Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas / Noonan syndrome: genetic and clinical update and treatment options

El síndrome de Noonan (SN) es una enfermedad de origen genético relativamente frecuente cuyas manifestaciones fundamentales son la talla baja, la cardiopatía congénita y un fenotipo facial característico. La causa del síndrome de Noonan y de otras enfermedades clínicamente solapadas como el síndrome de Noonan con lentiginosis múltiple (anteriormente llamado síndrome LEOPARD), el cardiofaciocutáneo o el síndrome de Costello, son mutaciones en genes que codifican para proteínas de la vía de señalización de las RAS-MAPKinasas. Debido a este sustrato común este grupo de enfermedades son denominadas colectivamente «rasopatías». A pesar de los avances genéticos de las últimas décadas, cerca de 20% de pacientes no tienen causa genética identificada, y el diagnóstico sigue siendo clínico. El síndrome de Noonan se caracteriza por una alta heterogeneidad clínica y genética, con afectación variable, y cambiante con la edad, de múltiples órganos y sistemas. Debido a esta variabilidad es fundamental que los médicos involucrados en su cuidado estén familiarizados con sus manifestaciones y conozcan las recomendaciones de seguimiento, incluido el seguimiento del crecimiento y desarrollo. Hasta la fecha los escasos datos de crecimiento con GH a talla adulta dan resultados de ganancia de talla moderados, semejantes a los obtenidos en el síndrome de Turner. La hiperactivación de la vía RAS-MAPK como base común de esta familia de enfermedades brinda una oportunidad única para el desarrollo de tratamientos dirigidos a la etiología de estos trastornos

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies». Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches

[Noonan syndrome: genetic and clinical update and treatment options]. / Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas.

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies¼. Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.

Estudios genéticos en diagnóstico prenatal. Recomendación (2018) / Genetic studies in prenatal diagnosis. Recommendation (2018)

El término diagnóstico prenatal comprende todas las modalidades de diagnóstico dirigidas a detectar durante la gestación una anomalía congénita que incluya trastornos estructurales o funcionales. Un porcentaje de las mismas se debe a factores genéticos. El presente documento pretende detallar las indicaciones actuales de las pruebas invasivas y de las no invasivas, describir las pruebas de laboratorio que se utilizan en el diagnóstico prenatal de alteraciones genéticas y proponer esquemas de trabajo para el estudio de estas alteraciones genéticas

The term prenatal diagnosis includes all diagnostic modalities aimed at detecting a congenital anomaly during pregnancy that includes structural or functional disorders. A percentage of them are due to genetic factors. This document intends to detail the current indications of invasive and non-invasive tests, describe the laboratory tests used in the prenatal diagnosis of genetic alterations, and propose work schemes for the study of these genetic alterations

Cribado neonatal de hiperplasia suprarrenal congénita / Newborn screening of congenital adrenal hiperplasia

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Neonatal screening for congenital adrenal hyperplasia: transitory elevation of 17-hydroxyprogesterone.

AIM: The aim of the study was to identify patients with transitory elevation (TE) of 17-hydroxyprogesterone (17-OHP) using neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) and to compare them with patients with 21-OHD. METHODS: This was a retrospective study of patients with high 17-OHP levels detected during newborn screening in Madrid, Spain. RESULTS: 17-OHP levels were significantly higher in the 33 21-OHD patients, who tended to present hyponatraemia and hyperkalemia. The TE-17-OHP group was characterized by normal initial physical examination (88.8% vs. 39.4%), lower gestational age and a higher number of stressful perinatal factors. 17-OHP levels decreased spontaneously in this group. Molecular diagnosis allowed us to discard the most frequent mutations associated with 21-OHD. CONCLUSIONS: Newborns with slightly increased 17-OHP levels and normal results for physical examination, acid-base equilibrium, glycemia, electrolytes and perinatal stress factors should be carefully evaluated. Decisions on treatment should be postponed until these results are available.

Two cases of LEOPARD syndrome--RAF1 mutations firstly described in children.

. LEOPARD syndrome 2 (LS-2) (OMIM #611554) is a rare, dominantly inherited genetic disorder affecting multiple organ systems. We report two unrelated females of different ages whose phenotype fits best in the category of LEOPARD syndrome, both with proven mutations in the RAF1 gene not previouslyreported in pediatric patients. In our 10-year-old patient, who was negative in the PTPN11 gene analysis but involving the RAF1 gene in a complementary analysis, the sequence variant Ser257Leu (770C > T, exon 7) was detected, which previously had been reported in only one 35-year-old woman with LS. The second patient was a two-year-old female infant with Ser259Leu mutation in the same gene, described in several patients with Noonan syndrome (NS) but not in LS patients of any age. The first girl had ventricular and supraventricular extrasystoles, and the second had episodes of paroxysmal supraventricular tachycardia. Echocardiographic examination revealed biventricular obstructive hypertrophic cardiomyopathy in both patients.

