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  • Review Article
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Management of disorders of sex development

Nature Reviews Endocrinology volume 10, pages 520–529 (2014)Cite this article

Subjects

Key Points

  • Disorders of sex development (DSDs) include at least 50 different congenital abnormalities of urogenital differentiation

  • The terms 'variations of sex development' and 'differences of sex development' can also be used to describe individuals with DSDs

  • Diagnosis of DSDs requires clinical assessment, morphological determination, endocrine evaluation and genetic studies; however, the pathogenetic mechanisms have only been elucidated in a subset of individuals with DSDs

  • Management of patients with DSDs should involve a group of specialists working in an interdisciplinary team in a dedicated Centre of Expertise

  • Important areas of DSD research include personalized approaches to patient management and the development of diagnostic strategies that combine modern genetic techniques with endocrine evaluations

Abstract

The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the development of the urogenital tract and reproductive system. A variety of genetic factors have been identified that affect sex development during gonadal differentiation or in specific disorders associated with altered androgen biosynthesis or action. The diagnosis of DSDs in individuals and the subsequent management of patients and their families requires a targeted and structured approach, involving a multidisciplinary team with effective communication between the disciplines. This approach includes distinct clinical, imaging, laboratory and genetic evaluations of patients with DSDs. Although treatment of patients with DSDs can include endocrine and surgical options, many patients have concerns that arise from past incorrect treatments that were founded on the traditional binary concept of the sexes. To dispel these concerns, it is necessary to create centres of expertise for DSDs that include physicians, surgeons, psychologists and specialists in diagnostic procedures to manage patients and their families. Additionally, the inclusion of trained peer support in the multidisciplinary DSD team seems to be integral to the supportive management of patients with DSDs. Most importantly, dealing with DSDs requires acceptance of the fact that deviation from the traditional definitions of gender is not necessarily pathologic.

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Figure 1: Composition of a team managing patients with disorders of sex development.
Figure 2: Evaluation of disorders of sex development by clinical, laboratory and genetic investigations.

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References

  1. Hughes, I. A., Houk, C., Ahmed, S. F. & Lee, P. A. Consensus statement on management of intersex disorders. Arch. Dis. Child. 91, 554–563 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Vilain, E. et al. We used to call them hermaphrodites. Genet. Med. 9, 65–66 (2007).

    PubMed  Google Scholar 

  3. Pasterski, V., Prentice, P. & Hughes, I. A. Consequences of the Chicago consensus on disorders of sex development (DSD): current practices in Europe. Arch. Dis. Child. 95, 618–623 (2010).

    CAS  PubMed  Google Scholar 

  4. Miyagawa, S. et al. Genetic interactions of the androgen and Wnt/β-catenin pathways for the masculinization of external genitalia. Mol. Endocrinol. 23, 871–880 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bashamboo, A. & McElreavey, K. Gene mutations associated with anomalies of human gonad formation. Sex. Dev. 7, 126–146 (2013).

    CAS  PubMed  Google Scholar 

  6. Ono, M. & Harley, V. R. Disorders of sex development: new genes, new concepts. Nat. Rev. Endocrinol. 9, 79–91 (2013).

    CAS  PubMed  Google Scholar 

  7. Koboldt, D. C., Steinberg, K. M., Larson, D. E., Wilson, R. K. & Mardis, E. R. The next-generation sequencing revolution and its impact on genomics. Cell 155, 27–38 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ledig, S. et al. Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci. Hum. Reprod. 25, 2637–2646 (2010).

    CAS  PubMed  Google Scholar 

  9. Hiort, O. The differential role of androgens in early human sex development. BMC Med. 11, 152 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ammerpohl, O. et al. Androgen receptor function links human sexual dimorphism to DNA methylation. PLoS ONE 8, e73288 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Piferrer, F. Epigenetics of sex determination and gonadogenesis. Dev. Dyn. 242, 360–370 (2013).

