Aggiornamento monografico
Sindrome adreno-genitale congenita da deficit di 21-idrossilasi
CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY
ANTONIO BALSAMO, ALESSANDRO CICOGNANI
Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, Mediche e Chirurgiche, Policlinico S. Orsola - Malpighi, Università di Bologna
Maggio 2005 - pagg. 293 -301
Abstract
Congenital adrenal hyperplasia (CAH) refers to a group of inherited disorders of adrenal steroidogenesis.
More than 90% of CAH is due to 21-hydroxylase deficiency (21-OH-D), found
in 1:10.000 to 1:15.000 live births as classical form and detected in about 2:100 of certain
populations as non classical form. Females with classical 21-OH-D present at birth genital virilization.
Potentially life-threatening adrenal crisis may characterize two-third to three-quarters
of patients of both sexes with the classical salt wasting (SW) form. Non classical patients
may present as precocious pubarche in children or polycystic ovarian syndrome in young women.
21-OH-D is caused by CYP21 gene mutations which in more than 90% of the cases result
from inter-genic recombination between the active CYP21 gene and the inactive CYP21P
pseudogene. The degree to which each mutation impairs enzymatic activity is strictly correlated
with the clinical severity of the disease. Glucocorticoid and mineralcorticoid replacement
therapies are the basics of treatment, although alternative strategies of treatment are
being developed. Neonatal screening may identify affected children before SW crises develop,
reducing mortality of this disease. Prenatal diagnosis and treatment should be performed
in families at risk for classical form, underlining them that long term results in dexamethasone
treated subjects have however lacking. Long term outcome shows an adult height generally
between 1 and 2 standard deviations under the familial target height and a fertility rate only
moderately reduced in female more than in male treated patients.
Parole chiave
21-hydroxylase deficiency
Congenital adrenal hyperplasia
Correlazione genotipo-fenotipo
Diagnosi e trattamento prenatale
Diagnosi e trattamento prenatali
Genotype/phenotype correlation
Iperplasia surrenale congenita
iperplasia surrenalica congenita
Neonatal screening
Prenatal diagnosis and treatment
screening neonatale
Suggerite dall'AI
Classificazione MeSH
Bibliografia
1. Pang S, Clark A, et al. CAH due to 21-hydroxylase
deficiency: newborn screening and its relationship
to the diagnosis and treatment of the disorder.
Screening 1993;2:105-39.
2. Speiser PW, Dupont J, Rubinstein P, Piazza A, Kastelan A & New MI. High frequency of nonclassic steroid 21-hydroxylase deficiency. American Journal of Human Genetics 1985; 37:650-67.
3. White PC, Speiser PW. Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21:245-91.
4. Barbaro M, Lajic S, Baldazzi L, Balsamo A, Pirazzoli P, Cicognani A, Wedell A, Cacciari E. Functional Analysis of two Recurrent Amino Acid Substitutions in the CYP21 Gene from Italian Patients with Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2004;89(5): 2402-7.
5. Balsamo A, Baldazzi L, Cicognani A, Barbaro M, Ragni L, Zappulla F, Maccaferri M, Cacciari E. CYP21 analysis and phenotype/genotype relationship in 155 Patients with steroid 21-hydroxylase deficiency from Italy. Ped Res 2001; 49(6):115A,P1-686.
6. Balsamo A, Cacciari E, Baldazzi L, Tartaglia L, Cassio A, Mantovani V, Piazzi S, Cicognani A, Pirazzoli P, Mainetti B, Zappulla F. CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia- Romagna region. Clin Endocrinol (Oxf) 2000; 53:117-25.
7. Prader A. Der Genitalbefund bein Pseudohermaphroditismus feminus des kongenitalen adrenogenitalen Syndroms. Morphologie, Haufigkeit, Entwicklung und Vererbung der verschiedenen Genitalformen. Helvetica Paediatrica Acta 1954;9:231-43.
8. Merke DP, Chrousos GP, Eisenhofer G, et al. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 2000;343:1362-8.
9. Karnak I, Senocak ME, Gogus S, et al. Testicular enlargement in patients with 11-hydroxylase deficiency. J Pediatr Surg 1997; 32:756-60.
10. Moran C, Azziz R, Carmina E, et al. 21 hydroxylase- deficient non classical adrenal hyparplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 2000;183:1468-74.
11. Levine LS, Dupont B, Lorenzen F, et al. Cryptic 21-hydroxylase deficiency in families of patients with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 1980;51: 1316-24.
12. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983;57:320-7.
13. Al-Alwan I, Navarro O, Daneman D, et al. Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. J Pediatr 1999;135:71-5.