Formas virilizantes simples de hiperplasia suprarrenal congénita: adaptación y validación prospectiva del cribado molecular de diagnóstico / Simple virilizing forms of congenital adrenal hyperplasia: adaptation and prospective validation of the molecular screening

Fundamento y objetivo: El análisis de mutaciones del gen CYP21A2 es de gran utilidad en el diagnóstico de la hiperplasia suprarrenal congénita (HSC). A diferencia de las formas pierde-sal, solo un 83% de las formas virilizantes simples (VS) se detectan con el cribado básico de mutaciones recurrentes. Las mutaciones raras con una distribución local podrían ser causantes de esta menor eficacia. El objetivo del presente trabajo es identificar nuevas variantes asociadas a formas VS en nuestra población y valorar su impacto en la eficiencia del cribado de diagnóstico.Pacientes y métodos: Fase preliminar: secuenciación de CYP21A2 en 13 pacientes con formas VS y caracterización molecular básica incompleta. Fase retrospectiva: se estudiaron 2.097 muestras de ADN (561 pacientes) para la mutación p.R426H. Fase prospectiva: incorporación de la mutación p.R426H al cribado básico de HSC en 1.041 muestras de ADN (245 pacientes) para la validación del estudio ampliado.Resultados: Se detectó la mutación p.R426H en 5 pacientes de la fase preliminar y 10 más posteriormente. La frecuencia estimada del alelo pp.R426H fue del 0,71% en total y del 7,14% en formas VS. Los haplotipos asociados al alelo mutado sugieren una diseminación preferente del mismo. Los fenotipos observados en los pacientes confirman la afectación moderada-severa de la actividad enzimática codificada. Conclusiones: La frecuencia alélica y su asociación a formas clínicas graves justifican la incorporación de la mutación p.R426H al panel de cribado molecular. La eficiencia diagnóstica mejora especialmente para las formas VS. Dos nuevos casos detectados prospectivamente demuestran la utilidad de esta nueva estrategia (AU)

Background and objective: Congenital Adrenal Hyperplasia (CAH) is not an infrequent genetic disorder for which mutation-based analysis for CYP21A2 gene is a useful tool. Contrarily to salt-wasting forms the basic mutation screening accounts only for 83% of simple virilising (SV) phenotypes. Rare alleles with a local distribution not included in the basic panel may reduce its diagnostic accuracy. Our aim is to explore underlying prevalent mutations among our partially characterised SV forms and to evaluate their potential impact in the mutation screening.Patients and methodsPreliminary study: CYP21A2 gene sequencing in 13 SV patients partially characterised. Retrospective targeted study: 2,097 DNA samples (561 patients) were re-analysed for p.R426H mutation. Prospective targeted study: incorporation of the p.R426H mutation to the initial exploration of CAH in 1,041 DNA samples to validate this extended screening.Results: p.R426H mutation was detected in five patients in the preliminary analysis and in ten more during targeted studies. A frequency for this mutation was 0.71% in the whole group and 7.14% in SV forms. Associated haplotypes were identical thus suggesting a preferential dissemination. The observed phenotypes correlated and confirmed the moderate-to-severe effect on the enzymatic activity.Conclusions: Our data relative to allelic frequency of the p.R426H mutation and its strong association to SV forms justify the incorporation of the p.R426H mutation into the basic screening panel because of the significant improvement in the initial characterization of affected patients, especially among those with SV forms. Two new cases detected remark the usefulness of this novel approach (AU)

[Simple virilizing forms of congenital adrenal hyperplasia: adaptation and prospective validation of the molecular screening]. / Formas virilizantes simples de hiperplasia suprarrenal congénita: adaptación y validación prospectiva del cribado molecular de diagnóstico.

