INTRODUCTION أ¢â‚¬â€œ The term congenital nephrotic syndrome refers to disease which is present at birth or within the three first months of life. Later onset, between three months and one year of age, is called infantile nephrotic syndrome. Most of these children have a genetic basis for the renal disease and a poor outcome. The precise diagnosis of the glomerular lesion is based on clinical, laboratory and histological criteria. The congenital nephrotic syndrome of Finnish type (CNF) and diffuse mesangial sclerosis are the two main causes. There are, however, rare secondary and possibly curable disorders, such as congenital nephrotic syndrome induced by syphilis or toxoplasmosis .
CONGENITAL NEPHROTIC SYNDROME OF FINNISH TYPE أ¢â‚¬â€œ CNF is most frequent in Finland, with initial studies suggesting an incidence of 1.2 per 10,000 births [1,2]. With prenatal screening, the incidence has fallen to 0.9 per 10,000 births [3]. CNF has also been described in various ethnic groups throughout the world [4-6].
CNF is inherited as an autosomal recessive trait, with both sexes being involved equally. There are no manifestations of the disease in heterozygous individuals.
Pathology أ¢â‚¬â€œ Light microscopic studies of renal biopsy specimens obtained early in the course of the disease show mild mesangial hypercellularity and increased mesangial matrix in the glomeruli [4,7]. No immune deposits are detected by immunofluorescence studies. Over time, there is an increase in mesangial matrix accompanied by progressive glomerulosclerosis.
Tubulointerstitial changes are also prominent in CNF. Irregular microcystic dilatation of proximal tubules is the most striking feature; however, this change is not specific and is not seen in all patients [8]. Later in the course, interstitial fibrosis, lymphocytic and plasma cell infiltration, tubular atrophy, and periglomerular fibrosis develop in parallel with sclerosis of the glomeruli.
Pathogenesis أ¢â‚¬â€œ It has been proposed that proteinuria in CNF results from an inherited error in the structure of the glomerular capillary filter. The abnormal gene was localized to the long arm of chromosome 19 in both Finnish and non-Finnish families [9-11].
The defective gene in CNF has been cloned and is named NPHS1 [12,13]. The gene encodes for a transmembrane protein, named nephrin, which is a member of the immunoglobulin family of cell adhesion molecules and is phosphorylated by Src family kinases [14]. Nephrin is specifically located at the slit diaphragm of the glomerular podocytes; this could explain the absence of slit diaphragms and foot processes in patients with CNF who have a mutant nephrin protein [15,16] and in mice with nephrin gene disruption [17].
In the original report, four different mutations in this gene were found to segregate with the disorder in affected Finnish families [12]; however, the two most common mutations, Fin-major and Fin-minor, account for nearly 90 percent of all affected Finnish patients [12,18]. In another study, 32 novel mutations in the nephrin gene were discovered in patients elsewhere in Europe and North America, but no abnormalities were found in seven affected individuals (including the 5' flanking region) [19]. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin [20]. These results may indicate genetic heterogeneity in the disease.
Clinical features أ¢â‚¬â€œ Most infants with the CNF are born prematurely (35 to 38 weeks), with a low birth weight for gestational age. The placenta is enlarged, being more than 25 percent of the total birth weight. Fetal distress is common and the cranial sutures are widely separated due to delayed ossification. Infants often have a small nose and low ears. Flexion deformities of the hips, knees, and elbows are thought to be secondary to the large placenta.
Edema is present at birth or appears during the first week of life in one-half of cases. Severe nephrotic syndrome with marked ascites is always present by three months. The proteinuria is highly selective early in the course of the disease and hematuria is uncommon, reflecting the lack of inflammation in the glomeruli. The urinary protein losses are accompanied by profound hypoalbuminemia and severe hypogammaglobulinemia due in part to loss of selectivity as the disease progresses. As a result of these changes, nutritional status and statural growth are poor, and affected infants are highly susceptible to bacterial infections (peritonitis, respiratory infections) and to thromboembolic complications due to the severity of the nephrotic syndrome. Hypothyroidism due to urinary losses of thyroxine-binding proteins is also common.
The blood urea nitrogen and creatinine concentrations are initially normal. Renal ultrasonography shows enlarged, hyperechogenic kidneys without normal corticomedullary differentiation.
End-stage renal failure invariably occurs between three and eight years of age. Prolonged survival is possible with aggressive supportive treatment, including dialysis and renal transplantation.
