Best Practice & Research Clinical Endocrinology & Metabolism
Volume 22, Issue 1 , Pages 119-134 , February 2008

Disorders of sex development: a new definition and classification

  • Ieuan A. Hughes (Professor, Head of Department of Paediatrics)

      Affiliations

    • Corresponding Author InformationTel.: +44 1223 336885; Fax: +44 1223 336996.

References 

  1. Hughes IA, Houk C, Ahmed SF, et al. Consensus statement on management of intersex disorders. Archives of Disease in Childhood. 2006;91:554–563
  2. Houk CP, Hughes IA, Ahmed SF, et al. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753–757
  3. Lee PA, Houk CP, Ahmed SF, et al. International Consensus Conference on Intersex organised by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006;118:e488–e500
  4. Hughes IA, Nihoul-Fékété C, Thomas B, et al. Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development. Best Practice & Research. Clinical Endocrinology & Metabolism. 2007;21:351–364
  5. Quigley CA, De Bellis A, Marschke KB, et al. Androgen receptor defects: historical, clinical and molecular perspectives. Endocrine Reviews. 1995;16:271–321
  6. Ahmed SF, Khwaja O, Hughes IA. The role of a clinical score in the assessment of ambiguous genitalia. BJU International. 2000;85:120–124
  7. Diamond M, Beh HG. Variations of sex development instead of disorders of sex development. Archives of Disease in Childhood. 2006;[Electronic letter, 27 July]
  8. Simmonds M. Was ‘variations of reproductive development’ considered?. Archives of Disease in Childhood. 2007;92:89
  9. Damiani D, Guerra-Júnior G. New definitions and classifications of the intersexual states: in which the Chicago consensus has contributed to the state of the art?. Arquivos Brasileiros de Endocrinologia e Metabologia. 2007;51:1013–1017
  10. Johannsen TH, Ripa CP, Mortensen EL, et al. Quality of life in 70 women with disorders of sex development. European Journal of Endocrinology. 2006;155:877–885
  11. Vilain E, Achermann JC, Eugster EA, et al. We used to call them hermaphrodites. Genetics in Medicine. 2007;9:65–66
  12. Coman DJ, White SM, Amor DJ. Two siblings with 46,XY DSD, congenital adrenal hypoplasia, aniridia, craniofacial, and skeletal abnormalities and intrauterine growth retardation: a new syndrome?. American Journal of Medical Genetics. Part A. 2007;143:2085–2088
  13. Looijenga LH, Hersmus R, Oosterhuis JW, et al. Tumor risk in disorders of sex development (DSD). Best Practice & Research. Clinical Endocrinology & Metabolism. 2007;21:480–495
  14. Schutzmann K, Brinkmann L, Schacht M, et al. Psychological distress, self-harming behaviour, and suicidal tendencies in adults with disorders of sex development. Archives of Sexual Behavior. 2007;[Epub ahead of print]
  15. Achermann JC, Hughes IA. Disorders of sex development. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams Textbook of Endocrinology. 11th edn. Philadelphia: Saunders; in press.
  16. Hughes IA. The testes. In: Sperling MA, editor. Pediatric Endocrinology. 3rd edn. Elsevier; in press.
  17. Lee YS, Cheng AW, Ahmed SF, et al. Genital anomalies in Klinefelter's syndrome. Hormone Research. 2007;68:150–155
  18. Shearer BM, Thorland EC, Gonzales PR, et al. Evaluation of a commercially available focused aCGH platform for the detection of constitutional chromosome anomalies. American Journal of Medical Genetics. Part A. 2007;143:2357–2370
  19. Lapaire O, Lu XY, Johnson KL, et al. Array-CGH analysis of cell-free fetal DNA in 10 mL of amniotic fluid supernatant. Prenatal Diagnosis. 2007;27:616–621
  20. Karcanias AC, Ichimura K, Mitchell MJ, et al. Analysis of sex chromosome abnormalities using X and Y chromosome DNA tiling path arrays. Journal of Medical Genetics. 2007;44:429–436
  21. Zimmermann B, Zhong XY, Holzgreve W, et al. Real-time quantitative polymerase chain reaction measurement of male fetal DNA in maternal plasma. Methods in Molecular Medicine. 2007;132:43–49