    CAS  PubMed  Google Scholar 

  12. Klebs, E. Handbuch der pathologischen Anatomie (August Hirschwald, 1876).

    Google Scholar 

  13. Money, J., Hampson, J. G. & Hampson, J. L. Hermaphroditism: recommendations concerning assignment of sex, change of sex and psychologic management. Bull. Johns Hopkins Hosp. 97, 284–300 (1955).

    CAS  PubMed  Google Scholar 

  14. Diamond, M. & Sigmundson, H. K. Sex reassignment at birth. Long-term review and clinical implications. Arch. Pediatr. Adolesc. Med. 151, 298–304 (1997).

    CAS  PubMed  Google Scholar 

  15. Diamond, M. & Sigmundson, H. K. Management of intersexuality. Guidelines for dealing with persons with ambiguous genitalia. Arch. Pediatr. Adolesc. Med. 151, 1046–1050 (1997).

    CAS  PubMed  Google Scholar 

  16. Diamond, M. & Beh, H. G. Changes in the management of children with intersex conditions. Nat. Clin. Pract. Endocrinol. Metab. 4, 4–5 (2008).

    PubMed  Google Scholar 

  17. Diamond, M. & Garland, J. Evidence regarding cosmetic and medically unnecessary surgery on infants. J. Pediatr. Urol. 10, 2–6 (2014).

    PubMed  Google Scholar 

  18. Meyer-Bahlburg, H. F. Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J. Clin. Endocrinol. Metab. 84, 3455–3458 (1999).

    CAS  PubMed  Google Scholar 

  19. Hines, M. Sex steroids and human behavior: prenatal androgen exposure and sex-typical play behavior in children. Ann. NY Acad. Sci. 1007, 272–282 (2003).

    CAS  PubMed  Google Scholar 

  20. Jurgensen, M., Hiort, O., Holterhus, P. M. & Thyen, U. Gender role behavior in children with XY karyotype and disorders of sex development. Horm. Behav. 51, 443–453 (2007).

    PubMed  Google Scholar 

  21. Lux, A., Kropf, S., Kleinemeier, E., Jurgensen, M. & Thyen, U. Clinical evaluation study of the German network of disorders of sex development (DSD)/intersexuality: study design, description of the study population, and data quality. BMC Public Health 9, 110 (2009).

    PubMed  PubMed Central  Google Scholar 

  22. Jurgensen, M. et al. Health-related quality of life in children with disorders of sex development (DSD). Eur. J. Pediatr. http://dx.doi.org/10.1007/s00431-014-2264-z.

  23. Jurgensen, M. et al. Psychosexual development in adolescents and adults with disorders of sex development—results from the German clinical evaluation study. J. Sex. Med. 10, 2703–2714 (2013).

    PubMed  Google Scholar 

  24. Kohler, B. et al. Satisfaction with genital surgery and sexual life of adults with XY disorders of sex development: results from the German clinical evaluation study. J. Clin. Endocrinol. Metab. 97, 577–588 (2012).

    PubMed  Google Scholar 

  25. Faisal Ahmed, S. et al. UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin. Endocrinol. (Oxf.) 75, 12–26 (2011).

    Google Scholar 

  26. Thyen, U., Lanz, K., Holterhus, P. M. & Hiort, O. Epidemiology and initial management of ambiguous genitalia at birth in Germany. Horm. Res. 66, 195–203 (2006).

    CAS  PubMed  Google Scholar 

  27. Deutscher Ethikrat. Stellungnahme Intersexualität [online], (2012).

  28. The European Union Committee of Experts on Rare Diseases. [online], (2014).

  29. Brain, C. E. et al. Holistic management of DSD. Best Pract. Res. Clin. Endocrinol. Metab. 24, 335–354 (2010).

    PubMed  PubMed Central  Google Scholar 

  30. Ahmed, F., Bryce, J. & Hiort, O. International networks for supporting research & clinical care in the field of DSD. Endocr. Dev. http://dx.doi.org/10.1159/000363676.

