Yang Guang'e, Song Conglei, He Fan, Zhang Kaili, Yang Bin
Department of Neurology, Anhui Children's Hospital, Children's Hospital of Fudan University, Hefei, Anhui 230052, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Jun 10;42(6):691-699. doi: 10.3760/cma.j.cn511374-20241010-00527.
To explore the clinical, genetic, therapeutic and prognostic characteristics of two children with Lesch-Nyhan syndrome (LNS) in order to enhance understanding of this disease and formulate more effective therapeutic strategies.
Clinical data were collected from two children clinically diagnosed with LNS who were treated at Anhui Provincial Children's Hospital from April 2023 to January 2024. Data were retrospectively collected and included clinical manifestations (symptoms, signs, laboratory and imaging findings), treatment course, and results of follow-up. Peripheral venous blood samples were obtained from child 1 and his parents. Whole-exome sequencing (WES) was performed. Candidate variants were validated by Sanger sequencing. Standard bioinformatic analysis of the raw WES data was conducted, including quality control, alignment, variant calling, and annotation. Candidate pathogenic variants were filtered using population frequency databases (e.g., gnomAD), disease databases (e.g., OMIM, ClinVar), and multiple in silico pathogenicity prediction tools (e.g., SIFT, PolyPhen-2, CADD). Phenotype matching was integrated using Human Phenotype Ontology (HPO) terms. Pathogenicity classification of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants (2015). This study was approved by the Medical Ethics Committee of Anhui Children's Hospital, Children's Hospital of Fudan University (Ethics No.: EYLL-2014-027).
Child 1, a 4-year-old boy, had presented with developmental delay for over 3 years, accompanied by abnormal postures and involuntary lip-biting. Physical examination revealed limb dystonia, anxious expression, lower lip damage, and communication difficulties. Laboratory tests showed hyperuricemia and renal stones. Genetic testing identified a hemizygote variant of the HPRT1 gene, c.135G>T (p.Arg45Ser), inherited from an asymptomatic carrier mother, which confirmed the diagnosis of LNS. This variant was absent from population databases (gnomAD, 1000 Genomes, dbSNP). Protein function prediction tools consistently indicated it as a pathogenic or likely pathogenic variant (SIFT, PolyPhen-2, CADD, and REVEL scores all reached pathogenic thresholds). Protein structural modeling revealed that the variant may disrupt the hydrogen-bonding network compromising the tetramer stability. ACMG classification designated it as likely pathogenic (PM1+PM2_Supporting+PM5+PP3). The patient was treated with benhaxol hydrochloride, baclofen, and clonazepam to improve his neurological symptoms, in addition with treatment with febuxostat from the Nephrology Department to manage his purine metabolism. After one year of follow-up, the patient's abnormal posture showed slight improvement, self-injurious behavior persisted but was managed with protective gloves, blood uric acid levels normalized, and renal stones decreased. Case 2, a 13-year-old boy, was hospitalized to the Nephrology Department due to urinary tract infection. Following successful control of the infection, his limb dystonia has worsened, leading to his transfer to the Neurology Ward. The patient had a history of delayed motor and language development, abnormal postures, and lip-biting self-injurious behavior, with elevated blood uric acid levels, leading to the diagnosis of LNS. His parents had declined genetic testing due to financial constraints. Following discharge, the patient did not adhere to the prescribed medication regimen or attend scheduled outpatient visits. The patient had died by the time of the 4-month follow-up contact.
Variants of the HPRT1 gene probably underlay the LNS in the two children, and the HPRT1 is the only known pathogenic gene for LNS. Early genetic diagnosis, strict adherence to multidisciplinary comprehensive treatment, and intensive intervention for self-injurious behaviors are crucial for improving the quality of life and prolonging the survival of children with LNS.
探讨两名莱施-奈恩综合征（LNS）患儿的临床、遗传、治疗及预后特征，以增进对该疾病的了解并制定更有效的治疗策略。
收集2023年4月至2024年1月在安徽省儿童医院接受治疗的两名临床诊断为LNS的患儿的临床资料。回顾性收集数据，包括临床表现（症状、体征、实验室及影像学检查结果）、治疗过程及随访结果。采集患儿1及其父母的外周静脉血样本。进行全外显子测序（WES）。通过桑格测序验证候选变异。对原始WES数据进行标准生物信息学分析，包括质量控制、比对、变异检测及注释。使用人群频率数据库（如gnomAD）、疾病数据库（如OMIM、ClinVar）及多种计算机致病性预测工具（如SIFT、PolyPhen-2、CADD）筛选候选致病变异。使用人类表型本体（HPO）术语进行表型匹配。根据美国医学遗传学与基因组学学会（ACMG）《序列变异解读标准与指南》（2015年）对变异进行致病性分类。本研究经安徽儿童医院、复旦大学附属儿科医院医学伦理委员会批准（伦理编号：EYLL-2014-027）。
患儿1为4岁男性，出现发育迟缓3年多，伴有姿势异常及不自主咬唇行为。体格检查发现肢体肌张力障碍、表情焦虑、下唇损伤及沟通困难。实验室检查显示高尿酸血症及肾结石。基因检测鉴定出HPRT1基因的半合子变异，c.135G>T（p.Arg45Ser），从无症状携带母亲遗传而来，确诊为LNS。该变异在人群数据库（gnomAD、千人基因组、dbSNP）中未出现。蛋白质功能预测工具一致表明其为致病性或可能致病性变异（SIFT、PolyPhen-2、CADD及REVEL评分均达到致病阈值）。蛋白质结构建模显示该变异可能破坏氢键网络，损害四聚体稳定性。ACMG分类将其指定为可能致病性（PM1+PM2_Supporting+PM5+PP3）。患者接受盐酸苯海索、巴氯芬及氯硝西泮治疗以改善神经症状，此外还接受肾内科非布司他治疗以控制嘌呤代谢。随访一年后，患者异常姿势稍有改善，自伤行为持续但通过防护手套进行管理，血尿酸水平恢复正常，肾结石减少。病例2为13岁男性，因尿路感染入住肾内科。感染成功控制后，其肢体肌张力障碍加重，转至神经内科病房。患者有运动及语言发育迟缓、姿势异常及咬唇自伤行为病史，血尿酸水平升高，诊断为LNS。其父母因经济原因拒绝基因检测。出院后，患者未坚持规定的药物治疗方案或按时门诊就诊。在4个月随访时患者已死亡。
HPRT1基因变异可能是这两名患儿LNS的病因，且HPRT
