RESUMO
OBJECTIVE: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. METHOD: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. RESULTS: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. CONCLUSION: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life.
Assuntos
Arritmias Cardíacas/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Gigantismo/diagnóstico por imagem , Glipicanas/genética , Cardiopatias Congênitas/diagnóstico por imagem , Hérnias Diafragmáticas Congênitas/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Ultrassonografia Pré-Natal , Anormalidades Múltiplas/genética , Arritmias Cardíacas/embriologia , Arritmias Cardíacas/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/embriologia , Gigantismo/genética , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Hérnias Diafragmáticas Congênitas/embriologia , Hérnias Diafragmáticas Congênitas/genética , Humanos , Deficiência Intelectual/embriologia , Deficiência Intelectual/genética , Masculino , Gravidez , Estudos RetrospectivosRESUMO
OBJECTIVE: To analyze TRAPPC2 gene mutation in a family with X-linked spondyloepiphyseal dysplasia tarda and to provide genetic counseling and prenatal diagnosis. METHODS: All of 4 exons of the TRAPPC2 gene and their flanking sequences in the proband and her father were analyzed with polymerase chain reaction and direct DNA sequencing. Genomic DNA of the probands' fetus was extracted from amniotic fluid sampled at 18th gestational week. Gender of the fetus was determined by the presence of SRY gene. The sequence of fetal TRAPPC2 gene was also analyzed. RESULTS: A c.209G>A mutation was identified in exon 4 of the TRAPPC2 gene in the proband and her father. The fetus of was determined to be a male and also have carried the c.209G>A mutation. CONCLUSION: A c.209G>A mutation of TRAPPC2 exon 4 probably underlies the clinical manifestations in this family. The proband is a carrier, and her fetus is a male carrying the same mutation. Prenatal diagnosis is an effective method for the prevention of the disease.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Osteocondrodisplasias/genética , Sequência de Bases , Feminino , Aconselhamento Genético , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Humanos , Dados de Sequência Molecular , Mutação Puntual , Gravidez , Diagnóstico Pré-NatalRESUMO
In humans, loss-of-function mutations in ZIC3 cause isolated cardiovascular malformations and X-linked heterotaxy, a disorder with abnormal left-right asymmetry of organs. Zic3 null mice recapitulate the human heterotaxy phenotype but also have early gastrulation defects, axial patterning defects and neural tube defects complicating an assessment of the role of Zic3 in cardiac development. Zic3 is expressed ubiquitously during critical stages of left-right patterning but its later expression in the developing heart remains controversial and the molecular mechanism(s) by which it causes heterotaxy are unknown. To define the temporal and spatial requirements, for Zic3 in left-right patterning, we generated conditional Zic3 mice and Zic3-LacZ-BAC reporter mice. The latter provide compelling evidence that Zic3 is expressed in the mouse node and absent in the heart. Conditional deletion using T-Cre identifies a requirement for Zic3 in the primitive streak and migrating mesoderm for proper left-right patterning and cardiac development. In contrast, Zic3 is not required in heart progenitors or the cardiac compartment. In addition, the data demonstrate abnormal node morphogenesis in Zic3 null mice and identify similar node dysplasia when Zic3 was specifically deleted from the migrating mesoderm and primitive streak. These results define the temporal and spatial requirements for Zic3 in node morphogenesis, left-right patterning and cardiac development and suggest the possibility that a requirement for Zic3 in node ultrastructure underlies its role in heterotaxy and laterality disorders.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Coração/embriologia , Proteínas de Homeodomínio/biossíntese , Organogênese/fisiologia , Fatores de Transcrição/biossíntese , Animais , Dextrocardia/embriologia , Dextrocardia/genética , Dextrocardia/patologia , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Síndrome de Heterotaxia/embriologia , Síndrome de Heterotaxia/genética , Síndrome de Heterotaxia/patologia , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Mutantes , Fatores de Transcrição/genéticaRESUMO
AIMS: We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development. METHODS AND RESULTS: Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype. CONCLUSIONS: These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.
Assuntos
Proteínas Contráteis/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Cardiopatias Congênitas/embriologia , Proteínas dos Microfilamentos/metabolismo , Prolapso da Valva Mitral/embriologia , Valva Mitral/embriologia , Mixoma/embriologia , Animais , Proteínas Contráteis/genética , Filaminas , Proteínas de Ligação ao GTP/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Cardiopatias Congênitas/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Prolapso da Valva Mitral/genética , Mixoma/genética , Proteína 2 Glutamina gama-Glutamiltransferase , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transglutaminases/metabolismo , Triptofano Hidroxilase/metabolismoRESUMO
Craniorachischisis is a rare neural tube defect in which both acrania and a complete schisis of the vertebral column are present. Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development and is characterized by a variable group of congenital anomalies that include complex cardiac malformations and situs inversus or situs ambiguous. We report a diamniotic twin pregnancy with two malformed fetuses affected one by craniorachischisis and the other by heterotaxya with paired right-sided viscera, asplenia, and complex congenital heart disease. The occurrence of severe congenital anomalies in both members of the twin pair implies a strong influence of genetic factors. At present, the genetic basis determining the different phenotypes observed in our twins is unknown. Our case with the simultaneous presence of both midline and laterality defects in twins supports the hypothesis that the midline plays a critical role in establishing left-right asymmetry in the body and that a mutation in a gene responsible for both heterotaxy and midline defects may be strongly supposed.