  31. Moran, M. E. & Karkazis, K. Developing a multidisciplinary team for disorders of sex development: planning, implementation, and operation tools for care providers. Adv. Urol. 2012, 604135 (2012).

    PubMed  PubMed Central  Google Scholar 

  32. Prader, A. Genital findings in the female pseudo-hermaphroditism of the congenital adrenogenital syndrome; morphology, frequency, development and heredity of the different genital forms. Helv. Paediatr. Acta 9, 231–248 (1954).

    CAS  PubMed  Google Scholar 

  33. Quigley, C. A. et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr. Rev. 16, 271–321 (1995).

    CAS  PubMed  Google Scholar 

  34. Sinnecker, G. H., Hiort, O., Nitsche, E. M., Holterhus, P. M. & Kruse, K. Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group. Eur. J. Pediatr. 156, 7–14 (1997).

    CAS  PubMed  Google Scholar 

  35. Ahmed, S. F., Khwaja, O. & Hughes, I. A. The role of a clinical score in the assessment of ambiguous genitalia. BJU Int. 85, 120–124 (2000).

    CAS  PubMed  Google Scholar 

  36. Thankamony, A. et al. Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ. Health Perspect. 122, 207–211 (2014).

    PubMed  Google Scholar 

  37. Tanner, J. M. & Eveleth, P. B. in Puberty: Biologic and Psychosocial Components (ed. Berenberg, S. R.) 256–273 (Stenfert Kroese, 1975).

    Google Scholar 

  38. Lloyd, J., Crouch, N. S., Minto, C. L., Liao, L. M. & Creighton, S. M. Female genital appearance: “normality” unfolds. BJOG 112, 643–646 (2005).

    PubMed  Google Scholar 

  39. Wunsch, L. Checklist for the structural description of the deep phenotype in disorders of sexual development. Int. J. Endocrinol. 2012, 816365 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hiort, O., Wunsch, L., Cools, M., Looijenga, L. & Cuckow, P. Requirements for a multicentric multidisciplinary registry on patients with disorders of sex development. J. Pediatr. Urol. 8, 624–628 (2012).

    PubMed  Google Scholar 

  41. Tzeng, W. Y., Chen, L. H., Cherng, C. G., Tsai, Y. N. & Yu, L. Sex differences and the modulating effects of gonadal hormones on basal and the stressor-decreased newly proliferative cells and neuroblasts in dentate gyrus. Psychoneuroendocrinology 42, 24–37 (2014).

    CAS  PubMed  Google Scholar 

  42. Zhou, J. N., Hofman, M. A., Gooren, L. J. & Swaab, D. F. A sex difference in the human brain and its relation to transsexuality. Nature 378, 68–70 (1995).

    CAS  PubMed  Google Scholar 

  43. Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J. Clin. Endocrinol. Metab. 87, 4048–4053 (2002).

  44. Handelsman, D. J. & Wartofsky, L. Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J. Clin. Endocrinol. Metab. 98, 3971–3973 (2013).

    CAS  PubMed  Google Scholar 

  45. Kulle, A. E., Riepe, F. G., Melchior, D., Hiort, O. & Holterhus, P. M. A novel ultrapressure liquid chromatography tandem mass spectrometry method for the simultaneous determination of androstenedione, testosterone, and dihydrotestosterone in pediatric blood samples: age- and sex-specific reference data. J. Clin. Endocrinol. Metab. 95, 2399–2409 (2010).

    CAS  PubMed  Google Scholar 

  46. Koal, T., Schmiederer, D., Pham-Tuan, H., Rohring, C. & Rauh, M. Standardized LC–MS/MS based steroid hormone profile-analysis. J. Steroid Biochem. Mol. Biol. 129, 129–138 (2012).

    CAS  PubMed  Google Scholar 

  47. Courant, F. et al. Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography–tandem mass spectrometry method. J. Clin. Endocrinol. Metab. 95, 82–92 (2010).

