Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Prenatal diagnosis and treatment of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 405–413 (2007)Cite this article

Abstract

Classical forms of congenital adrenal hyperplasia are caused by a severe deficiency of 21-hydroxylase, an enzyme involved in steroid biosynthesis, which triggers excessive androgen production before birth. Affected females experience virilization both physically and psychologically. Prenatal diagnosis and treatment of congenital adrenal hyperplasia has been implemented for more than 20 years. In utero gene-specific diagnosis is now feasible for fetal cell samples derived from chorionic villi or amniotic cells in culture, and this gene-specific diagnosis guides the treatment of the affected female fetus. Appropriate dexamethasone administration to the at-risk pregnant mother is effective in reducing genital virilization in the fetus, and thus avoids unnecessary genitoplasty in affected females. Current data from large human studies show the benefit and safety of prenatal treatment. Long-term follow-up of the safety of prenatal treatment is currently underway. This practice is a rare example of effective prenatal treatment to prevent a malformation caused by an inborn error of metabolism.

Key Points

  • The term congenital adrenal hyperplasia (CAH) applies to a group of disorders affecting the biosynthesis of cortisol; the most common form of CAH is 21-hydroxylase deficiency CAH (21-OHD CAH)

  • In classical (severe or moderately severe) forms of 21-OHD CAH, prenatal androgen excess leads to genital ambiguity in affected females

  • Prenatal diagnosis of 21-OHD CAH is accomplished via genetic analysis of fetal DNA obtained from chorionic villi sampling

  • When appropriately administered, prenatal treatment with dexamethasone is safe and effective in preventing ambiguity of genitalia of female fetuses affected with 21-OHD CAH

  • International follow-up studies of treated mothers and their offspring will confirm the short-term safety and efficacy of prenatal diagnosis and treatment of 21-OHD CAH

  • Studies to determine the long-term outcome of prenatal treatment are indicated and are underway

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Adrenal steroidogenesis in 21-hydroxylase deficiency congenital adrenal hyperplasia
Figure 2: The gene encoding 21-hydroxylase and its pseudogene
Figure 3: The human leukocyte antigen region of chromosome 6p
Figure 4: Simplified algorithm of treatment, diagnosis and decision-making for prenatal treatment of fetuses at risk for 21-hydroxylase deficiency congenital adrenal hyperplasia

Similar content being viewed by others

References

  1. New MI (2004) An update of congenital adrenal hyperplasia. Ann NY Acad Sci 1038: 14–43

    Article  CAS  Google Scholar 

  2. New MI (2006) Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 91: 4205–4214

    Article  CAS  Google Scholar 

  3. White PC and Speiser PW (2000) Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21: 245–291

    CAS  PubMed  Google Scholar 

  4. Hughes IA et al. (2006) Consensus statement on management of intersex disorders. Arch Dis Child 91: 554–563

    Article  CAS  Google Scholar 

  5. Crouch NS and Creighton SM (2004) Minimal surgical intervention in the management of intersex conditions. J Pediatr Endocrinol Metab 17: 1591–1596

    Article  Google Scholar 

  6. Therrell BJ et al. (1998) Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 101: 583–590

    Article  Google Scholar 

  7. Temeck JW et al. (1987) Genetic defects of steroidogenesis in premature pubarche. J Clin Endocrinol Metab 64: 609–617

    Article  CAS  Google Scholar 

  8. Pang S et al. (1985) Pitfalls of prenatal diagnosis of 21-hydroxylase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 61: 89–97

    Article  CAS  Google Scholar 

  9. Gruneiro-Papendieck L et al. (2001) Neonatal screening program for congenital adrenal hyperplasia: adjustments to the recall protocol. Horm Res 55: 271–277

    CAS  PubMed  Google Scholar 

  10. Allen DB et al. (1997) Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17-hydroxyprogesterone levels. J Pediatr 130: 128–133

    Article  CAS  Google Scholar 

  11. New MI et al. (1983) Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 57: 320–326

    Article  CAS  Google Scholar 

  12. Nebert DW et al. (1991) The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 10: 1–14

    Article  CAS  Google Scholar 

  13. Dupont B et al. (1977) Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet 2: 1309–1312

    Article  CAS  Google Scholar 

  14. White PC et al. (1986) Structure of the human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA 83: 5111–5115

    Article  CAS  Google Scholar 

  15. Stenson PD et al. (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21: 577–581

    Article  CAS  Google Scholar 

  16. Speiser PW et al. (1992) Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 90: 584–595

    Article  CAS  Google Scholar 

  17. Wilson RC et al. (1995) Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 80: 2322–2329

    CAS  PubMed  Google Scholar 

  18. Villee DB (1972) The development of steroidogenesis. Am J Med 53: 533–544

    Article  CAS  Google Scholar 

  19. Goto M et al. (2006) In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest 116: 953–960

    Article  CAS  Google Scholar 

  20. Jeffcoate T et al. (1965) Diagnosis of the adrenogenital syndrome before birth. Lancet 2: 553–555

    Article  CAS  Google Scholar 

  21. Mercado AB et al. (1995) Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 80: 2014–2020

    CAS  PubMed  Google Scholar 

  22. Wilson RC et al. (1995) Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene. J Clin Endocrinol Metab 80: 1635–1640

