Skip to main content
SpringerLink
Log in

Disorders of sex development: update on the genetic background, terminology and risk for the development of germ cell tumors

  • Review Article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

Considerable progress has been made on genetic mechanisms involved in disorders of sex development and on tumor formation in dysgenetic gonads. Clinical and psychological outcome of patients are, as far as evaluated, unsatisfactory at present. Guidelines are emerging in order to optimize long-term outcome in the future.

Data sources

The information obtained in this review is based on recent original publications and on the experience of our multidisciplinary clinical and research group.

Results

This review offers an update on our knowledge concerning gene mutations involving in disorders of sex development, on the renewed nomenclature and classification system, and on the mechanisms of tumor development in patients.

Conclusions

The consensus meeting on disorders of sex development has renewed our interest in clinical studies and long-term outcome of patients. Psychological research emphasizes the importance to consider male gender identity wherever possible in cases of severe undervirilization. Patient advocacy groups demand a more conservative approach regarding gonadectomy. Medical doctors, scientists and governmental instances are increasingly interested in the set-up of international research collaborations. As a consequence, it is expected that new guidelines for the optimal care of patients will be proposed in the coming years.

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.

Similar content being viewed by others

References

  1. Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES Consensus Group; ESPE Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child 2006;91:554–563.

    Article  PubMed  CAS  Google Scholar 

  2. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006;118:e488–500.

    Article  PubMed  Google Scholar 

  3. Brennan J, Capel B. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 2004;5:509–521.

    Article  PubMed  CAS  Google Scholar 

  4. Grumbach MM, Hughes IA, Conte FA. Disorders of sex differentiation. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KM, eds. Williams textbook of endocrinology, 10th ed. Philadelphia: W.B. Saunders (Elsevier), 2003: 842–1002.

    Google Scholar 

  5. Vaiman D, Pailhoux E. Mammalian sex reversal and intersexuality: deciphering the sex-determination cascade. Trends Genet 2000;16:488–494.

    Article  PubMed  CAS  Google Scholar 

  6. Kildal W, Kraggerud SM, Abeler VM, Heim S, Trope CG, Kristensen GB, et al. Genome profiles of bilateral dysgerminomas, a unilateral gonadoblastoma, and a metastasis from a 46, XY phenotypic female. Hum Pathol 2003;34:946–949.

    Article  PubMed  CAS  Google Scholar 

  7. Fleming A, Vilain E. The endless quest for sex determination genes. Clin Genet 2005;67:15–25.

    Article  PubMed  CAS  Google Scholar 

  8. Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 2001;185:17–25.

    Article  PubMed  CAS  Google Scholar 

  9. Wylie C. Germ cells. Curr Opin Genet Dev 2000;10:410–413.

    Article  PubMed  CAS  Google Scholar 

  10. Wilhelm D, Palmer S, Koopman P. Sex determination and gonadal development in mammals. Physiol Rev 2007;87:1–28.

    Article  PubMed  CAS  Google Scholar 

  11. Parma P, Radi O, Vidal V, Chaboissier MC, Dellambra E, Valentini S, et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet 2006;38:1304–1309.

    Article  PubMed  CAS  Google Scholar 

  12. Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, et al. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol 2006;4:e187.

    Article  PubMed  CAS  Google Scholar 

  13. Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet 2003;4:969–980.

    Article  PubMed  CAS  Google Scholar 

  14. Anderson RA, Sharpe RM. Regulation of inhibin production in the human male and its clinical applications. Int J Androl 2000;23:136–144.

    Article  PubMed  CAS  Google Scholar 

  15. Ferlin A, Foresta C. Insulin-like factor 3: a novel circulating hormone of testicular origin in humans. Ann N Y Acad Sci 2005;1041:497–505.

    Article  PubMed  CAS  Google Scholar 

  16. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46,XX woman. N Engl J Med 2004;351:792–798.

    Article  PubMed  CAS  Google Scholar 

  17. Miller WL. Disorders of androgen biosynthesis. Semin Reprod Med 2002;20:205–216.

    Article  PubMed  CAS  Google Scholar 

  18. Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab 2008;93:696–702.

    Article  PubMed  CAS  Google Scholar 

  19. Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 1995;16:271–321.

    PubMed  CAS  Google Scholar 

  20. Hannema SE, Scott IS, Hodapp J, Martin H, Coleman N, Schwabe JW, et al. Residual activity of mutant androgen receptors explains wolffian duct development in the complete androgen insensitivity syndrome. J Clin Endocrinol Metab 2004;89:5815–5822.

    Article  PubMed  CAS  Google Scholar 

  21. Boehmer AL, Brinkmann O, Bruggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 2001;86:4151–4560.

    Article  PubMed  CAS  Google Scholar 

  22. Ahmed SF, Hughes IA. The genetics of male undermasculinization. Clin Endocrinol (Oxf) 2002;56:1–18.

    Article  CAS  Google Scholar 

  23. Hiort O, Holterhus PM. The molecular basis of male sexual differentiation. Eur J Endocrinol 2000;142:101–110.

    Article  PubMed  CAS  Google Scholar 

  24. Houk CP, Lee PA. Intersexed states: diagnosis and management. Endocrinol Metab Clin North Am 2005;34:791–810, xi.

    Article  PubMed  Google Scholar 

  25. Cools M, Stoop H, Kersemaekers AM, Drop SL, Wolffenbuttel KP, Bourguignon JP, et al. Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads. J Clin Endocrinol Metab 2006;91:2404–2413.