    CAS  PubMed  Google Scholar 

  48. Kulle, A. E., Welzel, M., Holterhus, P. M. & Riepe, F. G. Principles and clinical applications of liquid chromatography–tandem mass spectrometry for the determination of adrenal and gonadal steroid hormones. J. Endocrinol. Invest. 34, 702–708 (2011).

    CAS  PubMed  Google Scholar 

  49. Kulle, A. E., Welzel, M., Holterhus, P. M. & Riepe, F. G. Implementation of a liquid chromatography tandem mass spectrometry assay for eight adrenal C-21 steroids and pediatric reference data. Horm. Res. Paediatr. 79, 22–31 (2013).

    CAS  PubMed  Google Scholar 

  50. Hiort, O. et al. Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency. Eur. J. Pediatr. 155, 445–451 (1996).

    CAS  PubMed  Google Scholar 

  51. Ng, K. L., Ahmed, S. F. & Hughes, I. A. Pituitary–gonadal axis in male undermasculinisation. Arch. Dis. Child. 82, 54–58 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Twesten, W. et al. Clinical, endocrine, and molecular genetic findings in patients with 17β-hydroxysteroid dehydrogenase deficiency. Horm. Res. 53, 26–31 (2000).

    CAS  PubMed  Google Scholar 

  53. Steinmetz, L. et al. Inhibin A production after gonadotropin stimulus: a new method to detect ovarian tissue in ovotesticular disorder of sex development. Horm. Res. 71, 94–99 (2009).

    CAS  PubMed  Google Scholar 

  54. Krone, N. et al. Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography tandem mass spectrometry (LC/MS/MS). J. Steroid Biochem. Mol. Biol. 121, 496–504 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wudy, S. A., Hartmann, M. & Homoki, J. Hormonal diagnosis of 21-hydroxylase deficiency in plasma and urine of neonates using benchtop gas chromatography–mass spectrometry. J. Endocrinol. 165, 679–683 (2000).

    CAS  PubMed  Google Scholar 

  56. Krone, N. et al. Genotype–phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. J. Clin. Endocrinol. Metab. 97, E257–E267 (2012).

    CAS  PubMed  Google Scholar 

  57. Kamrath, C., Hochberg, Z., Hartmann, M. F., Remer, T. & Wudy, S. A. Increased activation of the alternative “backdoor” pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis. J. Clin. Endocrinol. Metab. 97, E367–E375 (2012).

    CAS  PubMed  Google Scholar 

  58. Fluck, C. E. et al. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am. J. Hum. Genet. 89, 201–218 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. Rey, R. A. et al. Evaluation of gonadal function in 107 intersex patients by means of serum antimullerian hormone measurement. J. Clin. Endocrinol. Metab. 84, 627–631 (1999).

    CAS  PubMed  Google Scholar 

  60. Josso, N., Rey, R. A. & Picard, J. Y. Anti-Müllerian hormone: A valuable addition to the toolbox of the pediatric endocrinologist. Int. J. Endocrinol. 2013, 674105 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. Kubini, K. et al. Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys. J. Clin. Endocrinol. Metab. 85, 134–138 (2000).

    CAS  PubMed  Google Scholar 

  62. Lindhardt Johansen, M. et al. 45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function—a retrospective longitudinal study. J. Clin. Endocrinol. Metab. 97, E1540–E1549 (2012).

    PubMed  Google Scholar 

  63. Kaufmann, M., Straisfeld, C. & Pinsky, L. Male pseudohermaphroditism presumably due to target organ unresponsiveness to androgens. Deficient 5α-dihydrotestosterone binding in cultured skin fibroblasts. J. Clin. Invest. 58, 345–350 (1976).

    Google Scholar 

  64. Sinnecker, G. & Kohler, S. Sex hormone-binding globulin response to the anabolic steroid stanozolol: evidence for its suitability as a biological androgen sensitivity test. J. Clin. Endocrinol. Metab. 68, 1195–1200 (1989).

