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DOI: 10.1055/s-2002-35387
Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency in the Newborn and During Infancy
Publication History
Publication Date:
12 November 2002 (online)
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ABSTRACT
Congenital adrenal hyperplasia is a family of monogenic autosomal recessive disorders of steroidogenesis with protean clinical manifestations. The commonest form, 21-hydroxylase deficiency, is the most frequent cause of ambiguous genitalia in the newborn. The molecular features associated with abnormalities in the CYP21 gene are well characterized in relation to phenotypic manifestations. The concordance between genotype and phenotype is sufficiently robust as to be relevant and useful in planning treatment strategies. Thus, the dose of glucocorticoid replacement in the early years of life can be tailored according to the predicted degree of 21-hydroxylase enzyme deficiency in the anticipation that this may avoid hitherto excessive steroid replacement during the critical early years of growth and development. The means to prevent genital virilization in affected females is clearly demonstrated by the success of early dexamethasone administration to pregnant mothers at risk. Short-term outcome studies of children exposed to dexamethasone in utero indicate no significant adverse effects. Nevertheless, it is recommended that prenatal treatment programs to prevent a major congenital malformation of the urogenital system be conducted only as part of agreed national multicenter studies, which include a commitment to long-term outcome analyses.
KEYWORDS
Congenital adrenal hyperplasia - 21-hydroxylase - prenatal treatment - glucocorticoids - infancy - outcome
REFERENCES
- 1 Stocco D M, Reinhart A J, Miller W L. Proteins involved in mitochondrial cholesterol transport. In: Hughes IA, Clark AJL, eds. Adrenal Disease in Childhood: Clinical and Molecular Aspects Basel, Switzerland: Karger 2000 0: 37-62
- 2 Acerini C L, Hughes I A. 21-Hydroxylase deficiency defects and their phenotype. In: Hughes IA, Clark AJL, eds. Adrenal Disease in Childhood: Clinical and Molecular Aspects Basel, Switzerland: Karger 2000 0: 93-111
- 3 Higashi Y, Tanae A, Inoue H, Hiromasa T, Fujii-Kuriyama Y. Aberrant splicing and missense mutations cause steroid 21-hydroxylase (P-450(C21)) deficiency in humans: possible gene conversion products. Proc Natl Acad Sci U S A . 1988; 85 7486-7490
- 4 Tusie-Luna M, White P. Gene conversions and unequal crossovers between CYP21 (steroid 21 hydroxylase gene) and CYP21P involve different mechanisms. Proc Natl Acad Sci U S A . 1995; 92 10796-10800
- 5 Jiddou R R, Wei W L, Sane K S, Killeen A A. Single-nucleotide polymorphisms in intron 2 of CYP21P: evidence for a higher rate of mutation at CpG dinucleotides in the functional steroid 21-hydroxylase gene and application to segregation analysis in congenital adrenal hyperplasia. Clin Chem . 1999; 45 625-629
- 6 Krawczak M, Cooper D N. The human genome database. Available at: http//gdwww.gdb.org. Accessed April 2002
- 7 Lee H H. CYP21 mutations and congenital adrenal hyperplasia. Clin Genet . 2001; 59 293-301
- 8 Yokoyama Y, Teraoka M, Tsuji K. Rapid screening method to detect mutations in CYP21, the gene for 21-hydroxylase. Am J Med Genet . 2000; 94 28-31
- 9 Yang Y P, Corley N, Garcia-Heras J. Reverse dot-blot hybridisation as an improved tool for the molecular diagnosis of point mutations in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. Mol Diagn . 2001; 6 193-199
- 10 Higashi Y, Hiromasa T, Tanae A. Effects of individual mutations in the P-450 (C21) pseudogene on the P-450 (C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem . 1991; 109 638-644
- 11 White P G, Speiser P W. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev . 2000; 21 245-291
- 12 Bobba A, Marra E, Lattanzio P, Iolascon A, Giannattasio S. Characterization of the CYP21 gene 5' flanking region in patients affected by 21-OH deficiency. Hum Mutat . 2000; 15 481
- 13 Mornet E, Gibrat J-F. A 3D model of human P450c21: study of the putative effects of steroid 21-hydroxylase gene mutations. Hum Genet . 2000; 106 330-339
- 14 Pang S, Clark A. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: newborn screening and its relationship to the diagnosis and treatment of the disorder. Screening . 1993; 2 105-139
