家族性少年型肾单位肾痨的临床和基因诊断

Clinical and genetic diagnosis of familial juvenile nephronophthisis

目的探讨少年型肾单位肾痨(NPH)临床和基因诊断。方法通过NPHP1基因纯合缺乏检测方法确诊1例中国人家族性少年型NPH。患儿为9岁男孩,因发现肾功能下降、贫血半年入院。尿沉渣检查正常,蛋白阴性;Ccr8.76ml/(min·1.73m2)。肾脏病理检查可见肾单位肾痨-肾髓质囊性病(NPH-MCKD)三联征。其姐6岁死于尿毒症。提取患儿及父母外周血DNA,PCR分别扩增NPHP1基因内多个微卫星标记。结果根据起病隐匿,肌酐清除率下降,诊断慢性肾衰竭。有肾脏疾病家族史,结合病理拟诊NPH-MCKD。系谱分析示常染色体隐性遗传,出现肾衰竭年龄为9岁,拟诊少年型NPH。基因分析结果示患儿仅D2S1896、del-16和RanBP11/12三者PCR扩增产物为阳性,说明该患儿存在NPHP1基因大片段纯合缺失,确诊少年型NPH。结论通过临床和肾脏病理拟诊NPH及其分型,基因分析可确诊。本病例为国内首个完整诊断并获确诊病例。

Objectives Juvenile nephronophthisis is one of the most common genetic causes of chronic renal failure in children. Its clinical diagnosis is difficult because of the nonspecific symptoms, so the diagnosis is mostly relied on the gene analysis. However, no genetic diagnosis has been reported in China yet. One case of genetic diagnosis of juvenile in one Chinese boy was reported. Methods The boy, 9 years old, was admitted because of renal failure and anemia for 6 months. His sister died of uremia at age of 6 and had anemia at 1 year old. The bey looked pale. His haemoglobulin was 56 g/L, the urine sediment examination was normal, the specific gravity of urine was 1.005 and clearance of creatinine was 8.76 ml/（min·1.73 m^2）. The histological features consisted of the disintegration of tubular basement membrane, the atrophy and dilation of renal tubules, the interstitial cell infiltration and fibrosis. The peripheral blood DNA was extracted from this bey and his parents. Gene analysis was performed by PCR amplification of satellite markers which located within the known homologous deletion of NPHPI, including del-2, del-9, del-16, del-5- （5） 2, del-10, and markers outside the deletion （RanBPll/12 and D2S1896） were used as controls. Results The bey was diagnosed with chronic renal failure according to his medical history and decreased Ccr. Also he was diagnosed with NPH-MCKD clinically by family history and pathological characteristics. He was suspected to have juvenile nephronophthisis based on autosomal recessive inheritance and the age of renal failure. By PCR amplification, the satellite markers of del-2, del-9, del-5-（5）2 and del-10 were missed, which indicated that there was the common large homologous deletion （250 kb） in the NPHPI. So the diagnosis of juvenile nephronophthisis was confirmed. Conclusions Nephronophthisis would be suspected by clinical manifestations and pathological findings, and the confirmation come from gene analysis. The confirmation of diagnosis could contribute to the reasonable management for such patients. It was the first juvenile nephronophthisis case confirmed by gene analysis for Chinese.