    CAS  PubMed  Google Scholar 

  65. Holterhus, P. M. et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J. Clin. Endocrinol. Metab. 82, 3584–3589 (1997).

    CAS  PubMed  Google Scholar 

  66. Bertelloni, S. et al. Biochemical selection of prepubertal patients with androgen insensitivity syndrome by sex hormone-binding globulin response to the human chorionic gonadotropin test. Pediatr. Res. 41, 266–271 (1997).

    CAS  PubMed  Google Scholar 

  67. Appari, M. et al. Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome. J. Mol. Med. (Berl.) 87, 623–632 (2009).

    CAS  Google Scholar 

  68. Ohnesorg, T., Vilain, E. & Sinclair, A. H. The genetics of disorders of sex development in humans. Sex. Dev. http://dx.doi.org/10.1159/000357956.

  69. Hersmus, R. et al. SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal disorders of sex development (DSD) patients with a mosaic karyotype. BMC Med. Genet. 13, 108 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Tobias, E. & McElreavey, K. Next generation sequencing for disorders of sex development. Endocr. Dev. http://dx.doi.org/10.1159/000363615.

  71. Bashamboo, A. et al. Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination. Hum. Mol. Genet. http://dx.doi.org/10.1093/hmg/ddu074.

  72. Ledig, S., Hiort, O., Wunsch, L. & Wieacker, P. Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development. Eur. J. Endocrinol. 167, 119–124 (2012).

    CAS  PubMed  Google Scholar 

  73. Hiort, O. & Gillessen-Kaesbachb, G. Disorders of sex development in developmental syndromes. Endocr. Dev. 14, 174–180 (2009).

    Google Scholar 

  74. Baxter, R. M. & Vilain, E. Translational genetics for diagnosis of human disorders of sex development. Annu. Rev. Genomics Hum. Genet. 14, 371–392 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Gillam, L. H., Hewitt, J. K. & Warne, G. L. Ethical principles for the management of infants with disorders of sex development. Horm. Res. Paediatr. 74, 412–418 (2010).

    CAS  PubMed  Google Scholar 

  76. Gillam, L. H., Hewitt, J. K. & Warne, G. L. Ethical principles: an essential part of the process in disorders of sex development care. Horm. Res. Paediatr. 76, 367–368 (2011).

    CAS  PubMed  Google Scholar 

  77. Wiesemann, C., Ude-Koeller, S., Sinnecker, G. H. & Thyen, U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Eur. J. Pediatr. 169, 671–679 (2010).

    PubMed  Google Scholar 

  78. Hiort, O. et al. Puberty in disorders of somatosexual differentiation. J. Pediatr. Endocrinol. Metab. 16 (Suppl. 2), 297–306 (2003).

    CAS  PubMed  Google Scholar 

  79. Hiort, O., Thyen, U. & Holterhus, P. M. The basis of gender assignment in disorders of somatosexual differentiation. Horm. Res. 64 (Suppl. 2), 18–22 (2005).

    CAS  PubMed  Google Scholar 

  80. Thyen, U., Richter-Appelt, H., Wiesemann, C., Holterhus, P. M. & Hiort, O. Deciding on gender in children with intersex conditions: considerations and controversies. Treat. Endocrinol. 4, 1–8 (2005).

    PubMed  Google Scholar 

  81. Bertelloni, S. et al. 17β-Hydroxysteroid dehydrogenase-3 deficiency: from pregnancy to adolescence. J. Endocrinol. Invest. 32, 666–670 (2009).

    CAS  PubMed  Google Scholar 

  82. Werner, R. et al. Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency. Sex. Dev. 6, 161–168 (2012).

    CAS  PubMed  Google Scholar 

  83. Hochberg, Z. et al. Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5α-reductase 2 deficiency. J. Clin. Endocrinol. Metab. 81, 2821–2827 (1996).

