赖氨酸尿性蛋白耐受不良1家系(1例合并系统性红斑狼疮)报告并文献复习

摘要

目的 总结赖氨酸尿性蛋白耐受不良(LPI)1家系2例患者临床特征及基因突变的特点,提高对该病的认识.方法 收集PLI 1家系2例患儿(同胞姐弟)的临床资料,包括病史、肾脏病理、相关实验室检查和家族史等.采用外显子捕获法对患儿及其父母行全外显子测序(WES)并行生物信息学分析,行Sanger验证并在家系其他成员中进行突变分析.结果 先证者,女,10岁,断乳后反复呕吐和腹泻,抵触富含蛋白的食物,生长落后,身高低于同年龄、同性别儿童;5岁后鼻自发性出血,外周血"三系"(RBC、WBC、PLT)低于正常值,9.7岁后出现轻度蛋白尿和持续性镜下血尿;免疫系统受累,检出ANA和ds-DNA等多种自身抗体.血清铁蛋白、乳酸脱氢酶和血氨增高,尿乳清酸增高,血清和尿液赖氨酸、精氨酸和瓜氨酸改变不明显.肾活检病理提示狼疮性肾炎.家系调查发现,先证者之弟,男,6.5岁,断乳后反复呕吐,抵触富含蛋白食物,生长落后,身高低于同年龄、同性别儿童,血清铁蛋白、乳酸脱氢酶增高,尿乳清酸增高,血清、尿液赖氨酸、精氨酸和瓜氨酸改变不明显.先证者及其父母WES测序显示SLC7A7基因IVS4+1G>A纯合突变,突变来源其父母,先证者之弟也存在该突变.例1诊断为LPI合并SLE,例2诊断为LPI.结论 SLC7A7基因测序是确诊LPI的依据;LPI并发系统性红斑狼疮(SLE)非常罕见,SLC7A7是否为单基因型SLE致病基因需进一步研究.%ObjectiveTo summarize and review the clinical data of two children with lysinuric protein intolerance so as to improve its knowledge.MethodsClinical data of two cases with lysinuric protein intolerance were summarized, including clinical manifestations, laboratory findings, renal pathological changes and family investigation.This study used next generation sequencing to screen all exons of genome in proband and her parents.Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing and segregation analysis was performed using parental DNA and her brother samples.ResultsThe proband, a 10-year-old girl, presented with recurrent vomiting and episodes of diarrhea, aversion to protein-rich food and failure to thrive after weaning.She often had nasal hemorrhage since the age of 5 years.Peripheral blood cell count suggested white blood cell, red blood cell and platelet count were all under normal value.She had mild proteinuria and persistent microscopic hematuria at the age of 9.7 years.At the same time, laboratory tests showed that serum ferritin, lactate dehydrogenase and ammonia increased, and orotic acid increased in urine, but lysine, arginine and citrulline were not changed significantly in serum and urine.The pathology of renal biopsy suggested lupus nephritis.The proband's younger brother, 6.5-year-old, presented with recurrent vomiting, aversion to protein-rich food and failure to thrive after weaning.He had no episodes of diarrhea.laboratory tests also showed that serum ferritin, lactate dehydrogenase and ammonia increased, and orotic acid increased in urine, but lysine, arginine and citrulline were not changed significantly in serum and urine.Whole exon sequencing was performed in core family, including proband and her parents.Homozygous c.625+1G>A mutation in SLC7A7 gene was detected in proband, which was from her parents.The mutation was confirmed by Sanger sequencing in core family.The same mutation was found in proband's younger brother by Sanger sequencing.The proband was diagnosed as LPI complicted with SLE.The proband's younger brother was diagnosed as LPI.ConclusionDue to the heterogeneity of LPI and lack of understanding of LPI for clinicians, it is easy to cause misdiagnosis or miss diagnosis.The SLC7A7 gene sequencing is the basis for diagnosis.LPI patients with systemic lupus erythematosus (SLE) is very rare.LPI patients complicated with SLE need glucocorticoid or immunosuppressive therapy.Mutations in SLC7A7 gene can cause SLE.whether SLC7A7 is one of the genes causing a single gene type SLE needs further study.