14. Balsamo A, Baserga M, Burroni M, et al. Screening e accertamento diagnostico della sindrome adreno-genitale congenita da deficit di 21-idrossilasi. Rivista Italiana di Pediatria (IJP) 1998;24(5):861-9.
15. Cacciari E, Balsamo A, Cassio A, Piazzi S, Bernardi F, Salardi S, Cicognani A, Pirazzoli P, Zappulla F, Capelli M, Paolini M. Neonatal screening for congenital adrenal hyperplasia. Arch Dis Child 1983;58(10):803-6.
16. Therrel BLjr, Berembaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998;101:583-90.
17. Balsamo A, Cacciari E, Piazzi S, Cassio A, Bozza D, Pirazzoli P, Zappulla F. Congenital adrenal hyperplasia: neonatal mass screening compared to clinical diagnosis only in the Emilia-Romagna Region of Italy (1980-1995). Pediatrics 1996;98:362-7.
18. Mikami A, Fukushi M, Oda H, Fujita K, Fujieda K. Newborn screening for congenital adrenal hyperplasia in Sapporo City: sixteen years experience. Southeast Asian J Trop Med Public Health 1999;30(Suppl 2):100-2.
19. Minutti CZ, Lacey JM, Magera MJ, Hahn SH, McCann M, Schulze A, Cheillan D, Borche C, Chace DH, Lymp JF, Zimmerman D, Rinaldo P, Matern D. Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 2004;89(8):3687-93.
20. Nordenstrom A, Wedell A, Hagenfeldt L, Marcus C, Larsson A. Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants. Pediatrics 2001;108(4):E68.
21. New MI, Carlson A, Obeid J, Marshall I, Cabrera MS, Goseco A, Lin-Su K, Putnam AS, Wei JQ, Wilson RC. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86(12):5651-7.
22. Pang S, Clark AT, Freeman LC, et al. Maternal side effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. J Clin Endocrinol Metab 1992;75:249-56.
23. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippel WG, Speiser PW. Consensus statement on 21-hydroxylase deficiency from the European Society for Pediatric Endocrinology and the Lawson-Wilkins Pediatric Endocrine Society. Horm Res 2002;58:188-95.
24. Metzger DL, Wright NM, Veldhuis JD, Rogol AD, Kerrigan JR. Characterization of pulsatile secretion and clearance of plasma cortisol in premature and term neonates using deconvolution analysis. J Clin Endocrinol Metab 1993; 77:458-63.
25. Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD. Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab 1993;76:1505-10.
26. Carmina E, Lobo RA. Ovarian suppression reduces clinical and endocrine espression of late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Fertil Steril 1994; 62:738-43.
27. Spitzer P, Billaud L, Thalabard J, et al. Cyproterone acetate versus Hydrocortisone treatment in late onset congenital adrenal hyperplasia. J Clin Endocrinol Metab 1990;70:642-9.
28. Soliman AT, AlLamki M, AlSalmi I, et al. Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog. Metabolism 1997; 46(5):513-7.
29. Clark RV, Albertson BD, Munabi A, et al. Steroidogenic enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia. JClin Endocrinol Metab 1990;70:1408-13.
30. Van Wyk JJ, Gunther DF, Ritzen EM, et al. The use of adrenalectomy as a treatment for congenital adrenal hyperplasia. J Clin Endocrinol Metab 1996;81:3180-8.
31. Merke DP, Keil MF, Jones JV, Fields J, Hill S, Cutler GB Jr. Flutamide, testolactone and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2000;85(3):1114-20.
32. Quintos JB, Vogiatzi MG, Harbison MD, et al. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001;86:1511-7.
33. Tajima T, Okada T, Ma XM, Ramsey W, Bornstein S, Aguilera G. Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of 21-hydroxylase-deficient mice. Gene Ther 1999;6 (11):1898-903.
34. Schnitzer JJ, Donahoe PK. Surgical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:137-54.
35. Creighton SM, Minto CL, Steele SJ. Objective cosmetic and anatomical outcomes at adolescence of feminising surgery for ambiguous genitalia done in childhood. Lancet 2001;358 (9276):124-5.
36. Eugster EA, Di Meglio L, Wright JC, Freidemberg GR, Sesbadri R, Pescovitz OH. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 2001;138:26-32.
37. Balsamo A, Cicognani A, Baldazzi L, Barbaro M, Baronio F, Gennari M, Bal M, Cassio A, Kontaxaki K, Cacciari E. CYP21 genotype, adult height and pubertal development in 55 patients treated for 21-hydroxylase deficiency. J Clin Endocrinol Metab 2003;88(12):5680-8.
