Xinmiao Fan

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.

Cellular senescence is a hallmark of aging characterized by a permanent state of cell cycle arrest, accompanied by various molecular and cellular changes that disrupts tissue and organ homeostasis. This disruption contributes to the development and progression of numerous chronic diseases, including age-related hearing loss (ARHL), which is defined as a gradual and irreversible hearing impairment resulting from cochlear aging. Among the many changes associated with biological aging, ARHL ranks among the top three chronic conditions affecting older individuals, leading to communication difficulties, social isolation, depression, and cognitive decline. Notably, targeting cellular senescence has shown significant promise in extending lifespan; however, the relationship between age-related diseases, particularly ARHL, remains to be fully elucidated. In this discussion, we explore the hallmarks of cellular senescence, and highlights its impacts on peripheral presbycusis.

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.

Treacher Collins syndrome (TCS, OMIM 154500) is an autosomal disorder of craniofacial development with an incidence rate of 1/50,000 live births. Although TCOF1, POLR1D, and POLR1C, have been identified as the pathogenic genes for about 90% TCS patients, the pathogenic variants of about 8–11% cases remain unknown. The object of this study is to describe the molecular basis of 14 clinically diagnosed TCS patients from four families using Whole-exome sequencing (WES) followed by Sanger sequencing confirmation, and to analyze the effect of bone conduction hearing rehabilitation in TCS patients with bilateral conductive hearing loss. Four previously unreported heterozygous pathogenic variants (c.3047-2A > G, c.2478 + 5G > A, c.489delC, c.648delC) were identified in the TCOF1 gene, one in each of the four families. Sanger sequencing in family members confirmed co-segregation of the identified TCOF1 variants with the phenotype. The mean pure-tone threshold improvements measured 3 months after hearing intervention were 28.8 dB for soft-band BAHA, 36.6 ± 2.0 dB for Ponto implantation, and 27.5 dB SPL for Bonebridge implantation. The mean speech discrimination improvements measured 3 months after hearing intervention in a sound field with a presentation level of 65 dB SPL were 44%, 51.25 ± 5.06, and 58%, respectively. All six patients undergoing hearing rehabilitation in this study got a satisfied hearing improvement. WES combined with Sanger sequencing enables the molecular diagnosis of TCS and may detect other unknown causative genes. Bone conduction hearing rehabilitation may be an optimal option for TCS patients with bilateral conductive hearing loss.

Microtia-atresia is characterized by abnormalities of the auricle (microtia) and aplasia or hypoplasia of the external auditory canal, often associated with middle ear abnormalities. To date, no causal genetic mutations or genes have been identified in microtia-atresia patients. We designed a panel of 131 genes associated with external/middle or inner ear deformity. Targeted genomic capturing combined with next-generation sequencing (NGS) was utilized to screen for mutations in 40 severe microtia-atresia patients. Mutations detected by NGS were filtered and validated. And then mutations were divided into three categories—rare or novel variants, low-frequency variants and common variants—based on their frequency in the public database. The rare or novel mutations were prioritized by pathogenicity analysis. For the low-frequency variants and common variants, we used association studies to explore risk factors of severe microtia-atresia. Sixty-five rare heterozygous mutations of 42 genes were identified in 27 (67.5%) severe microtia-atresia patients. Association studies to determine genes that were potentially pathogenic found that PLEC, USH2A, FREM2, DCHS1, GLI3, POMT1 and GBA genes were significantly associated with severe microtia-atresia. Of these, DCHS1 was strongly suggested to cause severe microtia-atresia as it was identified by both low-frequency and common variants association studies. A rare mutation (c.481C > T, p.R161C) in DCHS1 identified in one individual may be deleterious and may cause severe microtia-atresia. We identified several genes that were significantly associated with severe microtia-atresia. The findings provide new insights into genetic background of external ear deformities.