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Journal of Genetic Counseling

, Volume 21, Issue 5, pp 615–624 | Cite as

Prenatal Treatment of Congenital Adrenal Hyperplasia—Not Standard of Care

  • Selma Feldman Witchel
  • Walter L. Miller
Commentary

Abstract

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common autosomal recessive disorder due to mutations in the CYP21A2 gene. Since genetic counselors play a crucial role in educating families about inherited disorders, they need to have thorough knowledge regarding the pathophysiology of CAH especially the effects on the fetus, the complex genetics of this disorder, and the controversies surrounding experimental prenatal dexamethasone treatment. Affected female fetuses may have varying degree of virilization of the external genitalia. Starting in the 1980’s, supraphysiologic glucocorticoid treatment was used to decrease the virilization of the external genitalia of affected female fetuses. However, recent clinical observations, animal studies and greater awareness of the details of human fetal adrenal physiology raise concerns regarding the safety of this prenatal treatment. We review the pathophysiology of CAH, the safety and ethical considerations of prenatal dexamethasone treatment and the views of multiple medical societies that conclude that this experimental therapy should only be done in prospective trials approved by ethical review boards.

Keywords

Congenital adrenal hyperplasia Ambiguous genitalia Prenatal dexamethasone Prenatal treatment CYP21A2 Ethics 