    CAS  PubMed  Google Scholar 

  84. Kang, H. J., Imperato-McGinley, J., Zhu, Y. S. & Rosenwaks, Z. The effect of 5α-reductase-2 deficiency on human fertility. Fertil. Steril. 101, 310–316 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Jurgensen, M., Hampel, E., Hiort, O. & Thyen, U. “Any decision is better than none” decision-making about sex of rearing for siblings with 17β-hydroxysteroid-dehydrogenase-3 deficiency. Arch. Sex. Behav. 35, 359–371 (2006).

    PubMed  Google Scholar 

  86. T'Sjoen, G. et al. Male gender identity in complete androgen insensitivity syndrome. Arch. Sex. Behav. 40, 635–638 (2011).

    PubMed  Google Scholar 

  87. Bundesregierung Deutschland. Gesetz zur Änderung personenstandsrechtlicher Vorschriften (Personenstandsrechts-Änderungsgesetz – PStRÄndG) [online] (2013).

  88. Creighton, S. M., Michala, L., Mushtaq, I. & Yaron, M. Childhood surgery for ambiguous genitalia: glimpses of practice changes or more of the same? Psycho. Sex. 5, 34–43 (2013).

    Google Scholar 

  89. United Nations General Assembly. Resolution 67/146. Intensifying global efforts for the elimination of female genital mutilations [online], (2012).

  90. Yankovic, F., Cherian, A., Steven, L., Mathur, A. & Cuckow, P. Current practice in feminizing surgery for congenital adrenal hyperplasia; a specialist survey. J. Pediatr. Urol. 9, 1103–1107 (2013).

    PubMed  Google Scholar 

  91. Steven, L. et al. Current practice in paediatric hypospadias surgery; a specialist survey. J. Pediatr. Urol. 9, 1126–1130 (2013).

    PubMed  Google Scholar 

  92. Wolffenbuttel, K. P. & Crouch, N. S. Timing of feminizing surgery. Endocr. Dev. http://dx.doi.org/10.1159/000363665.

  93. Wunsch, L., Holterhus, P. M., Wessel, L. & Hiort, O. Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis. BJU Int. 110, E958–E965 (2012).

    PubMed  Google Scholar 

  94. Looijenga, L. H., Van Agthoven, T. & Biermann, K. Development of malignant germ cells—the genvironmental hypothesis. Int. J. Dev. Biol. 57, 241–253 (2013).

    CAS  PubMed  Google Scholar 

  95. Cools, M. et al. Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth. Eur. J. Endocrinol. 166, 341–349 (2012).

    CAS  PubMed  Google Scholar 

  96. Kaprova-Pleskacova, J. et al. Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology. Mod. Pathol. 27, 721–730 (2013).

    PubMed  Google Scholar 

  97. Warne, G. L., Grover, S. & Zajac, J. D. Hormonal therapies for individuals with intersex conditions: protocol for use. Treat. Endocrinol. 4, 19–29 (2005).

    CAS  PubMed  Google Scholar 

  98. Bertelloni, S., Dati, E. & Baroncelli, G. I. Disorders of sex development: hormonal management in adolescence. Gynecol. Endocrinol. 24, 339–346 (2008).

    PubMed  Google Scholar 

  99. Jurgensen, M. et al. Psychosexual development in children with disorder of sex development (DSD)—results from the German Clinical Evaluation Study. J. Pediatr. Endocrinol. Metab. 23, 565–578 (2010).

    CAS  PubMed  Google Scholar 

  100. Han, T. S., Goswami, D., Trikudanathan, S., Creighton, S. M. & Conway, G. S. Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis. Eur. J. Endocrinol. 159, 179–185 (2008).

    CAS  PubMed  Google Scholar 

  101. Kiess, W. et al. Induction of puberty in the hypogonadal girl—practices and attitudes of pediatric endocrinologists in Europe. Horm. Res. 57, 66–71 (2002).

