nephrotic syndrome in the first year of life in two thirds of cases is caused by mutations in four genes ( nphs1 , nphs2 , wt1 , and lamb2 ) . the wilms tumor suppressor gene 1 ( wt1 ) encodes a transcription factor involved in kidney and gonadal development . drash syndrome ( dds ) and frasier syndrome ( fs ) , two syndromes characterized by nephrotic syndrome ( ns ) with either diffuse mesangial sclerosis ( dms ) in dds or focal segmental glomerulosclerosis ( fsgs ) in fs , genitourinary defects and a higher risk of developing wilms tumor in dds , or gonadal dysgerminoma in both dds and fs . .   recently published three children with fsgs on renal biopsy and wt1 mutations , who responded to intensified therapy consisting of oral cyclosporine a ( csa ) in combination with oral or intravenous glucocorticoids . the mechanism of csa action in minimal change disease was the inhibition of nuclear factor of activated t cell ( nfat ) signaling in t lymphocytes . however , the therapeutic effect of csa in genetic nephrotic syndrome is probably related to a direct influence of csa on podocytes .   in this report , we present a patient with denys  drash syndrome , in whom the calcineurin inhibitors were found to induce total remission . our patient is the first child of non - consanguineous young parents ( mother 32 , father 34  years ) without any past medical history of kidney diseases . the infant was born at 41  weeks gestation ( birth weight 3,450  g , length 55  cm ) . the delivery and neonatal period were normal . at the age of 7  months , she was hospitalized for the first time in the pediatric nephrology department because of proteinuria and hematuria , which was found in routine urinalysis performed before the vaccination . on admission , physical examination revealed no edema , normal female external genitalia , and normal body weight and height for chronological age . initial laboratory investigations revealed variable non - selective proteinuria 200960  mg / dl in morning sample , protein / creatinine ratio 27  g / g , hypoproteinemia ( 4.79  g / dl ) , hypoalbuminemia ( 3.0  g / dl ) , hypercholesterolemia ( 299  mg / dl ) , thrombocytosis ( 567    10/l ) , and reduced levels of igg and iga . the serum creatinine level was 0.23  mg / dl , urea was 8  mg / dl , and the glomerular filtration rate was 133  ml / min/1.73  m by the schwartz formula . antinuclear antibodies were negative , and the level of c3 and c4 were within normal limits . chromosomal analysis demonstrated karyotype 46 , xx , and the biopsy of the kidney demonstrated diffuse mesangial proliferation and diffuse fibrillar increase , what may represent early stage of diffuse mesangial sclerosis . the glomerular lesions contained high amount of fibrils in the mesangial matrix with diffuse mesangial proliferation . immunofluorescence on frozen sections using rabbit polyclonal antisera against human igg , iga , igm , and c3 revealed only weak segmental igm staining . the molecular genetic analysis was performed in the laboratory at the university of michigan in the usa . mutation analysis of exons 8 to 9 of wt1 was performed , and the mutation r394w ( c. 1180 c  >  t ) was found in our patient . the treatment with enalapril ( 1.25  mg / day ) , which was started after the admission and was continued for 11  months , did not change the proteinuria significantly . there was no reduction in proteinuria after 4-week oral prednisone treatment ( 60  mg / m / day ) . seven months later , we started the therapy with csa ( 6  mg / kg/24  h in two divided doses ) . the pre - dose / trough ( c0 ) csa level was 104.4  ng / ml . the serum total protein was ( 6.47  mg / dl ) , albumin ( 4.26  mg / dl ) , cholesterol 197  mg / dl , and platelet count 385    10/ql . creatinine level was 0.32  mg / dl and the glomerular filtration rate was 147  ml / min/1.73  m. the pre - dose / trough ( c0 ) csa level was 95.03  ng / ml . at the 6  month of the treatment , we decided for csa dose reduction to 4.5  mg / kg , but a month later , slight proteinuria was observed . now csa treatment is continued with the higher dose ( 6  mg / kg/24  h ) . the ultrasonography examination , performed every 3  months , has not revealed any signs of tumor . we report the benefits of csa treatment of the patient with glomerulopathy associated with wt1 mutation as seen in denys  drash syndrome . the girl in this report had early - onset srns secondary to dms , what was confirmed in kidney biopsy . genetic studies showed mutations in intron 9 of wt1 gene c. 1180 c  >  t. this is the most common mutation found in dds . mutations in exons 8 and 9 of the wt1 gene have been found in patients with isolated srns and in srns associated with wilms tumor or urogenital malformations . .   indicated that screening of wt1 exons 8 and 9 in patients with sporadic srns is sufficient to detect pathogenic wt1 mutations . it is possible that our patients have an incomplete form of dds ; however , it corresponds to the observation of ismaili et al . , who reported the presence of wilms tumor in only one of two patients with dds . chernin et al .   in the recent publication suggested that missense mutations can occur with and without wilms tumor . in our patient , in this situation , csa therapy was started with a significant reduction of proteinuria and remission of nephrotic syndrome . three months later , complete remission of proteinuria was found . whereas genetic forms of nephrotic syndrome do not respond to therapy with immunosuppressive drugs , partial remission has been reported following therapy with calcineurin inhibitors in patients with nphs2 , frasier syndrome , mutations of the phospholipase c epsilon gene ( plce1 ) , and alport syndrome [ 3 , 4 ] . reported three children with fsgs associated with wt1 mutation treated with combined csa and prednisone therapy given for 6 and 12  months . in long - term observation , the authors observed remission of ns and significant reduction of proteinuria . the therapy does not seem to be accompanied by a significant loss of renal function on the short term . we plan to continue the treatment with the lowest possible dose which controls the proteinuria . it was considered that the main effect of csa treatment in nephrotic syndrome caused by t cell dysfunction was the inhibition of nfat signaling in t cells . however , it was found that csa can also reduce proteinuria in non - immunological diseases , raising doubts about the above hypothesis . in genetic diseases , mechanisms similarly , the afferent arteriole vasoconstriction , which is induced by csa , does not seem to play the main role in the reduction of proteinuria . this fact was suggested by zietse et al . , who studied the influence of csa on proteinuria in different glomerulopathies and found the reduction of protein excretion in minimal change disease , but not in membranoproliferative glomerulonephritis or fsgs . the possible mechanism in genetic ns may be that proposed by faul et al . . the authors suggested the influence of csa on synaptopodin , an actin binding protein that was highly expressed in podocytes . it was shown that calcineurin caused the dephosphorylation of synaptopodin and caused proteinuria via its degradation . this mechanism seems to be possible because significant reduction ( 30% ) of csa dose caused the slight proteinuria in our patient , so we increased the dose to initial one . our observation seems to confirm the theory of mundel and reiser , who suggested that proteinuria is due to an enzymatic disease of the podocytes . it is likely that podocytes are a direct target of csa , which preserves the phosphorylation - dependent synaptopodin-14 - 3 - 3beta interaction , protects synaptopodin from degradation , and preserves a stable filtration barrier [ 7 , 17 ] . the fact that the antiproteinuric effect of csa results from a direct effect on podocytes explains not only its beneficial role in most steroid - resistant and steroid - dependent nephrotic syndromes but also the fact of cyclosporine dependency . our observation and observations of other authors [ 3 , 4 , 9 , 12 , 15 ] confirm the beneficial effect of csa treatment in genetic ns ; however , the potential nephrotoxicity of this drug will probably not allow the long - term use .
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 .