家族性渗出性玻璃体视网膜病变临床表型的相关因素分析

Analysis of factors affecting the clinical features of familial exudative vitreoretinopathy

目的观察并分析家族性渗出性玻璃体视网膜病变(FEVR)不同临床表型的相关因素。方法回顾性系列病例研究。2012年1月至2021年12月于北京大学人民医院眼科检查确诊的FEVR患者42例84只眼以及家系中一级亲属68名纳入研究。患者来自42个无血缘关系家庭。患者中,男性31例,女性11例;首诊年龄(16.6±33.7)个月。外院转诊21例,均为眼底筛查发现病变;首诊本院21例。早产儿、足月儿分别为4、38例。有FEVR阳性家族史2例。均为FEVR分期1~5期。年龄<5岁者,全身麻醉后广角数码儿童视网膜成像系统行荧光素眼底血管造影(FFA)检查;≥5岁者,行常规FFA检查。来自28个家系的一级亲属68名均行常规眼底检查及FFA检查。行基因检测26个家系,其中先证者26例,一级亲属57名。对已知参与FEVR的基因共受体低密度脂蛋白受体相关蛋白5(LRP5)、Wnt受体卷曲蛋白4(FZD4)、Norrie病(NDP)、四旋蛋白12(TSPAN12)、连环蛋白β1(CTNNB1)基因进行高通量测序和分子遗传学分析。观察患者临床表现及FEVR的基因型与临床表型相关性。结果42例中,首诊症状为斜视及眼球震颤13例,中位年龄12个月;不追物或视力相关症状8例。84只眼中,FEVR分期1期或2期、3期或4期、5期分别为50(59.5%,50/84)、31(36.9%,31/84)、3(3.6%,3/84)只眼。首诊年龄>3个月的23例中,至少1只眼病变分期为3期以上16例(69.6%,16/23)。行眼底检查的68名一级亲属中,眼底FEVR样改变22名(32.4%,22/68)。行基因检测的26个家系中,检出FEVR相关基因的16种变异13个家系(50%,13/26),其中LRP5基因突变10种,最常见。单基因突变10个家系,其中LRP5、FZD4、CTNNB1基因分别为6、2、2个家系;LRP5基因复合杂合突变1个家系;LRP5基因和NDP双基因突变1个家系;LRP5和TSPAN12双基因突变1个家系。携带致病性FEVR基因13例先证者中,双眼病变程度一致者6例,不一致者7例,基因突变和临床表型之间未见明显相关性。结论FEVR临床表型和基因型具有高度异质性;除首诊年龄外,未发现明确影响FEVR临床表现的因素。

Objective To observe and investigate the related factors that might affect clinical features of familial exudative vitreoretinopaty(FEVR)patients.Methods A retrospective chart study.From January 2012 and December 2021,42 patients with 84 eyes with a diagnosis of FEVR from Department of Ophthalmology,Peking University People's Hospital were included in the study.The patients came from 42 separate families.There were 31 males and 11 females,with an average age of first diagnosis was 16.6±33.7 months.There were 21 patients referred from other hospitals for the fundus disease found in eye screening after birth,21 patients were first seen in our hospital.There were 4 and 38 premature and full-term infants,respectively.Two patients with a positive family history of FEVR.All patients are FEVR stages 1-5.The wide-angle digital pediatric retinal imaging system after general anesthesia for fluorescein fundus angiography(FFA)examination were performed for patients aged<5 years.If patients≥5 years old,routine FFA examination was performed.Sixty-eight first-degree relatives from 28 families undergo routine fundus examinations and FFA examination.Genetic examination was performed for 26 families,including 26 probands and 57 first-degree relatives.Genetic examination were performed on gene the coreceptor of low density lipoprotein receptor-associated protein 5(LRP5),Wnt receptor coiled protein 4(FZD4),Norrie disease(NDP),tetraporin 12(TSPAN12),cateninβ1(CTNNB1)genes known to be involved in FEVR.The clinical features and the genotype of FEVR were observed in relation to the clinical phenotype.Results Among the 42 patients,13 patients were first observed by strabismus and nystagmus,with the median age of 12 months.Eight patients were complained non-chasing or vision-related symptoms.Among the 84 eyes,FEVR stage 1 or 2,3 or 4,and 5 were 50(59.5%,50/84),31(36.9%,31/84),and 3(3.6%,3/84)eyes,respectively.Among the 23 patients who were>3 months at first diagnosis,16 patients had at least one eye severer than stage 3(69.6%,16/23).Of the 68 first-degree relatives,22(32.4%,22/68)had FEVR-like changes.Among the 26 families that underwent genetic detection,13 families(50%,13/26)of 16 variants of FEVR-related genes were detected,of which 10 mutations of LRP5 gene were the most common.There were 10 families with single gene mutations,including 6,2 and 2 families of LRP5,FZD4 and CTNNB1 genes,respectively.One family of LRP5 gene mutations were compound heterozygous mutations,1 family with LRP5 gene mutaition combined with NDP gene mutation,and 1 family with LRP5 and TSPAN12 gene mutation.Among the proband with FEVR pathogenic genes,6 cases with similiar stage of both eyes,and 7 cases with inconsistent disease stages,and there was no obvious correlation between gene mutations and clinical phenotypes.Conclusion In addition to the age of first diagnosis,no exact factors affecting the clinical manifestations of FEVR are found,and the association between clinical phenotypic and genetic heterogeneity still needs to be further explored.