  22. Cirigliano V, Voglino G, Marongiu A, et al. Rapid prenatal diagnosis by QF-PCR: evaluation of 30,000 consecutive clinical samples and future applications. Annals of the New York Academy of Sciences. 2006;1075:288–298
  23. Boon EMJ, Schlecht HB, Martin P, et al. Y chromosome detection by Real Time PCR and pyrophosphorolysis-activated polymerisation using free fetal DNA isolated from maternal plasma. Prenatal Diagnosis. 2007;27:932–937
  24. Maron JL, Bianchi DW. Prenatal diagnosis using cell-free nucleic acids in maternal body fluids: a decade of progress. American Journal of Medical Genetics. Part A. 2007;145:5–17
  25. Bianchi DW, Zickwolf GK, Weil GJ, et al. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proceedings of the National Academy of Sciences of the United States of America. 1996;93:705–708
  26. Chiu RW, Poon LL, Lau TK, et al. Effects of blood-processing protocols on fetal and total DNA quantification in maternal plasma. Clinical Chemistry. 2001;47:1607–1613
  27. Stanghellini I, Bertorelli R, Capone L, et al. Quantitation of fetal DNA in maternal serum during the first trimester of pregnancy by the use of a DAZ repetitive probe. Molecular Human Reproduction. 2006;12:587–591
  28. Chim SS, Tong YK, Chiu RW, et al. Detection of the placental epigenetic signature of the maspin gene in maternal plasma. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:14753–14758
  29. Wataganara T, Chen AY, LeShane ES, et al. Changes of cell-free fetal DNA in maternal plasma after elective termination of pregnancy. Clinical Chemistry. 2005;51:217–219
  30. Bianchi DW. At-home fetal DNA gender testing: caveat emptor. Obstetrics & Gynecology. 2006;107:216–218
  31. Shozu M, Akasofu K, Harada T, et al. A new cause of female pseudohermaphroditism: placental aromatase deficiency. The Journal of Clinical Endocrinology and Metabolism. 1991;72:560–566
  32. Mullis PE, Yoshimura N, Kuhlmann B, et al. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries and bone densitometry in childhood. The Journal of Clinical Endocrinology and Metabolism. 1997;82:1739–1745
  33. Jones ME, Boon WC, McInnes K, et al. Recognizing rare disorders: aromatase deficiency. Nature Clinical Practice. Endocrinology & Metabolism. 2007;3:414–421
  34. Lin L, Ercan O, Raza J, et al. Variable phenotypes associated with aromatase (CYP19) insufficiency in humans. The Journal of Clinical Endocrinology and Metabolism. 2007;92:982–990
  35. Robins T, Carlsson J, Sunnerhagen M, et al. Molecular model of human CYP21 based on mammalian CYP2C5: structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia. Molecular Endocrinology. 2006;20:2946–2964
  36. Holt HB, Medbak S, Kirk D, et al. Recurrent severe hyperandrogenism during pregnancy: a case report. Journal of Clinical Pathology. 2005;58:439–442
  37. Miller WL. Minireview: regulation of steroidogenesis by electron transfer. Endocrinology. 2005;146:2544–2550
  38. Crisponi G, Porcu C, Piu ME. Antley-Bixler syndrome: case report and review of the literature. Clinical Dysmorphology. 1997;6:61–68
  39. Flück CE, Tajima T, Pandey AV, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genetics. 2004;36:228–230
  40. Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends in Endocrinology and Metabolism. 2004;15:432–438
  41. Shackleton C, Marcos J, Arlt W, et al. Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype. American Journal of Medical Genetics. Part A. 2004;129:105–112
  42. Krone N, Hanley NA, Arlt W. Age-specific changes in sex steroid biosynthesis and sex development. Best Practice & Research. Clinical Endocrinology & Metabolism. 2007;21:393–401
  43. Scott RR, Gomes LG, Huang N, et al. Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on co-existing 21-hydroxylase deficiency. The Journal of Clinical Endocrinology and Metabolism. 2007;92:2318–2322
  44. Miller WL. Steroid 17 alpha-hydroxylase deficiency – not rare everywhere. The Journal of Clinical Endocrinology and Metabolism. 2004;89:40–42
  45. Arlt W. P450 oxidoreductase deficiency and Antley-Bixler syndrome. Reviews in Endocrine & Metabolic Disorders. 2007 Oct 25;[Epub ahead of print]
  46. Dhir V, Ivison HE, Krone N, et al. Differential inhibition of CYP17A1 and CYP21A2 activities by the P450 oxidoreductase mutant A287P. Molecular Endocrinology. 2007;21:1958–1968
  47. Homma K, Hasegawa T, Nagai T, et al. Urine steroid hormone profile analysis in Cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone. The Journal of Clinical Endocrinology and Metabolism. 2006;91:2643–2649
  48. Bardoni B, Zanaria E, Guioli S, et al. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genetics. 1994;7:497–501
  49. Jordan BK, Mohammed M, Ching ST, et al. Up-regulation of WNT-4 signalling and dosage-sensitive sex reversal in humans. American Journal of Human Genetics. 2001;58:1102–1109
  50. Yu RN, Ito M, Saunders TL, et al. Role of Ahch in gonadal development and gametogenesis. Nature Genetics. 1998;20:353–357
  51. Capel B. R-spondin1 tips the balance in sex determination. Nature Genetics. 2006;38:1233–1234
  52. McElreavey K, Vilain E, Abbas N, et al. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proceedings of the National Academy of Sciences of the United States of America. 1993;90:3368–3372
  53. Rajender S, Rajani V, Gupta NJ, et al. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Molecular Human Reproduction. 2006;12:341–346
  54. Kim Y, Kobayashi A, Sekido R, et al. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biology. 2006;4:e187
  55. Biason-Lauber A, Konrad D, Navratil F, et al. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. The New England Journal of Medicine. 2004;351:792–798
  56. Hughes IA. Female development – all by default?. The New England Journal of Medicine. 2004;351:748–750
  57. Biason-Lauber A, De Filippo G, Konrad D, et al. WNT4 deficiency – a clinical phenotype distinct from the classic Mayer–Rokitansky–Kuster–Hauser syndrome: a case report. Human Reproduction. 2007;22:224–229
  58. Parma R, Radi O, Vidal V, et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nature Genetics. 2006;38:1304–1309
  59. DiNapoli L, Capel B. SRY and the standoff in sex determination. Molecular Endocrinology. 2007 Sept 20;[Epub ahead of print]
  60. Domenice S, Correa RV, Costa EM, et al. Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients. Brazilian Journal of Medical and Biological Research. 2004;37:145–150
  61. Lim HN, Berkovitz GD, Hughes IA, et al. Mutation analysis of subjects with 46,XX sex reversal and 46,XY gonadal dysgenesis does not support the involvement of SOX3 in testis determination. Human Genetics. 2000;107:650–652
  62. Ottolenghi C, Moreira-Filho C, Mendonca BB, et al. Absence of mutations involving the LIM homeobox domain gene LHX9 in 46,XY gonadal agenesis and dysgenesis. The Journal of Clinical Endocrinology and Metabolism. 2001;86:2465–2469
  63. Finelli P, Pincelli AI, Russo S, et al. Disruption of friend of GATA2 gene (FOG-2) by a de novo t(8;10) chromosomal translocation is associated with heart defects and gonadal dysgenesis. Clinical Genetics. 2007;71:195–204
  64. Hasegawa T, Fukami M, Sato N, et al. Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1. The Journal of Clinical Endocrinology and Metabolism. 2004;89:5930–5935
  65. Correa RV, Domenice S, Bingham NC, et al. A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency. The Journal of Clinical Endocrinology and Metabolism. 2004;89:1767–1772
  66. Lin L, Philibert P, Ferraz-de-Souza B, et al. Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. The Journal of Clinical Endocrinology and Metabolism. 2007;92:991–999
  67. Reuter AL, Goji K, Bingham NC, et al. A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency. European Journal of Endocrinology. 2007;157:233–238
  68. Mallet D, Bretones P, Michel-Calemard L, et al. Gonadal dysgenesis without adrenal insufficiency in a 46,XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency. The Journal of Clinical Endocrinology and Metabolism. 2004;89:4829–4832
  69. Philibert P, Zenaty D, Lin L, et al. Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Human Reproduction. 2007 Oct 16;[Epub ahead of print]
  70. Morris JM. The syndrome of testicular feminization male pseudohermaphrodites. American Journal of Obstetrics and Gynecology. 1953;65:1192–11211
  71. Liao G, Chen L-Y, Zhang A, et al. Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. The Journal of Biological Chemistry. 2003;278:5052–5061
  72. Ghali SA, Gottlieb B, Lumbroso R, et al. The use of androgen receptor amino/carboxyl-terminal interaction assays to investigate androgen receptor gene mutations in subjects with varying degrees of androgen insensitivity. The Journal of Clinical Endocrinology and Metabolism. 2003;88:2185–2193
  73. Jääskeläinen J, Deeb A, Schwabe JW, et al. Human androgen receptor gene ligand-binding-domain mutations leading to disrupted interaction between the N- and C-terminal domains. Journal of Molecular Endocrinology. 2006;36:361–368
  74. Thomas M, Dadgar N, Aphale A, et al. Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts. The Journal of Biological Chemistry. 2004;279:8389–8395
  75. Lonard DM, Lanz RB, O'Malley BW. Nuclear receptor coregulators and human disease. Endocrine Reviews. 2007;28:575–587
  76. Adachi M, Takayanagi R, Tomura A, et al. Androgen-insensitivity syndrome as a possible coactivators disease. The New England Journal of Medicine. 2000;343:856–862
  77. Hughes IA. A novel explanation for resistance to androgens. The New England Journal of Medicine. 2003;343:881–882
  78. Ahmed SF, Cheng A, Dovey L, et al. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. The Journal of Clinical Endocrinology and Metabolism. 2000;85:658–665
  79. Morel Y, Rey R, Teinturier C, et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. European Journal of Pediatrics. 2002;161:49–59
  80. Deeb A, Mason C, Lee YS, et al. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clinical Endocrinology. 2005;63:56–62
  81. Hughes IA, Northstone K, Golding J, et al. Reduced birth weight in boys with hypospadias: an index of androgen dysfunction?. Archives of Disease in Childhood. Fetal and Neonatal Edition. 2002;87:F150–F151
  82. Brouwers MM, Feitz WF, Roelofs LA, et al. Risk factors for hypospadias. European Journal of Pediatrics. 2007;166:671–678
  83. Baskin LS, Ebbers MB. Hypospadias: anatomy, etiology, and technique. Journal of Pediatric Surgery. 2006;41:463–472
  84. Gicquel C, Rossignol S, Cabrol S, et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver–Russell syndrome. Nature Genetics. 2005;37:1003–1007
  85. Sharpe RM, Irvine DS. How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health?. BMJ (Clinical Research Ed.). 2004;328:447–451
  86. Acerini CL, Hughes IA. Endocrine disrupting chemicals: a new and emerging public health problem?. Archives of Disease in Childhood. 2006;91:633–641
  87. Younglai EV, Wu YJ, Foster WG. Reproductive toxicology of environmental toxicants: emerging issues and concerns. Current Pharmaceutical Design. 2007;13:3005–3019
  88. Sharpe RM. Pathways of endocrine disruption during male sexual differentiation and masculinisation. Best Practice & Research. Clinical Endocrinology & Metabolism. 2006;20:91–110
  89. Bay K, Asklund C, Skakkebaek NE, et al. Testicular dysgenesis syndrome: possible role of endocrine disrupters. Best Practice & Research. Clinical Endocrinology & Metabolism. 2006;20:77–90
  90. Wolf CJ, LeBlanc GA, Gray LE. Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. Toxicological Sciences. 2004;78:135–143
  91. Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environmental Health Perspectives. 2005;113:1056–1061
  92. Hannema SE, Scott IS, Rajpert-De Meyts E, et al. Testicular development in the complete androgen insensitivity syndrome. The Journal of Pathology. 2006;208:518–527
  93. Hannema SE, Hughes IA. Neoplasia and intersex. In: Hay I, Wass J, editors. Clinical Endocrine Oncology. 2nd edn. Oxford: Blackwell; in press.

PII: S1521-690X(07)00105-4

doi: 10.1016/j.beem.2007.11.001

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 22, Issue 1 , Pages 119-134 , February 2008

Article Tools

* Image Usage & Resolution