    CAS  PubMed  Google Scholar 

  102. Drobac, S., Rubin, K., Rogol, A. D. & Rosenfield, R. L. A workshop on pubertal hormone replacement options in the United States. J. Pediatr. Endocrinol. Metab. 19, 55–64 (2006).

    PubMed  Google Scholar 

  103. Walvoord, E. Sex steroid replacement for induction of puberty in multiple pituitary hormone deficiency. Pediatr. Endocrinol. Rev. 6 (Suppl. 2), 298–305 (2009).

    PubMed  Google Scholar 

  104. Bertelloni, S., Baroncelli, G. I., Garofalo, P. & Cianfarani, S. Androgen therapy in hypogonadal adolescent males. Horm. Res. Paediatr. 74, 292–296 (2010).

    CAS  PubMed  Google Scholar 

  105. Bertelloni, S., Dati, E., Baroncelli, G. I. & Hiort, O. Hormonal management of complete androgen insensitivity syndrome from adolescence onward. Horm. Res. Paediatr. 76, 428–433 (2011).

    CAS  PubMed  Google Scholar 

  106. DSD-Life [online], (2014).

  107. I-DSD Registry [online], (2014).

  108. Ahmed, S. F., Rodie, M., Jiang, J. & Sinnott, R. O. The European disorder of sex development registry: a virtual research environment. Sex. Dev. 4, 192–198 (2010).

    CAS  PubMed  Google Scholar 

  109. Cox, K. et al. Novel associations in disorders of sex development: findings from the I-DSD registry. J. Clin. Endocrinol. Metab. 99, E348–E355 (2014).

    CAS  PubMed  Google Scholar 

  110. Arboleda, V. A. et al. Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development. Clin. Genet. 83, 35–43 (2013).

    CAS  PubMed  Google Scholar 

  111. Holterhus, P. M. et al. Intrinsic androgen-dependent gene expression patterns revealed by comparison of genital fibroblasts from normal males and individuals with complete and partial androgen insensitivity syndrome. BMC Genomics 8, 376 (2007).

    PubMed  PubMed Central  Google Scholar 

  112. Holterhus, P. M. et al. Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes. BMC Genomics 10, 292 (2009).

    PubMed  PubMed Central  Google Scholar 

  113. dsdfamilies [online], (2014).

Download references

Acknowledgements

The authors would like to acknowledge the support of the European Science Foundation (COST Action BM1303).

Author information

Authors and Affiliations

  1. Division of Experimental Paediatric Endocrinology and Diabetes, Department of Paediatric and Adolescent Medicine, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23562, Germany

    Olaf Hiort, Wiebke Birnbaum, Louise Marshall, Ralf Werner & Ulla Döhnert

  2. Department of Paediatric Surgery, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23562, Germany

    Lutz Wünsch

  3. Department of Gynaecology and Obstetrics, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23562, Germany

    Tatjana Schröder

  4. Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, Christian-Albrechts-University, Schwanenweg 20, Kiel, 24105, Germany

    Paul-Martin Holterhus

Authors
  1. Olaf Hiort
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  2. Wiebke Birnbaum
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  3. Louise Marshall
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  4. Lutz Wünsch
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  5. Ralf Werner
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  6. Tatjana Schröder
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  7. Ulla Döhnert
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  8. Paul-Martin Holterhus
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Contributions

O.H., W.B., L.M., L.W., R.W., T.S. and P.-M.H. researched data for the article. O.H., W.B., L.M., L.W., R.W., U.D. and P.-M.H. made substantial contributions to discussions of the content. O.H., W.B., L.W., R.W. and P.-M.H. wrote the article. O.H., W.B., L.M., L.W., R.W., T.S., U.D. and P.-M.H. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Olaf Hiort.

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Competing interests

The authors declare no competing financial interests.

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Hiort, O., Birnbaum, W., Marshall, L. et al. Management of disorders of sex development. Nat Rev Endocrinol 10, 520–529 (2014). https://doi.org/10.1038/nrendo.2014.108

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