References

  1. Asztalos, E. V., Murphy, K. E., Hannah, M. E., Willan, A. R., Matthews, S. G., Ohlsson, A., et al. (2010). Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. Pediatrics, 126, e1045–e1055.PubMedCrossRefGoogle Scholar
  2. Barker, D. J. P., Winter, P. D., Osmond, C., Margetts, B., & Simmonds, S. J. (1989). Weight in infancy and death from ischaemic heart disease. Lancet, 2, 577–580.PubMedCrossRefGoogle Scholar
  3. Barker, D. J. P., Bull, A. R., Osmond, C., & Simmonds, S. J. (1990). Fetal and placental size and risk of hypertension in adult life. British Medical Journal, 301, 259–262.PubMedCrossRefGoogle Scholar
  4. Barker, D. J., Hales, C. N., Fall, C. H., Osmond, C., Phipps, K., & Clark, P. M. (1993). Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 36, 62–67.PubMedCrossRefGoogle Scholar
  5. Bartha, J. L., Finning, K., & Soothill, P. W. (2003). Fetal sex determination from maternal blood at 6 weeks of gestation when at risk for 21-hydroxylase deficiency. Obstetrics & Gynecology, 101, 1135–1136.CrossRefGoogle Scholar
  6. Bevilacqua, E., Brunelli, R., & Anceschi, M. M. (2010). Review and meta-analysis: benefits and risks of multiple courses of antenatal corticosteroids. Journal of Maternal Fetal Neonatal Medicine, 23, 244–260.PubMedCrossRefGoogle Scholar
  7. Bidet, M., Bellanné-Chantelot, C., Galand-Portier, M. B., Tardy, V., Billaud, L., Laborde, K., et al. (2009). Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. Journal of Clinical Endocrinology & Metabolism, 94, 1570–1578.CrossRefGoogle Scholar
  8. Braga, L. H., & Pippi Salle, J. L. (2009). Congenital adrenal hyperplasia: a critical appraisal of the evolution of feminizing genitoplasty and the controversies surrounding gender reassignment. European Journal of Pediatric Surgery, 19, 203–210.PubMedCrossRefGoogle Scholar
  9. Brown, R. W., Diaz, R., Robson, A. C., Kotelevtsev, Y. V., Mullins, J. J., Kaufman, M. H., et al. (1996). The ontogeny of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. Endocrinology, 137, 794–797.PubMedCrossRefGoogle Scholar
  10. Casteràs, A., De Silva, P., Rumsby, G., & Conway, G. S. (2009). Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. Clinical Endocrinology (Oxf), 70, 833–837.CrossRefGoogle Scholar
  11. Celsi, G., Kistner, A., Aizman, R., Eklöf, A.-C., Ceccatelli, S., de Santiago, A., et al. (1998). Prenatal dexamethasone causes oligonephria, sodium retention, and higher blood pressure in the offspring. Pediatric Research, 4, 317–322.CrossRefGoogle Scholar
  12. Coleman, M. A., & Honour, J. W. (2004). Reduced maternal dexamethasone dosage for the prenatal treatment of congenital adrenal hyperplasia. BJOG Int J Obstet Gynecol, 111, 176–178.CrossRefGoogle Scholar
  13. Concolino, P., Mello, E., Zuppi, C., & Capoluongo, E. (2010). Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update of new CYP21A2 mutations. Clinical Chemistry & Laboratory Medicine, 48, 1057–1062.CrossRefGoogle Scholar
  14. Crochemore, C., Michaelidis, T. M., Fischer, D., Loeffler, J. P., & Almeida, O. F. (2002). Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation. FASEB Journal, 6, 761–770.CrossRefGoogle Scholar
  15. Crouch, N. S., Liao, L. M., Woodhouse, C. R., Conway, G. S., & Creighton, S. M. (2008). Sexual function and genital sensitivity following feminizing genitoplasty for congenital adrenal hyperplasia. Journal of Urology, 179, 634–638.PubMedCrossRefGoogle Scholar
  16. Czeizel, A. E., & Rockenbauer, M. (1997). Population-based case–control study of teratogenic potential of corticosteroids. Teratology, 56, 335–340.PubMedCrossRefGoogle Scholar
  17. David, M., & Forest, M. G. (1984). Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. Journal of Pediatrics, 105, 799–803.PubMedCrossRefGoogle Scholar
  18. de Vries, A., Holmes, M. C., Heijnis, A., Seier, J. V., Heerden, J., Louw, J., et al. (2007). Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. Journal of Clinical Investigation, 117, 1058–1067.PubMedCrossRefGoogle Scholar
  19. Dickinson, H., Walker, D. W., Wintour, E. M., & Moritz, K. (2007). Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse. American Journal of Physiology; Regulatory Integrative Comparative Physiology, 292, R453–R461.CrossRefGoogle Scholar