- 15 Thilen A, Larssen A. Congenital adrenal hyperplasia in Sweden 1969-1986. Acta Paediatr . 1990; 79 168-175
- 16 Torresani T, Grueters A, Scherz R. Improving the efficacy of newborn screening for congenital adrenal hyperplasia by adjusting the cut-off level of 17-hydroxyprogesterone to gestational age. Screening . 1994; 3 77-84
- 17 Allen D B, Hoffman G L, Fitzpatrick P. Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17-hydroxyprogesterone levels. J Pediatr . 1997; 130 128-133
- 18 Kari M A, Raivio O K, Stenman U H, Voutilainen R. Serum cortisol, dehydroepiandrosterone sulfate, and steroid-binding globulins in preterm neonates: effect of gestational age and dexamethasone therapy. Pediatr Res . 1996; 40 319-324
- 19 Honour J W, Torresani T, Toublanc J-E. Procedure for neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res . 2001; 55 201-205
- 20 Honour J W, Torresani T. Evaluation of neonatal screening for congenital adrenal hyperplasia. Horm Res . 2001; 55 206-211
- 21 Swerdlow A J, Higgins C D, Brook C G. Mortality in patients with congenital adrenal hyperplasia: a cohort study. J Pediatr . 1998; 133 516-520
- 22 Nordenstrom A, Thilen A, Hagenfeldt L, Larsson A, Wedell A. Genotyping is a valuable diagnostic complement to neonatal screening for congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab . 1999; 84 1505-1509
- 23 Fitness J, Dixit N, Webster D. Genotyping of CYP21, linked chromosome 6p markers, and a sex-specific gene in neonatal screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab . 1999; 84 960-969
- 24 Nordenstrom A, Wedell A, Hagenfeldt L, Marcus G, Larsson A. Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants. Pediatrics . 2001; 108 E68
- 25 Forest M. Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia. Curr Opin Endocrinol Diabet . 1998; 4 209-217
- 26 Lajic S, Wedell A, Bui T, Ritzen E, Holst M. Long-term somatic follow-up of parentally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab . 1998; 83 3572-3880
- 27 New M I, Carlson A, Obeid J. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab . 2001; 86 5651-5657
- 28 Seckl J R, Miller W L. How safe is long-term prenatal glucocorticoid treatment?. JAMA . 1997; 277 1077-1079
- 29 American Academy of Pediatrics. Technical report: congenital adrenal hyperplasia. Section on Endocrinology and Committee on Genetics. Pediatrics . 2000; 106 1511-1518
- 30 New M I. Prenatal treatment of congenital adrenal hyperplasia: author differs with technical report. Pediatrics . 2001; 107 804
- 31 Trautman P D, Meyer-Bahlburg H FL, Postelnek J, New M I. The effects of early prenatal dexamethasone on the cognitive and behavioural development of young children. Psychoneuroendocrinology . 1995; 20 339-349
- 32 Barker D P, Hales C N, Fall C HD. Type 2 (non-insulin dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia . 1993; 36 62-67
- 33 Barker D P. Mothers, Babies and Diseases Later in Life. London: BMJ Publishing Group; 1994
- 34 Chin D, Speiser P W, Imperato-McGinley J. Study of a kindred with classic congenital adrenal hyperplasia: diagnostic challenge due to phenotypic variance. J Clin Endocrinol Metab . 1998; 83 1940-1945
- 35 Quercia N, Chitayat D, Babul-Hirji R, New M I, Daneman D. Normal external genitalia in a female with classic congenital adrenal hyperplasia who was not treated during embryogenesis. Prenat Diagn . 1998; 18 83-85
- 36 Wilson R C, Mercads A B, Cheng K C, New M I. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab . 1995; 80 2327-2329
- 37 Wedell A, Thilen A, Ritzen E M, Slengler B, Luthman H. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestations. J Clin Endocrinol Metab . 1994; 78 1145-1152
- 38 Jääskeläinen J, Levo A, Voutilainen R, Partanen J. Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well-defined population. J Clin Endocrinol Metab . 1997; 82 3293-3297
- 39 Holzgreve W, Hahn S. Prenatal diagnosis using fetal cells and free fetal DNA in maternal blood. Clin Perinatol . 2001; 28 353-365
- 40 Vona G, Beroud C, Benachi A. Enrichment, immunomorphological, and genetic characterization of fetal cells circulating in maternal blood. Am J Pathol . 2002; 160 51-58