Assuntos
Anormalidades Múltiplas , Cardiopatias Congênitas/embriologia , Defeitos do Tubo Neural/embriologia , Aborto Induzido , Dextrocardia/diagnóstico por imagem , Dextrocardia/embriologia , Dextrocardia/genética , Feminino , Morte Fetal , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Idade Gestacional , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia , Humanos , Defeitos do Tubo Neural/diagnóstico por imagem , Defeitos do Tubo Neural/genética , Fenótipo , Gravidez , Situs Inversus/diagnóstico por imagem , Situs Inversus/embriologia , Situs Inversus/genética , Ultrassonografia Pré-NatalRESUMO
El objetivo del presente trabajo es realizar la selección de sexo de espermatozoides portadores del cromosoma sexual femenino, para lograr el embarazo y nacimiento de una niña. Paciente de 36 años, III gesta, dos embarazos simples y en gemelar, acude con su esposo a sonsultar por deseos de tener una hija. Se seleccionaron los espermatozoides portadores del cromosoma X y fueron teñidos con bisbenzimida y seleccionados por citometría de flujo con tecnología Microsort. La fracción enriquecida fue congelada. Se realizó a la paciente una inducción de la ovulación con agonista de GnRH y FSH. Se realizó la inyección intracitoplasmática de espermatozoides (ICSI) con los espermatozoides sexados a 9 ovocitos maduros. Se transfirieron dos embriones de 8 células. Se confirmó el embarazo y el sexo femenino diagnosticado por US y amniocentesis, con el nacimiento de una niña normal. Esta es la primera vez, que se aplica con éxito la selección de sexo de espermatozoides en Venezuela, lo que abre caminos para lograr tener un hijo del sexo deseado.
Assuntos
Humanos , Feminino , Criança , Citometria de Fluxo/métodos , Espermatozoides/transplante , Injeções de Esperma Intracitoplásmicas/métodos , Pré-Seleção do Sexo , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Ginecologia , ObstetríciaRESUMO
Neural tube defects, mostly believed to result from closure defects of the neural tube during embryonic development, are frequently observed congenital malformations in humans. Since the etiology of these defects is not well understood yet, many animal models for neural tube defects, either arising from spontaneous mutations or generated by gene targeting, are being studied. The Bent tail mouse is a model for X-linked neural tube defects. This mutant has a characteristic short and kinked tail. Exencephaly occurs in Bent tail embryos with a frequency of 11-16%. Laterality defects also belong to the phenotypic spectrum. In this study, we analyzed the embryonic phenotype in further detail using scanning electron microscopy during the stages of neurulation. We observed a number of defects in both wild type and Bent tail embryos, including a kinked neural tube, tight amnion, delay in axial rotation and even malrotation. The severity or frequency of most defects, the delay in axial rotation excluded, was significantly higher in Bent tail embryos compared to wild type embryos. Other abnormalities were seen in Bent tail embryos only. These defects were related to anterior and posterior neural tube closure and resulted in exencephaly and a closure delay of the posterior neuropore, respectively. The exencephalic phenotype was further analyzed by light microscopy in ED14 embryos, showing disorganization and overgrowth in the mesencephalon and rhombencephalon. In conclusion, the anterior and posterior neural tube closure defects in the Bent tail are strictly linked to the genetic defect in this mouse. Other phenotypic features described in this study also occur in the wild type genetic background of the Bent tail strain. Apparently, the genetic background contains elements conducive to these developmental abnormalities.
Assuntos
Sistema Nervoso Central/embriologia , Modelos Animais de Doenças , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Defeitos do Tubo Neural/embriologia , Animais , Encéfalo/anormalidades , Encéfalo/embriologia , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/metabolismo , Feminino , Genótipo , Proteínas de Homeodomínio/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Mutantes Neurológicos , Defeitos do Tubo Neural/genética , Fenótipo , Gravidez , Cauda/anormalidades , Cauda/embriologia , Fatores de Transcrição/genéticaRESUMO
OBJECTIVES: Prenatal identification of the different dentition morphotypes, which exist in the lower molar region of tabby (Ta) adult mice, and investigation of their origin. The mouse Ta syndrome and its counterpart anhidrotic (hypohidrotic) ectodermal dysplasia (EDA) in human are characterized by absence or hypoplasia of sweat glands, hair and teeth. DESIGN: Analysis of tooth morphogenesis using serial histological sections and 3D computer aided reconstructions of the dental epithelium in the cheek region of the mandible. SETTING AND SAMPLE POPULATION: Institute of Experimental Medicine, Academy of Sciences, Prague. Heads of 75 Ta homozygous and hemizygous mice and 40 wild type (WT) control mice aged from embryonic day (ED) 14.0-20.5 (newborns), harvested during 1995-2001. OUTCOME MEASURE: Prenatal identification of five distinct morphotypes of Ta dentition on the basis of differences in tooth number, size, shape, position and developmental stage and of the morphology of the enamel knot in the most mesial tooth primordium. RESULTS: The mesio-distal length of the dental epithelium was similar in the lower cheek region in Ta and WT mice. In Ta embryos, there was altered the mesio-distal segmentation of the dental epithelium giving rise to the individual tooth primordia. Prenatally, two basic morphotypes I and II and their particular subtypes (Ia, Ib, Ic, and IIa, IIb, respectively) of the developing dentition were identified from day 15.5. The incidence of the distinct morphotypes in the present sample did not differ from postnatal data. The proportion of the morphotype I and II was dependent on mother genotype. CONCLUSION: The different dentition morphotypes in Ta mice originate from a defect in the mesio-distal segmentation of the dental epithelium in mouse embryos. This defect presumably leads to variable positions of tooth boundaries that do not correspond to those of the WT molars. One tooth primordium of Ta mice might be derived from adjacent parts of two molar primordia in WT mice.