Aucella Filippo, Bisceglia Luigi, De Bonis Patrizia, Gigante Maddalena, Caridi Gianluca, Barbano Giancarlo, Mattioli Gerolamo, Perfumo Francesco, Gesualdo Loreto, Ghiggeri Gian Marco
Nephrology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Pediatr Nephrol. 2006 Oct;21(10):1393-8. doi: 10.1007/s00467-006-0225-0. Epub 2006 Aug 15.
WT1 mutations have been considered a rare cause of nephrotic syndrome but recent reports challenge this assumption. Exclusion of inherited forms is a basic point in any therapeutic strategy to nephrotic syndrome since they do not respond to drugs. We screened for WT1 mutations in 200 patients with nephrotic syndrome: 114 with steroid resistance (SRNS) and 86 with steroid dependence (SDNS) for whom other inherited forms of nephrotic syndrome (NPHS2, CD2AP) had been previously excluded. Three girls out of 32 of the group with steroid resistance under 18 years presented classical WT1 splice mutations (IVS9+5G>A, IVS9+4C>T) of Frasier syndrome. Another one presented a mutation coding for an amino acid change (D396N) at exon 9 that is typical of Denys-Drash syndrome. All presented resistance to drugs and developed end stage renal failure within 15 years. Two girls of the Frasier group presented a 46 XY karyotype with streak gonads while one was XX and had normal gonad morphology. In the two cases with IVS9+5G>A renal pathology was characterized by capillary wall thickening with deposition of IgG and C3 in one that was interpreted as a membrane pathology. Foam cells were diffuse in tubule-interstitial areas. In conclusion, WT1 splice mutations are not rare in females under 18 years with SRNS. This occurs in absence of a clear renal pathology picture and frequently in absence of phenotype change typical of Frasier syndrome. In adults and children with SDNS, screening analysis is of no clinical value. WT1 hot spot mutation analysis should be routinely done in children with SRNS; if the molecular screening anticipates any further therapeutic approach it may modify the long term therapeutic strategy.
WT1突变曾被认为是肾病综合征的罕见病因，但近期报告对这一假设提出了挑战。排除遗传性形式是任何肾病综合征治疗策略的基本要点，因为它们对药物无反应。我们对200例肾病综合征患者进行了WT1突变筛查：114例为激素抵抗型（SRNS），86例为激素依赖型（SDNS），此前已排除其他遗传性肾病综合征形式（NPHS2、CD2AP）。在18岁以下的32例激素抵抗组患者中，有3名女孩出现了Frasier综合征典型的WT1剪接突变（IVS9+5G>A、IVS9+4C>T）。另一名患者在外显子9处出现了编码氨基酸变化（D396N）的突变，这是Denys-Drash综合征的典型特征。所有患者均对药物耐药，并在15年内发展为终末期肾衰竭。Frasier组的两名女孩核型为46 XY，性腺呈条索状，而另一名为XX，性腺形态正常。在IVS9+5G>A的两例病例中，肾脏病理特征为毛细血管壁增厚，其中一例有IgG和C3沉积，被解释为膜性病变。泡沫细胞在肾小管间质区域弥漫分布。总之，WT1剪接突变在18岁以下的SRNS女性中并不罕见。这种情况在没有明确的肾脏病理表现时发生，且常常没有Frasier综合征典型的表型改变。对于成人和儿童SDNS患者，筛查分析无临床价值。对于SRNS儿童应常规进行WT1热点突变分析；如果分子筛查能为进一步的治疗方法提供依据，可能会改变长期治疗策略。