    CAS  PubMed  Google Scholar 

  23. Tukel T et al. (2003) A novel semiquantitative polymerase chain reaction/enzyme digestion-based method for detection of large scale deletions/conversions of the CYP21 gene and mutation screening in Turkish families with 21-hydroxylase deficiency. J Clin Endocrinol Metab 88: 5893–5897

    Article  CAS  Google Scholar 

  24. Lee HH et al. (2004) Use of PCR-based amplification analysis as a substitute for the Southern blot method for CYP21 deletion detection in congenital adrenal hyperplasia. Clin Chem 50: 1074–1076

    Article  CAS  Google Scholar 

  25. Nimkarn S et al. (1999) Congenital adrenal hyperplasia (21-hydroxylase deficiency) without demonstrable genetic mutations. J Clin Endocrinol Metab 84: 378–381

    Article  CAS  Google Scholar 

  26. Day DJ et al. (1996) Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees. Hum Mol Genet 5: 2039–2048

    Article  CAS  Google Scholar 

  27. Mao R et al. (2002) Prenatal diagnosis of 21-hydroxylase deficiency caused by gene conversion and rearrangements: pitfalls and molecular diagnostic solutions. Prenat Diagn 22: 1171–1176

    Article  CAS  Google Scholar 

  28. Grumbach MM and Shaw EB (1998) Further studies on the treatment of congenital adrenal hyperplasia with cortisone. IV: effect of cortisone and compound B in infants with disturbed electrolyte metabolism, by John F. Crigler Jr, MD, Samuel H. Silverman, MD, and Lawson Wilkins, MD, Pediatrics, 1952; 10: 397–413. Pediatrics 102: 215–221

    CAS  PubMed  Google Scholar 

  29. David M and Forest MG (1984) Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 105: 799–803

    Article  CAS  Google Scholar 

  30. Forest M et al. (1989) Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: up-date 88 of the French multicentric study. Endocr Res 15: 277–301

    Article  CAS  Google Scholar 

  31. New MI et al. (2001) Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 86: 5651–5657

    Article  CAS  Google Scholar 

  32. Saenger P (1984) Abnormal sex differentiation. J Pediatr 104: 1–17

    Article  CAS  Google Scholar 

  33. Meyer-Bahlburg HF et al. (2006) Gender development in women with congenital adrenal hyperplasia as a function of disorder severity. Arch Sex Behav 35: 667–684

    Article  Google Scholar 

  34. Seckl JR (2004) Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 151 (Suppl 3): SU49–SU62

    Article  Google Scholar 

  35. Seckl JR and Miller WL (1997) How safe is long-term prenatal glucocorticoid treatment? JAMA 277: 1077–1079

    Article  CAS  Google Scholar 

  36. New MI et al. (2003) Update: prenatal diagnosis for congenital adrenal hyperplasia in 595 pregnancies. Endocrinologist 13: 233–239

    Article  CAS  Google Scholar 

  37. Forest MG and Dorr HG (2003) Prenatal therapy in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: retrospective follow-up study of 253 treated pregnancies in 215 families. Endocrinologist 13: 252–259

    Article  Google Scholar 

  38. Trautman PD et al. (1996) Mothers' reactions to prenatal diagnostic procedures and dexamethasone treatment of CAH. J Psychosom Obstet Gynaecol 17: 175–181

    Article  CAS  Google Scholar 

  39. Lajic S et al. (1998) Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 83: 3872–3880

    CAS  PubMed  Google Scholar 

  40. Lajic S et al. (2004) Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 151 (Suppl 3): SU63–SU69

    Article  Google Scholar 

  41. Goldman A et al. (1978) Human foetal palatal corticoid receptors and teratogens for cleft palate. Nature 272: 464–466

    Article  CAS  Google Scholar 

  42. Raman PB et al. (1964) Conversion of progesterone-4-14c to 18-hydroxycorticosterone and aldosterone by mouse adrenals in vitro. Endocrinology 74: 865–869

    Article  CAS  Google Scholar 

  43. Nandi J et al. (1967) In vitro steroidogenesis by the adrenal glands of mice. Endocrinology 80: 576–582

    Article  CAS  Google Scholar 

  44. Yeh TF et al. (2004) Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 350: 1304–1313

    Article  CAS  Google Scholar 

  45. Slotkin TA et al. (1998) Glucocorticoid administration alters nuclear transcription factors in fetal rat brain: implications for the use of antenatal steroids. Brain Res Dev Brain Res 111: 11–24