Treatment أ¢â‚¬â€œ The nephrotic syndrome in CNF is always resistant to corticosteroids and immunosuppressive drugs, since this is not an immunologic disease. Furthermore these drugs may be harmful due to the already high susceptibility to infection. A retrospective study of 21 infants with CNF, for example, found that 63 verified and 62 suspected septic episodes occurred over a mean follow-up period of one year [21].
Standard conservative treatment includes daily or every other day albumin infusion, gamma globulin replacement, nutrition with a high-protein, low-salt diet, vitamin and thyroxine substitution, and prevention of infections and thrombotic complications. The diet is provided by tube feeding or by parenteral alimentation.
However, the rate of intercurrent complications remains high and growth and development are usually retarded. As a result, some patients may require bilateral nephrectomy to prevent continued massive protein losses before the development of renal failure.
A possible medical alternative to nephrectomy has been described in three children. The combination of an angiotensin converting enzyme inhibitor and indomethacin therapy, both of which should lower intraglomerular pressure, led to a marked fall in protein excretion and striking improvement in nutritional status and growth [22,23].
If nephrectomy is performed, dialysis is provided until the patient reaches a weight of 8 to 9 kg. At this stage, renal transplantation can be considered [24,25]. Nephrotic syndrome can develop in the transplanted organ, occurring in 13 of 51 allografts (25 percent) placed into 45 children [26]. All nine affected patients had the Fin-major/Fin-major genotype, which is associated with the absence of nephrin in the native kidneys. Antibodies directed against glomeruli were observed in eight affected patients. Four also had elevated anti-nephrin antibody levels, suggesting a possible cause for recurrent nephrosis.
Antenatal diagnosis أ¢â‚¬â€œ The CNF becomes manifest during early fetal life, beginning at the gestation age of 15 to 16 weeks. The initial symptom is fetal proteinuria, which leads to a more than 10-fold increase in the amniotic fluid alpha-fetoprotein (AFP) concentration. A parallel, but less important increase in the maternal plasma AFP level is observed. These changes are not specific, but they may permit the antenatal diagnosis of CNF in high risk families in which termination of the pregnancy might be considered [27].
However, false positive results do occur, often leading to abortion of healthy fetuses. In one study of 21 pregnancies that had been terminated because of increased AFP levels in amniotic fluid, only 12 fetuses were homozygous for nephrin gene mutations as determined by DNA sequencing [28]. The remaining nine were heterozygous carriers and would therefore not have developed CNF. The kidneys of both groups had a similar reduction in podocyte foot processes and slit pores.
Genetic linkage and haplotype analyses may diminish the risk of false positive results in informative families [29]. The four major haplotypes, which cover 90 percent of the CNF alleles in Finland, have been identified, resulting in a test with up to 95 percent accuracy. The recent identification of the gene responsible for the congenital nephrotic syndrome will soon permit antenatal diagnosis of the disease.
DIFFUSE MESANGIAL SCLEROSIS أ¢â‚¬â€œ Diffuse mesangial sclerosis is a second hereditary cause of infantile nephrotic syndrome associated with glomerular injury and rapid progression to end-stage renal failure. The same glomerular lesions are observed in the Drash syndrome which is characterized by the combination of nephropathy, male pseudohermaphroditism, and Wilms' tumor.
Diffuse mesangial sclerosis is seen exclusively in infancy [4,30-34] and appears to be transmitted in some families as an autosomal recessive trait [35]. The defective gene has not been identified.
Pathology أ¢â‚¬â€œ The glomerular lesions are characterized in the early stages by a fibrillar increase in mesangial matrix without mesangial cell proliferation [33-35]. The capillary walls are lined by hypertrophied podocytes. The fully developed lesion consists of the combination of thickening of the glomerular basement membranes and massive enlargement of mesangial areas, leading to reduction of the capillary lumens. The mesangial sclerosis eventually contracts the glomerular tuft into a sclerotic mass within a dilated urinary space. There is usually a corticomedullary gradient of involvement, with the deepest glomeruli being less affected. Tubules are severely damaged, especially in the deeper cortex where they are markedly dilated and often contain hyaline casts.
Electron microscopy reveals hypertrophic mesangial cells surrounded by an abundant mesangial matrix which often contains collagen fibrils. The podocytes are hypertrophied and contain many vacuoles. There is also irregular effacement of foot processes with focal detachment of the epithelial cell from the glomerular basement membrane.
Immunofluorescence shows mesangial deposits of IgM, C3, and C1q in the least affected glomeruli, while deposits of IgM and C3 outline the periphery of the sclerosed glomeruli. These immune deposits are probably nonspecific, occurring in areas of previous injury.
The same glomerular lesion is observed in the Drash syndrome (see below). As a result, all patients with diffuse mesangial sclerosis should be screened for the Drash syndrome. This consists of karyotyping in phenotypic females, looking for male pseudohermaphroditism with a 46 XY genotype, and ultrasonography should be performed in all patients, looking for Wilms' tumor and abnormal gonadal development. Some investigators also suggest that an assessment for mutations in the Wilms' tumor predisposing gene, WT1, should be performed to help identify individuals at risk for the tumor (see below) [36,37]. As an example, among 10 patients presenting with isolated diffuse mesangial sclerosis, four had mutations in the WT1 gene [37].
Pathogenesis أ¢â‚¬â€œ The pathogenesis of the isolated form of diffuse mesangial sclerosis is unknown. A primary defect involving the epithelial cell or one of the components of the glomerular extracellular matrix has been proposed.
Clinical and laboratory features أ¢â‚¬â€œ As opposed to the CNF, children with diffuse mesangial sclerosis appear normal at birth, with a normal birth weight and without placental enlargement. The nephrotic syndrome may be present at birth or even suspected in utero by the finding of an elevated plasma alpha-fetoprotein level in the mother or the discovery of large hyperechogenic kidneys [38]. More commonly, however, proteinuria with a bland urine sediment develops postnatally, increasing progressively during the first or the second year of life. Various types of extrarenal signs have been reported in isolated patients including nystagmus, cataract, mental retardation, microcephaly, severe myopia, muscular dystrophy.
All children progress to end-stage renal failure, frequently in association with hypertension. This usually occurs before age three, within a few months after the discovery of renal symptoms [34].
Treatment أ¢â‚¬â€œ Diffuse mesangial sclerosis is resistant to corticosteroids and immunosuppressive drugs. The degree of proteinuria it typically less severe than in the CNF and specific supplemental therapy is usually not required.
Treatment is supportive and consists of maintenance of electrolyte and water balance and adequate nutrition, prevention and treatment of infectious complications, and management of renal failure. Bilateral nephrectomy has been considered at the time of transplantation because of the theoretical risk of developing a Wilms' tumor. This issue remains unresolved, although Habib found no Wilms' tumor in the kidneys from 14 children with renal failure [34]. Recurrent disease does not develop in the transplant.
The combination of an angiotensin converting enzyme inhibitor and indomethacin therapy was used to treat one child with diffuse mesangial sclerosis [23]. The child had a sustained clinical response, normal growth pattern, and suffered no adverse effects.
DIFFUSE MESANGIAL SCLEROSIS WITH DRASH SYNDROME أ¢â‚¬â€œ Denys and Drash first reported the triad of progressive renal disease, male pseudohermaphroditism, and Wilms' tumor [39,40]. All of the patients were infants with heavy proteinuria progressing rapidly to renal failure. Incomplete forms of the syndrome were described and the glomerulopathy was identified as diffuse mesangial sclerosis [41].
Epidemiology and genetics أ¢â‚¬â€œ More than 60 cases of Drash syndrome have currently been reported [39-43]. The Drash syndrome is usually sporadic, although occurrence in two kindreds has been reported. However, constitutional mutations occur in the Wilms' tumor predisposing gene, WT1 [44].
Wilms' tumor is an embryonic kidney tumor thought to arise from aberrant mesenchymal stem cell differentiation secondary to the loss of a tumor suppressor gene or genes [45,46]. The WT1 gene lies at chromosomal position 11p13; it appears to encode a zinc finger protein which is probably a transcription factor [47-50]. WT1 is also expressed in the gonads, suggesting that the genital abnormalities in the Drash syndrome may result from pleiotropic effects of mutations in the WT1 gene itself. This hypothesis was first confirmed in a report which identified constitutional heterozygous mutations within the WT1 gene in some individuals with the Drash syndrome [51].
Subsequently, mutations of WT1 have been found in most patients with this syndrome. Most abnormalities are missense changes either in exon 9, which encodes for zinc finger 3 (with a mutational hot spot at an arginine residue thought to interact with the consensus DNA sequence), or in exon 8 which encodes for zinc finger 2 [52].
Clinical presentation أ¢â‚¬â€œ Diffuse mesangial sclerosis is a constant feature of the Drash syndrome. It is associated with the two other components of the triad in the complete form, but with only one of the two in the incomplete forms.