- 41 Lo Y M, Corbella N, Chamberlain P F. Presence of fetal DNA in maternal plasma and serum. Lancet . 1997; 350 485-487
- 42 Pentl B, Sekizawa A, Samura O. Detection of male and female fetal DNA in maternal plasma by multiplex fluorescent polymerase chain reaction amplification of short tandem repeats. Hum Genet . 2000; 106 45-49
- 43 Rijnders R JP, van der Schoot E, Bossers B, de Vroede M M J A, Christiaens G M L C. Fetal sex determination from maternal plasma in pregnancies at risk for congenital adrenal hyperplasia. Obstet Gynecol . 2001; 98 374-378
- 44 Thomas M R, Tutschek B, Frost A. The time of appearance and disappearance of fetal DNA from the maternal circulation. Prenat Diagn . 1995; 15 641-646
- 45 Ahmed S F, Hughes I A. The clinical assessment of Intersex. Curr Paediatr . 2000; 10 269-274
- 46 Murtaza L, Sibert J R, Hughes I A, Balfour I C. Congenital adrenal hyperplasia: are we detecting male salt-losers?. Arch Dis Child . 1980; 55 622-625
- 47 Kovacs J, Votava F, Heinze G. Lessons from 30 years of clinical diagnosis and treatment of congenital adrenal hyperplasia in five Middle European countries. J Clin Endocrinol Metab . 2001; 86 2958-2964
- 48 Prader A. Der genitalbefund beim psuedohermaphroditismus feminus der Kengenitalen adrenogenitalen syndromes. Helv Paediatr Acta . 1954; 9 231-248
- 49 Yu A C, Grant D B. Adult height in women with early-treated congenital adrenal hyperplasia (21-hydroxylase type): relation to body mass index in earlier childhood. Acta Paediatr . 1995; 84 899-903
- 50 Cheetham T D, Hughes I A. Optimizing the management of congenital adrenal hyperplasia. In: Kelnar CJH, ed. Clinical Paediatric Endocrinology London: Baillière Tindall 1996: 277-294
- 51 Girgis R, Winter J SD. The effects of glucocorticoid replacement therapy on growth, bone mineral density, and bone tumour markers in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab . 1997; 82 3926-3929
- 52 Premawardhana L K E D, Hughes I A, Read G F, Scanlon M F. Longer term outcome in females with congenital adrenal hyperplasia (CAH): the Cardiff experience. Clin Endocrinol (Oxf) . 1997; 46 327-332
- 53 Cornean R E, Hindmarsh P C, Brook C G. Obesity in 21-hydroxylase deficient patients. Arch Dis Child . 1998; 78 261-263
- 54 Speiser P W. Toward better treatment of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) . 1999; 51 273-274
- 55 Schwartz R P. Back to basics: early diagnosis and compliance improve final height outcome in congenital adrenal hyperplasia. J Pediatr . 2001; 138 3-5
- 56 Tomlinson J W, Stewart P M. Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase. Best Pract Res Clin Endocrinol Metab . 2001; 15 61-78
- 57 Phillipov G, Palermo M, Shackleton C H. Apparent cortisone reductase deficiency: a unique form of hypercortisolism. J Clin Endocrinol Metab . 1996; 81 3855-3860
- 58 Jamieson A, Wallace A M, Andrew R. Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1. J Clin Endocrinol Metab . 1999; 84 3570-3574
- 59 Whorwood C B, Warne G L. A possible defect in the inter-conversion between cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving cortisone acetate therapy. J Steroid Biochem Mol Biol . 1991; 39 461-470
- 60 Nordenstrom A, Marcus G, Axelson M, Wedell A, Ritzen E M. Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11β-hydroxysteroid dehydrogenase reductase activity. J Clin Endocrinol Metab . 1999; 84 1210-1213
- 61 Jinno K, Sakura N, Nomura S. Failure of cortisone acetate therapy in 21-hydroxylase deficiency in early infancy. Paediatr Int . 2001; 43 478-482
- 62 Tomlinson J W, Draper N, Mackie J. Absence of Cushingoid phenotype in a patient with Cushing's disease due to defective cortisone to cortisol conversion. J Clin Endocrinol Metab . 2002; 87 57-62
- 63 Kenny F M, Preeyasombat C, Migeon C J. Cortisol production rate: II. Normal infants, children, and adults. Pediatrics . 1966; 37 34-42
- 64 Peterson K E. The production of cortisol and corticosterone in children. Acta Paediatr Scand . 1980; 281 2-38
- 65 Linder B L, Esteban N V, Yergey A L. Cortisol production rate in childhood and adolescence. J Pediatr . 1990; 117 892-896
- 66 Metzger D L, Wright N M, Veldhuis J D, Rogol A D, Kerrigan J R. Characterization of pulsatile secretion and clearance of plasma cortisol in premature and term neonates using deconvolution analysis. J Clin Endocrinol Metab . 1993; 77 458-463