38. Iluizenga NA, Koper JW, De Lange P, et al. A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 1998;83:144-51.
39. Cameron FJ, Tebbutt N, Montalto J, et al. Endocrinology and auxology of sibships with non classical congenital adrenal hyperplasia. Arch Dis Child 1996;74:406-11.
40. Lo JC, Schwitzgebel VM, Tyrrel JB, et al. Normal female infants born of mather with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1999;84:930-6.
41. Feldman S, Billaud L, Thalabard JC, et al. Fertility in women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992;74:635-9.
42. Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001;86(7):3070-8.
43. Berembaum SA, Duck SC, Bryk K. Behavioural effects of prenatal versus postnatal androgen excess in children with 21-hydroxylase deficient congenital adrenal hyperplasia. J Clin Endocrinol Metab 2000;85:727-33.
44. Dittmann RW, Kappes ME, Kappes MH. Sexual behaviour in adolescent and adult females with congenital adrenal hyperplasia. Psychoneuroendocrinology 1992;17:153-170.
45. Reiner WG. Sex assignement in the neonate with intersex or inadequate genitalia. Arch Pediatr Adolesc Med 1997;151:1044-6.
2. Speiser PW, Dupont J, Rubinstein P, Piazza A, Kastelan A & New MI. High frequency of nonclassic steroid 21-hydroxylase deficiency. American Journal of Human Genetics 1985; 37:650-67.
3. White PC, Speiser PW. Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21:245-91.
4. Barbaro M, Lajic S, Baldazzi L, Balsamo A, Pirazzoli P, Cicognani A, Wedell A, Cacciari E. Functional Analysis of two Recurrent Amino Acid Substitutions in the CYP21 Gene from Italian Patients with Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2004;89(5): 2402-7.
5. Balsamo A, Baldazzi L, Cicognani A, Barbaro M, Ragni L, Zappulla F, Maccaferri M, Cacciari E. CYP21 analysis and phenotype/genotype relationship in 155 Patients with steroid 21-hydroxylase deficiency from Italy. Ped Res 2001; 49(6):115A,P1-686.
6. Balsamo A, Cacciari E, Baldazzi L, Tartaglia L, Cassio A, Mantovani V, Piazzi S, Cicognani A, Pirazzoli P, Mainetti B, Zappulla F. CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia- Romagna region. Clin Endocrinol (Oxf) 2000; 53:117-25.
7. Prader A. Der Genitalbefund bein Pseudohermaphroditismus feminus des kongenitalen adrenogenitalen Syndroms. Morphologie, Haufigkeit, Entwicklung und Vererbung der verschiedenen Genitalformen. Helvetica Paediatrica Acta 1954;9:231-43.
8. Merke DP, Chrousos GP, Eisenhofer G, et al. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 2000;343:1362-8.
9. Karnak I, Senocak ME, Gogus S, et al. Testicular enlargement in patients with 11-hydroxylase deficiency. J Pediatr Surg 1997; 32:756-60.
10. Moran C, Azziz R, Carmina E, et al. 21 hydroxylase- deficient non classical adrenal hyparplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 2000;183:1468-74.
11. Levine LS, Dupont B, Lorenzen F, et al. Cryptic 21-hydroxylase deficiency in families of patients with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 1980;51: 1316-24.
12. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983;57:320-7.
13. Al-Alwan I, Navarro O, Daneman D, et al. Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. J Pediatr 1999;135:71-5.
14. Balsamo A, Baserga M, Burroni M, et al. Screening e accertamento diagnostico della sindrome adreno-genitale congenita da deficit di 21-idrossilasi. Rivista Italiana di Pediatria (IJP) 1998;24(5):861-9.
15. Cacciari E, Balsamo A, Cassio A, Piazzi S, Bernardi F, Salardi S, Cicognani A, Pirazzoli P, Zappulla F, Capelli M, Paolini M. Neonatal screening for congenital adrenal hyperplasia. Arch Dis Child 1983;58(10):803-6.
16. Therrel BLjr, Berembaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998;101:583-90.
17. Balsamo A, Cacciari E, Piazzi S, Cassio A, Bozza D, Pirazzoli P, Zappulla F. Congenital adrenal hyperplasia: neonatal mass screening compared to clinical diagnosis only in the Emilia-Romagna Region of Italy (1980-1995). Pediatrics 1996;98:362-7.
18. Mikami A, Fukushi M, Oda H, Fujita K, Fujieda K. Newborn screening for congenital adrenal hyperplasia in Sapporo City: sixteen years experience. Southeast Asian J Trop Med Public Health 1999;30(Suppl 2):100-2.