  20. Dumić, M., Brkljacić, L., Speiser, P. W., Wood, E., Crawford, C., Plavsić, V., et al. (1990). An update on the frequency of nonclassic deficiency of adrenal 21-hydroxylase in the Yugoslav population. Acta Endocrinologica (Copenh)., 122, 703–710.Google Scholar
  21. Edwards, C. R., Benediktsson, R., Lindsay, R. S., & Seckl, J. R. (1993). Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet, 341, 355–357.PubMedCrossRefGoogle Scholar
  22. Esteban, N. V., Loughlin, T., Yergey, A. L., Zawadzki, J. K., Booth, J. D., Winterer, J. C., et al. (1991). Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. Journal of Clinical Endocrinology & Metabolism, 72, 39–45.CrossRefGoogle Scholar
  23. Evans, M. I., Chrousos, G. P., Mann, D. W., Larsen, J. W., Jr., Green, I., McCluskey, J., et al. (1985). Pharmacologic suppression of the fetal adrenal gland in utero. Attempted prevention of abnormal external genital masculinization in suspected congenital adrenal hyperplasia. JAMA, 253, 1015–1020.PubMedCrossRefGoogle Scholar
  24. Forest, M. G. (2004). Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Human Reproduction Update, 10, 469–485.PubMedCrossRefGoogle Scholar
  25. Forest, M. G., & Dorr, H. G. (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.CrossRefGoogle Scholar
  26. Forest, M. G., David, M., & Morel, Y. (1993). Prenatal diagnosis and treatment of 21-hydroxylase deficiency. Journal of Steroid Biochemistry & Molecular Biology, 45, 75–82.CrossRefGoogle Scholar
  27. Forest, M. G., Morel, Y., & David, M. (1998). Prenatal treatment of congenital adrenal hyperplasia. Trends in Endocrinology & Metabolism, 9, 284–289.CrossRefGoogle Scholar
  28. Fraser, F. C., & Fainstat, T. D. (1951). Production of congenital defects in the off-spring of pregnant mice treated with cortisone; progress report. Pediatrics, 8, 527–533.PubMedGoogle Scholar
  29. Fraser, F. C., & Sajoo, A. (1995). Teratogenic potential of corticosteroids in humans. Teratology, 51, 45–46.PubMedCrossRefGoogle Scholar
  30. Frias, J., Levine, L. S., Oberfield, S. E., Pang, S., Silverstein, J., et al. (2000). Technical report: congenital adrenal hyperplasia. Section on Endocrinology and Committee on Genetics. Pediatrics, 106, 1511–1518.CrossRefGoogle Scholar
  31. Goldman, A. S., Sharpior, B. H., & Katsumata, M. (1978). Human foetal palatal corticoid receptors and teratogens for cleft palate. Nature, 272, 464–466.PubMedCrossRefGoogle Scholar
  32. Goto, M., Hanley, K. P., Marcos, J., Wood, P. J., Wright, S., Postle, A. D., et al. (2006). In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. Journal of Clinical Investigation, 116, 953–960.PubMedCrossRefGoogle Scholar
  33. Harris, A., & Seckl, J. (2011). Glucocorticoids, prenatal stress and the programming of disease. Hormones & Behavior, 59, 279–289.CrossRefGoogle Scholar
  34. Hirvikoski, T., Nordenstrom, A., Lindholm, T., Lindblad, F., Ritzén, E. M., Wedell, A., et al. (2007). Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. Journal of Clinical Endocrinology & Metabolism, 92, 542–548.CrossRefGoogle Scholar
  35. Hirvikoski, T., Nordenstrom, A., Lindholm, F., Ritzén, E. M., & Lajic, S. (2008). Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems? European Journal of Endocrinology, 159, 309–316.PubMedCrossRefGoogle Scholar
  36. Hirvikoski, T., Lindholm, T., Lajic, S., & Nordenström, A. (2011). Gender role behaviour in prenatally dexamethasone-treated children at risk for congenital adrenal hyperplasia—a pilot study. Acta Paediatrica, 100(9), e112–e119. doi: 10.1111/j.1651-2227.2011.02260.x.PubMedCrossRefGoogle Scholar
  37. Hirvikoski, T., Nordenstrom, A., Wedell, A., Ritzen, & Lajic, S. (2012). Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: The Swedish experience and stand-point. Journal of Clinical Endocrinology and Metabolism. doi: 10.1210/jc.2012-1222.
  38. Holmes, M. C., Abrahamsen, C. T., French, K. L., Paterson, J. M., Mullins, J. J., & Seckl, J. R. (2006). The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. Journal of Neuroscience, 26, 3840–3844.PubMedCrossRefGoogle Scholar
  39. Huang, W. L., Beazley, L. D., Quinlivan, J. A., Evans, S. F., Newnham, J. P., & Dunlop, S. A. (1999). Effect of corticosteroids on brain growth in fetal sheep. Obstetrics & Gynecology, 94, 213–218.CrossRefGoogle Scholar
