Lin R Jun, Zeng Peter Y F, Fung Kevin, Khan Halema, Cecchini Matthew J, Woo Elissa, Hu Amanda, Anderson Jennifer, MacInnis Patrick, Karimi Amir, Ying Shengjie, Al Jawhri MohdWessam, Lin Sherman, Jarycki Laura, Shaikh Mushfiq H, Pan Harrison, Coburn Bryan, Mymryk Joe S, Inculet Richard, Barrett John W, Nichols Anthony C
Department of Otolaryngology - Head & Neck Surgery, Temerty Faculty of Medicine, University of Toronto, Unity Health Toronto, St. Michael's Hospital, Toronto, Ontario, Canada.
Department of Otolaryngology - Head & Neck Surgery, Western University, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
EBioMedicine. 2025 Apr;114:105629. doi: 10.1016/j.ebiom.2025.105629. Epub 2025 Mar 5.
First described in 1972, idiopathic subglottic stenosis (iSGS) is a serious chronic orphan disease characterised by recurrent scarring of the subglottis. Although the cause is unknown, iSGS is almost exclusively restricted to Caucasian females typically in their fourth to sixth decade. However, given its rare incidence (1:400,000), understanding the clinical trajectory and molecular factors associated with iSGS disease development and prognosis has been difficult. In the current study we sought to unravel the pathogenesis of iSGS at the clinical, transcriptional, and genetic level in a prospective cohort.
We prospectively enrolled 126 patients with iSGS, 104 controls, and 13 patients with traumatic SGS. Within this cohort, we profiled 114 human epiglottis and 121 human subglottis biopsies across three different conditions: control, iSGS, and intubation-related traumatic stenosis using bulk and single nucleus RNA-sequencing. Whole exome sequencing for germline variants was performed for 70 controls and 75 patients with iSGS.
Patients with iSGS received a median number of five (range 0-18) surgical dilations at a rate of 1.031 dilations (range: 0.12-6.2) per year. Older age at diagnosis and higher Cotton-Myers grade were associated with increased number of surgical dilations over time. Cohort-level bulk transcriptomics found that iSGS pathology was restricted within the subglottis and did not affect anatomically adjacent epiglottis, opposite to previous hypotheses. We further identified cellular subsets associated with iSGS prognosis and severity. Finally, patients with iSGS exhibit lower testosterone predicted using a polygenic score.
Together, our data refines our understanding of laryngeal biology and provides insights into the clinical trajectory of subglottic stenoses. Future research should explore the role of testosterone in the development of iSGS.
This study was funded by a grant from the American Laryngology Association (#1082), an Academic Medical Organization of Southwestern Ontario innovation fund grant (INN21-016), grant support from the Departments of Otolaryngology-Head and Neck Surgery at University of Toronto and Western University. ACN was supported by the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers Fund. PYFZ was supported by a Vanier Canada Graduate Scholarship and PSI foundation fellowship.
特发性声门下狭窄（iSGS）于1972年首次被描述，是一种严重的慢性罕见病，其特征为声门下反复瘢痕形成。尽管病因不明，但iSGS几乎仅见于高加索女性，通常为40至60岁。然而，鉴于其罕见的发病率（1:400,000），了解与iSGS疾病发展和预后相关的临床病程及分子因素一直很困难。在本研究中，我们试图在前瞻性队列中从临床、转录和基因水平揭示iSGS的发病机制。
我们前瞻性纳入了126例iSGS患者、104例对照者和13例创伤性声门下狭窄患者。在这个队列中，我们对114例人类会厌和121例人类声门下活检样本进行了三种不同状态下的分析：对照、iSGS以及插管相关创伤性狭窄，采用批量和单核RNA测序技术。对70例对照者和75例iSGS患者进行了种系变异的全外显子测序。
iSGS患者接受手术扩张的中位数为5次（范围0 - 18次），每年手术扩张率为1.031次（范围：0.12 - 6.2次）。诊断时年龄较大以及Cotton - Myers分级较高与随时间推移手术扩张次数增加相关。队列水平的批量转录组学研究发现，iSGS病变局限于声门下，并未影响解剖学上相邻的会厌，这与之前的假设相反。我们进一步确定了与iSGS预后和严重程度相关的细胞亚群。最后，使用多基因评分预测，iSGS患者的睾酮水平较低。
总之，我们的数据完善了我们对喉生物学的理解，并为声门下狭窄的临床病程提供了见解。未来的研究应探索睾酮在iSGS发病中的作用。
本研究由美国喉科学会（#1082）、安大略西南部学术医学组织创新基金资助（INN21 - 016）、多伦多大学和西安大略大学耳鼻咽喉 - 头颈外科系的资助支持。ACN得到了头颈癌生物学沃尔夫外科研究教授基金的支持。PYFZ得到了加拿大瓦尼尔研究生奖学金和PSI基金会奖学金的支持。
