Supplementary Material for: High Prevalence of Hearing Impairment in Primary Congenital Hypothyroidism

<b><i>Background:</i></b> An association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation. <b><i>Methods:</i></b> Audiometry was undertaken prospectively in 66 patients aged 3–21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies. <b><i>Results:</i></b> HI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT₄) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT₄ levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 μg/dL, <i>p</i> = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies. <b><i>Conclusions:</i></b> Our findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT₄ therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.

<b><i>研究背景：</i></b> 听力损伤（hearing impairment, HI）与先天性甲状腺功能减退症（congenital hypothyroidism, CH）之间的关联既往已有报道。然而，此类研究多为回顾性研究且样本量较小，研究结果存在异质性且结论尚不明确。本研究旨在评估CH患者群体中HI的患病率，并探究可能预测HI发生的相关因素，包括CH的严重程度、病因以及治疗启动时机。
<b><i>研究方法：</i></b> 本研究前瞻性纳入66名3~21岁确诊为原发性CH的患者，以及49名匹配的健康对照者，对所有受试者行纯音测听（audiometry）检查。所有确诊HI的患者均接受耳鼻喉科专科查体；对于存在感音神经性听力损失的患者，进一步行脑干听觉诱发电位测听（brainstem evoked response audiometry）。针对存在感音神经性HI的患者，采用耳聋相关基因二代测序（next-generation sequencing, NGS）检测panel进行检测，以排除其他潜在遗传病因。
<b><i>研究结果：</i></b> 本研究中19名CH患者（占比28.7%）合并HI。其中5例（7.6%）为中至重度双侧感音神经性听力损伤，14例（21.2%）为轻度传导性HI。14例传导性HI患者中，5例（36%）为双侧病变。所有对照者均未出现HI。合并HI与未合并HI的CH患者在确诊年龄、左甲状腺素（levothyroxine, LT₄）启动治疗年龄、性别及种族方面均无显著差异。HI患者的筛查总甲状腺素（total thyroxine, TT₄）平均水平较非HI患者呈降低趋势（3.42 μg/dL vs. 5.34 μg/dL），但差异未达统计学显著性（p=0.095）。对5例感音神经性耳聋患者行NGS检测，未发现与HI相关的致病基因变异，提示此类患者的HI可能由CH导致，而非其他遗传病因。
<b><i>研究结论：</i></b> 本研究结果显示，CH患者群体中HI的患病率较高，且以传导性听力损伤为主。HI的发生与CH的病因以及LT₄治疗启动延迟均无关联。建议对确诊CH的儿童行纯音测听检查，并可考虑进行定期复查，以早期发现获得性HI，避免未确诊耳聋带来的长期后遗症。