目的

探讨1型神经纤维瘤病（NF1）合并肾病综合征（NS）患儿的临床特征及诊疗措施，并文献复习总结NF1和NS患儿的潜在关联发病机制。

方法

选择2021年2月，于华中科技大学附属湖北省妇幼保健院就诊的1例NF1合并NS患儿（患儿1）为研究对象。采用回顾性分析法，收集其临床资料、全外显子组测序（WES）及Sanger测序验证结果。根据美国医学遗传学与基因组学学会（ACMG）制定的指南，对其检出的变异致病性进行分析。以“1型神经纤维瘤病” “肾病综合征”“肾炎”及“neurofibromatosis type 1 nephritis” “neurofibromatosis type 1 nephrotic syndrome”为中、英文关键词，在万方数据服务平台、中国知网、Pub Med等中英文数据库中，对关于NF1合并NS患儿临床研究的相关文献进行检索。本次检索年限设定为2001年1月1日至2024年12月30日。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》的要求。监护人对患儿诊治过程均知情同意，并签署临床研究知情同意书。

结果

①患儿1为男性，12岁，因“全身浮肿2 d”于2021年1月14日收入病例收集医院儿童肾病风湿免疫科治疗。对其入院查体见全身咖啡斑，双腋下多发小雀斑，右肾区见直径约为0.5 cm 瘤体2枚。实验室检查结果显示，大量蛋白尿、低蛋白血症、高脂血症，入院对其诊断为NF1合并NS。入院后，对患儿1采取足量糖皮质激素诱导治疗措施，尿蛋白转阴后出院。患儿1出院后第7天，在无诱因情况下再次出现蛋白尿，再次入本院治疗。对其肾穿刺组织病理学检查结果提示为肾小球足细胞病变；全外显子组测序（WES）发现，NF1 基因17号染色体42号外显子6361-6362del TC缺失突变（NM_001042492），移码变异，符合ACMG 致病性标准。对其采取甲泼尼龙片联合他克莫司治疗措施尿蛋白转阴后，再次出院，②文献复习共纳入17例NF1合并NS患者，年龄为3～70岁，儿童期发病者为5例（29.4%），10例（58.8%）经基因检测确诊为NF1，合并肾损伤类型包括膜性肾病、局灶节段性肾小球硬化（FSGS）、Ig A 肾病等。

结论

NF1合并NS临床少见，根据基因检测结果对患者进行临床确诊至关重要。m TOR 信号通路异常可能介导足细胞损伤，导致蛋白尿，激素联合免疫抑制剂治疗或为NF1合并NS患儿的有效治疗方案。

Objective

To explore the clinical characteristics and diagnosis of children with neurofibromatosis type 1（NF1）complicated with nephrotic syndrome（NS），and to investigate the potential association mechanism between NF1 and NS through a literature review.

Methods

A 12-year-old male child with NF1 complicated with NS （Child 1）who was admitted to the Hubei Maternal and Child Health Hospital affiliated to Huazhong University of Science and Technology in February 2021 was selected as the research subject.A retrospective analysis was conducted to collect the clinical data，whole-exome sequencing（WES）results，and Sanger sequencing validation results of child 1.The pathogenicity of the detected variants was analyzed according to the guidelines established by the American College of Medical Genetics and Genomics （ACMG）.Keywords such as"neurofibromatosis type 1""nephrotic syndrome""nephritis"and their English equivalents were used to search relevant literature in databases such as Wanfang Data Service Platform，China National Knowledge Infrastructure （CNKI），and Pub Med.The search period was set from January 1，2001，to December 30，2024.This study adhered to the requirements of the revised 2013 DeclarationofHelsinkiofthe WorldMedicalAssociation.Informed consent was obtained from the guardians of the child.

Results

①Child 1，a boy，was admitted to the pediatric nephrology and rheumatology immunology department of Hubei Maternal and Child Health Hospital on January 14，2021，due to"generalized edema for 2 days".Physical examination upon admission revealed café-au-lait spots over the entire body，multiple small freckles in both axillae，and two tumors approximately 0.5 cm in size in the right renal area.Laboratory tests showed massive proteinuria，hypoalbuminemia，and hyperlipidemia，leading to a diagnosis of NF1 complicated with NS.After admission，the child was treated with adequate glucocorticoids to induce remission，and proteinuria turned negative before discharge.Seven days after discharge，the child again presented with proteinuria without any identifiable cause.Renal biopsy histopathological examination suggested podocyte lesions.Whole-exome sequencing（WES）revealed a deletion mutation （6361-6362del TC）in exon 42 of the NF1 gene on chromosome 17（NM_001042492），causing a frameshift variant，which met the ACMG pathogenicity criteria.Treatment with methylprednisolone tablets combined with tacrolimus was administered，and proteinuria turned negative again before discharge.②Literature review：A total of 17 patients were included，aged 3 to 70 years，with childhood-onset in 5 cases （29.4%）.Ten cases （58.8%）were confirmed to have NF1 through genetic testing.The types of renal injury associated with NF1 included membranous nephropathy，focal segmental glomerulosclerosis （FSGS），and Ig A nephropathy.

Conclusions

NF1 complicated with NS is clinically rare，and genetic testing is crucial for a definitive diagnosis.Abnormalities in the m TOR signaling pathway may mediate podocyte damage，leading to proteinuria.Combined treatment with glucocorticoids and immunosuppressants may be an effective therapeutic approach.