目的 探讨NPHP3基因相关肾单位肾痨（nephronophthisis, NPH）患儿的临床、影像与病理特征及与疾病进展的关系。 方法 回顾分析10个家系13例经基因确诊的NPHP3基因相关NPH患儿的临床、影像及病理特征及其与疾病进展的关系。 结果 13例患儿起病中位年龄为1.9岁，进展至终末期肾病（ESRD）的中位年龄为3.3岁。首发症状：贫血最为常见，占46.2%，其次为肾脏超声异常，占38.5%。影像学69.2%（9/13）双肾增大，61.5%（8/13）肾囊肿，肾囊肿可在疾病早期出现，分布于皮髓质交界处和肾皮质；起病时肾脏大小正常组与增大组之间，进展至ESRD的年龄无显著差异（P>0.05）。囊肿最大直径与ESRD进展无显著相关性（P>0.05）。肾脏病理均表现为慢性肾小管间质性肾病、部分患儿肾小管基底膜无增厚；少数影像学未发现囊肿患儿，病理仍见到肾囊肿。婴儿型NPH的肝脏病变显著高于少年型（P<0.05），心脏受累仅见于婴儿型患者。 结论 本组NPHP3基因相关NPH患儿以婴儿型为主，起病早、进展快。肾脏增大、肾小管基底膜可无增厚、肾囊肿早期出现及可分布于肾皮质等特征有别于经典型NPH。肾外表现以肝、心脏受累多见，主要发生于婴儿型。本研究进一步揭示了NPHP3基因突变患者临床病理特征与疾病分型和进展的关系，有利于疾病的早期识别、临床检测和预后评估，并为遗传咨询提供了科学依据。
Abstract
Objective To investigate the clinical, imaging and pathological features of nephronophthisis (NPH) associated with NPHP3 gene in pediatric patients and their relationships with disease progression. Methods The clinical, imaging and pathological characteristics of 13 genetically confirmed pediatric patients from 10 families with NPHP3-associated NPH were retrospectively analyzed and the associations between these features and disease progression were examined. Results The median age at onset of the 13 patients was 1.9 years, and the median age at progression to end-stage renal disease (ESRD) was 3.3 years. The most common initial clinical manifestations were anemia (46.2%) and abnormal renal ultrasound findings (38.5%). Imaging result showed bilateral renal enlargement (69.2%) and renal cysts (61.5%). Renal cyst could emerge at the early stage of the disease and reside on corticomedullary, as well as cortex. There was no significant difference in age at progression to ESRD between the groups with normal renal size and those with enlarged kidneys at onset (P>0.05). Maximum cyst diameter was not significantly associated with progression to ESRD (P>0.05). Renal pathology uniformly demonstrated chronic tubulointerstitial nephropathy, thickness of tubular basement membrane was absent in some patient, in a few patients without cysts on imaging, renal cysts were nevertheless observed pathologically. Hepatic involvement was significantly more common in the infantile form than in the juvenile form (P<0.05), while cardiac involvement occurred only in infantile patients. Conclusions In this study, NPHP3-associated NPH predominantly presented in the infantile form, with early onset and rapid progression. Renal enlargement, absence of thickening of tubular basement membrane, early emerging of renal cysts and its distribution on the renal cortex, distinguish NPHP3-associated NPH from classic NPH. Extrarenal manifestations mainly involved the liver and heart and were predominantly observed in infantile patients. This finding offers early diagnostic clues for rapidly progressive cases and provides a basis for guiding clinical monitoring (for example, emphasizing assessment of hepatic and cardiac function) and genetic counseling.
关键词
肾单位肾痨； /
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NPHP3； /
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肾囊肿； /
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终末期肾病； /
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慢性肾小管间质性肾病
Key words
Nephronophthisis; /
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NPHP3; /
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Renal cyst; /
End-stage renal disease /
Chronic tubulointerstitial nephropathy
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参考文献
[1] Wolf MTF, Bonsib SM, Larsen CP, et al. Nephronophthisis: a pathological and genetic perspective[J]. Pediatr Nephrol, 2024, 39(7):1977-2000. DOI:10.1007/s00467-023-06174-8.
[2] Gupta S, Ozimek-Kulik JE, Phillips JK. Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease[J]. Genes, 2021, 12(11): 1762. DOI: 10.3390/genes12111762.
[3] 周建华. 肾单位肾痨的临床和分子遗传学研究进展[J]. 临床肾脏病杂志, 2017, 17(11): 644-647.
Zhou JH. Nephronophthisis: advances in clinical and molecular genetic research[J]. Journal of Clinical Nephrology, 2017, 17(11): 644-647.
[4] McConnachie DJ, Stow JL, Mallett AJ. Ciliopathies and the Kidney: A Review[J]. Am J Kidney Dis, 2021, 77(3): 410-419. DOI: 10.1053/j.ajkd.2020.08.012.
[5] Adamiok-Ostrowska A, Piekiełko-Witkowska A. Ciliary Genes in Renal Cystic Diseases[J]. Cells, 2020, 9(4): 907. DOI: 10.3390/cells9040907.
[6] Konig JC, Karsay R, Gerss J, et al. Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis[J]. Kidney Int Rep, 2022, 7(9): 2016-2028. DOI: 10.1016/j.ekir.2022.05.035.
