World Journal of Pediatrics

, Volume 5, Issue 2, pp 93–102 | Cite as

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

  • Martine CoolsEmail author
  • Leendert H. J. Looijenga
  • Katja P. Wolffenbuttel
  • Sten L. S. Drop
Review Article



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.


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.


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.

Key words

consensus germ cell tumor nomenclature risk sex development 


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  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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. 5.
    Vaiman D, Pailhoux E. Mammalian sex reversal and intersexuality: deciphering the sex-determination cascade. Trends Genet 2000;16:488–494.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Fleming A, Vilain E. The endless quest for sex determination genes. Clin Genet 2005;67:15–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 2001;185:17–25.PubMedCrossRefGoogle Scholar
  9. 9.
    Wylie C. Germ cells. Curr Opin Genet Dev 2000;10:410–413.PubMedCrossRefGoogle Scholar
  10. 10.
    Wilhelm D, Palmer S, Koopman P. Sex determination and gonadal development in mammals. Physiol Rev 2007;87:1–28.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 13.
    Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet 2003;4:969–980.PubMedCrossRefGoogle Scholar
  14. 14.
    Anderson RA, Sharpe RM. Regulation of inhibin production in the human male and its clinical applications. Int J Androl 2000;23:136–144.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Miller WL. Disorders of androgen biosynthesis. Semin Reprod Med 2002;20:205–216.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Ahmed SF, Hughes IA. The genetics of male undermasculinization. Clin Endocrinol (Oxf) 2002;56:1–18.CrossRefGoogle Scholar
  23. 23.
    Hiort O, Holterhus PM. The molecular basis of male sexual differentiation. Eur J Endocrinol 2000;142:101–110.PubMedCrossRefGoogle Scholar
  24. 24.
    Houk CP, Lee PA. Intersexed states: diagnosis and management. Endocrinol Metab Clin North Am 2005;34:791–810, xi.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 31.
    Scully RE. Gonadoblastoma. A review of 74 cases. Cancer 1970;25:1340–1356.PubMedCrossRefGoogle Scholar
  32. 32.
    Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet 1987;25:191–218.PubMedCrossRefGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 35.
    Page DC. Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads. Development 1987;101Suppl:151–155.PubMedGoogle Scholar
  36. 36.
    Lau YF. Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. Am J Hum Genet 1999;64:921–927.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 46.
    van Niekerk WA, Retief AE. The gonads of human true hermaphrodites. Hum Genet 1981;58:117–122.PubMedCrossRefGoogle Scholar
  47. 47.
    Berthelsen JG, Skakkebaek NE. Value of testicular biopsy in diagnosing carcinoma in situ testis. Scand J Urol Nephrol 1981;15:165–168.PubMedCrossRefGoogle Scholar

Copyright information

© Children's Hospital, Zhejiang University School of Medicine and Springer-Verlag GmbH 2009

Authors and Affiliations

  • Martine Cools
    • 1
    Email author
  • Leendert H. J. Looijenga
    • 2
  • Katja P. Wolffenbuttel
    • 3
  • Sten L. S. Drop
    • 4
  1. 1.Department of Pediatrics, Division of Pediatric EndocrinologyUniversity Hospital GentGentBelgium
  2. 2.Department of Pathology, Erasmus Medical CenterJosephine Nefkens Institute, Daniel Den Hoed Cancer ClinicRotterdamThe Netherlands
  3. 3.Department of UrologySofia Children’s HospitalRotterdamThe Netherlands
  4. 4.Department of PediatricsSofia Children’s HospitalRotterdamThe Netherlands

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