Expertos Invitados





GENETICA Y PRESENTACION DE LA DEFICIENCIA DE 21-HIDROXILASA

(especial para SIIC © Derechos reservados)
La deficiencia de 21-hidroxilasa es una de las enfermedades hereditarias autosómicas recesivas más comunes en los seres humanos. En el presente artículo se describen su incidencia, clasificación, fisiopatología, genética molecular, diagnóstico y fenotipo.
trakakis9.jpg Autor:
Eftihios Trakakis
Columnista Experto de SIIC
Artículos publicados por Eftihios Trakakis
Coautores
George Simeonides* Vassilis Vaggopoulos* Demetrios Laggas** Charalambos Chrelias** George Labos* Demetrios Kassanos*** 
Researcher, University of Athens, Atenas, Grecia*
Lecture, University of Athens, Atenas, Grecia**
Associate Professor, University of Athens, Atenas, Grecia***
Recepción del artículo
18 de Febrero, 2007 		Aprobación
23 de Abril, 2007
Primera edición
25 de Septiembre, 2007 		Segunda edición, ampliada y corregida
7 de Junio, 2021

GENETICA Y PRESENTACION DE LA DEFICIENCIA DE 21-HIDROXILASA

Resumen
La hiperplasia suprarrenal congénita debida a una deficiencia de la enzima 21-hidroxilasa (21-OH) se distingue en sus formas clásica y no clásica y también es una de las enfermedades hereditarias autonómicas recesivas más frecuentes de los seres humanos. La forma clásica se presenta con una tasa de 1:5 000 a 1:15 000 entre los recién nacidos vivos de Estados Unidos y Europa, mientras que la forma no clásica se presenta normalmente en el 0.2% de la población blanca general. Tres alelos se asocian con el locus de 21-OH y pueden combinarse de distintas formas en los individuos que no están afectados, aquellos que son portadores heterocigotas o los que están afectados por la enfermedad clásica o no clásica. Los signos y síntomas variables de hiperandrogenismo son comunes a ambos tipos de trastornos. Los adelantos importantes en biología molecular y análisis genético de las últimas dos décadas han conducido a la creación de nuevos métodos sensibles para el análisis y el estudio del ADN, como la reacción en cadena de la polimerasa y el análisis por Southern blot. Por lo tanto, se ha descubierto que la síntesis de 21-OH está controlada por dos genes, el gen CYP21B activo y seudogén CYP21A. Las tres formas de la enfermedad tienen una secuencia conocida de cambios genéticos debidos a mutaciones en proteínas aisladas o series completas de genes a causa de translocaciones o deleciones de material genético.

Palabras clave
hiperplasia suprarrenal congénita, deficiencia de 21-hidroxilasa, genética, presentación clínica


Artículo completo
(castellano)
Extensión:  +/-15.73 páginas impresas en papel A4
Exclusivo para suscriptores/assinantes

Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: Current Concepts

Abstract
Congenital adrenal hyperplasia due to deficiency of the enzyme 21-hydroxylase (21-OH), is distinguished in its classical and non-classical form and it is also one of the most common autosomal recessive inherited diseases in humans. The classical form appears in a rate between 1:5,000 and 1:15,000 among the live neonates of North America and Europe while the non-classical form occurs in approximately 0.2 percent of the general white populations. Three alleles are associated with the 21-OH locus and can be combined in various ways to individuals who are either unaffected, heterozygote carriers, or affected with classical or nonclassical disease. Variable signs and symptoms of hyperandrogenism are common to both types of the disorder. The significant advances in molecular biology and gene analysis over the past two decades have led to the development of novel sensitive methods of DNA analysis and study, such as polymerase chain reaction and southern blot analysis. Thus it has been revealed that the synthesis of 21-OH is controlled by two genes, the active CYP21B gene and the CYP21A pseudogene. All three forms of the disease have a known sequence of gene changes owing to mutations in isolated proteins or whole series of genes owing to translocations or deletions of genetic material.

