Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia

Current Opinion in Endocrinology and Diabetes

Volumn 4, Issue 3, 1997, Pages 209-217

  Forest, Maguelone G ^a  

^a HÔPITAL DEBROUSSE   (France)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0001305482     PISSN: 10683097     EISSN: None     Source Type: Journal    
DOI: 10.1097/00060793-199706000-00005     Document Type: Review

References (85)

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9. Migeon CJ: Comments about the need for prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1990, 70:836-837.
10. Forest MG, David M, Morel Y: Prenatal diagnosis and treatment of 21-hydroxylase deficiency. J Steroid Biochem Mol Biol 1993, 45:75-82.
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16. Morel Y, Murena M, Nicolino M, Carel JC, David M, Forest MG: Correlation between genetic lesions of the CYP21B gene and the clinical forms of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: report of a large study of 355 CAH chromosomes. Horm Res 1992, 37:13.
17. Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna M-T, Lesser M, New MI, White PC: Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 1992, 90:584-595.
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19. Wilson RC, Mercado AB, Cheng KC, New MI: Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995, 80:2322-2329. This paper includes the cases reported by Speiser et al. (J Clin Invest 1992, 90:5584-5595). In fact, genotype corresponded with phenotype in the vast majority of cases, an anecdotal case to the contrary notwithstanding.
20. 5 genomes) occurred in both. This suggests that gene conversion must occur by a mechanism other than unequal crossing over.
21. Gunn SK, Sherman LD, Therrell BL, Owerbach DI: Molecular genetics of 21-hydroxylase deficiency late-onset adrenal hyperplasia. Semin Reprod Endocrinol 1993, 11:347-352.
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25. Helmberg A, Tusie-Luna M, Tabarelli M, Kofler R, White PC: R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions. Mol Endocrinol 1992, 6:1318-1322.
26. Lajic S, Wedell A: An intron 1 splice mutation and a nonsense mutation (W23X) in a CYP21 causing severe congenital adrenal hyperplasia. Hum Genet 1996, 98:182-184. Direct DNA sequencing of the steroid 21-hydroxylase gene (CYP21) revealed two novel mutations in two patients with severe CAH. The first (nonsense mutation Trp23stop) was found in a woman affected with a salt-virilizing form of CAH carrying the lle173Asn mutation on the other allele. The second (mutation of the canonic splice acceptor site in intron 1) was found in a boy with a salt-losing form of CAH and was associated with the well-known splice mutation in intron 2 on the other allele.
27. Tussie-Luna MT, Ramirez-Jimenez S, Ordonez-Sanchez ML, Cabello-Villegas J, Altamirano-Bustamante N, Calzada-Leon R, Robles-Valdes C, Mendoza-Morfin F, Mendez JP, Teran-Garcia-Bustamante M: Low frequency of deletion alleles in patients with steroid 21-hydroxylase deficiency in a Mexican population. Hum Genet 1996, 98:376-379. This report showed a very low incidence (< 1%) of deletion alleles in the CYP21 gene in CAH patients in a Mexican population. Was this a result of variable frequency among populations or a bias of detection of salt wasters due to the early death of undiagnosed infants?
28. Donohoue PA, Guethlein L, Collins MM, Van-Dop C, Migeon CJ, Bias WB, Schmeckpeper BJ: The HLA-A3, Cw6, B47, DR7 extended haplotypes in salt losing 21-hydroxylase deficiency and in the Old Order Amish: identical class I antigens and class II alleles with at least two crossover sites in the class III region. Tissue Antigens 1995, 46:163-172. A description of a new extended haplotype characterizing the American population with Amish ancestry.
29. New MI, White PC: Genetic disorders of steroid hormone synthesis and metabolism. Baillieres Clin Endocrinol Metab 1995, 9:525-554.
30. Frasier SD, Thorneycroft IH, Weiss BA, Norton R: Elevated amniotic fluid concentration of 17α-hydroxyprogesterone in congenital adrenal hyperplasia. J Pediatr 1975, 86:310-312.
31. Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI: Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1995, 80:2014-2020. In this report of a large series of prenatal diagnoses in 239 at-risk women, 37 infants were CAH affected and 21 were females. Thirteen were treated prenatally. Prenatal treatment administered at or before 10 weeks was effective in nine females born with normal (n = 4) or slightly virilized (Prader stages 1 to 2; n = 5) genitalia. No significant enduring side effects were noted in either the mothers or the fetuses. In a few instances an error was made in prenatal diagnosis based on steroid analysis (n = 3), HLA typing (n = 3), or DNA analysis (n = 6). Overall, prenatal diagnosis was accurate in 95% of the cases, and proper prenatal treatment was effective in significantly reducing or eliminating virilization in all CAH-affected females. Results also indicate that treatment is safe.