    Article  CAS  Google Scholar 

  46. Uno H et al. (1990) Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I: hippocampus. Brain Res Dev Brain Res 53: 157–167

    Article  CAS  Google Scholar 

  47. Joint LWPES/ESPE CAH Working Group (2002) 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

  48. Newnham JP (2001) Is prenatal glucocorticoid administration another origin of adult disease? Clin Exp Pharmacol Physiol 28: 957–961

    Article  CAS  Google Scholar 

  49. Trautman PD et al. (1995) Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20: 439–449

    Article  CAS  Google Scholar 

  50. Hall C et al. (2004) Behavioral and physical masculinization are related to genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 89: 419–424

    Article  CAS  Google Scholar 

  51. Pang SY et al. (1990) Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 322: 111–115

    Article  CAS  Google Scholar 

  52. Speiser P (1999) Prenatal treatment of congenital adrenal hyperplasia. J Urol 162: 534–536

    Article  CAS  Google Scholar 

  53. Rijnders RJ et al. (2001) Fetal sex determination from maternal plasma in pregnancies at risk for congenital adrenal hyperplasia. Obstet Gynecol 98: 374–378

    CAS  PubMed  Google Scholar 

  54. Morel Y et al. (2003) 21 hydroxylase deficiency: new strategies emerging from molecular studies [French]. Ann Endocrinol (Paris) 64: 456–470

    CAS  Google Scholar 

  55. Tusie-Luna MT et al. (1991) A mutation (Pro-30 to Leu) in CYP21 represents a potential nonclassic steroid 21-hydroxylase deficiency allele. Mol Endocrinol 5: 685–692

    Article  CAS  Google Scholar 

  56. Speiser PW et al. (1988) Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1. N Engl J Med 319: 19–23

    Article  CAS  Google Scholar 

  57. Helmberg A et al. (1992) R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions. Mol Endocrinol 6: 1318–1322

    CAS  PubMed  Google Scholar 

  58. Owerbach D et al. (1992) Pro-453 to ser mutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency. Mol Endocrinol 6: 1211–1215

    CAS  PubMed  Google Scholar 

  59. White PC et al. (1984) HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation. Proc Natl Acad Sci USA 81: 7505–7509

    Article  CAS  Google Scholar 

  60. Higashi Y et al. (1988) Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products. Proc Natl Acad Sci USA 85: 7486–7490

    Article  CAS  Google Scholar 

  61. White PC et al. (1994) Mutations in steroid 21-hydroxylase (CYP21). Hum Mutat 3: 373–378

    Article  CAS  Google Scholar 

  62. Amor M et al. (1988) Mutation in the CYP21B gene (Ile-172-Asn) causes steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85: 1600–1607

    Article  CAS  Google Scholar 

  63. Tusie-Luna M et al. (1990) Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem 265: 20916–20922

    CAS  PubMed  Google Scholar 

  64. Globerman H et al. (1988) Nonsense mutation causing steroid 21-hydroxylase deficiency. J Clin Invest 82: 139–144

    Article  CAS  Google Scholar 

  65. Chiou SH et al. (1990) A missense mutation at Ile172—Asn or Arg356—Trp causes steroid 21-hydroxylase deficiency. J Biol Chem 265: 3549–3552

    CAS  PubMed  Google Scholar 

  66. Wedell A and Luthman H (1993) Steroid 21-hydroxylase (P450c21): a new allele and spread of mutations through the pseudogene. Hum Genet 91: 236–240

    Article  CAS  Google Scholar 

  67. Nimkarn S and New MI (2006) Prenatal diagnosis and treatment of congenital adrenal hyperplasia. Horm Res 67: 53–60

    PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported in part by US Public Health Service grant HD00072. The authors would like to thank Naomi Horowitz for her editorial support.

Author information

Authors and Affiliations

  1. in the Department of Pediatrics at Mount Sinai School of Medicine, S Nimkarn is an Assistant Professor of Pediatrics, and MI New is Professor of Pediatrics and Director of the Adrenal Steroids Disorders Program, New York, NY, USA.,

    Saroj Nimkarn & Maria I New

Authors
  1. Saroj Nimkarn
    View author publications

    Search author on:PubMed Google Scholar

  2. Maria I New
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Maria I New.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nimkarn, S., New, M. Prenatal diagnosis and treatment of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Nat Rev Endocrinol 3, 405–413 (2007). https://doi.org/10.1038/ncpendmet0481

Download citation

  • Received:

  • Accepted:

  • Issue date:

  • DOI: https://doi.org/10.1038/ncpendmet0481

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing