Skip to main content
SpringerLink
Log in

Frasier syndrome: early gonadoblastoma and cyclosporine responsiveness

  • Brief Report
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Frasier syndrome is characterized by progressive glomerulopathy that is unresponsive to corticosteroids, male pseudohermaphroditism, and an increased risk of genitourinary tumors. Of 21 girls with steroid-resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) who were screened for mutations in the WT1 gene, two showed Frasier syndrome. Both patients had donor splice-site mutations in intron 9 of the WT1 gene and a male karyotype (46, XY). Long-term therapy with cyclosporine resulted in partial remission in both cases. One patient showed foci of gonadoblastoma in the excised dysgenetic gonads. This report highlights the need for screening for mutations in the WT1 gene in girls with steroid-resistant FSGS. Patients with Frasier syndrome might benefit from early gonadectomy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470

    Article  PubMed  CAS  Google Scholar 

  2. Wagner N, Wagner KD, Xing Y, Scholz H, Schedl A (2004) The major podocyte protein nephrin is transcriptionally activated by the Wilms’ tumor suppressor WT1. J Am Soc Nephrol 15:3044–3051

    Article  PubMed  Google Scholar 

  3. Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M (1998) Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/–KTS splice isoforms. Hum Mol Genet 7:709–714

    Article  PubMed  CAS  Google Scholar 

  4. Mucha B, Ozaltin F, Hinkes BD, Hasselbacher K, Ruf RG, Schutheiss M, Hangan D, Hoskins BE, Everding AS, Bogdanovic R, Seeman T, Hoppe B, Hildebrandt F, Members of the APN Study Group (2006) Mutations in the Wilms’ tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. Pediatr Res 59:325–331

    Article  PubMed  CAS  Google Scholar 

  5. Aucella F, Bisceglia L, De Bonis P, Gigante M, Caridi G, Barbano G, Mattioli G, Perfumo F, Gesualdo L, Ghiggeri GM (2006) WT1 mutations in nephrotic syndrome revised. High prevalence in young girls, associations and renal phenotypes. Pediatr Nephrol 21:1393–1398

    Article  PubMed  Google Scholar 

  6. Cho HY, Lee JH, Choi HJ, Lee BH, Ha IS, Choi Y, Cheong HI (2008) WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:63–70

    Article  PubMed  Google Scholar 

  7. Ruf RG, Schultheiss M, Lichtenberger A, Karle SM, Zalewski I, Mucha B, Everding AS, Neuhaus T, Patzer L, Plank C, Haas JP, Ozaltin F, Imm A, Fuchshuber A, Bakkaloglu A, Hildebrandt F (2004) Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int 66:564–570

    Article  PubMed  CAS  Google Scholar 

  8. Malina M, Cinek O, Janda J, Seeman T (2009) Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation. Pediatr Nephrol 24:2051–2053

    Article  PubMed  Google Scholar 

  9. Gellermann J, Querfeld U (2008) Case report: long-term immunosuppressive treatment of FSGS due to WT1 mutations. Pediatr Nephrol 23:1639, abstract P171

    Google Scholar 

  10. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938

    Article  PubMed  CAS  Google Scholar 

  11. Niaudet P, Gubler MC (2006) WT1 and glomerular diseases. Pediatr Nephrol 21:1653–1660

    Article  PubMed  Google Scholar 

  12. Joki-Erkkila MM, Karikoski R, Rantala I, Lenko HL, Visakorpi T, Heinonen PK (2002) Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in a adolescent with chronic renal failure: a case of Frasier syndrome. J Pediatr Adolesc Gynecol 15:145–149

    Article  PubMed  Google Scholar 

  13. Frasier SD, Bashore RA, Mosier HD (1964) Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins. J Pediatr 64:740–745

    Article  PubMed  CAS  Google Scholar 

  14. Tajima T, Sasaki S, Tanaka Y, Kusunoki H, Nagashima T, Nonomura K, Fujieda K (2003) 46, XY phenotypic male with focal segmental glomerulosclerosis caused by the WT1 splice site mutation. Horm Res 60:302–305

    Article  PubMed  CAS  Google Scholar 

  15. Saxena AK, van Tuil C, Schultze-Everding A (2006) Frasier syndrome in a pre-menarchal girl: laparoscopic resection of gonadoblastoma. Eur J Pediatr 165:917–919