  40. Ishimoto, H., & Jaffe, R. B. (2011). Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocrine Reviews, 32, 317–355.PubMedCrossRefGoogle Scholar
  41. Joint ESPE/LWPES Working Group (Writing Committee: Clayton PE Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW) (2002). Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Hormone Research, 58, 188–195.Google Scholar
  42. Joint LWPES/ESPE CAH Working Group (Writing Committee: Clayton PE Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW) (2002). Consensus statement on 21-hydroxylase deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology. Journal of Clinical Endocrinology & Metabolism, 87, 4048–4953.Google Scholar
  43. Kari, M. A., Raivio, K. O., Stenman, U.-H., & Voutilainen, R. (1996). Serum cortisol, dehydroepiandrosterone sulfate, and sterol-binding globulins in preterm neonates: effects of gestational age and dexamethasone therapy. Pediatric Resesarch, 40, 319–324.CrossRefGoogle Scholar
  44. Kerrigan, J. R., Veldhuis, J. D., Leyo, S. A., Iranmanes, H. A., & Rogol, A. D. (1993). Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. Journal of Clinical Endocrinology & Metabolism, 76, 1505–1510.CrossRefGoogle Scholar
  45. Kleinle, S., Lang, R., Fischer, G. F., Vierhapper, H., Waldhauser, F., Födinger, M., et al. (2009). Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect. Journal of Clinical Endocrinology & Metabolism, 94, 3954–3958.CrossRefGoogle Scholar
  46. Koppens, P. F., Hoogenboezem, T., & Degenhart, H. J. (2002). Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes. Human Genetics, 111, 405–410.PubMedCrossRefGoogle Scholar
  47. Lajic, S., Wedell, A., Bui, T.-H., Ritzén, E. M., & Holst, M. (1998). Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. Journal of Clinical Endocrinology & Metabolism, 83, 3872–3880.CrossRefGoogle Scholar
  48. Linder, B. L., Esteban, N. V., Yergey, A. L., Winterer, J. C., Loriaux, D. L., & Cassorla, F. (1990). Cortisol production rate in childhood and adolescence. Journal of Pediatrics, 117, 892–896.PubMedCrossRefGoogle Scholar
  49. Lindsay, R. S., Lindsay, R. M., Edwards, C. R., & Seckl, J. R. (1996a). Inhibition of 11-beta-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring. Hypertension, 27, 1200–1204.PubMedCrossRefGoogle Scholar
  50. Lindsay, R. S., Lindsay, R. M., Waddell, B. J., & Seckl, J. R. (1996b). Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. Diabetologia, 39, 1299–1305.PubMedCrossRefGoogle Scholar
  51. Lo, Y. M., Corbetta, N., Chamberlain, P. F., Rai, V., Sargent, I. L., Redman, C. W., et al. (1997). Presence of fetal DNA in maternal plasma and serum. Lancet, 350, 485–487.PubMedCrossRefGoogle Scholar
  52. Lo, Y. M., Tein, M. S., Lau, T. K., Haines, C. J., Leung, T. N., Poon, P. M., et al. (1998). Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. American Journal of Human Genetics, 62, 768–775.PubMedCrossRefGoogle Scholar
  53. Mathews, S. G. (2001). Antenatal glucocorticoids and the developing brain: mechanisms of action. Seminars in Neonatology, 6, 309–317.CrossRefGoogle Scholar
  54. Mercado, A. B., Wilson, R. C., Cheng, K. C., Wei, J. Q., & New, M. I. (1995). Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Journal of Clinical Endocrinology & Metabolism, 80, 2014–2020.CrossRefGoogle Scholar
  55. Meyer-Bahlburg, H. F. L., Dolezal, C., Baker, S. W., Carlson, A. D., Obeid, J. S., & New, M. I. (2004). Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. Journal of Clinical Endocrinology & Metabolism, 89, 610–614.CrossRefGoogle Scholar
  56. Miller, W. L. (1994). Genetics, diagnosis, and management of 21-hydroxylase deficiency. Journal of Clinical Endocrinology & Metabolism, 78, 241–246.CrossRefGoogle Scholar
  57. Miller, W. L. (1999). Dexamethasone treatment of congenital adrenal hyperplasia—an experimental therapy of unproven safety. Journal of Urology, 162, 537–540.PubMedCrossRefGoogle Scholar
  58. Miller, W. L., & Auchus, R. J. (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews, 32, 81–151.PubMedCrossRefGoogle Scholar
  59. Miller, W. L., & Morel, Y. (1989). Molecular genetics of 21-hydroxylase deficiency. Annual Review of Genetics, 23, 371–393.PubMedCrossRefGoogle Scholar
