Lin Fujun, Zhang Dan, Chang Juan, Tang Xuanli, Guan Wenbin, Jiang Gengru, Zhu Chun, Bian Fan
Renal Division, Department of Internal Medicine, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Renal Division, Department of Internal Medicine, Xin Hua Hospital (Chongming Branch) Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Eur J Med Genet. 2018 Feb;61(2):84-88. doi: 10.1016/j.ejmg.2017.10.014. Epub 2017 Oct 25.
Target antigens in idiopathic membranous nephropathy (MN) include the phospholipase A2 receptor (PLAR), and in some cases, the thrombospondin type 1 domain-containing 7A (THSD7A). A notable phenomenon is the high rate of cancer (reported to be as high as 20%) in patients with THSD7A-associated MN. Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by NF1 gene mutation, and clinically characterized by multiple cutaneous neurofibromas and café-au-lait spots. In this article, we report a patient with NF1 who developed THSD7A-associated MN when the NF1 skin lesions deteriorated. The patient, a 62-year-old male, was referred to us for nephrotic syndrome for 6 months. Physical examination revealed multiple cutaneous nodules throughout the entire body, and the patient noted recent increase in the numbers of these skin lesions. Cutaneous nodules excisional biopsy suggested NF1 and Sanger sequencing using genomic DNA extracted from peripheral blood revealed a previously reported heterozygous frameshift NF1 mutation (c.1541_1542delAG, p. Gln514fs). Renal biopsy revealed MN and immunohistochemistry (IHC) showed enhanced staining of THSD7A as well as PLAR along the glomerular basement membrane whereas the serum level of THSD7A and PLAR were both within normal range. The neurofibroma tissues were positive for THSD7A but not for PLAR on IHC. The patient did not respond to 6-month treatment with glucocorticosteroid and cyclophosphamide. In this exceptional case, strong positive staining of THSD7A in both skin and renal biopsy samples, together with the temporal association between nephrotic syndrome and skin lesions and lack of treatment response, suggested the possibility that MN could be the result of immune response to THSD7A in NF1. This report may improve understanding of the mechanistic link between MN and cancer.
特发性膜性肾病（MN）的靶抗原包括磷脂酶A2受体（PLAR），在某些情况下还包括含血小板反应蛋白1型结构域7A（THSD7A）。一个值得注意的现象是，与THSD7A相关的MN患者中癌症发生率很高（据报道高达20%）。1型神经纤维瘤病（NF1）是一种由NF1基因突变引起的常染色体显性疾病，临床特征为多发性皮肤神经纤维瘤和牛奶咖啡斑。在本文中，我们报告了一名NF1患者，当其NF1皮肤病变恶化时发生了与THSD7A相关的MN。该患者为62岁男性，因肾病综合征6个月前来就诊。体格检查发现全身有多个皮肤结节，患者注意到这些皮肤病变的数量最近有所增加。皮肤结节切除活检提示为NF1，使用从外周血提取的基因组DNA进行桑格测序，发现了先前报道的杂合移码NF1突变（c.1541_1542delAG，p.Gln514fs）。肾活检显示为MN，免疫组织化学（IHC）显示沿肾小球基底膜THSD7A以及PLAR染色增强，而THSD7A和PLAR的血清水平均在正常范围内。神经纤维瘤组织在IHC上THSD7A呈阳性，但PLAR呈阴性。该患者接受糖皮质激素和环磷酰胺治疗6个月无效。在这个特殊病例中，皮肤和肾活检样本中THSD7A均呈强阳性染色，以及肾病综合征与皮肤病变之间的时间关联和缺乏治疗反应，提示MN可能是NF1中对THSD7A免疫反应的结果。本报告可能有助于增进对MN与癌症之间机制联系的理解。