The clinical course of the nephropathy is not different from that described above in isolated diffuse mesangial sclerosis. However, Wilms' tumor may be the first clinical manifestation of the syndrome. Thus, careful renal ultrasonography should be performed, looking for nephroblastoma, in any patient found to have diffuse mesangial sclerosis. The tumor may be unilateral or bilateral and is associated in a few cases with nodules of nephroblastomatosis [35,44].
Male pseudohermaphroditism, characterized by ambiguous genitalia or female phenotype with dysgenetic testis or streak gonads, is observed in all 46 XY patients. In contrast, all 46 XX children appear to have a normal female phenotype, with normal ovaries, when the information was available. The finding of a normal male phenotype seems to exclude the diagnosis of Drash syndrome.
IDIOPATHIC NEPHROTIC SYNDROME أ¢â‚¬â€œ Idiopathic nephrosis rarely occurs at birth, more commonly presenting during the first year of life. All the morphological variants of idiopathic nephrotic syndrome seen in older children can occur at this time including minimal change disease, diffuse mesangial proliferation, and focal and segmental glomerular sclerosis.
Establishing the diagnosis of one of these disorders may be important clinically, since steroid-responsiveness with a favorable course can be seen [6,53]. However, most affected infants are resistant to therapy and many progress to end-stage renal disease.
Such cases are often familial and an autosomal recessive mode of inheritance has been observed. A causative gene for one of the autosomal recessive forms of this disorder has been identified using a positional cloning technique directed at the chromosomal area 1q25-31 [54]. It encodes an integral membrane protein, podocin, which is found exclusively in glomerular podocytes.
A locus on chromosome 2p appears to be responsible for some forms of steroid-sensitive idiopathic nephrosis, which is inherited in an autosomal recessive fashion [55]. Some affected families, however, do not display linkage to this locus, suggesting additional genetic heterogeneity.
OTHER أ¢â‚¬â€œ A number of other disorders are infrequent causes of infantile nephrotic syndrome:
أ¢â‚¬آ¢ Congenital syphilis can cause membranous nephropathy [56,57]. Histological examination often shows a mixed pattern with membranous nephropathy and mesangial proliferation. Penicillin treatment leads to the resolution of the syphilis and the renal abnormalities.
أ¢â‚¬آ¢ The nephrotic syndrome may be induced by congenital toxoplasmosis [58]. Proteinuria may be present at birth or may develop during the first three months, in association with ocular or neurological symptoms. Histological examination often shows mesangial proliferation with or without focal glomerulosclerosis. Treatment of toxoplasmosis or steroid therapy usually leads to remission of the proteinuria.
أ¢â‚¬آ¢ Congenital or infantile nephrotic syndrome has been reported in association with cytomegalovirus, rubeola virus, human immunodeficiency virus, and mercury intoxication.
أ¢â‚¬آ¢ The Galloway syndrome is characterized by microcephaly, mental retardation, hiatus hernia, and the nephrotic syndrome [59]. It appears to be transmitted as an autosomal recessive trait. The nephrotic syndrome is usually severe, resistant to steroid therapy and present from the first days of life. Renal biopsy reveals focal and segmental glomerulosclerosis. The underlying defect is not known.
References
1. Hallman, N, Hjelt, L. Congenital nephrotic syndrome. J Pediatr 1959; 55:152.
2. Hallman, N, Norio, R, Rapola, J. Congenital nephrotic syndrome. Nephron 1973; 11:101.
3. Levy, M, Feingold, J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000; 58:925.
4. Habib, R, Bois E. Heterogeneity of early onset nephrotic syndromes in infants (nephrotic syndrome "in infants"). Anatomical, clinical and genetic study of 37 cases. Helv Paediatr Acta 1973; 28:91.
5. Kaplan, BS, Bureau, MA, Drummond, KN. The nephrotic syndrome in the first year of life: Is a pathologic classification possible? J Pediatr 1974; 85:615.
6. Sibley, RK, Mahan, J, Mauer, SM, Vernier, RL. A clinicopathologic study of forty eight infants with nephrotic syndrome. Kidney Int 1985; 27:544.
7. Huttunen, RP, Rapola, J, Vilska, J, Hallman, N. Renal pathology of congenital nephrotic syndrome of Finnish type. A quantitative light microscopic study on 50 patients. Int J Pediatr Nephrol 1980; 1:10.
8. Rapola, J, Sariola, H, Ekblom, P. Pathology of fetal congenital nephrosis: Immunohistochemical and ultrastructural studies. Kidney Int 1984; 25:701.