  60. Moss, T. J., Doherty, D. A., Nitsos, I., Sloboda, D. M., Harding, R., & Newnham, J. P. (2005). Effects into adulthood of single or repeated antenatal corticosteroids in sheep. American Journal of Obstetrics & Gynecology, 192, 146–152.CrossRefGoogle Scholar
  61. Murphy, K. E., Hannah, M. E., Willan, A. R., Hewson, S. A., Ohlsson, A., Kelly, E. N., et al. (2008). Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet, 372, 2143–2151.PubMedCrossRefGoogle Scholar
  62. Nandagopal, R., Sinaii, N., Avila, N. A., Van Ryzin, C., Chen, W., Finkielstain, G. P., et al. (2011). Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families. European Journal of Endocrinology, 164, 977–984.PubMedCrossRefGoogle Scholar
  63. New, M. I., Carlson, A., Obeid, J., Marshall, I., Cabrera, M. S., Goseco, A., et al. (2001). Extensive personal experience: prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. Journal of Clinical Endocrinology & Metabolism, 86, 5651–5657.CrossRefGoogle Scholar
  64. Nordenskjöld, A., Holmdahl, G., Frisén, L., Falhammar, H., Filipsson, H., Thorén, M., et al. (2008). Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia. Journal of Clinical Endocrinology & Metabolism, 93, 380–386.CrossRefGoogle Scholar
  65. Nordenström, A., Frisén, L., Falhammar, H., Filipsson, H., Holmdahl, G., Janson, P. O., et al. (2010). Sexual function and surgical outcome in women with congenital adrenal hyperplasia due to CYP21A2 deficiency: clinical perspective and the patients’ perception. Journal of Clinical Endocrinology & Metabolism, 95, 3633–3640.CrossRefGoogle Scholar
  66. Pang, S., Clark, A. T., Freeman, L. C., Dolan, L. M., Immken, L., Mueller, O. T., et al. (1992). Maternal side-effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. Journal of Clinical Endocrinology & Metabolism, 75, 249–253.CrossRefGoogle Scholar
  67. Parajes, S., Quinteiro, C., Domínguez, F., & Loidi, L. (2008). High frequency of copy number variations and sequence variants at CYP21A2 locus: implication for the genetic diagnosis of 21-hydroxylase deficiency. PLoS One, 3(5), e2138.PubMedCrossRefGoogle Scholar
  68. Partsch, C. J., Sippell, W. G., MacKenzie, I. Z., & Aynsley-Green, A. (1991). The steroid hormonal milieu of the undisturbed human fetus and mother at 16–20 weeks gestation. Journal of Clinical Endocrinology & Metabolism, 73, 969–974.CrossRefGoogle Scholar
  69. Quinlivan, J. A., Dunlop, S. A., Newnham, J. P., Evans, S. F., & Beazley, L. D. (1999). Repeated, but not single, maternal administration of corticosteroids delays myelination in the brain of fetal sheep. Perinat Neonatal Med, 4, 47–55.Google Scholar
  70. Reipe, F. G., & Sippell, W. G. (2007). Recent advances in diagnosis, treatment and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Reviews in Endocrine & Metabolic Disorders, 8, 349–363.CrossRefGoogle Scholar
  71. Reisch, N., Arlt, W., & Krone, N. (2011). Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hormone Research in Paediatrics, 76, 73–85.PubMedCrossRefGoogle Scholar
  72. Rijnders, R. J., van der Schoot, C. E., Bossers, B., de Vroede, M. A., & Christiaens, G. C. (2001). Fetal sex determination from maternal plasma in pregnancies at risk for congenital adrenal hyperplasia. Obstetrics & Gynecology, 98, 374–378.CrossRefGoogle Scholar
  73. Ritzén, E. M. (1998). Prenatal treatment of congenital adrenal hyperplasia: a commentary. Trends in Endocrinology & Metabolism, 9, 293–295.CrossRefGoogle Scholar
  74. Rivkees, S. A., & Crawford, J. D. (2000). Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth. Pediatrics, 106, 767–773.PubMedCrossRefGoogle Scholar
  75. Robert, E., Vollset, S. E., Botto, L., Lancaster, P. A. L., Merlob, P., Mastroiacovo, P., et al. (1994). Malformation surveillance and maternal drug exposure: the MADRE project. Risk Safety Med, 6, 78–118.Google Scholar
  76. Rodriguez-Pinilla, E., & Martinez-Frias, M. L. (1998). Corticosteroids during pregnancy and oral clefts: a case–control study. Teratology, 58, 2–5.PubMedCrossRefGoogle Scholar
  77. Rowland, J. M., & Hendrickx, A. G. (1983). Corticosteroid teratogenicity. Advances in Veterinary Science & Comparative Medicine, 27, 99–128.Google Scholar
