RESUMEN
Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%-15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated pheno-types, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS.
Asunto(s)
Mutación , Síndrome de Noonan/genética , Proteína SOS1/genética , Animales , Modelos Animales de Enfermedad , Femenino , Corazón/embriología , Heterocigoto , Homocigoto , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Mutantes , Ratones Transgénicos , Mutagénesis Sitio-Dirigida , Síndrome de Noonan/embriología , Síndrome de Noonan/metabolismo , Fenotipo , Embarazo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteínas de Unión al GTP rac/metabolismoAsunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Análisis Mutacional de ADN , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leucemia Mielomonocítica Juvenil/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Síndrome de Noonan/embriologíaRESUMEN
Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement. To understand the developmental stage- and cell type-specific consequences of the NS SHP2 gain-of-function mutation, Q79R, we generated transgenic mice in which the mutated protein was expressed during gestation or following birth in cardiomyocytes. Q79R SHP2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, while, in the postnatal cardiomyocyte, Q79R SHP2 expression was completely benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding of the Q79R transgenics into ERK1/2-null backgrounds confirmed the pathway's necessity and sufficiency in mediating mutant SHP2's effects. Our data establish the developmental stage-specific effects of Q79R cardiac expression in NS; show that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities; and suggest that ERK1/2 modulation could have important implications for developing therapeutic strategies in CHD.
Asunto(s)
Trastornos de los Cromosomas/enzimología , Defectos del Tabique Interventricular/enzimología , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Síndrome de Noonan/enzimología , Proteínas Tirosina Fosfatasas/biosíntesis , Sustitución de Aminoácidos , Animales , Trastornos de los Cromosomas/embriología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Trastornos de los Cromosomas/terapia , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica/genética , Regulación Enzimológica de la Expresión Génica/genética , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/genética , Defectos del Tabique Interventricular/patología , Defectos del Tabique Interventricular/prevención & control , Ventrículos Cardíacos/embriología , Ventrículos Cardíacos/enzimología , Ventrículos Cardíacos/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Transgénicos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Mutación Missense , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Síndrome de Noonan/embriología , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Síndrome de Noonan/terapia , Proteína Fosfatasa 2 , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteínas Tirosina Fosfatasas/genéticaRESUMEN
OBJECTIVE: Noonan syndrome is one of the most common genetic syndromes manifesting at birth. Still, it is diagnosed late, often during infancy. Diagnosis is difficult because prenatal ultrasound findings are unspecific and the dysmorphias after birth can be subtle. CASES: Two women were referred to our university hospital because of an increased nuchal translucency in the first trimester of pregnancy. Further ultrasound examination showed the bilateral presence of distended jugular lymph sacs. Karyotyping revealed euploidy in both fetuses. The second trimester ultrasound scan showed a persistence of the jugular lymph sacs together with a nuchal fold, indicating a disturbed lymphatic development. There were no other anomalies. In 1 case the jugular lymph sacs containing newly formed lymph node tissue remained visible until 35 weeks' gestation. Both newborns were diagnosed with Noonan syndrome after birth. Postnatal echocardiography revealed a mild pulmonary stenosis. CONCLUSION: Distension of the jugular lymph sacs is known to cause nuchal edema and normally resolves after the first trimester. In case of persistence of the jugular lymphatic sacs beyond the second trimester of pregnancy, the diagnosis of Noonan syndrome and subsequent DNA testing should be considered.