9. Kestila, M, et al. Congenital nephrotic syndrome of the Finnish type maps to the long arm of chromosome 19. Am J Hum Genet 1994; 54:757.
10. Lenkkeri, U, Mannikko, M, McCready, P, et al. Am J Hum Genet 1999; 64:51.
11. Savage, JM, Jefferson, JA, Maxwell, AP, et al. Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families. Arch Dis Child 1999; 80:466.
12. Kestilط¸آ¹, M, Lenkkeri, U, Mط¸آ¹nnikkط¸ع¯, M, et al. Positionally cloned gene for a novel glomerular protein أ¢â‚¬â€œ nephrin أ¢â‚¬â€œ is mutated in congenital nephrotic syndrome. Mol Cell 1998; 1:575.
13. Pollak, MR. Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint. J Am Soc Nephrol 2002; 13:3016.
14. Lahdenpera, J, Kilpelainen, P, Liu, XL, Pikkarainen, T. Clustering-induced tyrosine phosphorylation of nephrin by Src family kinases. Kidney Int 2003; 64:404.
15. Ruotsalainen, V, Ljungberg, P, Wartiovaara, J, et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci U S A 1999; 96:7962.
16. Tryggvason, K. Unraveling the mechanisms of glomerular ultrafiltration: Nephrin, a key component of the slit diaphragm. J Am Soc Nephrol 1999; 10:2440.
17. Rantanen, M, Palmen, T, Patari, A, et al. Nephrin TRAP Mice Lack Slit Diaphragms and Show Fibrotic Glomeruli and Cystic Tubular Lesions. J Am Soc Nephrol 2002; 13:1586.
18. Patrakka, J, Kestila, M, Wartiovaara, J, et al. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int 2000; 58:972.
19. Lenkkeri, U, Mannikko, M, McCready, P, et al. Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 1999; 64:51.
20. Shih, NY, Li, J, Karpitskii, V, et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 1999; 286:312.
21. Ljungberg, P, Holmberg, C, Jalanko, H. Infection in infants with congenital nephrosis of the Finnish type. Pediatr Nephrol 1997; 11:148.
22. Pomeranz, A, Wolach, B, Bernheim, J, et al. Successful treatment of Finnish congenital nephrotic syndrome with captopril and indomethacin. J Pediatr 1995; 126:140.
23. Heaton, PA, Smales, O, Wong, W. Congenital nephrotic syndrome responsive to captopril and indometacin. Arch Dis Child 1999; 81:174.
24. Mahan, JD, Mauer, SM, Sibley, RK, Vernier, RC. Congenital nephrotic syndrome: The evolution of medical management and results of renal transplantation. J Pediatr 1984; 105:548.
25. Holmberg, C, Jalanko, H, Koskimies, O, et al. Renal transplantation in small children with congenital nephrotic syndrome of the Finnish type. Transplant Proc 1991; 23:1378.
26. Patrakka, J, Ruotsalainen, V, Reponen, P, et al. Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 2002; 73:394.
27. Ryynط¸آ¹nen, M, Seppط¸آ¹lط¸آ¹, M, Kuusela, P, et al. Antenatal screening for congenital nephrosis in Finland by maternal serum alpha-fetoprotein. Br J Obstet Gynaecol 1983; 90:437.
28. Patrakka, J, Martin, P, Salonen, R, et al. Proteinuria and prenatal diagnosis of congenital nephrosis in fetal carriers of nephrin gene mutations. Lancet 2002; 359:1575.
29. Mannikko, M, Kestila, M, Lenkkeri, U, et al. Improved prenatal diagnosis of the congenital nephrotic syndrome of the Finnish type based on DNA analysis. Kidney Int 1997; 51:868.
30. Beale, MC, Staver, DS, Kissane, JM, Robson, AM. Congenital glomerulosclerosis and nephrotic syndrome in 2 infants. Am J Dis Child 1979; 133:842.
31. Rumpelt, HJ, Bachmann, HJ. Infantile nephrotic syndrome with diffuse mesangial sclerosis: A disturbance of glomerular basement membrane development? Clin Nephrol 1980; 13:146.
32. Kikuta, Y, Yoshimura, Y, Saito, T, et al. Nephrotic syndrome with diffuse mesangial sclerosis in identical twins. J Pediatr 1983; 102:586.
33. Urbach, J, Drukker, A, Rosenmann, E. Diffuse mesangial sclerosis: Light, immunofluorescent and electron microscopy findings. Int J Pediatr Nephrol 1985; 6:101.
