46-XY Denys-Drash Syndrome. Is There a Role for Nephron-sparing Modalities in Management of Renal Masses? A Report of 2 Cases.

Denys-Drash syndrome (DDS) is a combination of genital and urinary anomalies that are mostly associated with renal and gonadal malignancies. We report 2 patients who presented with genital ambiguity and were diagnosed as 46-XY DDS. Both patients had renal masses during follow-up and underwent partial nephrectomy aiming to have transplant at older age.

Challenges to congenital genetic disorders with "RNA-targeting" chemical compounds.

Patients of congenital diseases such as Down syndrome (DS) and Duchenne muscular dystrophy (DMD) have abnormalities in their chromosomes and/or genes. Therefore, it has been considered that drug treatments can serve to do little for these patients more than to patch over each symptom temporarily when it arises. Although we cannot normalize their chromosomes and genes with chemical drugs, we may be able to manipulate the amounts and patterns of mRNAs transcribed from patients' DNAs with small chemicals. Based on this simple idea, we have looked for chemical compounds which can be applicable for congenital diseases and found that protein kinase inhibitors such as INDY, TG003, and SRPIN340 are promising as clinical drugs for DS, DMD, and DDS, respectively.

[Clinical and pathological features of Denys-Drash syndrome: report of 3 cases].

OBJECTIVE: To study the clinical and pathological features of Denys-Drash syndrome (DDS). METHOD: Three DDS cases who were treated in our department from December 2009 to June 2011 were subjected to this study by reviewing of literature. RESULT: Both case 1 and case 2 were female, with karyotype 46, XX. Case 3 was male with bilateral cryptorchidism. The ages of nephropathy onset of the three cases were 1 year and 9 months, 2 years and 8 moths, and 3 months respectively. Proteinuria in case 2 and case 3 were evidenced to be resistant to steroid. Case 1 was partially responsive to tacrolimus, plasma albumin and cholesterol were improved, although proteinuria was persistent after Tacrolimus was administered. Remission was achieved in case 2 after administration of cyclosporine A and later tacrolimus, and her renal function remains normal till present (4 years and 9 months). Residue renal histology revealed diffused mesangial sclerosis (DMS) in all three patients. All of the three patients had developed right unilateral Wilms tumor. A novel WT1 missense mutation exon 9 c.1213C > G was detected in case 1. WT1 exon 9 c.1168C > T nonsense mutation and exon 8 c.1130A > T missense mutation were detected in case 2 and case 3, respectively. CONCLUSION: The clinical manifestation of nephropathy in DDS is variable. The majority present with early onset nephropathy and reach renal failure before the age of 4 years. But in a few patients, nephropathy can also be present much later and progress slowly. Proteinuria in DDS is resistant to steroid but is responsive to calcineurin inhibitors, including Cyclosporine A. The effectiveness of tacrolimus was also observed in this study. DDS is evidently caused by WT1 mutation. DMS is the characteristic renal pathological change in DDS.

The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations.

Children with steroid-resistant nephrotic syndrome secondary to WT1-associated glomerulopathies (WT1-GP) were considered unresponsive to cyclosporin A (CsA). This assumption is challenged by the findings of recent studies. The patients of these studies had different types of WT1 mutations and varying clinical presentations. However, all of them were of young age and the favourable response to CsA might be the result of treatment at an early stage of the disease. The additional administration of angiotensin-converting enzyme inhibitors may have contributed to the positive outcome. We review recent data on the role of WT1 in the development of WT1-GP and discuss putative therapeutic targets explaining the therapeutic effect of CsA.

Effect of cyclosporin A on proteinuria in the course of glomerulopathy associated with WT1 mutations.

Denys-Drash syndrome (DDS) is characterized by progressive glomerulopathy caused by diffuse mesangial sclerosis (DMS), genitourinary defects, and a higher risk of developing Wilms' tumor. It is commonly assumed that the DMS is unresponsive to any medications. In this report, we present a patient with Denys-Drash syndrome, in whom the cyclosporine A (CsA) was found to induce total remission. This observation and observations of other authors confirm that in genetic forms of nephrotic syndrome, the proteinuric effect of CsA may be due to a non-immunologic mechanism. We confirm the beneficial effect of CsA treatment in DDS; however, the potential nephrotoxicity of this drug will probably not allow long-term use.