Key words
congenital adrenal hyperplasia, genetics, clinical presentation, 21-hydroxylase defficiency


Full text
(english)
 para suscriptores/ assinantes
Clasificación en siicsalud
Artículos originales > Expertos del Mundo >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Endocrinología y Metabolismo
Relacionadas: Bioquímica, Genética Humana, Medicina Interna



Comprar este artículo
Extensión: 15.73 páginas impresas en papel A4

file05.gif (1491 bytes) Artículos seleccionados para su compra



Enviar correspondencia a:
Eftihios Trakakis, National School Public Health, University of Athens , 15772, Maikina 41 Zografos, Atenas, Grecia
Bibliografía del artículo
1. New MI, Dupont B, Grumbach K. Congenital adrenal hyperplasia and related condition. In: Stanbury IB, Wyngaarden JB, Fredrieksen DS, Goldstein JL (eds). The metabolic basis of inherited disease, 5th ed. New York, McGraw-Hill pp. 973-1000, 1983.
2. White P, New MI, Dupont B. Congenital adrenal hyperplasia. N Engl J Med 25:150-156, 1987.
3. Speiser PW, Dupont B, Rubenstein P, Piaza A, Kastelan A, New M . High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37:650-657, 1985.
4. Azziz R, Dewailly P, Owerbach P. Nonclassic adrenal hyperplasia: current concepts (clinical review 56). J Clin Endocrinol Metab 78:810-815, 1994.
5. White DC, New MI. Genetic basis of endocrine disease 2: congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 74:6-11, 1992.
6. Knochenbauer E, Cortet-Rudelli C, Gunnigham R, Conway-Mayers B, Dewailly D, Azziz R. Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism. J Clin Endocrinol Metab 82:479-485, 1997.
7. Chetkowski RS, Defazio J, Shamonki, Judd H, Chang R. The incidence of late onset congenital adrenal hyperplasia due to 21 hydroxylase deficiency among hirsute women. J Clin Endocrinol Metab 58:595-598, 1984.
8. Kuttenn F, Guillin P, Girrard E, Billaud L, Vinvens M, Boucekkine C et al. Late onset adrenal hyperplasia in hirsutism. N Engl J Med 313:224-231, 1985.
9. White PC, Grossberger D, Onufer BJ, Chaplin D, New M, Dupont B et al. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Acad Sci USA 82:521-525, 1985.
10. Trakakis E. Clinical classical and molecular genetics of 21-hydroxylase deficiency. Current concepts. Archives of Hellenic Medicine 19:534-538, 2002.
11. Trakakis E, Laggas D, Salamalekis E, Greatsas G. 21-hydroxylase deficiency: From molecular genetics to clinical presentation. J Endocrinol Invest 28:187-192, 2005.
12. Rogoff D, Gomez-Sanchez CE, Foecking MF, Wortsman J, Slominski A. Steroidogenesis in the human skin: 21-hydroxylation in cultured keratinocytes. J Steroid Biochem Mol Biol 78:77-78, 2001.
13. Forest M. Recent advances in the diagnosis and management of CAH due to 21-hydroxylase deficiency. Human Reproduction Update 10:469-485, 2004.
14. Merke D, Bornstein S. Congenital adrenal hyperplasia. Lancet 365:2125-2136, 2005.
15. Merke D, Chrousos G, Eisenhofer G, Weise M, Keil M, Rogol A. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 343:1362-1368, 2003.
16. Beaujean D, Rosenbaum C, Muller HW, Willemsen J, Lenders J, Bornstein S. Combinatorial code of growth factors and neuropeptides define neuroendocrine differentiation in PC12 cells. Exp Neurol 184:348-358, 2003.
17. Brown J, Fishman L, Carballera A. Studies of the neuronal trans differentiation procass in cultured human pheochromocytoma cells: effects of steroids with differing functional groups on catecholamine content and cell morphology. Steroids 63:587-594, 1998.
18. Evinger M, Towle A, Park D, Lee P, Joh T. Glucocorticoids stimulate transcription on the rat phenylethanolamine N-methyltransferase gene in vivo and in vitro. Cell Mol Neurobiol 12:193-215, 1992.