34. Habib, R. Nephrotic syndrome in the first year of life. Pediatr Nephrol 1993; 7:347.
35. Habib, R, Gubler, MC, Antignac, C, Gagnadoux, MF. Diffuse mesangial sclerosis: A congenital glomerulopathy with nephrotic syndrome. In: Advances in Nephrology, Grunfeld, JP (Ed), Year Book, Chicago, 1993, p. 43.
36. Schumacher, V, Scharer, K, Wuhl, E, et al. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int 1998; 53:1594.
37. Jeanpierre, C, Denamur, E, Henry, I, et al. Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am J Hum Genet 1998; 62:824.
38. Spear, GS, Steinhaus, KA, Quddusi, A. Diffuse mesangial sclerosis in a fetus. Clin Nephrol 1991; 36:46.
39. Denys, P, Malvaux, P, Van den Berghe, H, et al. Association d'un syndrome anatomopathologique de pseudo-hermaphrodisme masculin, d'une tumeur de Wilms, d'une nط£آ©phropathie parenchymateuse et d'un mosaicisme XX/XY. Arch Fr Pediatr 1967; 24:729.
40. Drash, A, Sherman, F, Hartmann, W, Blizzard, RM. A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension and degenerative renal disease. J Pediatr 1970; 76:585.
41. Habib, R, Loirat, C, Gubler, MC, et al. The nephropathy associated with male pseudohermaphroditism and Wilms' tumor (Drash syndrome: A distinctive glomerular lesion, report of 10 cases. Clin Nephrol 1985; 24:269.
42. Gallo, GB, Chemes, HE. The association of Wilm's tumor, male pseudohermaphroditism and diffuse glomerular disease (Drash syndrome): Report of 8 cases with clinical and morphologic findings and review of the literature. Pediatr Pathol 1987; 7:175.
43. Jadresic, L, Leake, J, Gordon, I, Dillon, MJ, Grant, DB, Pritchard, J. Clinicopathologic review of twelve children with nephropathy, Wilms' tumor and genital abnormalities (Drash syndrome). J Pediatr 1990; 117:717.
44. Coppes, MJ, Campbell, CE, Williams, BR. The role of WT1 in Wilms tumorigenesis. FASEB J 1993; 7:886.
45. Weinberg, RA. Tumor suppressor genes. Science 1991; 254:1138.
46. Huff, V. Wilms tumor genetics. Am J Med Genet 1998; 79:260.
47. Call, KM, Glaser, T, Ito, CY, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60:509.
48. Gessler, M, Pouska, A, Cavenee, W, et al. Homozygous deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping. Nature 1990; 343:774.
49. Haber, DA, Buckler, AJ, Glaser, T, et al. An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 1990; 61:1257.
50. Lee, SB, Huang, K, Palmer, R, et al. The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 1999; 98:663.
51. Pelletier, J, Bruening, W, Li, FP, et al. WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumor. Nature 1991; 353:431.
52. Little, M, Wells, C. A clinical overview of WT1 mutations. Hum Mutat 1997; 9:209.
53. Fuchshuber, A, Gribouval, O, Ronner, V, et al. Clinical and genetic evaluation of familial steroid-responsive nephrotic syndrome in childhood. J Am Soc Nephrol 2001; 12:374.
54. Boute, N, Gribouval, O, Roselli, S, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome [In Process Citation]. Nat Genet 2000; 24:349.
55. Ruf, RG, Fuchshuber, A, Karle, SM, Lemainque, A. Identification of the first gene locus (SSNS1) for steroid-sensitive nephrotic syndrome on chromosome 2p. J Am Soc Nephrol 2003; 14:1897.
56. Kaplan, BS, Wiglesworth, FW, Marks, MI, Drummond, KN. The glomerulopathy of congenital syphilis أ¢â‚¬â€œ an immune deposit disease. J Pediatr 1972; 81:1154.
57. Losito, A, Bucciarelli, E, Massi-Benedetti, F, Lato, M. Membranous glomerulonephritis in congenital syphilis. Clin Nephrol 1979; 12:32.
58. Shahin, B, Papadopoulou, ZL, Jenis, EH. Congenital nephrotic syndrome associated with congenital toxoplasmosis. J Pediatr 1974; 85:366.
59. Galloway, WH, Mowat, AP. Congenital microcephaly with hiatus hernia and nephrotic syndrome in two sibs. J Med Genet 1968; 5:319.