    Article  PubMed  CAS  Google Scholar 

  26. Hersmus R, de Leeuw BH, Wolffenbuttel KP, Drop SL, Oosterhuis JW, Cools M, et al. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Mol Cell Endocrinol 2008;291:1–10.

    Article  PubMed  CAS  Google Scholar 

  27. Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 2006;27:468–484.

    Article  PubMed  CAS  Google Scholar 

  28. Cools M, van Aerde K, Kersemaekers AM, Boter M, Drop SL, Wolffenbuttel KP, et al. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab 2005;90:5295–5303.

    Article  PubMed  CAS  Google Scholar 

  29. Looijenga LH, Hersmus R, Oosterhuis JW, Cools M, Drop SL, Wolffenbuttel KP. Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab 2007;21:480–495.

    Article  PubMed  CAS  Google Scholar 

  30. Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol 1976;124:293–300.

    PubMed  CAS  Google Scholar 

  31. Scully RE. Gonadoblastoma. A review of 74 cases. Cancer 1970;25:1340–1356.

    Article  PubMed  CAS  Google Scholar 

  32. Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet 1987;25:191–218.

    Article  PubMed  CAS  Google Scholar 

  33. Tsuchiya K, Reijo R, Page DC, Disteche CM. Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet 1995;57:1400–1407.

    PubMed  CAS  Google Scholar 

  34. Salo P, Kaariainen H, Petrovic V, Peltomaki P, Page DC, de la Chapelle A. Molecular mapping of the putative gonadoblastoma locus on the Y chromosome. Genes Chromosomes Cancer 1995;14:210–214.

    Article  PubMed  CAS  Google Scholar 

  35. Page DC. Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads. Development 1987;101Suppl:151–155.

    PubMed  Google Scholar 

  36. Lau YF. Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. Am J Hum Genet 1999;64:921–927.

    Article  PubMed  CAS  Google Scholar 

  37. Lau Y, Chou P, Iezzoni J, Alonzo J, Komuves L. Expression of a candidate gene for the gonadoblastoma locus in gonadoblastoma and testicular seminoma. Cytogenet Cell Genet 2000;91:160–164.

    Article  PubMed  CAS  Google Scholar 

  38. Kersemaekers AM, Honecker F, Stoop H, Cools M, Molier M, Wolffenbuttel K, et al. Identification of germ cells at risk for neoplastic transformation in gonadoblastoma. Hum Pathol 2005;36:512–521.

    Article  PubMed  CAS  Google Scholar 

  39. Schnieders F, Dork T, Arnemann J, Vogel T, Werner M, Schmidtke J. Testis-specific protein, Y-encoded (TSPY) expression in testicular tissues. Hum Mol Genet 1996;5:1801–1807.

    Article  PubMed  CAS  Google Scholar 

  40. Cools M, Honecker F, Stoop H, Veltman JD, de Krijger RR, Steyerberg E, et al. Maturation delay of germ cells in trisomy 21 fetuses results in increased risk for the development of testicular germ cell tumors. Hum Pathol 2006;37:101–111.

    Article  PubMed  Google Scholar 

  41. Honecker F, Stoop H, de Krijger RR, Chris Lau YF, Bokemeyer C, Looijenga LH. Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. J Pathol 2004;203:849–857.

    Article  PubMed  CAS  Google Scholar 

  42. Stoop H, Honecker F, Cools M, de Krijger R, Bokemeyer C, Looijenga LH. Differentiation and development of human female germ cells during prenatal gonadogenesis: an immunohistochemical study. Hum Reprod 2005;20:1466–1476.

    Article  PubMed  CAS  Google Scholar 

  43. Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M, et al. Oct4 is required for primordial germ cell survival. EMBO Rep 2004;5:1078–1083.

    Article  PubMed  CAS  Google Scholar 

  44. Schnieders F, Dork T, Arnemann J, Vogel T, Werner M, Schmidtke J. Testis-specific protein, Y-encoded (TSPY) expression in testicular tissues. Hum Mol Genet 1996;5:1801–1807.

    Article  PubMed  CAS  Google Scholar 

  45. Looijenga LH, Hersmus R, Gillis AJ, Pfundt R, Stoop HJ, van Gurp RJ, et al. Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT 1 as candidate chromosome 9 gene. Cancer Res 2006;66:290–302.

    Article  PubMed  CAS  Google Scholar 

  46. van Niekerk WA, Retief AE. The gonads of human true hermaphrodites. Hum Genet 1981;58:117–122.

    Article  PubMed  Google Scholar 

  47. Berthelsen JG, Skakkebaek NE. Value of testicular biopsy in diagnosing carcinoma in situ testis. Scand J Urol Nephrol 1981;15:165–168.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital Gent, De Pintelaan 185, 9000, Gent, Belgium

    Martine Cools

  2. Department of Pathology, Erasmus Medical Center, Josephine Nefkens Institute, Daniel Den Hoed Cancer Clinic, Postbus 2040, 3000 DR, Rotterdam, The Netherlands

    Leendert H. J. Looijenga

  3. Department of Urology, Sofia Children’s Hospital, Dr Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands

    Katja P. Wolffenbuttel

  4. Department of Pediatrics, Sofia Children’s Hospital, Dr Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands

    Sten L. S. Drop

Authors
  1. Martine Cools
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leendert H. J. Looijenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katja P. Wolffenbuttel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sten L. S. Drop
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martine Cools.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cools, M., Looijenga, L.H.J., Wolffenbuttel, K.P. et al. Disorders of sex development: update on the genetic background, terminology and risk for the development of germ cell tumors. World J Pediatr 5, 93–102 (2009). https://doi.org/10.1007/s12519-009-0020-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-009-0020-7

Key words

Search

Navigation