Skip to main content
SpringerLink
Log in
Book cover

Disorders|Differences of Sex Development pp 65–75Cite as

46,XX DSD

  • Chapter
  • First Online:

  • 426 Accesses

Abstract

46,XX DSD comprises the most common group of genital variations, with congenital adrenal hyperplasia (CAH) being the most important, not only because of its frequency but also because of its life-threatening complications without treatment. The different conditions are described, showing the range of genetic and enzymatic anomalies that lead to excess androgen production, causing abnormal virilisation of a female foetus. The non-hormonal anatomical defects of genital development are also mentioned.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Achermann JC, Ito M, Hindmarsh PC, et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999;22(2):125–6.

    Article  CAS  PubMed  Google Scholar 

  • Aittomaki K, Herva R, Stenman UH, et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab. 1996;81(10):3722–6.

    CAS  PubMed  Google Scholar 

  • Aksglaede L, Jorgensen N, Skakkebaek NE, et al. Low semen volume in 47 adolescents and adults with 47,XXY Klinefelter or 46,XX male syndrome. Int J Androl. 2009;32(4):376–84.

    Article  CAS  PubMed  Google Scholar 

  • al-Jurayyan NA. Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency in Saudi Arabia: clinical and biochemical characteristics. Acta Paediatr. 1995;84(6):651–4.

    Article  CAS  PubMed  Google Scholar 

  • Arakane F, Kallen CB, Watari H, et al. Steroidogenic acute regulatory protein (StAR) acts on the outside of mitochondria to stimulate steroidogenesis. Endocr Res. 1998;24(3–4):463–8.

    Article  CAS  PubMed  Google Scholar 

  • Baker BY, Lin L, Kim CJ, et al. Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab. 2006;91(12):4781–5.

    Article  CAS  PubMed  Google Scholar 

  • Baumgartner-Parzer SM, Nowotny P, Heinze G, et al. Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population. J Clin Endocrinol Metab. 2005;90(2):775–8.

    Article  CAS  PubMed  Google Scholar 

  • Berenbaum SA. Cognitive function in congenital adrenal hyperplasia. Endocrinol Metab Clin N Am. 2001;30(1):173–92.

    Article  CAS  Google Scholar 

  • Berenbaum SA, Beltz AM, Bryk K, et al. Gendered peer involvement in girls with congenital adrenal hyperplasia: effects of prenatal androgens, gendered activities, and gender cognitions. Arch Sex Behav. 2018;47(4):915–29.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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. Hum Reprod. 2007;22(1):224–9.

    Article  CAS  PubMed  Google Scholar 

  • Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet. 2000;67(6):15z.

    Google Scholar 

  • Bongiovanni AM, Eberlein WR. Plasma and urinary corticosteroids in the hypertensive form of congenital adrenal hyperplasia. J Biol Chem. 1956;223(1):85–94.

    CAS  PubMed  Google Scholar 

  • Bose HS, Sugawara T, Strauss JF 3rd, et al. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. International congenital lipoid adrenal hyperplasia consortium. N Engl J Med. 1996;335(25):1870–8.

    Article  CAS  PubMed  Google Scholar 

  • Chung BC, Hu MC, Guzov VM, et al. Structure and expression of the CYP21 (P450c21, steroid 21-hydroxylase) gene with respect to its deficiency. Endocr Res. 1995;21(1–2):343–52.

    Article  CAS  PubMed  Google Scholar 

  • Concolino P, Mello E, Zuppi C, et al. Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update of new CYP21A2 mutations. Clin Chem Lab Med. 2010;48(8):1057–62.

    Article  CAS  PubMed  Google Scholar 

  • Costa-Santos M, Kater CE, Auchus RJ. Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab. 2004;89(1):49–60.

    Article  CAS  PubMed  Google Scholar 

  • Croft B, Ohnesorg T, Hewitt J, et al. Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nat Commun. 2018;9(1):5319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Darlington Statement. 2017. https://darlington.org.au.

  • Dessens AB, Slijper FME, Drop SLS. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav. 2005;34(4):389–97.

    Article  PubMed  Google Scholar 

  • Feder EK, Dreger A. Still ignoring human rights in intersex care. J Pediatr Urol. 2016;12(6):436–7.

    Article  PubMed  Google Scholar 

  • Finkielstain GP, Chen W, Mehta SP, et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2010;96(1):E161–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fluck CE, Pandey AV, Huang N, et al. P450 oxidoreductase deficiency–a new form of congenital adrenal hyperplasia. Endocr Dev. 2008;13:67–81.

    Article  CAS  PubMed  Google Scholar 

  • Fujieda K, Tajima T. Molecular basis of adrenal insufficiency. Pediatr Res. 2005;57(5 Pt 2):62R–9R.

    Article  PubMed  Google Scholar 

  • Fujieda K, Tajima T, Nakae J, et al. Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. J Clin Invest. 1997;99(6):1265–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hall CM, Jones JA, Meyer-Bahlburg HFL, et al. Behavioral and physical masculinization are related to genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2004;89(1):419–24.

    Article  CAS  PubMed  Google Scholar 

  • Halper A, Hooke MC, Gonzalez-Bolanos MT, et al. Health-related quality of life in children with congenital adrenal hyperplasia. Health Qual Life Outcomes. 2017;15(1):194.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hamed SA, Metwalley KA, Farghaly HS. Cognitive function in children with classic congenital adrenal hyperplasia. Eur J Pediatr. 2018;177(11):1633–40.

    Article  CAS  PubMed  Google Scholar 

  • Higashi Y, Yoshioka H, Yamane M, et al. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A. 1986;83(9):2841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hines M, Brook C, Conway GS. Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH). J Sex Res. 2004;41(1):75–81.

    Article  PubMed  Google Scholar 

  • Hughes IA. Congenital adrenal hyperplasia. Trends Endocrinol Metab. 1990a;1(3):123–8.

    Article  CAS  PubMed  Google Scholar 

  • Hughes IA. Monitoring treatment in congenital adrenal hyperplasia. Arch Dis Child. 1990b;65(3):333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imai T, Yanase T, Waterman MR, et al. Canadian mennonites and individuals residing in the Friesland region of The Netherlands share the same molecular basis of 17 alpha-hydroxylase deficiency. Hum Genet. 1992;89(1):95–6.

    Article  CAS  PubMed  Google Scholar 

  • Jaaskelainen J, Tiitinen A, Voutilainen R. Sexual function and fertility in adult females and males with congenital adrenal hyperplasia. Horm Res. 2001;56(3–4):73–80.

    CAS  PubMed  Google Scholar 

  • John M, Menon SK, Shah NS, et al. Congenital adrenal hyperplasia 11beta-hydroxylase deficiency: two cases managed with bilateral adrenalectomy. Singap Med J. 2009;50(2):e68–70.

    CAS  Google Scholar 

  • Kacem M, Moussa A, Khochtali I, et al. Bilateral adrenalectomy for severe hypertension in congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency: long term follow-up. Ann Endocrinol. 2009;70(2):113–8.

    Article  CAS  Google Scholar 

  • Kelso WM, Nicholls ME, Warne GL, et al. Cerebral lateralization and cognitive functioning in patients with congenital adrenal hyperplasia. Neuropsychology. 2000;14(3):370–8.

    Article  CAS  PubMed  Google Scholar 

  • Khoury K, Barbar E, Ainmelk Y, et al. Gonadal function, first cases of pregnancy, and child delivery in a woman with lipoid congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2009;94(4):1333–7.

    Article  CAS  PubMed  Google Scholar 

  • Kimberley N, Hutson JM, Southwell BR, et al. Vaginal agenesis, the hymen, and associated anomalies. J Pediatr Adolesc Gynecol. 2012;25(1):54–8.

    Article  CAS  PubMed  Google Scholar 

  • Kolon TF, Ferrer FA, McKenna PH. Clinical and molecular analysis of XX sex reversed patients. J Urol. 1998;160(3 Pt 2):1169–72. discussion 1178.

    Article  CAS  PubMed  Google Scholar 

  • Koppens PF, Hoogenboezem T, Degenhart HJ. Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes. Hum Genet. 2002;111(4–5):405–10.

    Article  CAS  PubMed  Google Scholar 

  • Krob G, Braun A, Kuhnle U. True hermaphroditism: geographical distribution, clinical findings, chromosomes and gonadal histology. Eur J Pediatr. 1994;153(1):2–10.

    Article  CAS  PubMed  Google Scholar 

  • Levine LS, Dupont B, Lorenzen F, et al. Genetic and hormonal characterization of cryptic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1981;53(6):1193–8.

    Article  CAS  PubMed  Google Scholar 

  • Levine LS, Zachmann M, New MI, et al. Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group. N Engl J Med. 1978;299(17):911–5.

    Article  CAS  PubMed  Google Scholar 

  • Lourenco D, Brauner R, Lin L, et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009;360(12):1200–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lutfallah C, Wang W, Mason JI, et al. Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab. 2002;87(6):2611–22.

    CAS  PubMed  Google Scholar 

  • MacKay D, Nordenstrom A, Falhammar H.Bilateral adrenalectomy in congenital adrenal hyperplasia: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2018. https://doi.org/10.1210/jc.2018-00217.

  • Meyer-Bahlburg HF. What causes low rates of child-bearing in congenital adrenal hyperplasia? J Clin Endocrinol Metab. 1999;84(6):1844–7.

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Bahlburg HF, Dolezal C, Baker SW, et al. Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav. 2008;37(1):85–99.

    Article  PubMed  Google Scholar 

  • Meyer-Bahlburg HF, Gruen RS, New MI, et al. Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behav. 1996;30(4):319–32.

    Article  CAS  PubMed  Google Scholar 

  • Miller WL. Steroid 17alpha-hydroxylase deficiency–not rare everywhere. J Clin Endocrinol Metab. 2004;89(1):40–2.

    Article  CAS  PubMed  Google Scholar 

  • Mulaikal RM, Migeon CJ, Rock JA. Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 1987;316(4):178–82.

    Article  CAS  PubMed  Google Scholar 

  • Nordenstrom A, Forest MG, Wedell A. A case of 3beta-hydroxysteroid dehydrogenase type II (HSD3B2) deficiency picked up by neonatal screening for 21-hydroxylase deficiency: difficulties and delay in etiologic diagnosis. Horm Res. 2007;68(4):204–8.

    PubMed  Google Scholar 

  • Parajes S, Loidi L, Reisch N, et al. Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency. J Clin Endocrinol Metab. 2010;95(2):779–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Razzaghy-Azar M, Karimi S, Shirazi E. Gender identity in patients with congenital adrenal hyperplasia. Int J Endocrinol Metab. 2017;15(3):e12537.

    PubMed  PubMed Central  Google Scholar 

  • 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. Mol Endocrinol. 2006;20(11):2946–64.

    Article  CAS  PubMed  Google Scholar 

  • Rosa S, Steigert M, Lang-Muritano M, et al. Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17alpha-hydroxylase/17,20-lyase deficiency. Horm Res Paediatr. 2010;73(3):198–204.

    Article  CAS  PubMed  Google Scholar 

  • Rosler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase deficiency) among Jews from Morocco. Am J Med Genet. 1992;42(6):827–34.

    Article  CAS  PubMed  Google Scholar 

  • Rosler A, Levine LS, Schneider B, et al. The interrelationship of sodium balance, plasma renin activity and ACTH in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1977;45(3):500–12.

    Article  CAS  PubMed  Google Scholar 

  • Rosler A, Weshler N, Leiberman E, et al. 11 Beta-hydroxylase deficiency congenital adrenal hyperplasia: update of prenatal diagnosis. J Clin Endocrinol Metab. 1988;66(4):830–8.

    Article  CAS  PubMed  Google Scholar 

  • Simard J, Moisan AM, Morel Y. Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase deficiency. Semin Reprod Med. 2002;20(3):255–76.

    Article  CAS  PubMed  Google Scholar 

  • Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349(8):776–88.

    Article  CAS  PubMed  Google Scholar 

  • Sutton E, Hughes J, White S, et al. Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Investig. 2011;121(1):328–41.

    Article  CAS  PubMed  Google Scholar 

  • Tapanainen JS, Vaskivuo T, Aittomaki K, et al. Inactivating FSH receptor mutations and gonadal dysfunction. Mol Cell Endocrinol. 1998;145(1–2):129–35.

    Article  CAS  PubMed  Google Scholar 

  • Tian Q, Yao F, Sha G, et al. Genotyping of a Chinese family with 46,XX and 46,XY 17-hydroxylase deficiency. Gynecol Endocrinol. 2009;25(8):485–90.

    Article  CAS  PubMed  Google Scholar 

  • Tonkin-Hill G. Identifying the resource needs of adolescents with Differences of Sex Development. Faculty of Medicine, University of Melbourne, Melbourne; 2018.

    Google Scholar 

  • Tucker EJ, Grover SR, Bachelot A, et al. Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum. Endocr Rev. 2016;37(6):609–35.

    Article  PubMed  Google Scholar 

  • Vallerie AM, Breech LL. Update in Müllerian anomalies: diagnosis, management, and outcomes. Curr Opin Obstet Gynecol. 2010;22(5):381–7.

    Google Scholar 

  • Van Wyk JJ, Gunther DF, Ritzen EM, et al. The use of adrenalectomy as a treatment for congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1996;81(9):3180–90.

    PubMed  Google Scholar 

  • Van Wyk JJ, Ritzen EM. The role of bilateral adrenalectomy in the treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2003;88(7):2993–8.

    Article  PubMed  CAS  Google Scholar 

  • Vorona E, Zitzmann M, Gromoll J, et al. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007;92(9):3458–65.

    Article  CAS  PubMed  Google Scholar 

  • White PC, Medscape. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol. 2009;5(9):490–8.

    Article  CAS  PubMed  Google Scholar 

  • Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab. 2000;85(8):2664–9.

    CAS  PubMed  Google Scholar 

  • Wudy SA, Hartmann M, Homoki J. Hormonal diagnosis of 21-hydroxylase deficiency in plasma and urine of neonates using benchtop gas chromatography-mass spectrometry. J Endocrinol. 2000;165(3):679–83.

    Article  CAS  PubMed  Google Scholar 

  • Zainuddin AA, Grover SR, Soon CH, et al. A Multi-center cross-sectional study of Malaysian females with congenital adrenal hyperplasia: Their body image and their persepctives on feminizing surgery. J Pediatr Adolesc Gynecol. 2020 (epub ahead of print 3 May 2020).

    Google Scholar 

Download references

Acknowledgements

With acknowledgements and thanks to the original writers of this chapter: Professor Garry L. Warne, Dr. Jacqueline Hewitt.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Diabetes, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Michele A. O’Connell

  2. Murdoch Children’s Research Institute, Melbourne, VIC, Australia

    Michele A. O’Connell, Sonia R. Grover & Aurore Bouty

  3. Department of Gynaecology, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Sonia R. Grover

  4. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

    Sonia R. Grover

  5. Department of Urology, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Aurore Bouty

Authors
  1. Michele A. O’Connell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonia R. Grover
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aurore Bouty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michele A. O’Connell .

Editor information

Editors and Affiliations

  1. Department of Urology, The Royal Children’s Hospital, Melbourne, VIC, Australia

    John M. Hutson

  2. Department of Gynaecology, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Sonia R. Grover

  3. Endocrinology & Diabetes, Royal Children's Hospital Endocrinology & Diabetes, Melbourne, VIC, Australia

    Michele A. O'Connell

  4. Department of Urology, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Aurore Bouty

  5. Department of Gynaecology, The Royal Children’s Hospital, Melbourne, VIC, Australia

    Chloe A. Hanna

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

O’Connell, M.A., Grover, S.R., Bouty, A. (2020). 46,XX DSD. In: Hutson, J., Grover, S., O'Connell, M., Bouty, A., Hanna, C. (eds) Disorders|Differences of Sex Development. Springer, Singapore. https://doi.org/10.1007/978-981-13-7864-5_6

Download citation

Publish with us

Policies and ethics

Search

Navigation