Asunto(s)
Cromosomas Humanos Par 20/genética , Cromosomas Humanos Par 4/genética , Síndrome de Ellis-Van Creveld/genética , Enfermedades Uterinas/genética , Enfermedades Vaginales/genética , Adulto , Preescolar , Segregación Cromosómica , Femenino , Ligamiento Genético , Genotipo , Haplotipos , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , Polidactilia/genética , EmbarazoRESUMEN
Tuberous sclerosis complex (TSC) is an autosomal dominant condition whose signs and symptoms may vary from a few hypopigmented skin spots to epilepsy, severe mental retardation, and renal failure. The disease is caused by mutations in either TSC1 or TSC2 gene, at chromosome 9q34 and 16p13.3. Inactivation of both alleles at TSC1 or TSC2 loci is associated with the development of hamartomas in different organs, and only rarely with malignant neoplasms. In this study we present a 6-year-old boy with TSC and with a malignant islet cell tumor of the pancreas. Mutation analysis of DNA extracted from peripheral blood cells of the patient identified an R1459X de novo mutation in exon 33 of the TSC2 gene. Immunohistochemical analysis with anti-tuberin antibodies on paraffin-embedded tissue sections showed loss of tuberin immunostaining in tumor cells but normal expression in residual normal pancreas. DNA analysis of tumor and normal cells showed chromosome 16p13 loss of heterozygosity in malignant pancreatic islet cell tumor but not in normal pancreas. These findings suggest a role for tuberin, the TSC2 gene product, in the pathogenesis of malignant pancreatic endocrine tumor.
Asunto(s)
Carcinoma de Células de los Islotes Pancreáticos/genética , Genes Supresores de Tumor/fisiología , Neoplasias Pancreáticas/genética , Proteínas Represoras/genética , Esclerosis Tuberosa/genética , Carcinoma de Células de los Islotes Pancreáticos/complicaciones , Niño , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Mutación/genética , Neoplasias Pancreáticas/complicaciones , Esclerosis Tuberosa/complicaciones , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorAsunto(s)
Anomalías Múltiples/genética , Enfermedad Celíaca/genética , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/genética , Anomalías Múltiples/diagnóstico , Adolescente , Enfermedad Celíaca/diagnóstico , Niño , Preescolar , Síndrome de DiGeorge/diagnóstico , Cara/anomalías , Femenino , Humanos , Masculino , Fenotipo , Insuficiencia Velofaríngea/genéticaRESUMEN
We report clinical and molecular findings in 14 patients with cleidocranial dysplasia (CCD), a well defined skeletal disorder with characteristic clinical findings and autosomal dominant inheritance. We identified ten heterozygous base changes in the RUNX2 gene, including six novel mutations [c.522insA, c.389G>A (W130X), c.662T>G (V221G), IVS2+T>A, c.1111_1129del19, and c.873_874delCA]. We did not establish a clear correlation between clinical features and genotype, the phenotypes of all patients analyzed falling within the range of variation described in CCD without an effect related to the length of the predicted protein. In two cases, however, a limb-girdle myopathy affecting the shoulder muscles was also identified. Our data add new variants to the repertoire of RUNX2 mutations in CCD.
Asunto(s)
Displasia Cleidocraneal/genética , Mutación , Proteínas de Neoplasias , Factores de Transcripción/genética , Sustitución de Aminoácidos/genética , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal , Femenino , Fibroblastos/química , Fibroblastos/metabolismo , Mutación del Sistema de Lectura/genética , Humanos , Italia , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: RSH/Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome due to an inborn error of cholesterol metabolism and is characterized by developmental delay, facial anomalies, hypospadias, congenital heart defect (CHD), postaxial polydactyly, and 2-3 toe syndactyly. CHD is found in half of the propositi, and a specific association with atrioventricular canal defect (AVCD) and anomalous pulmonary venous return has been demonstrated. METHODS: We report on an additional patient with RSH/SLOS presenting with complete AVCD and anomalous pulmonary venous return, and discuss the possible relationship of the Sonic Hedgehog (SHH) pathway as causative factor of these CHDs and those in heterotaxia patients with postaxial polydactyly syndromes. RESULTS: Anatomic similarities between heterotaxia and CHDs of several syndromes with postaxial polydactyly have been noted previously, considering the frequent association of AVCD with common atrium in these conditions. It is known that both CHDs of heterotaxia and postaxial polydactyly can be related to abnormalities of the SHH pathway. Cholesterol has a critical role in the formation of normally active hedgehog proteins. It could be hypothesized that specific types of CHDs in RSH/SLOS can be caused by modifications of the SHH protein related to the defect of cholesterol biosynthesis. CONCLUSIONS: The specific association of AVCD and anomalous pulmonary venous return in patients with RSH/SLOS and the finding of AVCD +/- common atrium in several syndromes with polydactyly leads to the hypothesis that heterotaxia due to SHH anomalies could be involved in a large spectrum of conditions. Perturbations in different components of the SHH pathway could lead to several developmental errors presenting with partially overlapping clinical manifestations.
Asunto(s)
Cardiopatías Congénitas/genética , Polidactilia/genética , Situs Inversus/genética , Síndrome de Smith-Lemli-Opitz/genética , Transactivadores/genética , Consanguinidad , Deshidrocolesteroles/sangre , Ecocardiografía , Femenino , Cromatografía de Gases y Espectrometría de Masas , Cardiopatías Congénitas/diagnóstico por imagen , Proteínas Hedgehog , Humanos , Lactante , Masculino , Síndrome de Smith-Lemli-Opitz/metabolismo , Síndrome de Smith-Lemli-Opitz/patología , Transactivadores/metabolismoRESUMEN
Oxidative stress has been proposed as a pathogenic mechanism of atherosclerosis, cell aging, and neurologic disorders in Down syndrome. This study demonstrates a systemic decrease of all glutathione forms, including glutathionyl-hemoglobin, in the blood of children with Down syndrome. Furthermore, we obtained a disequilibrium, in vivo, between the antioxidant enzyme activities.
Asunto(s)
Síndrome de Down/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Glutatión/metabolismo , Superóxido Dismutasa/metabolismo , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Síndrome de Down/enzimología , Femenino , Humanos , Masculino , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Anomalías Múltiples/diagnóstico , Aorta Torácica/anomalías , Cromosomas Humanos Par 22 , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Defectos del Tabique Interventricular/diagnóstico , Defectos del Tabique Interventricular/genética , Estudios de Casos y Controles , Niño , Preescolar , Aberraciones Cromosómicas , Estudios de Cohortes , Ecocardiografía , Femenino , Humanos , Lactante , Angiografía por Resonancia Magnética , Masculino , Pronóstico , Valores de ReferenciaRESUMEN
Se describe una niña que presenta las características del síndrome de Nager, que consisten principalmente en una disostosis mandibulofacial con anomalías radiales. La mayoría de los casos son esporádicos pero hay evindencias que sugieren herencia monogénica. El diagnóstico prenatal ecográfico puede ser útil.
