同卵双胎Alport综合征临床表型分析

Clinical phenotype of Alport syndrome in monozygotic twins

目的了解同卵双胎Alport综合征患者之间临床表型是否一致。方法选择登记于基于网络的遗传性肾脏病注册登记系统、2000年1月至2019年3月就诊于北京大学第一医院且符合纳入标准和排除标准的同卵双胎Alport综合征患儿为研究对象,回顾性分析其临床资料和尿液表皮生长因子水平。结果纳入来自3个无亲缘关系家庭的3对X连锁Alport综合征同卵双胎男性患儿。双胎间基因型状态一致性评价倾向于肯定同卵关系。双胎1为足月儿,余均为早产儿;1A出生体重正常(2500 g),而1B为足月小样儿(2450 g),双胎2出生体重相差较大(2A为2450 g、2B为1900 g),双胎3出生体重基本相同;虽生后抚养环境一致,但体格发育双胎1B明显落后于1A,余双胎基本相同。双胎1和2肾脏表现并不完全一致,1A、1B均表现为大量蛋白尿和肾功能下降,但1B肾功能更差,末次随访时1A为慢性肾脏病(CKD)3期,而1B为CKD4期;双胎2肾功能均正常,但2A表现为显性蛋白尿(24 h尿蛋白定量0.22 g/d)而2B的24 h尿蛋白定量正常、有微量白蛋白尿(尿白蛋白肌酐比为65 mg/g);双胎3肾脏表现基本一致。3对双胎的尿表皮生长因子与尿肌酐的比值(uEGF/Cr)与年龄匹配的健康对照组相比,uEGF/Cr均显著降低,且在双胎之间,估算肾小球滤过率越低的患儿其uEGF/Cr也越低。目前双胎间眼部表现一致,即双胎2和双胎3均表现双眼黄斑颞侧薄变,而双胎1均无眼部改变。此外,双胎间的听力表现也一致,双胎1均具有双耳轻度中低频感音神经性耳聋,而双胎2和双胎3双耳纯音测听结果均正常。结论同卵双胎X连锁Alport综合征男性患儿肾脏表型可以存在差异,眼部和听力表现可以一致。低出生体重和生后体格发育差异可能影响肾功能进展。

Objective To analyze the consistency of the clinical phenotype of Alport syndrome between monozygotic twins.Methods This retrospective study included identical twins with Alport syndrome who met the inclusion and exclusion criteria and were admitted to Peking University First Hospital from January 2000 to March 2019.Their clinical data and urinary epidermal growth factor(uEGF)level were extracted from the on-line registry system of hereditary kidney diseases,and analyzed retrospectively.Results Three pairs of monozygotic twins with X-linked Alport syndrome from three non-consanguineous families were included.The consistency of the genotype status between the twins tended to confirm their monozygotic relationship.The first twins were term infants,and the twin 1A had a normal birth weight(2500 g)while twin 1B was small for gestational age(2450 g).The other two pairs of twins were preterm,with different birth weights between twins 2(2A is 2450 g,2B is 1900 g),but similar birth weights between twins 3.Although raised in the same environment,compared with twin 1A,1B had obvious growth retardation.However,growth rate in the remaining twins were consistent.The renal abnormalities were not exactly the same between both twins 1 and twins 2,but was almost the same in twins 3.Both 1A and 1B were characterized by massive proteinuria and renal dysfunction,whereas 1B had worse renal function.At the last follow-up,1A was diagnosed with stage 3 of chronic kidney disease(CKD)whereas 1B was CKD stage 4.Although renal function in twins 2 were normal,2A had prominent proteinuria(24 h urinary total protein:0.22 g)while 2B only had microalbuminuria(urinary albumin-to-creatinine ratio:65 mg/g).Compared with the age-matched healthy controls,the concentration of uEGF normalized by urine creatinine(uEGF/Cr)were significantly lower in these twins.Besides,the twin-boy who had lower estimated glomerular filtration rates had lower uEGF/Cr.However,the extrarenal manifestations such as ocular and acoustic abnormalities were similar between the twins.Twins 2 and 3 showed bilateral temporal retinal thinning,and twins 1 both had binaural mild mid-low frequency sensorineural deafness.Conclusions Renal manifestations of X-linked Alport syndrome in monozygotic twins may differ from each other,whereas the extrarenal manifestations including ocular and acoustic abnormalities may be consistent.Low birth weight and growth retardation may be associated with the progression of renal dysfunction.