Advertisement

Ambiguous Genitalia and Problems with Sexual Differentiation

  • Moris Angulo
Chapter

Abstract

Ambiguity of a newborn’s genitalia or clinical situations in which determining the sex of a newborn is not clear represent a true dilemma in the nursery. Ambiguous genitalia are due to under-masculinization of genetic males or virilization of genetic females. Although congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in a newborn, other causes should be considered after ruling out this inherited adrenal condition. Having a systematic approach to the problem and an understanding of the processes of main genetic factors and sex hormones involved in sex determination and differentiation will help the clinician to better diagnose, counsel, and manage these challenging patients.

Keywords

Ambiguous genitalia Sex determination Sex differentiation Adrenal hyperplasia Gonadal dysgenesis 

References

  1. 1.
    Hamerton JL, Canning N, Ray M, et al. A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities. Clin Genet. 1975;4:223–43.Google Scholar
  2. 2.
    Blackless M, Charuvastra A, Derryck A, et al. How sexually dimorphic are we? Am J Hum Biol. 2000;12:151–66.CrossRefGoogle Scholar
  3. 3.
    Jost A, Vigier B, Prépin J, Perchellet JP. Studies on sex differentiation in mammals. Recent Prog Horm Res. 1973;29:1–41.PubMedGoogle Scholar
  4. 4.
    Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International consensus conference on intersex. Pediatrics. 2006;118:e488–500.CrossRefGoogle Scholar
  5. 5.
    Eggers S, Sinclair A. Mammalian sex determination–insights from humans and mice. Chromosom Res. 2012;20:215–38.CrossRefGoogle Scholar
  6. 6.
    Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol. 2013;9:79–91.CrossRefGoogle Scholar
  7. 7.
    Krone N, Dhir V, Ivison HE, Arlt W. Congenital adrenal hyperplasia and P450 oxidoreductase deficiency. Clin Endocrinol. 2007;66:162–72.CrossRefGoogle Scholar
  8. 8.
    White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245–91.PubMedGoogle Scholar
  9. 9.
    Nordenström A, Ahmed S, Jones J, Coleman M, Price DA, Clayton PE, Hall CM. Female preponderance in congenital adrenal hyperplasia due to CYP21 deficiency in England: implications for neonatal screening. Horm Res. 2005;63:22–8.PubMedGoogle Scholar
  10. 10.
    Pang S, Shook MK. Current status of neonatal screening for congenital adrenal hyperplasia. Curr Opin Pediatr. 1997;9:419–23.CrossRefGoogle Scholar
  11. 11.
    Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin N Am. 2001;30:15–30.CrossRefGoogle Scholar
  12. 12.
    van der Kamp HJ, Wit JM. Neonatal screening for congenital adrenal hyperplasia. Eur J Endocrinol. 2004 Nov;151(Suppl 3):U71–5.CrossRefGoogle Scholar
  13. 13.
    NNSIS 2009 National Newborn Screening Information System. Available at http://www2.uthscsa.edu/nnsis.
  14. 14.
    Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: a study of 25 patients. J Clin Endocrinol Metab. 1983;56:222–9.CrossRefGoogle Scholar
  15. 15.
    Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics. 1998 Apr;101:583–90.CrossRefGoogle Scholar
  16. 16.
    Allen DB, Hoffman GL, Fitzpatrick P, Laessig R, Maby S, Slyper A. Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17-hydroxyprogesterone levels. J Pediatr. 1997;130:128–33.CrossRefGoogle Scholar
  17. 17.
    al Saedi S, Dean H, Dent W, Stockl E, Cronin C. Screening for congenital adrenal hyperplasia: the Delfia screening test overestimates serum 17-hydroxyprogesterone in preterm infants. Pediatrics. 1996 Jan;97:100–2.PubMedGoogle Scholar
  18. 18.
    Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome—a review. J Pediatr Adolesc Gynecol. 2008 Dec;21(6):305–10.  https://doi.org/10.1016/j.jpag.2007.09.006.CrossRefPubMedGoogle Scholar
