目的：通过高通量测序分析进行基因诊断，鉴别视网膜病变中的神经纤维瘤病，为其早诊早治提供重要依据。方法：回顾性分析眼遗传病高通量测序数据库中的NF1和NF2基因变异，根据ACMG/AMP指南解析变异致病性；进一步结合患者的临床表型、家族史以及其他检查结果，综合判断明确是否患有神经纤维瘤病，同时进行疾病的进展和随访的研究分析。结果：通过分析不同眼部表型家系的高通量测序结果，共在11例先证者中发现NF1和NF2基因的10个可能致病变异，包括7个NF1变异和3个NF2变异。这11例先证者的初始诊断包括家族性渗出性玻璃体视网膜病变、黄斑/视网膜发育不良、斜视、视网膜色素变性、Coats病和牵牛花综合征等。其中，在1例初诊为家族性渗出性玻璃体视网膜病变的患儿中，检测到3个基因的致病变异，即NF2: c.122G>A/p.(W41*)、RS1: c.520C>T/p.(R174W)和NYX: c.1027C>T/p.(R343C)。随访检查发现，该患儿的复杂眼部表型符合NF2、RS1和NYX致病变异的临床改变，且MRI检查发现双侧前庭神经鞘瘤、脊髓室管膜瘤和多发性神经鞘瘤改变。除该患者外，还有4例患者在随访中发现存在牛奶咖啡斑或雀斑样色素沉着等皮肤改变，1 例合并小脑神经纤维瘤浸润。结论: 高通量测序分析能有效检测出神经纤维瘤病相关基因的变异，有助于筛选非典型表现的神经纤维瘤病，为疾病的早期诊断，尤其是对严重中枢神经系统病变的早期筛查和及时干预，提供了重要依据。

Objective: To identify neurofibromatosis in retinopathy through high-throughput sequencing analysis and provide important indicators for early diagnosis and treatment. Methods: Variants in NF1 and NF2 were selected from in-house high-throughput sequencing, including targeted exome sequencing, exome sequencing and whole genome sequencing, of individuals with different eye conditions. Pathogenic or likely pathogenic variants were assessed according to ACMG/AMP criteria. All the available clinical data, including clinical manifestation, family history and other examination results, were summarized and further analyzed to determine whether neurofibromatosis. Results: Based on the results of in-house high-throughput sequencing, a total of ten pathogenic or likely pathogenic variants in NF1 and NF2 were identified in 11 unrelated cases with various eye conditions, including three NF2 variants in four cases and seven NF1 variants in seven cases. The unrelated cases with NF1 and NF2 variants had initial clinical manifestation similar to familial exudative vitreoretinopathy (FEVR), macular or retinal dystrophy, strabismus, retinitis pigmentosa, Coats disease, or morning glory syndrome. In one of these cases, who was diagnosed as FEVR at the initial visit, three pathogenic variants of three different genes were identified, namely NF2: c.122G>A/p.(W41*), RS1: c.520C>T/p.(R174W) and NYX: c.1027C>T/p.(R343C). Follow-up examination on this case revealed a complex retinopathy, which were consistent with clinical presentations due to pathogenic variants in NF2, RS1, and NYX, as well as bilateral vestibular schwannomas, spinal ependymoma and multiple schwannomas by MRI. In addition to this patient, a follow-up examination on four of the seven cases present Café-au-lait macules or freckling, which could be easily neglected if neurofibromatosis is not realized on the initial visit, while one had neurofibromatosis in cerebellum. Conclusions: Complex retinopathy may present as the initial sign of neurofibromatosis, and high-throughput sequencing analysis for neurofibromatosis related genes contribute to early diagnosis of neurofibromatosis and facilitating early identification of vital systemic complication.

目的：回顾2型神经纤维瘤病(neurofibromatosis type 2, NF2)患者的眼部表现，分析NF2眼部病变的临床和影像学特征，以助该病的早期诊断。方法：收集来自深圳市眼科医院的1例和来自中山眼科中心的3例NF2患者完整的临床资料并进行总结分析。结果：这4例患者均因眼部异常首诊于眼科且符合曼彻斯特诊断标准。4例患者中，3例为NF2早发型(<20岁)，1例为晚发型(>20岁)，男女比例1∶1。3例患者因视力下降、1例患者因复视首诊于眼科。3例行眼底光学相干断层成像(optical coherence tomography, OCT)检查显示，视网膜错构瘤2例，视网膜前膜2例，视盘隆起2例，视网膜神经纤维层和节细胞层变薄1例。其他表现包括麻痹性斜视2例，复视1例，白内障1例，球后段视神经增粗1例，眼眶肿瘤1例。结论：NF2的眼部表现多种多样，可出现在神经症状和听力损失之前。详细的眼科检查及影像学检查对年轻患者的早期诊断非常有价值，有助于选择更好的治疗计划。

Objective: Review the ocular manifestations of patients with neurofibromatosis type 2 (NF2), and analyze the clinical and imaging features of the ocular lesions in NF2, so as to facilitate the early diagnosis of this disease. Methods: The complete medical records of 1 case from Shenzhen Eye Hospital and 3 cases of NF2 from Zhongshan Ophthalmic Center were collected. Results: All four patients were first diagnosed in ophthalmology due to eye symptoms and met the Manchester diagnostic criteria. Of the four patients, three were NF2 early hairstyles (<20 years old), one was late hairstyle (>20 years old), and the male-to-female ratio was 1:1. Three patients were first diagnosed in the ophthalmology department due to decreased visual acuity, and one patient was first diagnosed due to diplopia. Optical coherence tomography (OCT) examinations were performed on three patients, which showed that there were two cases of retinal hamartoma, two cases of epiretinal membrane, two cases of optic disc elevation, and one case of thinning of the retinal nerve fiber layer and ganglion cell layer. Other manifestations included two cases of paralytic strabismus, one case of diplopia, one case of cataract, one case of thickening of the retrobulbar optic nerve, and one case of orbital tumor. Conclusions: The ocular manifestations of NF2 are diverse and can precede neurological symptoms and hearing loss. Detailed ophthalmic examinations and imaging studies are highly valuable for early diagnosis in young patients, aiding in the selection of a better treatment plan.