J Korean Med Sci.  2006 Feb;21(1):160-164. 10.3346/jkms.2006.21.1.160.

Two Cases of Isolated Diffuse Mesangial Sclerosis with WT1 Mutations

• Hahn H
• Cho YM
• Park YS
• You HW
• Cheong HI

• KMID: 2157801
• DOI: http://doi.org/10.3346/jkms.2006.21.1.160

Abstract

Here we report two cases of isolated diffuse mesangial sclerosis (IDMS) with early onset end-stage renal failure. These female patients did not show abnormalities of the gonads or external genitalia. Direct sequencing of WT1 PCR products from genomic DNA identified WT1 mutations in exons 8 (366 Arg>His) and 9 (396 Asp>Tyr). These mutations have been reported previously in association with Denys-Drash syndrome (DDS) with early onset renal failure. Therefore we suggest that, at least in part, IDMS is a variant of DDS and that investigations for the WT1 mutations should be performed in IDMS patients. In cases with identified WT1 mutations, the same attention to tumor development should be required as in DDS patients, and karyotyping and serial abdominal ultrasonograms to evaluate the gonads and kidney are warranted.

Keyword

Denys-Drash Syndrome; Diffuse Mesangial Sclerosis; WT1 Proteins; Genes, Wilms Tumor

MeSH Terms

Base Sequence
DNA/chemistry/genetics
DNA Mutational Analysis
Fatal Outcome
Female
Glomerular Mesangium/*pathology
Humans
Infant
Infant, Newborn
*Mutation
Nephrosclerosis/*genetics
WT1 Proteins/*genetics

Figure

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  Fig. 1 Renal biopsy showing glomeruli with diffuse mesangial sclerosis (PAS, ×200).

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  Fig. 2 Sequence analysis of WT1 exon 8 from the DNA of patient 1, with a G>A alteration changing amino acid 366 from Arg to His.

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  Fig. 3 Renal biopsy showing small glomeruli with mesangial sclerosis and collapsed capillary lumens. Some tubules are dilated and contain protein casts, with epithelial degeneration and regenerative activity (PAS, ×400).

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  Fig. 4 Sequence analysis of WT1 exon 9 from the DNA of patient 2, with a heterozygous G>T alteration changing amino acid 396 from Asp to Tyr, and a heterozygous polymorphism of 395 Ser (TCC) > Ser (TCA).

Reference

1. Little M, Wells C. A clinical overview of WT1 gene mutations. Hum Mutat. 1997. 9:209–225.

2. Dressler GR. Transcription factors in renal development: the WT1 and pax-2 story. Semin Nephrol. 1995. 15:263–271.

3. Moore AW, McInnes L, Kreidberg J, Hastie ND, Schedl A. YAC complementation shows a requirement for WT1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development. 1999. 126:1845–1857.

4. Guo JK, Menke AL, Gubler MC, Clarke AR, Harrison D, Hammes A, Hastie ND, Schedl A. WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. Hum Mol Genet. 2002. 11:651–659.

5. Englert C. WT1; More than a transcription factor? Trends Biochem Sci. 1998. 23:389–393.

6. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier , Houssman D, Jaenisch R. WT-1 is required for early kidney development. Cell. 1993. 74:679–691.

7. Wilhelm D, Englert C. The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev. 2002. 16:1839–1851.

8. Denys P, Malvaux P, van den Berghe H, Tanghe W, Proesmans W. De pseudohermaphrodisme masculin, d'une tumeur de Wilms, d'une nephropathie parenchymateuse et d'un mosaicisme XX/XY. Archives Francaises de Pediatrie. 1967. 24:729–739.

9. Drash A, Sherman F, Harmann WH, Blizzard RM. A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension and degenerative renal disease. J Pediatr. 1970. 76:585–593.

10. Habib R, Loirat C, Gubler MC, Niaudet P, Bensman A, Levy M, Broyer M. The nephropathy associated with male pseudohermaphroditism and Wilms' tumor (Drash syndrome): a distinctive glomerular lesion? Report of 10 cases. Clin Nephrol. 1985. 24:269–278.

11. Jadresic L, Leake J, Gordon I, Dillon MJ, Grant DB, Pritchard J, Risdon RA, Barratt TM. Clinicopathologic review of twelve children with nephropathy, Wilms' tumor, and genital abnormalities (Drash syndrome). J Pediatr. 1990. 117:717–725.

12. Manivel JC, Sibley RK, Dehner LP. Complete and incomplete Drash syndrome: a clinicopathologic study of five cases of a dysontogenetic-neoplastic complex. Hum Pathol. 1987. 18:80–89.

13. Hastie ND. The genetics of Wilms' tumor-a case of disrupted development. Ann Rev Genet. 1994. 28:523–558.

14. Jeanpierre C, Denamur E, Henry I, Cabanis MO, Luce S, Cecille A, Elion J, Peuchmaur M, Loirat C, Niaudet P, Gubler MC, 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. 1998. 62:824–833.

15. Schumacher V, Schärer K, Wühl E, Altrogge H, Bonzel KE, Guschmann M, Neuhaus TJ, Pollastro RM, Kuwertz-Bröking E, Bulla M, Tondera AM, Mundel P, Helmchen U, Waldherr R, Weirich A, Royer-Pokora B. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int. 1998. 53:1594–1600.

16. Little M, Carman G, Donaldson E. Novel WT1 exon 9 mutation (D396Y) in a patient with early onset Denys Drash syndrome. Hum Mutat. 2000. 15:389.

17. Holmberg C, Tryggvason K, Kestila MK, Jalanko HJ. Avner ED, Harmon WE, Niaudet P, editors. Congenital nephrotic syndrome. Pediatric Nephrology. 2004. 5th ed. Philadelphia: Lippincott Williams and Wilkins;503–516.

18. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991. 67:437–447.

19. McElreavey K, Fellous M. Sex determination and the Y chromosome. Am J Med Genet. 1999. 89:176–185.

20. McTaggart SJ, Algar E, Chow CW, Powell HR, Jones CL. Clinical spectrum of Denys-Drash and Frasier syndrome. Pediatr Nephrol. 2001. 16:335–339.

21. Demmer L, Primack W, Loik V, Brown R, Therville N, McElreavey K. Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female. J Am Soc Nephrol. 1999. 10:2215–2218.

22. Ito S, Ikeda M, Takada A, Kikuchi H, Hata J, Honda M. Nephrotic syndrome and end-stage renal disease with WT1 mutation detected at 3 years. Pediatr Nephrol. 1999. 13:790–791.

23. Ito S, Takata A, Hataya H, Ikeda M, Kikuchi H, Hata J, Honda M. Isolated diffuse mesangial sclerosis and Wilms tumor suppressor gene. J Pediatr. 2001. 138:425–427.

24. Hu M, Zhang GY, Arbuckle S, Graf N, Shun A, Silink M, Lewis D, Alexander SI. Prophylactic bilateral nephrectomies in two paediatric patients with missense mutations in the WT1 gene. Nephrol Dial Transplant. 2004. 19:223–226.