探讨AMN基因突变相关Imerslund-Gräsbeck综合征(IGS)患儿的临床表现、肾脏病理学特征及其可能机制，并结合文献分析其肾脏受累特点。

选择2025年8月19日于四川大学华西第二医院天府医院儿童肾脏科收治的1例AMN基因突变相关IGS患儿(患儿1)为研究对象。采用回顾性分析方法，对其临床表现、实验室检查结果、肾脏组织病理学活检结果及基因检测结果进行分析。采用本研究设计的检索策略，检索关于AMN基因突变相关IGS研究相关文献，进行文献复习。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。

①患儿1为男性，11岁7个月AMN基因突变相关IGS患儿，主要表现为反复巨幼细胞性贫血、维生素B₁₂缺乏及持续性蛋白尿。对患儿1的尿蛋白成分分析提示以肾小管性蛋白尿为主，并伴白蛋白尿增高。其肾活检结果显示轻度系膜增生(光镜)；电镜下可见约70%毛细血管袢肾小球基底膜(GBM)弥漫性变薄，并伴足细胞足突节段性融合。对患儿1全外显子组测序(WES)发现，AMN基因纯合移码突变c.624del(p.Ser209ArgfsTer51)；Sanger测序证实其父母均为该位点杂合携带者。该变异在gnomAD、ClinVar及HGMD数据库中均未见收录，检索相关文献亦未见报道；依据美国医学遗传学与基因组学学会(ACMG)/分子病理学协会(AMP)指南，该变异判定为致病性。②文献复习结果显示，共纳入AMN基因突变相关IGS患儿文献22篇，连同本研究患儿1，共33例患儿纳入分析，其中贫血32例(97.0%)、维生素B₁₂水平降低31例(93.9%)、蛋白尿29例(87.9%)。AMN基因突变相关IGS主要表现为巨幼细胞性贫血、维生素B₁₂缺乏和蛋白尿，多于婴幼儿期至学龄前期起病；经维生素B₁₂替代治疗后，贫血和维生素B₁₂缺乏多可改善，而蛋白尿常持续存在。另纳入报道IGS肾活检资料的文献12篇，连同本研究患儿1，共22例患儿接受肾活检。IGS患儿肾脏病理学改变总体较轻；已明确基因型者中，AMN基因突变相关患儿多表现为轻微病理学改变，而CUBN基因变异相关患儿还可伴近端肾小管相关异常。

本研究患儿1发生AMN基因c.624del(p.Ser209ArgfsTer51)纯合移码突变(新型变异)。AMN基因突变相关IGS患儿除近端肾小管重吸收功能异常外，还可合并肾小球超微结构异常，表现为肾小球基底膜变薄及足细胞足突改变，其临床意义仍有待进一步研究、证实。

To investigate the clinical manifestations, renal pathological characteristics, and potential mechanisms of Imerslund-Gräsbeck syndrome (IGS) caused by AMN gene mutations, and to analyze the characteristics of renal involvement through a literature review.

A male child (patient 1), aged 11 years and 7 months, diagnosed with AMN mutation-related IGS at the Department of Pediatric Nephrology, West China Second University Hospital (Tianfu), Sichuan University on August 19, 2025, was selected as the research subject. A retrospective analysis was conducted on clinical manifestations, laboratory examinations, renal biopsy findings, and genetic testing results. Additionally, a literature search was performed regarding AMN gene mutation-related IGS and the renal pathological findings associated with IGS. The procedures followed in this study were in line with the requirements of the newly revised World Medical Association Declaration of Helsinki in 2013.

①The primary clinical features of patient 1 included recurrent megaloblastic anemia, vitamin B₁₂ deficiency, and persistent proteinuria. Urinary protein component analysis indicated predominantly tubular proteinuria accompanied by elevated albuminuria. Light microscopy of the renal biopsy revealed mild mesangial proliferation. Electron microscopy showed diffuse thinning of the glomerular basement membrane (GBM) in approximately 70% of the capillary loops, along with segmental fusion of podocyte foot processes. Whole exome sequencing (WES) identified a novel homozygous frameshift mutation in the AMN gene: c. 624del (p.Ser209ArgfsTer51). Sanger sequencing confirmed that both parents were heterozygous carriers of this variant. This variant was not recorded in the gnomAD, ClinVar, or HGMD databases, and no relevant published reports were identified in the literature search. According to the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. ② The literature review identified 22 publications on pediatric patients with AMN mutation-related IGS. Including patient 1 from the present study, a total of 33 patients were included in the analysis, among whom anemia was reported in 32 cases (97.0%), decreased serum vitamin B₁₂ levels in 31 cases (93.9%), and proteinuria in 29 cases (87.9%). AMN mutation-related IGS is mainly characterized by megaloblastic anemia, vitamin B₁₂ deficiency, and proteinuria, with onset occurring predominantly from infancy to the preschool years. Following vitamin B₁₂ replacement therapy, anemia and vitamin B₁₂ deficiency were generally improved, whereas proteinuria often persisted. In addition, 12 publications reporting renal biopsy findings in patients with IGS were included; together with patient 1 from the present study, a total of 22 patients underwent renal biopsy. Renal pathological changes in patients with IGS were generally mild; among cases with a defined genotype, patients with AMN mutations usually exhibited only mild pathological alterations, whereas those with CUBN variants could also present with proximal tubular abnormalities.

Patients with IGS associated with the novel homozygous frameshift mutation of the AMN gene may exhibit ultrastructural glomerular abnormalities: specifically GBM thinning and podocyte alterations, in addition to impaired proximal renal tubular reabsorption. The clinical significance of these findings warrants further investigation.