肾病综合征合并寻常性鱼鳞病临床特征及相关基因突变研究

Clinical features of the nephrotic syndrome associated with ichthyosis vulgaris and analysis of related gene mutation

目的研究肾病综合征（nephrotic syndrome，NS）合并寻常性鱼鳞病（ichthyosis vulgaris，Ⅳ）患儿的临床特征，探讨FLG基因及NPHS2基因与疾病之间的关系。方法分析我院3例NS合并Ⅳ患儿的临床、病理资料，并采用聚合酶链反应-单链构象多态性、DNA测序法，分析患儿NPHS2基因及患儿和3个家系中的部分Ⅳ患者的FLG基因。结果①3例NS合并Ⅳ患儿（1号女性，2号、3号为男性）对激素及多种免疫抑制剂治疗反应均差，随访观察1．5～4年未缓解。②1号患儿的兄长死于“尿毒症”，其他2个家系中无肾脏疾病患者。③初次肾活检，2例为轻度系膜增生性肾小球肾炎，1例为微小病变；其中2例患儿在第1次肾活检的1年半后，重复肾活检，进展为中度系膜增生性肾小球肾炎。④3例患儿及3个家系中部分Ⅳ患者均具有FLG基因常见的突变类型R501X和（或）2282del4，没有发现NPHS2基因突变。结论3例NS合并Ⅳ患儿对激素及免疫抑制剂均耐药，肾脏病理损害进展较快，提示患儿对激素及免疫抑制剂耐药可能与FLG基因相关联。

Objective To study clinical features of 3 children who presented with nephrotic syndrome （NS） associated with ichthyosis vulgaris （Ⅳ）, and to detect relationship between NS associated with Ⅳ in patients and FLG gene or NPHS2 gene. Method Clinical and kidney pathological data of the 3 patients were analyzed and progress of pathologic damage in the patient kidney was observed through repeated percutaneous renal biopsy. Using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing, the diversity of the expression of NPHS2 gene in the 3 patients were analyzed, and FLG gene in the 3 patients and parts of their family members with Ⅳ was detected. Result （1） The age of the 3 patients （patient 1 was a girl and patients 2 and 3 were boys） suffering from NS was 3 years and 8 months, 2 years and 6 months, and 5 years and 3 months, respectively. The age of onset of Ⅳ was 1 year and 6 months, 10 months, and 2 years and 6 months, respectively. All the 3 patients were resistant to steroid therapy. Despite multi-immunosuppressive therapy, no clinical response was achieved. The patients were followed up for 1.5 to 4. 0 years. The patients displayed continuous proteinuria, renal function was normal, but their heights were lower than other children at the same age. （2） The older brother of patient 1 died of uremia. The other patients＇ family members did not have kidney disease. （3） Renal histopathology showed that the patients 1 and 2 had mild mesangial proliferative glomerulonephritis （MsPGN） and the patient 3 had minimal change disease （MCD）. One and a half years after the first renal biopsy, the patients 1 and 2 underwent repeated renal biopsy. Renal histopathology showed that the 2 patients＇ disease developed to medium MsPGN. （4） None of the 3 patients had NPHS2 gene mutation. All the three patients had R501X and 2282de14 which are the common gene mutation type of the FLG, and all the patients were heterozygote. With the detection of the FLG gene of the part of the patients of the three families, the second patient＇s grandfather had the R501X homozygote mutation and the others were the R501X heterozygote mutation and 2282de14 heterozygote mutation. Conclusion The 3 cases of NS associated with Ⅳ had no response to steroid and multi-immunosuppressive therapy, the renal damage observed by histopathology progressed fast. The children with NS associated with Ⅳ displayed R501X heterozygote mutation and 2282de14 heterozygote mutation of FLG gene, which suggested that the absence of response to steroid and multi-immunosuppressive therapy may be related to the FLG gene.