About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372C>T (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868G>A (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.

1.
Buscher AK, Konrad M, Nagel M, Witzke O, Kribben A, Hoyer PF, Weber S: Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. Clin Nephrol 2012;78:47-53.
2.
Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W: [Association of an anatomo-pathological syndrome of male pseudohermaphroditism, Wilms' tumor, parenchymatous nephropathy and XX/XY mosaicism]. Arch Fr Pediatr 1967;24:729-739.
3.
Drash A, Sherman F, Hartmann WH, Blizzard RM: A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease. J Pediatr 1970;76:585-593.
4.
Frasier SD, Bashore RA, Mosier HD: Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J Pediatr 1964;64:740-745.
5.
Lehnhardt A, Karnatz C, Ahlenstiel-Grunow T, Benz K, Benz MR, Budde K, Buscher AK, Fehr T, Feldkotter M, Graf N, Hocker B, Jungraithmayr T, Klaus G, Koehler B, Konrad M, Kranz B, Montoya CR, Muller D, Neuhaus TJ, Oh J, Pape L, Pohl M, Royer-Pokora B, Querfeld U, Schneppenheim R, Staude H, Sparta G, Timmermann K, Wilkening F, Wygoda S, Bergmann C, Kemper MJ: Clinical and molecular characterization of patients with heterozygous mutations in Wilms tumor suppressor gene 1. Clin J Am Soc Nephrol 2015;10:825-831.
6.
Lipska BS, Ranchin B, Iatropoulos P, Gellermann J, Melk A, Ozaltin F, Caridi G, Seeman T, Tory K, Jankauskiene A, Zurowska A, Szczepanska M, Wasilewska A, Harambat J, Trautmann A, Peco-Antic A, Borzecka H, Moczulska A, Saeed B, Bogdanovic R, Kalyoncu M, Simkova E, Erdogan O, Vrljicak K, Teixeira A, Azocar M, Schaefer F; PodoNet Consortium: Genotype-phenotype associations in WT1 glomerulopathy. Kidney Int 2014;85:1169-1178.
7.
Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K: Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 1997;17:467-470.
8.
Schumacher V, Schneider S, Figge A, Wildhardt G, Harms D, Schmidt D, Weirich A, Ludwig R, Royer-Pokora B: Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc Natl Acad Sci U S A 1997;94:3972-3977.
9.
Bockenhauer D, van't Hoff W, Chernin G, Heeringa SF, Sebire NJ: Membranoproliferative glomerulonephritis associated with a mutation in Wilms' tumour suppressor gene 1. Pediatr Nephrol 2009;24:1399-1401.
10.
Kohler B, Biebermann H, Friedsam V, Gellermann J, Maier RF, Pohl M, Wieacker P, Hiort O, Gruters A, Krude H: Analysis of the Wilms' tumor suppressor gene (WT1) in patients 46,XY disorders of sex development. J Clin Endocrinol Metab 2011;96:E1131-E1136.
11.
Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, Huff V: Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am J Med Genet A 2004;127A:249-257.
12.
Menke AL, IJpenberg A, Fleming S, Ross A, Medine CN, Patek CE, Spraggon L, Hughes J, Clarke AR, Hastie ND: The wt1-heterozygous mouse; a model to study the development of glomerular sclerosis. J Pathol 2003;200:667-674.
13.
Shimamura R, Fraizer GC, Trapman J, Lau YfC, Saunders GF: The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor. Clin Cancer Res 1997;3(12 pt 2):2571-2580.
14.
Gao F, Zhang J, Wang X, Yang J, Chen D, Huff V, Liu YX: Wt1 functions in ovarian follicle development by regulating granulosa cell differentiation. Hum Mol Genet 2014;23:333-341.
15.
Blanchet P, Daloze P, Lesage R, Papas S, Van Campenhout J: XY gonadal dysgenesis with gonadoblastoma discovered after kidney transplantation. Am J Obstet Gynecol 1977;129:221-222.
16.
Kottgen A, Hsu CC, Coresh J, Shuldiner AR, Berthier-Schaad Y, Gambhir TR, Smith MW, Boerwinkle E, Kao WH: The association of podocin R229Q polymorphism with increased albuminuria or reduced estimated GFR in a large population-based sample of US adults. Am J Kidney Dis 2008;52:868-875.
17.
Santin S, Tazon-Vega B, Silva I, Cobo MA, Gimenez I, Ruiz P, Garcia-Maset R, Ballarin J, Torra R, Ars E; FSGS Spanish Study Group: Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2011;6:344-354.
18.
Kerti A, Csohany R, Szabo A, Arkossy O, Sallay P, Moriniere V, Vega-Warner V, Nyiro G, Lakatos O, Szabo T, Lipska BS, Schaefer F, Antignac C, Reusz G, Tulassay T, Tory K: NPHS2 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome. Pediatr Nephrol 2013;28:751-757.
19.
Weber S, Buscher AK, Hagmann H, Liebau MC, Heberle C, Ludwig M, Rath S, Alberer M, Beissert A, Zenker M, Hoyer PF, Konrad M, Klein HG, Hoefele J: Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing. Pediatr Nephrol 2016;31:73-81.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.