19. Charmandari E, Eisenhofer G, Mehlinger S, Caplos A, Wesley R, Keil M et al. Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency. J Clin Endocrinol Metab 87:3031-3037, 2002.
20. Weise M, Mehlinger S, Drinkard B, Hoizers S, Eisenhofer G, Charmandari E et al. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high intensity exercise. J Clin Endocrinol Metab 59:591-597, 2004.
21. Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, Giedd JN. Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab 88:1760-1765, 2003.
22. New MI. Nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab epub a head August 2006.
23. Srikanth MS, West BR, Ishitani M, Isaacs H Jr, Applebaum H, Costin G. Benign testicular tumors in children with congenital adrenal hyperplasia. J Pediatr Surg 27:639-41, 1992.
24. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 349:776-788, 2003.
25. Dupont B, Oberfield SE, Smithwick EM et al. Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet II:1309-1311, 1997.
26. White PC, Speiser PW. CAH due to 21-hydroxylase deficiency. Endoc Rev 21:3245-3291, 2000.
27. Pollack MS, Levine LS, O'Neill CJ et al. HLA linkage and B14, DR1 Bfs haplotype association with the genes for late onset and cryptic 21-hydroxylase deficiency. Am J Hum Genet 33:540-52, 1981.
28. Levine LS, Dupont B, Lorensn F, Pang S, Pollack MS, Oberfield S et al. Cryptic 21-hydroxylase deficiency in families of patients with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 51:1316-1324, 1980.
29. White PC, Viten A, Dupont B, New M. Characterization of frequent deletions causing 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85:4436-4440, 1988.
30. Morell Y, Miller WL. Clinical and Molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Adv Hum Genet 20:1-68, 1991.
31. Owerbach D, Baillard AZ, Draznin MB. Salt wasting congenital adrenal hyperplasia: detection and characterization of mutations in the steroid 21-hydroxtlase gene, CYP 21, using the polymerase chain reaction. J Clin Endocrinol Metab 74:553-58, 1992.
32. White PC. Genetics of steroid 21-hydroxylase deficiency. Rec Prog Horm Res 43:305-316, 1987.
33. Chiou SH, Hu MC, Chung BC. A messence mutation of lle172 Ò Asn or Arg356 Ò Trp causes steroid 21-hydroxylase deficiency. J Biol Chem 256:3549-3552, 1990.
34. Dracopoulou M, Maniati M, Dacou C. The spectrum of molecular defects of the CYP 21 gene in the Hellenic population: Variable concordance between genotype and phenotype in the different forms of CAH. J Clin Endocrinol Metab 86:2845-2848, 2001.
35. Speicer PW, New MI, White PC. Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14DR1. N Engl J Med 319:19-23, 1988.
36. Tusie-Luna MT, Speiser PW, Dumic Ml, New MI, White PC. A mutation (Pro 30 Ò Leu) in CYP 21 represents a potential non-classic steroid 21-hydroxylase deficiency allele. Mol Endocrinol 5:685-692, 1991.
37. Owerbach D, Sherman L, Ballard A, Azziz R. Pro-453 Ò Ser mutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency. Mol Endocrinol 6:1211-1215, 1992.
38. Dardis A, Bergada I, Rivaola M, Belgoroski A. Mutations of steroid 21-hydroxylase gene in an American population of 36 patients with classical congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 82:3293-3297, 1997.
39. Fardella C, Pogge H, Pindela P, Soto J, Torrealba L, Cattani A et al. Salt-wasting congenital adrenal hyperplasia: detection of mutation in CYP21B gene in a Chilean population. J Clin Endocrinol Metab 83:3357-3360, 1998.