32. Dupont B, Oberfield SE, Smithwick ER, Lee TD, Levine LS: Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet 1977, ii:1309-1312.
33. Forest MG: Pitfalls in prenatal diagnosis of 21-hydroxylase deficiency by amniotic fluid steroid analysis? Ann N Y Acad Sci 1985, 458:130-147.
34. Forest MG, Bétuel H, Couillin P, Boué A: Prenatal diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency by steroid analysis in the amniotic fluid of mid-pregnancy: comparison with HLA-typing in 17 pregnancies at risk for CAH. Prenat Diagn 1981, 1:197-207.
35. 4 steroids in fetuses with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and in anencephalic fetuses. J Clin Endocrinol Metab 1980, 51:223-229.
36. Pollack MS, Levine LS, Pang S, Owens RP, Nitowsky HM, Maurer D, New MI, Duchon M, Merkatz IR, Sahs G, Dupont B: Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) by HLA typing. Lancet 1979, i:1107-1108.
37. Rhoads GG, Jackson LG, Schlesselman SE, De La Cruz FF, Desnick RJ, Golbus MS, Ledbetter DH, Lubs HA, Mahoney MJ, Pergament E, Simpson JL, Carpenter RJ, Elias S, Ginsberg NA, Goldberg JD, Hobbins JC, Lynch L, Shiono PH, Wapner RJ, Zachary JM: The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989, 320:609-617.
38. Mornet E, Boué J, Raux-Demay M, Couillin P, Oury J, Dumez Y, Dausset J, Cohen D, Boué A: First trimester prenatal diagnosis of 21-hydroxylase deficiency by linkage analysis to HLA-DNA probes and by 17-hydroxyprogesterone determination. Hum Genet 1986, 73:358-364.
39. Forest MG, Bétuel H, David M: Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update 88 of the French multicentric study. Endocr Res 1989, 15:277-301.
40. Morel Y, David M, Forest MG, Bétuel H, Hauptmann G, André J, Bertrand J, Miller WL: Gene conversions and rearrangements cause discordance between Inheritance of forms of 21-hydroxylase deficiency and HLA types. J Clin Endocrinol Metab 1989, 68:592-599.
41. Speiser PW, White PC, Dupont J, Zhu D, Mercado AB, New MI: Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency by allele-specific hybridization and southern blot. Hum Genet 1994, 93:424-428.
42. Morel Y, Murena M, Fores MG, Nicolino M, David M: Frequency of the 8 known deleterious point mutations of the CYP21B gene in more than 100 families with 21-hydroxylase deficiency (CAH): implications for prenatal diagnosis [abstract 1379]. Proceedings of the 73rd Annual Meeting of the Endocrine Society 1991. Bethesda, MD: The Endocrine Society; 1991:375.
43. Owerbach D, Draznin MB, Carpenter FRJ, Greenberg F: Prenatal diagnosis of 21-hydroxylase deficiency congenital adrenal hyperplasia using the polymerase chain reaction. Hum Genet 1992, 89:109-110.
44. Wilson RC, Wei JQ, Cheng KC, Mercado AB, New Mi: Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene. J Clin Endocrinol Metab 1995, 80:1635-1640. This method, developed for the detection of eight of the most common mutations in the CYP21 gene by ethidium bromide-stained agarose gel electrophoresis after allele-specific polymerase chain reaction, is rapid and avoids the use of radioactivity.
45. Day DJ, Speiser PW, White PC, Barany F: Detection of steroid 21-hydroxylase alleles using gene-specific PCR and a multiplexed ligation detection reaction. Genomics 1995, 29:152-162. This novel method of genetic analysis of CAH utilizes gene-specific PCR amplification in conjunction with thermostable DNA ligase to discriminate single nucleotide variations in a multiplexed ligation detection assay. The assay is designed to be used with either fluorescent or radioactive detection of ligation products by electrophoresis on denaturing acrylamide gels and is adaptable to automation.
46. Chung BC, Hu MC, Guzov VM, Wu DA: Structure and expression of the CYP21 (P450C21, steroid hydroxylase) gene with respect to its deficiency. Endocr Res 1995, 21:343-352. This report provides a description of a fast diagnostic method to detect common mutations in the CYP21 gene by a two-step gene amplification procedure coupled to restriction digestion, and a procedure for the production of active P-450c21 in Escherichia coli. The importance of low growth temperature and long induction time for abundant synthesis is stressed.