BACKGROUND AND OBJECTIVE: Congenital Adrenal Hyperplasia (CAH) is not an infrequent genetic disorder for which mutation-based analysis for CYP21A2 gene is a useful tool. Contrarily to salt-wasting forms the basic mutation screening accounts only for 83% of simple virilising (SV) phenotypes. Rare alleles with a local distribution not included in the basic panel may reduce its diagnostic accuracy. Our aim is to explore underlying prevalent mutations among our partially characterised SV forms and to evaluate their potential impact in the mutation screening. PATIENTS AND METHODS: Preliminary study: CYP21A2 gene sequencing in 13 SV patients partially characterised. Retrospective targeted study: 2,097 DNA samples (561 patients) were re-analysed for p.R426H mutation. Prospective targeted study: incorporation of the p.R426H mutation to the initial exploration of CAH in 1,041 DNA samples to validate this extended screening. RESULTS: p.R426H mutation was detected in five patients in the preliminary analysis and in ten more during targeted studies. A frequency for this mutation was 0.71% in the whole group and 7.14% in SV forms. Associated haplotypes were identical thus suggesting a preferential dissemination. The observed phenotypes correlated and confirmed the moderate-to-severe effect on the enzymatic activity. CONCLUSIONS: Our data relative to allelic frequency of the p.R426H mutation and its strong association to SV forms justify the incorporation of the p.R426H mutation into the basic screening panel because of the significant improvement in the initial characterization of affected patients, especially among those with SV forms. Two new cases detected remark the usefulness of this novel approach.

[Premature androgenetic alopecia in adult male with nonclassic 21-OH deficiency. A novel nonsense CYP21A2 mutation (Y336X) in 2 affected siblings]. / Alopecia androgénica prematura en un varón con déficit de 21-hidroxilasa no clásico. Nueva mutación grave (Y336X) del gen CYP21A2 en 2 hermanos afectados.

BACKGROUND AND OBJECTIVE: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency mainly manifests with symptoms and signs of hyperandrogenism, which are usually obvious in women and sometimes obvious in children or adolescents, but are rarely observed in adult men especially with increasing age. Male pattern alopecia is considered an androgenetic and age-related symptom. However, its early appearance should raise the suspicion of an underlying endocrinological disease, and biochemical screening should be done. PATIENTS AND METHOD: Here we present the case of 2 siblings (female and male) where the man complains about premature alopecia. RESULTS: Molecular study of CYP21A2 revealed that both siblings were compound heterozygotes for the mild mutation (V281L) and for a novel nonsense mutation (Y336X). CONCLUSIONS: Given the high prevalence of carriers with severe mutations, we discuss the risk for such patients of conceiving a child with a classical disease and the need for a reliable molecular diagnosis in order to provide accurate genetic counselling.

Alopecia androgénica prematura en un varón con déficit de 21-hidroxilasa no clásico. Nueva mutación grave (Y336X) del gen CYP21A2 en 2 hermanos afectados / Premature androgenetic alopecia in adult male with nonclassic 21-OH deficiency. A novel nonsense CYP21A2 mutation (Y336X) in 2 affected siblings

Fundamento y objetivo: La hiperplasia suprarrenal congénita por déficit de 21-hidroxilasa en su forma no clásica se manifiesta por síntomas y signos de hiperandrogenismo, que suelen ser evidentes en la mujer, pero pueden no serlo en el niño y adolescente, y que rara vez se reconocen en el varón adulto. La alopecia androgénica en el varón se considera un síntoma andrógeno y dependiente de la edad, pero su aparición temprana debe hacer sospechar un trastorno endocrinológico y obliga a realizar el estudio bioquímico correspondiente. Pacientes y método: Se presenta el caso de 2 hermanos (mujer y varón) en quienes el motivo de consulta del varón fue la alopecia prematura. Resultados: El estudio molecular del gen CYP21A2 detectó en ambos una mutación grave (Y336X), no descrita anteriormente, en heterocigosis compuesta con la mutación leve (V281L). Conclusiones: Dada la alta frecuencia de portadores de mutación grave en la población (1:60), se discute el riesgo de presentación de una forma clásica de la deficiencia en la descendencia de estos pacientes y la necesidad del diagnóstico molecular para el consejo genético

Background and objective: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency mainly manifests with symptoms and signs of hyperandrogenism, which are usually obvious in women and sometimes obvious in children or adolescents, but are rarely observed in adult men especially with increasing age. Male pattern alopecia is considered an androgenetic and age-related symptom. However, its early appearance should raise the suspicion of an underlying endocrinological disease, and biochemical screening should be done. Patients and method: Here we present the case of 2 siblings (female and male) where the man complains about premature alopecia. Results: Molecular study of CYP21A2 revealed that both siblings were compound heterozygotes for the mild mutation (V281L) and for a novel nonsense mutation (Y336X). Conclusions: Given the high prevalence of carriers with severe mutations, we discuss the risk for such patients of conceiving a child with a classical disease and the need for a reliable molecular diagnosis in order to provide accurate genetic counselling

Hiperplasia suprarenal congénita. Correlación genotipo/fenotipo / No disponible

No disponible