogenic protein (BMP) signaling pathway in the zebrafish model. This study demonstrates the role of FBLN2 in CNCC development and BMP pathway regulation, and highlights FBLN2 as a candidate gene for Goldenhar syndrome, which may have implications for the selection of potential screening targets and the development of treatments for conditions like microtia-atresia.

Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder, typically inherited as an autosomal dominant condition. Here, we report on a family in which germline mosaicism for TCS was likely present. The proband was diagnosed with TCS based on the typical clinical features and a pathogenic variant TCOF1 (c.4369_4373delAAGAA, p.K1457Efs*12). The mutation was not detected in his parents' peripheral blood DNA samples, suggesting a de novo mutation had occurred in the proband. However, a year later, the proband's mother became pregnant, and the amniotic fluid puncture revealed that the fetus carried the same mutation as the proband. Prenatal ultrasound also indicated a maxillofacial dysplasia with unilateral microtia. The mother then disclosed a previous birth history in which a baby had died of respiratory distress shortly after birth, displaying a TCS-like phenotype. Around the same time, the proband's father was diagnosed with mild bilateral conductive hearing loss. Based on array data, we concluded that the father may have had germline mosaicism for TCOF1 mutation. Our findings highlight the importance of considering germline mosaicism in sporadic de novo TCOF1 mutations when providing genetic consulting, and prenatal diagnosis is important when the proband's parents become pregnant again.

Hereditary deafness is a common neurosensory disorder, and 148 non-syndromic deafness genes have been identified to date. Gene therapy has been used to treat a variety of genetic diseases, but no gene therapy drug for hereditary deafness has been approved for clinical use. At present, several clinical trials of gene therapy for hereditary deafness are underway. However, few normative documents have been issued to guide the standardization of gene therapy for hearing loss, and this document is the first global gene therapy guideline for hereditary hearing loss. The guidelines were jointly developed and drafted by experienced audiologists, virologists and biologists who are vigorously involved in inner ear gene therapy research in the Hearing, Speech and Communication Subsociety of Biophysical Society of China, Audiology Development Foundation Of China and Audiology Subsociety of Jiangsu Medical Association. These guidelines cover preclinical research and clinical practice of gene therapy for hereditary deafness, including indications, key points of pre-clinical research, patient selection criteria, pre-clinical preparation, drug efficacy, drug safety evaluation criteria, ethical review, etc. We hope that the guidelines will promote the standardization of clinical practice related to gene therapy for hereditary deafness in China and around the world.

The aim of this study was to compare the outcomes of different mapping procedures based on anatomic or default frequency distribution in postlingual deafness adults who underwent cochlear implantation (CI). Forty-eight adults with postlingual deafness who underwent CI (MED-EL) from January 2021 to May 2022 in our hospital were prospectively recruited. The participants were randomly assigned to two groups (the anatomic group and the default group). Postoperative computerized tomography (CT) scans were evaluated with Otoplan® to determine the angular insertion depth (AID) and the specific locations of the intracochlear electrodes. Anatomic maps were imported into MAESTRO 9.0 software (MED-EL) for anatomy-based fitting for anatomic group, while default mapping program was set up for the default group. Hearing thresholds, Speech Recognition Scores (SRS), and subjects’ auditory and musical abilities were evaluated 1 year after using the CI. Differences were determined in two groups using Stata statistical software, with significance defined as p < 0.05. SRS under noisy conditions was significantly greater for anatomic group than the default group (p = 0.02). Under quiet conditions, however, mean hearing thresholds (0.5, 1, 2, and 4 kHz) and SRS did not differ significantly between the two groups (p = 0.07). Modified questionnaires showed that auditory (p = 0.02) and musical (p = 0.01) quality were significantly better following the anatomic mapping than the default procedure. CI program based on the anatomic distribution may bring better SRS under noise conditions as well as better auditory and musical qualities than based on the default frequency distribution.

Zygotic genome activation (ZGA) is critical for early embryo development and is meticulously regulated by epigenetic modifications. H3K4me3 is a transcription-permissive histone mark preferentially found at promoters, but its distribution across genome features remains incompletely understood. In this study, we investigated the genome-wide enrichment of H3K4me3 during early embryo development and embryonic stem cells (ESCs) in both sheep and mice. We discovered that broad H3K4me3 domains were present in MII stage oocytes and were progressively diminished, while promoter H3K4me3 enrichment was increased and correlated with gene upregulation during ZGA in sheep. Additionally, we reported the dynamic distribution of H3K4me3 at the transposable elements (TEs) during early embryo development in both sheep and mice. Specifically, the H3K4me3 distribution of LINE1 and ERVL, two subsets of TEs, was associated with their expression during early embryo development in sheep. Furthermore, H3K4me3 enrichment in TEs was greatly increased during ZGA following Kdm5b knockdown, and the distribution of RNA polymerase II (Pol2) in TEs was also markedly increased in Kdm5b knockout ESCs in mice. These findings suggest that H3K4me3 plays important roles in regulating TE expression through interaction with RNA Pol2, providing valuable insights into the regulation of ZGA initiation and cell fate determination by H3K4me3.