- 67 Derendorf H, Möllmann C, Tunn S, Krieg M. Pharmacokinetics and oral bioavailability of hydrocortisone. J Clin Pharmacol . 1991; 31 473-476
- 68 Charmandari E, Johnston A, Brook C GD, Hindmarsh P C. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol . 2001; 169 65-70
- 69 Wilkins L, Lewis R A, Klein R, Rosemberg E. Suppression of androgen secretion by cortisone in a case of congenital adrenal hyperplasia: a preliminary report. Bull Johns Hopkins Hosp . 1950; 86 249
- 70 Bartter F C, Forbes A P, Leaf A. Congenital adrenal hyperplasia associated with the adrenogenital syndrome: an attempt to correct its disordered hormonal pattern. J Clin Invest . 1950; 29 797
-
71 Royal College of Paediatrics and Child Health. Medicines for Children
1st ed. London: RCPCH Publications Ltd 1999: 271-273
- 72 Fawcett J P, Boulton D W, Jiang R, Woods D J. Stability of hydrocortisone oral suspensions prepared from tablets and powder. Ann Pharmacother . 1995; 29 987-990
- 73 Merke D P, Cho D, Calis K A, Keil M F, Chrousos G P. Hydrocortisone suspension and hydrocortisone tablets are not bioequivalent in the treatment of children with congenital adrenal hyperplasia. J Clin Endocrinol Metab . 2001; 86 441-445
- 74 Maesaka H, Suwa S, Tachibana K, Katsumata N. Prolonged activation of hypothalamo-pituitary-ovarian axis during early infancy in female patients with salt-losing 21-hydroxylase deficiency. Pediatr Res . 1985; 19 1258-1262
- 75 Barnes R B, Rosenfield R L, Ehrmann D A. Ovarian hyperandrogenism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab . 1994; 79 1328-1333
- 76 Belgorosky A, Chahin S, Rivarola M A. Elevation of serum luteinizing hormone levels during hydrocortisone treatment in infant girls with 21-hydroxylase deficiency. Acta Paediatr . 1996; 85 1172-1175
- 77 Uli N, Chin D, David R. Menstrual bleeding in a female infant with congenital adrenal hyperplasia: altered maturation of the hypothalamo-pituitary-ovarian axis. J Clin Endocrinol Metab . 1997; 82 3298-3302
- 78 Watanabe T, Someya T, Minamitani K. Genital bleeding in a 2-month-old infant with congenital adrenal hyperplasia. Clin Pediatr Endocrinol . 2000; 89-93
- 79 Finer N N, Craft A, Vaucher Y E, Clark R H, Sola A. Postnatal steroids: short-term gain, or long-term pain?. J Pediatr . 2000; 137 9-13
- 80 Barrington K J. The adverse neurodevelopmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;1:1. Available at: http://www.biomedcentral.com/1471-2431/1/1
- 81 Shen S X, Young M C, Hinuhosa-Sandoval M, Hughes I A. 17OH-Progesterone response to acute dexamethasone administration in congenital adrenal hyperplasia. Horm Res . 1989; 32 136-141
- 82 Chrousos G P. Adrenal suppression versus clinical glucocorticoid deficiency in the premature infant: no simple answers. J Clin Endocrinol Metab . 2001; 86 473-474
- 83 Young M C, Hughes I A. Response to treatment of congenital adrenal hyperplasia in infancy. Arch Dis Child . 1990; 65 441-444
- 84 Young M C, Robinson J A, Read G F, Riad-Fahmy D, Hughes I A. 17-Hydroxyprogesterone rhythms in congenital adrenal hyperplasia. Arch Dis Child . 1988; 63 617-623
- 85 Bode H H, Rivkees S A, Cowley D M, Pardy K, Johnson S. Home monitoring of 17-hydroxyprogesterone levels in congenital adrenal hyperplasia with filter paper blood samples. J Pediatr . 1999; 134 185-189
- 86 Schwartz R P. Home monitoring of 17-hydroxyprogesterone levels: ``throw away the wine jug, mom, the filter paper just arrived''. J Pediatr . 1999; 134 140-142
- 87 Dressendorfer R A, Strasburger C J, Bidlingmaier F. Development of a highly sensitive nonisotopic immunoassay for the determination of salivary 17-hydroxyprogesterone: reference ranges throughout childhood and adolescence. Pediatr Res . 1998; 44 650-655
- 88 Walker J, Hughes I A, Wood P J. Bloodspot testosterone assay suitable for study of neonates and monitoring of children with congenital adrenal hyperplasia. Ann Clin Biochem . 1999; 36 477-482
- 89 Thilen A, Woods K A, Perry L A. Early growth is not increased in untreated moderately severe 21-hydroxylase deficiency. Acta Paediatr . 1995; 84 894-898
- 90 Creighton S M, Minto C L, Steele S J. Objective cosmetic and anatomical outcome at adolescence of feminising surgery for ambiguous genitalia done in childhood. Lancet . 2001; 358 124-125