Al-Asad Reef K, Montigny Drew J, O'Malley Jennifer T, Welling D Bradley, Jung David H, Eckhard Andreas H, Kempfle Judith S
The Eaton-Peabody Laboratories, The Massachusetts Eye and Ear Department of Otolaryngology - Head and Neck Surgery, Boston, MA, United States.
University of Massachusetts Chan Medical School, Worcester, MA, United States.
Front Neurol. 2025 Aug 15;16:1650470. doi: 10.3389/fneur.2025.1650470. eCollection 2025.
Sensorineural hearing loss (SNHL) is a hallmark symptom in patients with neurofibromatosis type 2-associated schwannomatosis (NF2-SWN), a genetic condition caused by mutations in the Neurofibromin II gene that encodes the tumor suppressor protein Moesin-Ezrin-Radixin-Like Protein (Merlin; also known as schwannomin). These mutations lead to the development of various tumors, including schwannomas, ependymomas and meningiomas along the vestibular nerve and the cerebellopontine angle. Original theories attributed SNHL in NF2-SWN to the mechanical compression of the vestibulocochlear nerve from the tumor itself, in addition to secretion of toxic tumor byproducts. However, the observation that SNHL can progress independently of tumor size and growth dynamics challenges this view and reveals a critical gap in our understanding of its underlying etiology. To better define cochlear changes associated with hearing loss in NF2-SWN, immunohistochemical cell type markers were used on archival postmortem temporal bone samples from both NF2-SWN patients and healthy controls and quantified the number and cellular density of neural (TUJ1), glial (SOX10), and immune cells (IBA1) within apical, middle, and basal turns of the cochlea. Our findings demonstrated a significant loss of spiral ganglion neurons, a slight increase of Schwann cells, and marked activation of cochlear macrophages in NF2-SWN cases. These findings indicate the contribution of cochlear macrophage-mediated inflammation and Schwann cell dysregulation in the pathophysiology of SNHL in NF2-SWN.
感音神经性听力损失（SNHL）是2型神经纤维瘤病相关的神经鞘瘤病（NF2-SWN）患者的标志性症状，NF2-SWN是一种由神经纤维瘤蛋白II基因突变引起的遗传性疾病，该基因编码肿瘤抑制蛋白膜突蛋白-埃兹蛋白-根蛋白样蛋白（Merlin；也称为神经鞘瘤蛋白）。这些突变导致各种肿瘤的发生，包括沿前庭神经和桥小脑角的神经鞘瘤、室管膜瘤和脑膜瘤。最初的理论认为，NF2-SWN中的SNHL除了肿瘤分泌有毒副产物外，还归因于肿瘤本身对前庭蜗神经的机械压迫。然而，SNHL可独立于肿瘤大小和生长动态而进展这一观察结果挑战了这一观点，并揭示了我们对其潜在病因理解上的关键差距。为了更好地定义与NF2-SWN听力损失相关的耳蜗变化，我们对NF2-SWN患者和健康对照的存档尸检颞骨样本使用免疫组化细胞类型标记物，并对耳蜗顶回、中回和底回内的神经细胞（TUJ1）、神经胶质细胞（SOX10）和免疫细胞（IBA1）的数量和细胞密度进行了量化。我们的研究结果表明，NF2-SWN病例中螺旋神经节神经元显著减少，雪旺细胞略有增加，耳蜗巨噬细胞明显激活。这些发现表明，耳蜗巨噬细胞介导的炎症和雪旺细胞失调在NF2-SWN的SNHL病理生理学中起作用。
