RESUMO
TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.
Assuntos
Estudos de Associação Genética , Perda Auditiva , Proteínas de Membrana , Serina Endopeptidases , Humanos , Feminino , Masculino , Serina Endopeptidases/genética , Adulto , Proteínas de Membrana/genética , Perda Auditiva/genética , Criança , Pessoa de Meia-Idade , Adolescente , Pré-Escolar , Genótipo , Estudos de Coortes , Fenótipo , Mutação de Sentido Incorreto , Estudos Transversais , Adulto Jovem , Estudos Retrospectivos , Idoso , Proteínas de NeoplasiasRESUMO
INTRODUCTION: A chronically discharging modified radical mastoid cavity may require surgical intervention. We aim to explore two techniques. OBJECTIVE: To compare outcomes of subtotal petrosectomy (STP) and canal wall reconstruction with bony obliteration technique (CWR-BOT). STUDY DESIGN: Retrospective cohort study. SETTING: A tertiary referral center. PATIENTS: All patients with a chronically discharging mastoid cavity surgically treated at the Radboud University Medical Center by STP or CWR-BOT in 2015 to 2020, excluding patients with preoperative cholesteatoma. MAIN OUTCOME MEASURES: Dry ear rate, audiometry, and rehabilitation. SECONDARY OUTCOME MEASURES: Healing time, number of postoperative visits, complications, cholesteatoma, and need for revision surgeries. RESULTS: Thirty-four (58%) patients underwent STP, and 25 (42%) CWR-BOT. A dry ear was established in 100% of patients (STP) and 87% (CWR-BOT). The air-bone gap (ABG) increased by 12 dB in STP, and decreased by 11 dB in CWR-BOT. Postoperative ABG of CWR-BOT patients was better when preoperative computed tomography imaging showed aerated middle ear aeration. ABG improvement was higher when ossicular chain reconstruction took place. Mean follow-up time was 32.5 months (STP) versus 40.5 months (CWR-BOT). Healing time was 1.2 months (STP) versus 4.1 months (CWR-BOT). The number of postoperative visits was 2.5 (STP) versus 5 (CWR-BOT). Cholesteatoma was found in 15% (STP) versus 4% (CWR-BOT) of patients. Complication rate was 18% (STP) and 24% (CWR-BOT) with a need for revision in 21% (STP) and 8% (CWR-BOT), including revisions for cholesteatoma. CONCLUSION: STP and CWR-BOT are excellent treatment options for obtaining a dry ear in patients with a chronically discharging mastoid cavity. This article outlines essential contributing factors in counseling patients when opting for one or the other. Magnetic resonance imaging with diffusion-weighted imaging follow-up should be conducted at 3 and 5 years postoperatively.