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Rev Esp Endocrinol Pediatr 2010;1 Suppl(1):19-32 | Doi. 10.3266/RevEspEndocrinologPediatr.pre2010.Nov.9 |
Insuficiencia suprarrenal de origen genético |
Sent for review: 6 Nov. 2010 | Accepted: 6 Nov. 2010 | Published: 8 Nov. 2010 |
Begoña Ezquieta Zubicaray |
Laboratorio de Diagnóstico Molecular. Hospital Materno Infantil. Hospital G. Universitario Gregorio Marañón. Madrid |
Correspondence:Begoña Ezquieta Zubicaray, Laboratorio de Diagnóstico Molecular, Hospital Materno Infantil. Hospital G. Universitario Gregorio Marañón, Madrid |
Tabla 1 - Prueba sin título |
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Este resumen se ha enfocado a presentar brevemente las características genéticas de las distintas enfermedades congénitas, de presentación perinatal y tardía, que asocian insuficiencia suprarrenal primaria, secundaria de origen central u originada por fallo en otro tipo tisular. Nos ha interesado abundar en aspectos relacionados con la base molecular, mecanismo y recurrencia de las alteraciones, patrón hereditario y frecuencia de la enfermedad que fundamentan el consejo genético de las mismas. La insuficiencia suprarrenal que se desarrolla en etapas posteriores y es consecuencia de defectos congénitos que afectan a proteínas cuya función se ejerce en otros tipos tisulares, se describe a continuación. Con excepción de la deficiencia de esteroide 21-hidroxilasa, los déficits congénitos que causan HSC, al igual que todos los que hemos mencionado, son extremadamente raros. El 90-95% de los casos se deben a 21OHD, que constituye en sus formas graves una entidad ”menos rara”, nunca una entidad frecuente (1:14.000). Sí pueden considerarse frecuentes las formas no clásicas, alélicas de las primeras y con las que comparten alelos severos, y los portadores (frecuencia deducida 1:60). El hecho de que exista en la HSC la posibilidad de una intervención prenatal, bien un tratamiento preventivo de la virilización de los fetos femeninos o una intervención reproductiva con selección preimplantacional, unido a la frecuencia de portadores en población general, hace imprescindible el consejo genético adecuado que ha de fundamentarse en los datos genotípicos. La determinación de 17Oh progesterona en la etapa neo y perinatal mediante inmunoensayos directos no está exenta de interferencias por otros esteroides( 6,55). Las elevaciones transitorias de 17OHP neonatales causan falsos positivos para HSC en las determinaciones del cribado neonatal(7). En ausencia de pruebas bioquímicas más específicas como el tánden masas, el diagnóstico molecular actúa como herramienta secundaria de confirmación. La utilización del dato genotípico como dato de diagnóstico “previo” a la aparición de la forma clínica exige que esté bien validado el impacto fenotípico de cada uno de los alelos deficientes preferentemente en un número elevado de individuos (correlación genotipo/fenotipo). Si el locus es complejo debe ser especialmente verificada la validez del abordaje molecular aplicado, tanto en pacientes como en cromosomas normales. Algunos fallos de correlación descritos en el pasado resultaron tan sólo abordajes incorrectos: falsos homozigotos para la recurrente mutación de procesamiento del intrón 2 (c.293-13AoC>G alias 655G) al fallar la amplificación de uno de los alelos con la variante normal(56); falsos homocigotos para la mutación leve p.Val282Leu (alias p.Val281Leu) que eran en realidad hemizigotos por deleción(57), falsos alelos leves portadores de p.Pro31Leu (alias p.Pro30Leu) que presentaban la conversión adicional(58,59) en 5´, falsos portadores de la mutación grave p.Gln319Stop (p.Gln318Stop) en alelos con duplicación del gen8, Figura 1A). La HSC-21OHD, con su amplio espectro de formas clínicas, elevada frecuencia de la enfermedad y número limitado de alelos deficientes (incluso las variantes raras muestran recurrencia en distintas poblaciones) que incluye variantes leves y graves bien tipificadas, ha constituido un ejemplo único para realizar la validación clínica del abordaje molecular(60). |
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