47. Ezquieta B, Varela JM, Jariego C, Oliver A, Gracia R: Nonisotopic detection of point mutations in CYP21B gene in steroid 21-hydroxylase deficiency. Clin Chem 1996, 42:1108-1110. This study describes a new method using a chemiluminescent substrate for the detection of point mutation. The protocol appears safe, rapid, and sensitive and can be performed in laboratories without special installations.
48. Witchel SS, Lee PA, Trucco M: Who is a carrier? Detection of unsuspected mutations in 21-hydroxylase deficiency. Am J Med Genet 1996, 61:2-9. Genotyping of extended relatives of patients with CAH revealed two families each segregating three mutations, one of which was not carried by the propositus. This illustrates the difficulties of the genetic analysis of 21-hydroxylase deficiency and emphasizes the high frequency of mutant CYP21 alleles in the general population.
49. Morel Y, Murena M, Nicolino M, Forest MG: Molecular genetics of the congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In Cellular and Molecular Biology of the Adrenal Cortex. Edited by Saez JM, Brownie AC, Capponi A, Chambazs EM. Paris: Colloque INSERM/John Libbey Eurotext Ltd; 1992:123-136.
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51. Wedell A, Chun X, Luthman H: A steroid 21-hydroxylase allele concomitantly carrying four disease-causing mutations is not uncommon in the Swedish population. Hum Genet 1994, 93:204-206.
52. Siegel SF, Lee PA, Rudert WA, Swinyard M, Trucco M: Phenotype/genotype correlations in 21-hydroxylase deficiency. Adolesc Pediatr Gynecol 1995, 8:9-16.
53. Kohn B, Day D, Alemzadeh R, Enerio D, Patel SV, Pelczar JV, Speiser PW: Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia. Am J Med Genet 1995, 57:450-454. This report provides another example of the variable phenotypic expression of the mutation 656A→G causing abnormal splicing of exons 2 and 3 in CYP21. In this particular case, the unusual event was the delayed expression of a severe salt-wasting form of CAH. This case shows that pediatricians should still consider the diagnosis of CAH in infants who present with hyponatremia and vascular collapse beyond the neonatal period.
54. Schulze E, Scharer G, Rogatzki A, Priebe L, Lewicka S, Bettendorf M, Hoepffner W, Heinrich UE, Schwabe U: Divergence between genotype and phenotype in relatives of patients with the intron 2 mutation of steroid 21-hydroxlyase. Endocr Res 1995, 21:359-364. In this study of a large series of 95 CAH patients with either the salt-wasting or simple-virilizing form, the intron 2 splice mutation was the most frequently found (35%), with a strong genetic association with the salt-wasting form, although it was found in 20% of simple-virilizing patients. Homozygous splice mutation was found in relatives with no phenotypic expression. This could reflect a variable degree of normal splicing mRNA and different phenotypic severity in intron mutations as found in thalassemia.
55. Witchel SF, Bhamidipati DK, Hoffman EP, Cohen JB: Phenotype heterogeneity associated with the splicing mutation in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1996, 81:4081-4088. Comparison of the phenotypic features with the molecular genotypes showed phenotypic heterogeneity extending from classic salt-losing CAH to asymptomatic CAH. Numerous sequence variations were found in intron 2, most often at nucleotides 601 and 683. Transient transfection experiments showed that the 3′ portion of intron 2 is sufficient to transfer the effect of the 656A→G mutation to a chimeric heterologous gene. This single nucleotide change alters the splice acceptor site at the intron 2/exon boundary. It is hypothesized that other sequence variations influence the competitive slicing signals at the intron 2/exon 3 junction.
56. Rumsby G, Massoud AF, Avery C, Brook CGD: Non-expression of a common mutation in the 21-hydroxylase gene: implications for prenatal diagnosis and carrier testing. J Med Genet 1996, 33:798-799. The observations of this study illustrate the difficulties of DNA analysis and the problems in the management of future pregnancies, as well as the interpretation of the risk associated with carrier status for the intron 2 splice mutation.
57. Forest MG, Pugeat M, Monneret MP, Rigaud C, David M, Morel Y: Normative data for the response of plasma 21-deoxycortisol to ACTH stimulation: efficient screening test for the heterozygocy of 21-hydroxylase deficiency in the general population. Horm Res 1994, 41:110.
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67. Dörr HG, Sippell WG: Prenatal dexamethasone treatment in pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: effect on midgestational amniotic fluid steroid levels. J Clin Endocrinol Metab 1993, 76:117-120.
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69. Sivan E, Koch S, Reece EA: Sonographic prenatal diagnosis of ambiguous genitalia. Fetal Diagn Ther 1995, 10:311-314. This case report illustrates that abnormal genital development can be made sonographically and can serve as a tool to monitor the success of prenatal steroid therapy of fetal CAH.
