Importance Familial exudative vitreoretinopathy (FEVR) is a nonsyndromic autosomal dominant retinal disorder commonly caused by variants in the FZD4 gene. This study investigates the potential role beyond ocular abnormalities for FZD4 gene variants in patients with FEVR. Objective To evaluate the role of FZD4 in symptoms beyond those associated with FEVR through a patient with biallelic variants in FZD4. Design, Setting, and Participants This case series included the DNA testing and phenotyping of 1 patient proband and her parents, combined with signaling assays, to determine the association of patient-derived compound heterozygous variants on FZD4 signaling and biologic function. Main Outcomes and Measures FZD4 genes were tested using next-generation sequencing and Sanger sequencing. Cell-based assays measured the effect of the variants on FZD4 signaling. Results The proband presented with absent red reflexes from complete tractional retinal detachments diagnosed at 3 days of age and failed the newborn screening hearing test. Auditory brainstem response at 6 months of age showed bilateral mild to moderate high-frequency sensorineural hearing loss. The patient manifested developmental delays in speech and walking. Intravenous fluorescein angiography (IVFA) of the patient's parents detected stage 1 FEVR. Genetic testing revealed 2 FZD4 variants in the patient, each variant found in 1 parent. Signaling assays confirmed that the presence of both variants was associated with significantly worse signaling activity compared with the heterozygous state. Conclusions and Relevance Results of this case series suggest that extraocular syndromic FEVR was associated with FZD4 variants. The decrease in FZD4 signaling owing to the biallelic nature of the disease resulted in hearing deficits, developmental delays, and a more severe retinal phenotype.

中文翻译：

---

FZD4 双等位基因变异儿童的严重家族性渗出性玻璃体视网膜病变、先天性听力损失和发育迟缓。

重要性 家族性渗出性玻璃体视网膜病变 (FEVR) 是一种非综合征性常染色体显性遗传的视网膜疾病，通常由 FZD4 基因的变异引起。本研究调查了 FZD4 基因变异在 FEVR 患者眼部异常之外的潜在作用。目的通过 FZD4 双等位基因变异的患者评估 FZD4 在 FEVR 相关症状之外的症状中的作用。设计、设置和参与者 本案例系列包括 1 名患者先证者及其父母的 DNA 检测和表型分析，并结合信号分析，以确定患者衍生的复合杂合变体与 FZD4 信号传导和生物学功能的关联。主要结果和措施 FZD4 基因使用下一代测序和 Sanger 测序进行测试。基于细胞的测定测量了变体对 FZD4 信号传导的影响。结果 先证者在 3 日龄时诊断为完全牵引性视网膜脱离，红色反射消失，新生儿听力测试未通过。6 个月大时的听觉脑干反应显示双侧轻度至中度高频感音神经性听力损失。患者表现出言语和行走发育迟缓。患者父母的静脉内荧光素血管造影 (IVFA) 检测到 1 期 FEVR。基因检测显示患者体内有 2 个 FZD4 变体，每个变体在 1 个父母中发现。信号分析证实，与杂合状态相比，两种变体的存在与显着更差的信号活性相关。结论和相关性 该病例系列的结果表明，眼外综合征 FEVR 与 FZD4 变异相关。由于该疾病的双等位基因性质，FZD4 信号传导的减少导致听力缺陷、发育迟缓和更严重的视网膜表型。