19. Minutti CZ, Lacey JM, Magera MJ, Hahn SH, McCann M, Schulze A, Cheillan D, Borche C, Chace DH, Lymp JF, Zimmerman D, Rinaldo P, Matern D. Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 2004;89(8):3687-93.
20. Nordenstrom A, Wedell A, Hagenfeldt L, Marcus C, Larsson A. Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants. Pediatrics 2001;108(4):E68.
21. New MI, Carlson A, Obeid J, Marshall I, Cabrera MS, Goseco A, Lin-Su K, Putnam AS, Wei JQ, Wilson RC. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86(12):5651-7.
22. Pang S, Clark AT, Freeman LC, et al. Maternal side effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. J Clin Endocrinol Metab 1992;75:249-56.
23. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippel WG, Speiser PW. Consensus statement on 21-hydroxylase deficiency from the European Society for Pediatric Endocrinology and the Lawson-Wilkins Pediatric Endocrine Society. Horm Res 2002;58:188-95.
24. Metzger DL, Wright NM, Veldhuis JD, Rogol AD, Kerrigan JR. Characterization of pulsatile secretion and clearance of plasma cortisol in premature and term neonates using deconvolution analysis. J Clin Endocrinol Metab 1993; 77:458-63.
25. Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD. Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab 1993;76:1505-10.
26. Carmina E, Lobo RA. Ovarian suppression reduces clinical and endocrine espression of late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Fertil Steril 1994; 62:738-43.
27. Spitzer P, Billaud L, Thalabard J, et al. Cyproterone acetate versus Hydrocortisone treatment in late onset congenital adrenal hyperplasia. J Clin Endocrinol Metab 1990;70:642-9.
28. Soliman AT, AlLamki M, AlSalmi I, et al. Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog. Metabolism 1997; 46(5):513-7.
29. Clark RV, Albertson BD, Munabi A, et al. Steroidogenic enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia. JClin Endocrinol Metab 1990;70:1408-13.
30. Van Wyk JJ, Gunther DF, Ritzen EM, et al. The use of adrenalectomy as a treatment for congenital adrenal hyperplasia. J Clin Endocrinol Metab 1996;81:3180-8.
31. Merke DP, Keil MF, Jones JV, Fields J, Hill S, Cutler GB Jr. Flutamide, testolactone and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2000;85(3):1114-20.
32. Quintos JB, Vogiatzi MG, Harbison MD, et al. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001;86:1511-7.
33. Tajima T, Okada T, Ma XM, Ramsey W, Bornstein S, Aguilera G. Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of 21-hydroxylase-deficient mice. Gene Ther 1999;6 (11):1898-903.
34. Schnitzer JJ, Donahoe PK. Surgical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:137-54.
35. Creighton SM, Minto CL, Steele SJ. Objective cosmetic and anatomical outcomes at adolescence of feminising surgery for ambiguous genitalia done in childhood. Lancet 2001;358 (9276):124-5.
36. Eugster EA, Di Meglio L, Wright JC, Freidemberg GR, Sesbadri R, Pescovitz OH. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 2001;138:26-32.
37. Balsamo A, Cicognani A, Baldazzi L, Barbaro M, Baronio F, Gennari M, Bal M, Cassio A, Kontaxaki K, Cacciari E. CYP21 genotype, adult height and pubertal development in 55 patients treated for 21-hydroxylase deficiency. J Clin Endocrinol Metab 2003;88(12):5680-8.
38. Iluizenga NA, Koper JW, De Lange P, et al. A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 1998;83:144-51.
39. Cameron FJ, Tebbutt N, Montalto J, et al. Endocrinology and auxology of sibships with non classical congenital adrenal hyperplasia. Arch Dis Child 1996;74:406-11.
40. Lo JC, Schwitzgebel VM, Tyrrel JB, et al. Normal female infants born of mather with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1999;84:930-6.
41. Feldman S, Billaud L, Thalabard JC, et al. Fertility in women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992;74:635-9.
42. Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001;86(7):3070-8.
43. Berembaum SA, Duck SC, Bryk K. Behavioural effects of prenatal versus postnatal androgen excess in children with 21-hydroxylase deficient congenital adrenal hyperplasia. J Clin Endocrinol Metab 2000;85:727-33.
44. Dittmann RW, Kappes ME, Kappes MH. Sexual behaviour in adolescent and adult females with congenital adrenal hyperplasia. Psychoneuroendocrinology 1992;17:153-170.
45. Reiner WG. Sex assignement in the neonate with intersex or inadequate genitalia. Arch Pediatr Adolesc Med 1997;151:1044-6.