  78. Safari, H. R., Fassett, M. J., Souter, I. C., Alsulyman, O. M., & Goodwin, T. M. (1998). The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled study. American Journal of Obstetrics & Gynecology, 179, 921–924.CrossRefGoogle Scholar
  79. Samarasinghe, R. A., Di Maio, R., Volonte, D., Galbiati, F., Lewis, M., Romero, G., et al. (2011). Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation. Proceedings National Academy of Science (U S A), 108(40), 16657–16662.CrossRefGoogle Scholar
  80. Seckl, J. R. (2004). Prenatal glucocorticoids and long-term programming. European Journal of Endocrinology, 151, U49–U62.PubMedCrossRefGoogle Scholar
  81. Seckl, J. R., & Miller, W. L. (1997). How safe is long-term prenatal glucocorticoid treatment? JAMA, 277, 1077–1079.PubMedCrossRefGoogle Scholar
  82. Sloboda, D. M., Challis, J. R. G., Moss, T. J. M., & Newnham, J. P. (2005). Synthetic glucocorticoids: antenatal administration and long-term implications. Current Pharmaceutical Design, 11, 1459–1472.PubMedCrossRefGoogle Scholar
  83. Speiser, P. W., & Miller, W. L. (2008). Prenatal treatment of classic CAH with dexamethasone: pro vs. con. Endocrine News, 33, 15–18.Google Scholar
  84. Speiser, P. W., & White, P. C. (2003). Congenital adrenal hyperplasia. New England Journal of Medicine, 349, 776–788.PubMedCrossRefGoogle Scholar
  85. Speiser, P. W., Dupont, B., Rubinstein, P., Piazza, A., Kastelan, A., & New, M. I. (1985). High frequency of nonclassical steroid 21-hydroxylase deficiency. American Journal of Human Genetics, 37, 650–667.PubMedGoogle Scholar
  86. Speiser, P. W., New, M. I., Tannin, G. M., Pickering, D., Yang, S. Y., & White, P. C. (1992). Genotype of Yupik Eskimos with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Human Genetics, 88, 647–648.PubMedCrossRefGoogle Scholar
  87. Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., et al. (2010). Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism, 95, 4133–4160.CrossRefGoogle Scholar
  88. Styne, D. M., Richards, G. E., Bell, J. J., Conte, F. A., Morishima, A., Kaplan, S. L., et al. (1977). Growth patterns in congenital adrenal hyperplasia—Correlation of glucocorticoid therapy with stature. In P. Lee, L. Plotnick, A. Kowarski, & C. Migeon (Eds.), Congenital adrenal hyperplasia (pp. 247–261). Baltimore: University Park Press.Google Scholar
  89. Tajima, T., & Fujieda, K. (2008). Prenatal diagnosis and treatment of steroid 21-hydroxylase deficiency. Clinical Pediatric Endocrinology, 17, 95–102.CrossRefGoogle Scholar
  90. Therrell, B. L., Jr., Berenbaum, S. A., Manter-Kapanke, V., Simmank, J., Korman, K., Prentice, L., et al. (1998). Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics, 101, 583–590.PubMedCrossRefGoogle Scholar
  91. Uno, H., Lohmiller, L., Thieme, C., Kemnitz, J. W., Engle, M. J., Roeker, E. B., et al. (1990). Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Developmental Brain Research, 53, 157–167.PubMedCrossRefGoogle Scholar
  92. Wang, X., Zuckerman, B., Pearson, C., Kaufman, G., Chen, C., Wang, G., et al. (2002). Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA, 287, 195–202.PubMedCrossRefGoogle Scholar
  93. White, P. C. (2001). Congenital adrenal hyperplasias. Best Practice & Research. Clinical Endocrinology & Metabolism, 15, 17–41.CrossRefGoogle Scholar
  94. White, P. C., Mune, T., & Agarwal, A. K. (1997). 11β-hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocrine Reviews, 18, 135–156.PubMedCrossRefGoogle Scholar
  95. Wilson, R. C., Nimkarn, S., Dumić, M., Obeid, J., Azar, M. R., Najmabadi, H., et al. (2007). Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Molecular Genetics & Metabolism, 90, 414–421.CrossRefGoogle Scholar
  96. Witchel, S. F., & Azziz, R. (2011). Congenital adrenal hyperplasia. Journal of Pediatric & Adolescent Gynecology, 24(3), 116–126.CrossRefGoogle Scholar

Copyright information

© National Society of Genetic Counselors, Inc. 2012

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Pediatric Endocrinology, Children’s Hospital of Pittsburgh of UPMCUniversity of PittsburghPittsburghUSA
  2. 2.Department of Pediatrics, Division of Pediatric Endocrinology, HSE 1427University of California, San FranciscoSan FranciscoUSA

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