  19. 19.
    Hughes IA, Deeb A. Androgen resistance. Best Pract Res Clin Endocrinol Metab 2006;20(4):577–598. PMID 17161333.  https://doi.org/10.1016/j.beem.2006.11.003.CrossRefGoogle Scholar
  20. 20.
    Cools M, Van Aerde K, Kersemaekers AM, 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 Sep;90(9):5295–303.CrossRefGoogle Scholar
  21. 21.
    Hannema SE, Scott IS, Rajperts-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA. Testicular development in the complete androgen insensitivity syndrome. J Pathol. 2006;208:518–52.CrossRefGoogle Scholar
  22. 22.
    Hurt WG, Bodurtha JN, McCall JB, Ali MM, Hurt WG, Bodurtha JN, McCall JB, Ali MM. Seminoma in pubertal patient with androgen insensitivity syndrome. Am J Obstet Gynecol. 1989;161:530–1.CrossRefGoogle Scholar
  23. 23.
    Page DC. Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads. Development. 1987;101:151e5.Google Scholar
  24. 24.
    McCann-Crosby B, Mansouri R, Dietrich JE, McCullough LB, Sutton VR, Austin EG, et al. State of the art review in gonadal dysgenesis: challenges in diagnosis and management. Int J Pediatr Endocrinol. 2014;2014:4.CrossRefGoogle Scholar
  25. 25.
    Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet. 1987;25:191e218.CrossRefGoogle Scholar
  26. 26.
    Lubahn DB, Joseph DR, Sullivan PM, et al. Cloning of human androgen receptor and complementary DNA and localization to the X chromosome. Science. 1988;240:327.CrossRefGoogle Scholar
  27. 27.
    Brinkmann AO, Faber PW, Rooij v, et al. The human androgen receptor: domain structure, genomic organization and regulation of expression. J Steroid Biochem. 1989;34:307.CrossRefGoogle Scholar
  28. 28.
    Houk CP, Lee PA. Consensus statement on terminology and management: disorders of sex development. Sex Dev. 2008;2(4–5):172–80.CrossRefGoogle Scholar
  29. 29.
    Esoterix endocrinology syllabus. hCG stimulation testing. www.essoterix.com. Available at http://www.esoterix.com/files/Endocrinology_Syllabus_3.22.11.pdf. Accessed 13 May 2014.
  30. 30.
    Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med. 1979 May;300(22):1233–7.CrossRefGoogle Scholar
  31. 31.
    Saenger P, Goldman AS, Levine LS, et al. Prepubertal diagnosis of steroid 5 alpha-reductase deficiency. J Clin Endocrinol Metab. 1978 Apr;46(4):627–34.CrossRefGoogle Scholar
  32. 32.
    Hiort O, Sinnecker GH, Willenbring H, Lehners A, Zöllner A, Struve D. Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase deficiency. J Clin Endocrinol Metab. 1996;81:3415–8.PubMedGoogle Scholar
  33. 33.
    Okeigwe I, Kuohung W. 5-alpha reductase deficiency: a 40-year retrospective review. Curr Opin Endocrinol Diabetes Obes. 2014;21(6):483–7.CrossRefGoogle Scholar
  34. 34.
    Hersmus R, Kalfa N, de Leeuw B, et al. FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). J Pathol. 2008;215(1):31–8.CrossRefGoogle Scholar
  35. 35.
    Barbaro M, Wedell A, Nordenström A. Disorders of sex development. Semin Fetal Neonatal Med. 2011;16(2):119–27.CrossRefGoogle Scholar
  36. 36.
    Abbas N, McElreavey K, Leconiat M, Vilain E, Jaubert F, Berger R, Nihoul-Fekete C, Rappaport R, Fellous M. Familial case of 46,XX male and 46,XX true hermaphrodite associated with a paternal-derived SRY-bearing X chromosome. C R Arcad Sci III. 1993;316:375–83.Google Scholar
  37. 37.
    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;91:554–63.CrossRefGoogle Scholar
  38. 38.
    Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E. Clinical, Endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007;92:3458–65.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.SUNY/Stony Brook School of MedicineStony BrookUSA
  2. 2.Division of GeneticsNYU Winthrop HospitalMineolaUSA

Personalised recommendations