儿童Alport综合征的临床、病理及基因分析

Clinical,Pathological and Genetic Analysis of Alport Syndrome in Children

目的探讨Alport综合征的基因型⁃表型相关性。方法回顾性分析2016年1月至2020年12月北京儿童医院收治的经过二代测序技术检出COL4A基因突变的Alport综合征患儿的临床特征及病理特点。结果共有55例患儿纳入研究。所有患儿均有血尿,肉眼血尿31例(56.4%),镜下血尿24例(43.6%);血尿伴蛋白尿39例(70.9%)。12例(21.8%)患儿存在肾外表现;36例(65.4%)患儿存在家族史。32例患者接受病理检查,符合Alport综合征特异病理改变的有23例。X连锁Alport综合征患者36例(65.4%);常染色体隐性Alport综合征5例(9.1%),常染色体显性Alport综合征10例(18.2%),双基因突变患者4例(7.3%)。COL4A基因错义突变占62.5%,其中67.5%的错义突变导致甘氨酸替换。X连锁Alport综合征男性与女性患儿蛋白尿程度及听力损失比较,差异有统计学意义(P<0.05);常染色体隐性与常染色体显性Alport综合征的蛋白尿程度比较,差异有统计学意义(P=0.044),起病年龄存在临界统计学差异(P=0.050);肾功能损害的患儿与肾功能正常的患儿听力损失比较,差异有统计学意义(P=0.001)。结论多数COL4A基因突变导致甘氨酸替换。X连锁Alport综合征男性患儿蛋白尿程度及听力损失重于女性患儿。常染色体隐性Alport综合征起病年龄较常染色体显性早,蛋白尿程度重。存在听力损失的患儿肾脏表型更重。Alport综合征早期临床表现多样,病理可以表现不典型,应用二代测序技术可以提高Alport综合征的诊断率,减少误诊。

Objective To explore the phenotype⁃genotype correlation of Alport syndrome in children.Methods Retrospectively analyze the clinical and pathological features of 55 patients with Alport syndrome with COL4A mutations detected by second⁃generation sequencing,who were treated at Beijing Children's Hospital from January 2016 to December 2020.Results A total of 55 children with Alport syndrome were included.All cases had hematuria,including 31 cases(56.4%)with gross hematuria and 24 cases(43.6%)with microscopic hematuria.A total of 39(70.9%)patients also had proteinuria.Extrarenal manifestations were present in 12 patients(21.8%).36(65.4%)patients had a family history of Alport syndrome.32 patients underwent pathological examination and 23 of them had the specific pathological changes of Alport syndrome.In 55 cases,36(65.4%)were diagnosed as X⁃linked Alport syndrome,5(9.1%)were diagnosed as autosomal recessive Alport syndrome,10(18.2%)were diagnosed as autosomal dominate Alport syndrome,and 4(7.3%)were diagnosed as digenic Alport syndrome.Missense mutations in COL4A genes accounted for 62.5%,67.5%of missense mutations resulted in glycine substitution.There were statistical significances in proteinuria degree and hearing loss between male and female patients with XLAS(P<0.05)as well as statisti⁃cal significance in the degree of proteinuria between autosomal recessive Alport syndrome and autosomal dominate Alport syndrome(P=0.044),and there was critical statistical significance in the age of onset.There was statistical significance in hearing loss between children with renal impairment and children with normal renal function(P=0.001).Conclusions Most of the pathogenic variants in COL4A genes that cause Alport syndrome result in glycine substitutions.The degree of proteinuria and hearing loss of males with XLAS were greater than those of females.The degree of proteinuria in autosomal recessive Alport syndrome was greater than that of children with autosomal dominate Alport syndrome,and the age of onset was earlier than that of autosomal dominate Alport syndrome.Renal manifestation was more severe in children with hearing loss.The early clinical manifestations of Alport syndrome are diverse and pathological manifestations may be atypical.The application of next⁃generation sequencing can reduce misdiagnosises of Alport syndrome.