40. Bachega T, Billerback A, Madureira G, Marcondes J, Longui C, Leite M et al. Molecular genotyping in Brazilian patients with the classical forms of 21- hydroxylase deficiency. J Clin Endocrinol Metab 83:4416-4419, 1998.
41. Kharrat M, Tardy V, M'Rad R, Maazoul F , Jemaa L, Refai M et al. Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation. J Clin Endocrinol Metab 89:368-374, 2004.
42. Brodie B, Wentz A. Late onset congenital adrenal hyperplasia: a gynecologist's perspective. Fertil Steril 48:178-88, 1987.
43. Chryssikopoylos A, Sarandakou A, Phocas I, Rizos D, Trakakis E, Zervas I. Hormonal profiles and HLA typing in a family with non-classical 21- hydroxylase deficiency. Recent Developments in Fertility and Sterility Series. Edited by Y. Boutalemb and A. Gzouli. The Parthenon Publising Group 198:53-58, 1990.
44. Trakakis E, Chryssikopoulos A, Phocas I, Sarandakou A, Rizos D. The incidence of 21-hydroxylase deficiency in Greek hyperandrogenic women: screening and diagnosis. Gynecol Endocrinol 12:89-96, 1998.
45. Kohn B, Levine LS, Pollack MS, Pang S, Lorenzen F, Levy D et al. Late onset steroid 21-hydroxylase deficiency: a variant of clasisical CAH. J Clin Endocrinol Metab 55:817-827, 1982.
46. Fife D, Rappaport EB. Prevalence of salt-losing among congenital adrenal hyperplasia patients. Clin Endocrinol 19:259-264, 1993.
47. Trakakis E, Chryssikopoulos A, Sarandakou A, Phocas I, Rizos D, Gregoriou O et al. Hypothalamic-Pituitary-Thyroidal axis dysfunction and cortisol secretion in patients with non classical congenital adrenal hyperplasia. Int J Fertil 46:37-41.
48. Knochenbauer E, Cortet-Rudelli C, Gunnigham R, Conway-Mayers B, Dewailly D, Azziz R. Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism. J Clin Endocrinol Metab 82:479-485, 1997.
49. Lajic S, Clauin S, Robins T, Vexiau P, Blanche H, Bellanne C et al. Novel mutations in CYP21 detected in individuals with hyperandrogenism. J Clin Endocrinol Metab 87:2824-2829, 2002.
50. Speiser PW, Knochenhauer ES, Dewailly D, Fruzzeti F, Marcondes J, Azziz R. A multicenter study of women with nonclassical congenital adrenal hyperplasia: Relationship between genotype and phenotype. Mol Gen Metab 5:27-34, 2000.
51. Wilson R, Mercano A, Cheng K, New M. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 80:2322-2329, 1995.
52. Rumsby G, Avey C, Conway G, Honour J. Genotype-phenotype analysis in late onset 21-hydroxylase deficiency in comparison to the classical forms. Clin Endocrinol (Oxf) 48:707-11, 1998.
53. Speiser PW. Molecular diagnosis of CYP21 mutations in CAH: Implications for genetic counseling. Am J Pharmacogenomics 1:101-110, 2001.
54. Pinto G, Tardy V, Trivin C, Thalassinos C, Lordat S, Nihoul C et al. Follow up of 68 children with congenital adrenal hyperplasia due to 21 hydroxylase deficiency: revelance of genotype to management. J Clin Endocrinol Metab 88:2624-2633, 2003.
55. Deneux C, Tardy V, Dib A, Mornet E, Billaud L, Charron D et al. Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 86:207-13, 2001.
56. Dolzan V, Solyon J, Fekete G, Kovacs J, Rakosnikova V, Votara F, et al. Mutational spectrum of steroid 21-hydroxylase and the genotype- phenotype association in Middle European patients with congenital adrenal hyperplasia. Eur J Endocrinol 153:99-106, 2005.
57. Coleman MA, Honour JW. Reduced maternal dexamethazone dosage for the prenatal treatment of CAH. BJOG 111:176-178, 2004.
 
 
 
 
 
 
 
 
 
 
 
 
Está expresamente prohibida la redistribución y la redifusión de todo o parte de los contenidos de la Sociedad Iberoamericana de Información Científica (SIIC) S.A. sin previo y expreso consentimiento de SIIC.
ua31618
Inicio/Home

Copyright siicsalud © 1997-2024 ISSN siicsalud: 1667-9008