70. Karaviti LP, Mercado AB, Mercado MB, Speiser PW, Buegeleisen M, Crawford C, Antonina L, White PC, New MI: Prenatal diagnosis/treatment in families at risk for infants with steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). J Steroid Biochem Mol Biol 1992, 41:445-451.
71. Forest MG, Dorr HG: Prenatal treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: European experience in 223 pregnancies at risk. Clin Courier 1993, 11:2-3.
72. Speiser PW, Laforgia N, Kato K, Pareira J, Khan R, Yang SY, Whorwood C, White PC, Elias S, Schriock E, Schriock E, Simpson JL, Taslimi M, Najjar J, May S, Mills G, Crawford C, New MI: First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab 1990, 70:838-848.
73. Forest MG, Morel Y, David M: Prenatal treatment of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. In Sexual Differentiation and Maturation. Edited by Hibi I, Tanakas T. Rome: Chrissengraf; 1996:77-89. An update of the French multicenter study (80 cases), the European questionnaire in a total of 254 at-risk pregnant women, and a review of the world literature.
74. Forest MG, Dörr HG: Prenatal treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: European experience in 223 pregnancies at risk. Pediatr Res 1993, 33:S3.
75. Couper JJ, Hutson JM, Warne GL: Hydrometrocolpos following prenatal dexamethasone treatment for congenital adrenal hyperplasia (21-hydroxylase deficiency). Eur J Pediatr 1993, 152:9-11.
76. Odink RJH, Boué A, Jansen M: The value of chorion villus sampling in early detection of 21-hydroxylase deficiency. Pediatr Res 1988, 23:131.
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78. Romer TE, Ginalska-Malinowska M: Successful prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency: is prenatal diagnosis in a mother at risk essential? Endokrynol Pol 1987, 38:125-130.
79. Hann EA, Serjeantson SW, Norman R, Rollond AK, Antonis P, Richards RI, Penfold JL: Prenatal diagnosis and successful intrauterine treatment of a female fetus with 21-hydroxylase deficiency. Med J Aust 1992, 156:132-135.
80. Malunovicz EM, Ginalska-Malinowska M, Romer TE, Bal K: The influence of prenatal dexamethasone treatment (dx) on excretion of urinary steroids in newborns (nbs). Horm Res 1996, 46(S2):104. This study measured several urinary steroids, marker metabolites from either the fetal or the permanent zone of the adrenal cortex, on day 3 to 9 of life in 11 newborns treated prenatally with dexamethasone. By comparison with 12 untreated girls with CAH and eight normal newborns, a certain heterogeneity in fetal adrenal response to maternal treatment was found. This is a pilot study, which needs more samples for confirmation and a more prolonged observation of postnatal adrenal function for practical conclusions.
81. Trautman PD, Meyer-Bahlburg HF, Postelnek J, New MI: Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 1995, 20:439-449. This is a preliminary study on the effect of early prenatal exposure to dexamethasone. Cognitive and behavioral development, behavior problems, and temperament were examined in 26 children (0.5 to 5.5 years of age) whose mothers had been treated with dexamethasone during pregnancy, and these children were compared with 17 children from untreated pregnant women at risk for CAH. In each group, there were three children with CAH. Assessments were made from mother-completed standard questionnaires. No differences in cognitive abilities or behavior were found. However, children exposed to dexamethasone in utero showed more shyness, greater emotionality, less sociability, a trend toward greater avoidance, and higher total problem scores than unexposed children. Larger sample groups and direct examination of the children are needed before drawing conclusions.
82. Levine LS, Pang SY: Prenatal diagnosis and treatment of congenital adrenal hyperplasia. J Pediatr Endocrine 1994, 7:193-200.
83. Dörr HG, Sippell WG, Willig RP: Pranatale Diagnostik und Therapie des Adrenogenitalen Syndroms (AGS) moit 21-hydroxylasee-Defeckt. Monatsschr Kinderheilkd 1992, 140:661-663.
84. Plante E, Boliek C, Binkiewicz A, Erly WK: Elevated androgen, brain development and language/learning disabilities in children with congenital adrenal hyperplasia. Dev Med Child Neurol 1996, 38:423-437. Children with CAH were considered as a test population for the theory that elevated testosterone alters prenatal brain development and increases the risk of learning disabilities. The findings indicate that an elevated rate for language-based learning disabilities and altered brain asymmetries co-occur in families with the gene for CAH.
85. Forest MG, Morel Y, David M: Prenatal treatment of congenital hyperplasia (CAH) due to 21-hydroxylase deficiency: pubertal development in the first CAH female patient treated prenatally. Abstracts of the 9th International Congress of Endocrinology 1995. Bethesda, MD: The Endocrine Society; 1991:375.