ORPHA: 656; DO: 0080383;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p13 | Nephrotic syndrome, type 4 | 256370 | Autosomal dominant | 3 | WT1 | 607102 |
A number sign (#) is used with this entry because of evidence that this form of renal disease, referred to here as nephrotic syndrome type 4 (NPHS4), is caused by heterozygous mutation in the Wilms tumor suppressor gene (WT1; 607102) on chromosome 11p13.
Mutation in the WT1 gene can also cause isolated Wilms tumor (194070), as well as Denys-Drash syndrome (DDS; 194080), which is characterized by nephrotic syndrome and the additional features of male pseudohermaphroditism, with or without Wilms tumor.
Nephrotic syndrome, a malfunction of the glomerular filter, leads to proteinuria, edema, and, in steroid-resistant nephrotic syndrome, end-stage renal disease (ESRD). Renal histopathology in NPHS4 due to WT1 mutations most often shows diffuse mesangial sclerosis (DMS), but can also show focal segmental glomerulosclerosis (FSGS). Both of these terms refer to pathologic findings and may be associated with the same clinical phenotype, namely nephrotic syndrome (review by Schumacher et al., 1998).
For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).
Mendelsohn et al. (1982) reported 5 children in 2 related Israeli Arab families with a clinical picture characterized by onset in infancy of asymptomatic proteinuria with subsequent development of the nephrotic syndrome and progression to renal failure and death before the age of 3 years. The clinical picture and renal histopathology were those described by Habib and Bois (1973) as infantile mesangial sclerosis. Familial occurrence had been noted by Habib and Bois (1973), Rossenbeck et al. (1966), and Gonzales et al. (1977).
Jeanpierre et al. (1998) studied 10 patients with nephrotic syndrome and renal insufficiency associated with diffuse mesangial sclerosis on renal biopsy. These patients were selected on the basis of the presence of renal mesangial sclerosis in the absence of structural urogenital abnormalities and Wilms tumor. Three of the patients were male. One male and 3 female patients underwent normal pubertal development, whereas the other patients were still too young. Follow-up examinations had not demonstrated Wilms tumor, and there were no other congenital abnormalities and no family history of developmental or renal abnormalities. The parents of 1 patient were consanguineous. Jeanpierre et al. (1998) also reported 10 other patients with diffuse mesangial sclerosis on renal biopsy in the context of DDS. Nine of the patients had the 46,XY karyotype and genital abnormalities ranging from testicular ectopia to female phenotype. One patient had the 46,XX karyotype and streaked ovaries. Unilateral WT was diagnosed in 2 patients, and gonadoblastoma was diagnosed in 2 other patients. For all 20 patients, the age at which the first symptoms of nephrotic syndrome were observed varied from birth to 4.3 years. The age at end-stage renal disease was 18 days to 4.5 years, except for 1 patient who developed ESRD at age 11 years 6 months. Two patients died of ESRD during the first month of life. Two patients, aged 6 years and 2.9 years, had not yet developed ESRD.
Schumacher et al. (1998) identified WT1 mutations in 10 children with early-onset nephrotic syndrome. Two genotypically female girls had isolated congenital/infantile nephrotic syndrome. Seven other patients, all of whom were genotypic males, had additional urogenital features consistent with DDS, such as uterus/vagina, ambiguous genitalia, or micropenis. The eighth child, a genotypic female, developed Wilms tumor at age 18 months, and was thus classified as having incomplete DDS. Renal biopsy showed diffuse mesangial sclerosis in 8 and focal segmental glomerulosclerosis in 2 cases. End-stage renal disease was reached either concomitantly or within 4 months after onset of nephrotic syndrome in 7 patients. Four children developed Wilms tumor either before or concomitant with nephrotic syndrome. No WT1 mutations were found in 7 other children with isolated nephrotic syndrome who appeared to have a slower progression than the first group and who did not have Wilms tumor. Schumacher et al. (1998) proposed that patients with early-onset, rapidly progressive nephrotic syndrome and diffuse mesangial or focal segmental glomerulosclerosis on renal biopsy should be tested for WT1 mutations to identify those at risk for developing Wilms tumor.
The transmission pattern of NPHS4 in the patients reported by Jeanpierre et al. (1998) was consistent with autosomal dominant inheritance.
Of 10 patients with nephrotic syndrome associated with diffuse mesangial sclerosis on renal biopsy, 10 with DDS, and 4 with only urogenital abnormalities and/or Wilms tumor, Jeanpierre et al. (1998) identified heterozygous mutations in the WT1 gene in 16, 4 of whom presented with renal dysfunction. Two of the 4 mutations had previously been identified in patients with DDS (607102.0006 and 607102.0012), one had previously been identified in patients with Frasier syndrome (607102.0018), and one was novel (607102.0022). An analysis of genotype/phenotype correlations showed an association between mutations in exons 8 and 9 of the WT1 gene and nephrotic syndrome; among patients with nephrotic syndrome and diffuse mesangial sclerosis, there was a higher frequency of exon 8 mutations among 46,XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype. There was also statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.
Ito et al. (2001) described 7 Japanese patients with nephrotic syndrome associated with diffuse mesangial sclerosis. WT1 mutations were detected in 2 of these patients.
In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic terms 'focal segmental glomerulosclerosis' (FSGS) and 'diffuse mesangial sclerosis' (DMS) have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature.
Gonzales, G., Kleinknecht, C., Gubler, M. C., Lenoir, G. Syndromes nephrotiques familiaux. Rev. Pediat. 13: 427-433, 1977.
Habib, R., Bois, E. Heterogenite des syndromes nephrotiques a debut precoce du nourrison (syndrome nephrotique 'infantile'). Helv. Paediat. Acta 28: 91-107, 1973. [PubMed: 4706144]
Ito, S., Takata, A., Hataya, H., Ikeda, M., Kikuchi, H., Hata, J., Honda, M. Isolated diffuse mesangial sclerosis and Wilms tumor suppressor gene. J. Pediat. 138: 425-427, 2001. [PubMed: 11241056] [Full Text: https://doi.org/10.1067/mpd.2001.111317]
Jeanpierre, C., Denamur, E., Henry, I., Cabanis, M.-O., Luce, S., Cecille, A., Elion, J., Peuchmaur, M., Loirat, C., Niaudet, P., Gubler, M.-C., Junien, C. 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. 62: 824-833, 1998. [PubMed: 9529364] [Full Text: https://doi.org/10.1086/301806]
Mendelsohn, H. B., Krauss, M., Berant, M., Lichtig, C. Familial early-onset nephrotic syndrome: diffuse mesangial sclerosis: clinico-pathological study of a kindred. Acta Paediat. Scand. 71: 753-758, 1982. [PubMed: 7180443] [Full Text: https://doi.org/10.1111/j.1651-2227.1982.tb09514.x]
Rossenbeck, H. G., Margraf, O., Hofmann, D. Ueber das infantile nephrotische Syndrom bei kongenitaler Glomerulonephritis. Dtsch. Med. Wschr. 91: 348-355, 1966.
Schumacher, V., Scharer, K., Wuhl, E., Altrogge, H., Bonzel, K.-E., Guschmann, M., Neuhaus, T. J., Pollastro, R. M., Kuwertz-Broking, E., Bulla, M., Tondera, A.-M., Mundel, P., Helmchen, U., Waldherr, R., Weirich, A., Royer-Pokora, B. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int. 53: 1594-1600, 1998. [PubMed: 9607189] [Full Text: https://doi.org/10.1046/j.1523-1755.1998.00948.x]