    Article  PubMed  Google Scholar 

  16. Blanchet P, Daloze P, Lesage R, Papas S, Compenhout JV (1977) XY gonadal dysgenesis with gonadoblastoma discovered after kidney transplantation. Am J Obstet Gynecol 129:221–222

    PubMed  CAS  Google Scholar 

  17. Simpson JL D, Chaganti RSK, Mourandian J, German J (1982) Chronic renal disease, myotonic dystrophy and gonadoblastoma in XY gonadal dysgenesis. J Med Genet 79:73–76

    Article  Google Scholar 

  18. Haning RV Jr, Chesney RW, Moorthy AV, Gilbert EF (1985) A syndrome of chronic renal failure and XY gonadal dysgenesis in young phenotypic females without gonadal ambiguity. Am J Kidney Dis 6:40–48

    PubMed  Google Scholar 

  19. Kikuchi H, Takata A, Akasaka Y, Fukuzawa R, Yoneyama H, Kurosawa Y, Honda M, Kamiyama Y, Hata J (1998) Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome? J Med Genet 35:45–48

    Article  PubMed  CAS  Google Scholar 

  20. Kohsaka T, Tagawa M, Takekoshi Y, Yanagisawa H, Tadokoro K, Yamada M (1999) Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome. Hum Mutat 14:466–470

    Article  PubMed  CAS  Google Scholar 

  21. Okuhara K, Tajima T, Nakae J, Sasaki S, Tochimaru H, Abe S, Fujieda K (1999) A Japanese case with Frasier syndrome caused by the splice junction mutation of WT1 gene. Endocr J 46:639–642

    Article  PubMed  CAS  Google Scholar 

  22. Koziell A, Charmandari E, Hindmarsh PC Rees L, Scambler P, Brook CG (2000) Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy. Clin Endocrinol 52:519–524

    Article  CAS  Google Scholar 

  23. Melo KFS, Martin RM, Costa EMF, Carvalho FM, Jorge AA, Arnhold IJP, Mendonca BB (2002) An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis. J Clin Endocrinol Metab 87:2500–2505

    Article  PubMed  CAS  Google Scholar 

  24. Perez de Nanclares G, Castano L, Bilbao JR, Vallo A, Rica I, Vela A, Martul P (2002) Molecular analysis of Frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis. J Pediatr Endocrinol Metab 15:1047–1050

    PubMed  CAS  Google Scholar 

  25. Shimoyama H, Nakajima M, Naka H, Park YD, Hori K, Morikawa H, Yoshioka A (2002) A girl with bilateral ovarian tumors: Frasier syndrome. Eur J Pediatr 161:81–83

    Article  PubMed  Google Scholar 

  26. Love JD, DeMartini SD, Coppola CP (2006) Prophylactic bilateral salpingo-oopherectomy in a 17-year-old with Frasier syndrome reveals gonadoblastoma and seminoma: a case report. J Pediatr Surg 41:E1–E4

    Article  PubMed  Google Scholar 

  27. De Andrade JGR, Guaragna MS, Soardi FC, Guerra-Junior G, De Mello MP, Maciel-Guerra AT (2008) Clinical and genetic findings of five patients with WT1-related disorders. Arq Bras Endocrinol Metab 52:1236–1243

    Article  Google Scholar 

  28. Subbiah V, Huff V, Wolff JE, Ketonen L, Lang FF Jr, Stewart J, Langford L, Herzog CE (2009) Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT-IVS9 mutation: a 46 XY phenotypic female with Frasier syndrome. Pediatr Blood Cancer 53:1349–1351

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

    Aditi Sinha, Ashima Gulati, Pankaj Hari & Arvind Bagga

  2. Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India, 110029

    Sonika Sharma

  3. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

    Alok Sharma

  4. Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India

    Sandeep Agarwala

Authors
  1. Aditi Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonika Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashima Gulati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alok Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandeep Agarwala
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pankaj Hari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arvind Bagga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arvind Bagga.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sinha, A., Sharma, S., Gulati, A. et al. Frasier syndrome: early gonadoblastoma and cyclosporine responsiveness. Pediatr Nephrol 25, 2171–2174 (2010). https://doi.org/10.1007/s00467-010-1518-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-010-1518-x

Keywords

Search

Navigation