[7] Petzold F, Billot K, Chen X, et al. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies[J]. Kidney Int, 2023, 104(2): 378-387. DOI:1 0.1016/j.kint.2023.05.007.
[8] Sun L, Tong H, Wang H, et al. High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients[J]. Nephrology (Carlton, Vic.), 2016, 21(3): 209-216. DOI: 10.1111/nep.12563.
[9] Salomon R, Saunier S, Niaudet P. Nephronophthisis[J]. Pediatr Nephrol, 2009, 24(12): 2333-2344. DOI:10.1007/s00467-008-0840-z.
[10]Yue Z, Lin H, Li M, et al. Clinical and pathological features and varied mutational spectra of pathogenic genes in 55 Chinese patients with nephronophthisis[J]. Clin Chim Acta, 2020, 506: 136-144. DOI: 10.1016/j.cca.2020.03.015.
[11]赖佳泳, 孙良忠, 刘雅清, 等. 20例 NPHP1基因缺陷肾单位消耗病患者的临床和基因突变特点[J]. 中华肾脏病杂志, 2024, 40(4): 277-288. DOI: 10.3760/cma.j.cn441217-20230516-00518.
Lai JY, Sun LZ, Liu YQ, et al. Clinical and genetic mutation characteristics in 20 patients with nephronophthisis caused by NPHP1 gene defect[J]. Chinese Journal of Nephrology, 2024, 40(4): 277-288. DOI: 10.3760/cma.j.cn441217-20230516-00518.
[12]Omran H, Fernandez C, Jung M, et al. Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree[J]. Am J Hum Genet, 2000, 66(1): 118-127. DOI: 10.1086/302705.
[13]Olbrich H, Fliegauf M, Hoefele J, et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis[J]. Nat Genet, 2003, 34(4): 455-459. DOI: 10.1038/ng1216.
[14]Thuy PX, Jang T, Moon E. Vinblastine Resistance Is Associated with Nephronophthisis 3-Mediated Primary Cilia via Intraflagellar Transport Protein 88 and Apoptosis-Antagonizing Transcription Factor[J]. Int J Mol Sci, 2024, 25(19): 10369. DOI: 10.3390/ijms251910369.
[15]Bergmann C, Fliegauf M, Bruchle NO, et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia[J]. Am J Hum Genet, 2008, 82(4): 959-970. DOI: 10.1016/j.ajhg.2008.02.017.
[16]Abdullah U, Farooq M, Fatima A, et al. Homozygous mutation in the NPHP3 gene causing foetal nephronophthisis[J]. Nephrology (Carlton), 2017, 22(10): 818-820. DOI: 10.1111/nep.13097.
[17]Leeman KT, Dobson L, Towne M, et al. NPHP3 mutations are associated with neonatal onset multiorgan polycystic disease in two siblings[J]. J Perinatol, 2014, 34(5): 410-411. DOI :10.1038/jp.2014.20.
[18]Tory K, Rousset-Rouvière C, Gubler M, et al. Mutations of NPHP2 and NPHP3 in infantile nephronophthisis[J]. Kidney Int, 2009, 75(8): 839-847. DOI: 10.1038/ki.2008.662.
[19]Li J, Su X, Zhang H, et al. Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP[J]. Pediatr Nephrol, 2023, 38(5): 1609-1620. DOI: 10.1007/s00467-022-05763-3.
[20]Focșa I, Budișteanu M, Bălgrădean M. Clinical and genetic heterogeneity of primary ciliopathies (Review)[J]. Intl J Mol Med, 2021, 48(3): 5009. DOI: 10.3892/ijmm.2021.5009.
[21] Chaki M, Hoefele J, Allen SJ, et al. Genotype–phenotype correlation in 440 patients with NPHP-related ciliopathies[J]. Kidney Int, 2011, 80(11): 1239-1245. DOI: 10.1038/ki.2011.284.
[22] He J, Zhou H, Meng J, et al. Cardamonin retards progression of autosomal dominant polycystic kidney disease via inhibiting renal cyst growth and interstitial fibrosis[J]. Pharmacol Res, 2020, 155: 104751. DOI: 10.1016/j.phrs.2020.104751.
[23] Dong K, Zhang C, Tian X, et al. Renal plasticity revealed through reversal of polycystic kidney disease in mice[J]. Nat Genet, 2021, 53(12): 1649-1663. DOI: 10.1038/s41588-021-00946-4.
[24] Noitem R, Yuajit C, Soodvilai S, et al. Steviol slows renal cyst growth by reducing AQP2 expression and promoting AQP2 degradation[J]. Biomed Pharmacother, 2018, 101: 754-762. DOI: 10.1016/j.biopha.2018.02.139.
[25] Raina R, Lomanta F, Singh S, et al. Cystic Diseases of the Kidneys: From Bench to Bedside[J]. Indian J Nephrol, 2023, 33(2): 83-92. DOI: 10.4103/ijn.ijn_318_21.
[26] Olinger E, Alawi IA, Riyami MSA, et al. A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families[J]. Hum Mutat, 2021, 42(10): 1221-1228. DOI: 10.1002/humu.24251.
基金
国家重点研发计划（2022YFF1202600）
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