Asunto(s)
Edema/diagnóstico , Enfermedades Fetales/diagnóstico , Sistema Linfático/anomalías , Síndrome de Noonan/diagnóstico , Ultrasonografía Prenatal , Adulto , Muestra de la Vellosidad Coriónica , Edema/diagnóstico por imagen , Edema/embriología , Femenino , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/genética , Enfermedades Fetales/patología , Pruebas Genéticas , Edad Gestacional , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Cariotipificación , Nacimiento Vivo , Sistema Linfático/diagnóstico por imagen , Mutación , Síndrome de Noonan/diagnóstico por imagen , Síndrome de Noonan/embriología , Síndrome de Noonan/patología , Medida de Translucencia Nucal , Embarazo , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteínas Tirosina Fosfatasas/genética , Ultrasonografía Prenatal/métodosRESUMEN
Prenatal molecular genetic diagnosis for Noonan syndrome I is reported. Noonan syndrome was suspected because of large cystic hygroma colli, massive pleural effusion and ascites at 23 weeks of gestation and normal karyotype (46,XX). DNA was prepared from amnion cells and screened for mutations in the PTPN11 gene. In exon 8, a missense mutation (S285F) was found. Delivery was induced at 33 weeks of gestation because of silent cardiotocography (CTG). Despite immediate drainage of the hydrothorax, mechanical ventilation was insufficient and the child died 9 h after birth due to severe pulmonary hypoplasia. Pleural punctate was enriched for small lymphocytes and thus was characterized as chylus. Prenatal ultrasound findings in Noonan syndrome usually are unspecific and rarely lead to a diagnosis. However, with the combination of cystic hygroma, pleural effusion, ascites and normal karyotype Noonan syndrome should be considered and DNA testing for PTPN11 mutations may be appropriate. Malformations of lymphatic vessels and/or chylothorax in Noonan syndrome seem to be more frequent than usually anticipated.
Asunto(s)
Anomalías Múltiples/diagnóstico por imagen , Síndrome de Noonan/diagnóstico , Diagnóstico Prenatal , Anomalías Múltiples/embriología , Adulto , Ascitis/diagnóstico por imagen , Ascitis/embriología , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular/genética , Cariotipificación , Linfangioma Quístico/diagnóstico por imagen , Linfangioma Quístico/embriología , Mutación , Síndrome de Noonan/diagnóstico por imagen , Síndrome de Noonan/embriología , Síndrome de Noonan/patología , Derrame Pleural/diagnóstico por imagen , Derrame Pleural/embriología , Embarazo , Segundo Trimestre del Embarazo , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteínas Tirosina Fosfatasas/genética , UltrasonografíaRESUMEN
Growth failure is a consistent finding at birth in infants with Turner syndrome. However, the time of onset and pattern of growth deficiency is unknown. To determine the presence of growth failure in the second trimester in fetuses with Turner syndrome, second trimester fetuses that had a complete autopsy at the Central Laboratory for Human Embryology at the University of Washington were studied. A control group of specimens with normal findings was selected and compared with a study group with Turner syndrome documented by karyotype. Footlength and crown-rump length were measured directly with a ruler and femur, tibia, fibula, humerus, ulna and radius were measured from X-rays. Crown-rump length was used as the indicator of gestational age. Statistical comparisons between the normal and study groups were performed by multiple regression. Long bone measurements were made on 105 normal and 13 Turner fetuses. Footlength and the six long bones showed evidence of statistically significant growth failure. Fetuses with 45,X/46,XX mosaic Turner syndrome may demonstrate a lesser degree of growth retardation, at least for footlength, than those with a 45,X karyotype, but small numbers limited the analysis. We conclude that the growth failure consistently demonstrated in newborns with Turner syndrome begins early in gestation and is well-established by mid-pregnancy.
Asunto(s)
Retardo del Crecimiento Fetal/etiología , Síndrome de Noonan/embriología , Síndrome de Turner/embriología , Antropometría , Femenino , Humanos , Masculino , Embarazo , Segundo Trimestre del Embarazo , Análisis de RegresiónAsunto(s)
Neoplasias de Cabeza y Cuello/embriología , Linfangioma/embriología , Síndrome de Noonan/complicaciones , Femenino , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Linfangioma/complicaciones , Linfangioma/diagnóstico , Síndrome de Noonan/embriología , Embarazo , Diagnóstico Prenatal/métodosRESUMEN
Twenty-one patients with Noonan syndrome are presented. Telecanthus low-set ears, epicanthus and facial asymmetry were the commoner facial stigmata. Pterygium colli, pectus excavatum-carinatum and mild physical and mental retardation were also common features. Pulmonary stenosis and patent ductus arteriosus were the most frequent cardiac anomalies. Wide QRS, left axis deviation, giant Q waves and a negative pattern in V6 were useful electrocardiographic signs. We speculate that the Noonan syndrome could be considered as a branchial arch development syndrome.