Sunwoo Yoon, Choi Naye, Min Jeesu, Kim Jihyun, Ahn Yo Han, Kang Hee Gyung
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, South Korea.
Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea.
Front Pediatr. 2023 Jan 11;10:1054082. doi: 10.3389/fped.2022.1054082. eCollection 2022.
Single gene pathogenic mutations have been implicated in up to 30% of pediatric steroid-resistant nephrotic syndrome (SRNS) cases, mostly in infantile patients. Among them is , which has been recently discovered and encodes the laminin α5 chain. The laminin α5β2γ1 heterotrimer is an essential component of the glomerular basement membrane and is necessary for embryogenesis and immune modulation. Biallelic variants have been identified in one adult and ten pediatric nephrotic syndromes (NS) patients with variable phenotypes. Biallelic truncating mutations in this gene have recently been proven to cause SRNS. Here, we present another case of infantile SRNS related to novel compound heterozygous variations of (c.3434G > A, p.Cys1145Tyr and c.6883C > T, p.Gln2295*), the first reported case with one missense and one nonsense allele. A 10-month-old female patient presented with eyelid edema and massive proteinuria without any extrarenal symptoms or family history. The patient was diagnosed with SRNS. Renal biopsy revealed focal segmental glomerulosclerosis with widely effaced epithelial foot processes and a "moth-eaten" appearance. She progressed to end stage kidney disease (ESKD), requiring dialysis at 31 months of age, and underwent a deceased-donor kidney transplant at 6 years of age. Four months after transplantation, she developed Ebstein-Barr Virus (EBV) infection related to post-transplantation lymphoproliferative disorder (PTLD). After chemotherapy, the patient remained healthy with adequate renal function without disease recurrence for the past 7 years. We also identified previous cases of biallelic variants associated with the nephrotic phenotype and analyzed the available clinical and genetic information. All reported patients had an onset of NS ranging from 3 months to 8 years, with no other syndromic features. Response to therapy and renal outcomes varied greatly; most patients exhibited steroid resistance, five progressed to ESKD, and two received kidney transplantation (KT). There was one report of PTLD. Our patient's phenotype was markedly more severe than those with biallelic missense variants and somewhat less severe than those with two truncating variants. defects may also play a role in PTLD, though no conclusions can be made with such limited cases. should be considered a candidate gene for SRNS and should be actively tested in cases with no other genetic diagnosis.
单基因致病突变在高达30%的儿童激素抵抗性肾病综合征（SRNS）病例中被发现，主要见于婴儿患者。其中， 最近被发现，它编码层粘连蛋白α5链。层粘连蛋白α5β2γ1异源三聚体是肾小球基底膜的重要组成部分，对胚胎发育和免疫调节至关重要。在一名成人和十名患有不同表型的儿童肾病综合征（NS）患者中发现了双等位基因变异。最近已证实该基因的双等位基因截短突变会导致SRNS。在此，我们报告另一例与 （c.3434G＞A，p.Cys1145Tyr和c.6883C＞T，p.Gln2295*）的新型复合杂合变异相关的婴儿SRNS病例，这是首例报告的一个错义等位基因和一个无义等位基因的病例。一名10个月大的女性患者出现眼睑水肿和大量蛋白尿，无任何肾外症状或家族史。该患者被诊断为SRNS。肾活检显示局灶节段性肾小球硬化，上皮足突广泛消失，呈“虫蚀样”外观。她进展为终末期肾病（ESKD），31个月大时需要透析，6岁时接受了尸体供肾移植。移植后四个月，她发生了与移植后淋巴细胞增殖性疾病（PTLD）相关的EB病毒（EBV）感染。化疗后，患者在过去7年中肾功能良好，保持健康，无疾病复发。我们还确定了先前与肾病表型相关的双等位基因 变异病例，并分析了现有的临床和基因信息。所有报告的患者NS发病年龄在3个月至8岁之间，无其他综合征特征。对治疗的反应和肾脏结局差异很大；大多数患者表现为激素抵抗，5例进展为ESKD，2例接受了肾移植（KT）。有一例PTLD报告。我们患者的表型明显比双等位基因错义变异患者严重，比两个截短变异患者稍轻。 缺陷可能在PTLD中也起作用，尽管如此有限的病例无法得出结论。 应被视为SRNS的候选基因，在没有其他基因诊断的病例中应积极进行检测。
