Lesch-Nyhan综合征的诊治分析

Analysis of diagnosis and treatment of Lesch-Nyhan syndrome

目的探讨Lesch-Nyhan综合征的病因、临床诊断和治疗策略。方法回顾性分析2019年8月郑州市第一人民医院收治的2例严重运动障碍、智力障碍和复杂性泌尿系结石患者的病例资料。例1,男,9岁,因泌尿系多发结石入院。入院前1年因双肾多发结石、膀胱结石于外院行经尿道膀胱结石钬激光碎石取石术。术后结石成分分析结果为无水尿酸结石。术后1周复查膀胱充盈良好,未见残留结石。本次入院前1周复查彩色多普勒超声示双肾多发结石并膀胱结石。既往发育落后,智力低下。足月剖宫产,无出生缺氧、窒息及抢救史。查体:清醒状态,任何刺激均无语言反应;右侧鼻唇沟浅,口角左斜;竖头、独坐、站立等大运动丧失;躯干呈扭转性痉挛状态,四肢肌力2~3级,四肢呈痉挛性肌张力增高状态,四肢关节僵硬,双手呈握拳状,无不自主运动和肌束震颤;肱二头肌反射、膝腱反射未引出,病理反射阳性。血尿酸517μmol/L。例2,男,6岁,为例1胞弟。家属代诉例2患儿间断发热2年余,每次发热持续时间和体温表述不清,未予特殊治疗。体征和查体与例1类似。影像学检查提示双肾结石。血尿酸373μmol/L。为明确诊断,联合河南省人民医院遗传研究所会诊并行基因检测。采用全外显子测序技术对例2和其父母进行全外显子检测,采用Sanger测序技术对例2和其父母进行突变位点检测验证。查找NCBI-Homologene数据库中人HPRT1基因的同源序列,并与其他物种进行对比,分析蛋白的保守性。利用在线网站PredictProtein(http://www.predactprotein)对HPRT1基因的二维结构进行预测。结果基因测序结果显示,例2的HPRT1基因存在1个新发突变(c.571T>G[p.Tyr191Asp]),该突变遗传自患儿母亲。结合患儿临床表现和基因检测结果诊断为Lesch-Nyhan综合征。基因分析结果显示,191位置氨基酸Tyr和其前后氨基酸均具有高度的保守性,191位置氨基酸参与蛋白的β折叠。对例2进行最低剂量的别嘌呤醇和儿童常规剂量的枸橼酸氢钾钠颗粒治疗,并予低嘌呤饮食。治疗3个月后复查血尿酸降至255μmol/L,泌尿系结石较前未见明显增多。结论结合患儿临床表现和HPRT1基因检测结果可诊断Lesch-Nyhan综合征。对于此类患者,最低剂量的别嘌呤醇和儿童常规剂量的枸橼酸氢钾钠颗粒治疗,结合饮食治疗的效果较好。

Objective To explore the etiology,clinical diagnosis and treatment strategy of Lesch Nyhan syndrome.Methods We retrospectively analyzed 2 patients with severe dyskinesia,mental retardation and complicated renal calculi who were admitted to the first people's Hospital of Zhengzhou in August 2019.Case 1,male,9 years old,had multiple urinary calculi for 1 year.The patient came to the local hospital because double multiple kidney stones and bladder stonesa year ago.The patient had been treated with transurethral holmium laser lithotripsy for bladder stones.The results of infrared spectrum showed that the bladder stone was anhydrous uric acid stone.A week ago,color Doppler ultrasound showed multiple kidney stones and bladder stones.The patient was underdeveloped,mentally retarded and had a full-term cesarean section.There was no history of hypoxia,asphyxia and rescue of the patient.He had the following clinical manifestations:In the waking state,he was no language response to any stimulation.The nasolabial fold on the right was shallow and the corner of the mouth was oblique to the left.He lost the large movements such as lifting head,sitting alone,standing.The trunk showed torsion spasticity,limb muscle strength 2-3,limbs showing spastic hypertonia,limb joints stiff,hands showing fist-like,no involuntary movement and muscle fasciculation.The biceps reflex and knee tendon reflex were not elicited,and the pathological reflex was positive.Serum uric acid was 517μmol/L.The Case 2 came from the same family,male,6 years old,had the similar symptoms to his elder brother case 1.The family members complained on behalf of the child about intermittent fever for more than 2 years.The imaging examination of case 2 revealed kidney stones.Serum uric acid was 373μmol/L.Whole Exome Sequencing and Sanger Sequencing were used to find the genetic causes of the two siblings.The NCBI-Homologene database was used to find the homologous sequence of the human HPRT1 gene,and the human HPRT1 gene sequence was compared with other species to analyze the protein conservation.The online website PredictProtein(http://www.predactprotein)was used to predict the two-dimensional structure of the HPRT1 gene.The reported cases were summarized and same with the treatment plan.Results A De novo mutation[c.571T>G(p.Tyr191Asp)]was found in the HPRT1 gene of the child,which was inherited from the mother.Lesch Nyhan syndrome can be diagnosed by the results of gene examination combined with clinical manifestations.The amino acid Tyr at the 191 position and the amino acids before and after it were highly conserved.Amino acid 191 was involved in the β-strand of the protein.We treated the patients with the lowest dose of allopurinol and children's conventional dose of potassium sodium bicitrate granules,and low purine diet.After 3 months of treatment,the serum uric acid was decreased,and the urinary calculi did not increase significantly.Conclusions Combining with the clinical manifestations of children,HPRT1 gene might be the cause of pediatric disease and the two siblings could be diagnosed as Lesch-Nyhan syndrome.For such patients,the lowest dose of allopurinol and children's conventional dose of potassium sodium hydrogen citrate granule combined with diet could be more effective.