RESUMO
Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Homeodomínio/genética , Deformidades Congênitas dos Membros/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/metabolismo , Animais , Doenças do Desenvolvimento Ósseo/embriologia , Doenças do Desenvolvimento Ósseo/metabolismo , Modelos Animais de Doenças , Feminino , Deleção de Genes , Proteínas de Homeodomínio/metabolismo , Humanos , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/metabolismo , Mutação com Perda de Função , Masculino , Camundongos Endogâmicos C57BL , Família Multigênica , Fatores de Transcrição/metabolismoRESUMO
OBJECTIVE: We present partial monosomy 8p (8p23.2âpter) and partial trisomy 15q (15q21.2âqter) and incidental detection of a familial chromosome translocation of paternal origin in a pregnancy associated with increased nuchal translucency (NT) and an abnormal maternal serum screening result. CASE REPORT: A 29-year-old primigravid woman underwent chorionic villus sampling (CVS) at 13 weeks of gestation because of an increased NT thickness of 3.2 mm at 12 weeks of gestation and an abnormal maternal serum screening for Down syndrome result with a calculated risk of 1/29. Her husband was 33 years old, and there was no family history of congenital malformations. CVS revealed a derived chromosome 8 or der(8). Cytogenetic analysis of the parents revealed a karyotype of 46,XY,t(8;15)(p21.3;q13) in the father and a karyotype of 46,XX in the mother. The CVS result was 46,XY,der(8)t(8;15)(p21.3;q13)pat. The woman requested for amniocentesis at 16 weeks of gestation. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a result of arr 8p23.3p23.2 (191,530-2,625,470) × 1.0, arr 15q21.2q26.3 (50,903,432-102,338,129) × 3.0 with a 2.434-Mb deletion of 8p23.3-p23.2 including DLGAP2, CLN8 and ARHGEF10, and a 51.435-Mb duplication of 15q21.2-q26.3 including CYP19A1 and IGF1R. Conventional cytogenetic analysis of cultured amniocytes revealed the result of 46,XY,der(8) t(8;15)(p23.2;q21.2)pat in the fetus. The pregnancy was subsequently terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism. CONCLUSION: Maternal serum screening and NT screening may incidentally detect familial unbalanced reciprocal translocations, and aCGH analysis is useful for a precise determination of the breakpoints of the translocation and the involvement of the related genes under such a circumstance.
Assuntos
Anormalidades Múltiplas/diagnóstico , Translocação Genética/genética , Trissomia/diagnóstico , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Aborto Eugênico , Adulto , Amostra da Vilosidade Coriônica , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 8/genética , Hibridização Genômica Comparativa , Análise Citogenética , Feminino , Humanos , Achados Incidentais , Masculino , Testes para Triagem do Soro Materno , Medição da Translucência Nucal , Herança Paterna/genética , Gravidez , Trissomia/genéticaRESUMO
OBJECTIVE: We present a novel homozygous splice site mutation in the PIGN gene identified by whole exome sequencing and explored the genotype-phenotype correlation. CASE REPORT: A healthy 32-year-old woman underwent an ultrasound at 13 + 5 weeks of gestation. The ultrasound revealed multiple anomalies again including cystic hygroma, omphalocele and a ventricular septal defect. The pregnancy was subsequently terminated, and whole exome sequencing revealed a novel homozygous splice site mutation in the PIGN gene c.963 G > A (p.Gln321Gln). The same variant was also detected by pedigree-based Sanger sequencing in both parents as heterozygous, while they had normal karyotypes. CONCLUSION: Our case report enhances the phenotype-genotype correlation associated with homozygous loss of function mutations in the PIGN gene.
Assuntos
Anormalidades Múltiplas/diagnóstico , DNA Recombinante/genética , Mutação com Perda de Função/genética , Fosfotransferases/genética , Ultrassonografia Pré-Natal , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Aborto Eugênico , Adulto , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Linhagem , Gravidez , Sequenciamento do ExomaRESUMO
OBJECTIVES: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Vermis Cerebelar/anormalidades , Cerebelo/anormalidades , Anormalidades do Olho/diagnóstico por imagem , Doenças Renais Císticas/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Neuroimagem , Diagnóstico Pré-Natal/métodos , Retina/anormalidades , Rombencéfalo/anormalidades , Anormalidades Múltiplas/embriologia , Adulto , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/embriologia , Cerebelo/diagnóstico por imagem , Cerebelo/embriologia , Anormalidades do Olho/embriologia , Feminino , Idade Gestacional , Humanos , Doenças Renais Císticas/embriologia , Imageamento por Ressonância Magnética , Imagem Multimodal , Malformações do Sistema Nervoso/embriologia , Gravidez , Retina/diagnóstico por imagem , Retina/embriologia , Estudos Retrospectivos , Rombencéfalo/diagnóstico por imagem , Rombencéfalo/embriologia , Índice de Gravidade de Doença , Ultrassonografia Pré-NatalRESUMO
Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms. The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway. We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids.
Assuntos
Encéfalo/anormalidades , Cílios/genética , Ciliopatias/embriologia , Anormalidades Craniofaciais/embriologia , Proteínas Hedgehog/fisiologia , Prosencéfalo/embriologia , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Encéfalo/embriologia , Cerebelo/anormalidades , Cerebelo/embriologia , Transtornos da Motilidade Ciliar/embriologia , Transtornos da Motilidade Ciliar/genética , Ciliopatias/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Encefalocele/embriologia , Encefalocele/genética , Anormalidades do Olho/embriologia , Anormalidades do Olho/genética , Regulação da Expressão Gênica no Desenvolvimento , Holoprosencefalia/embriologia , Holoprosencefalia/genética , Humanos , Doenças Renais Císticas/embriologia , Doenças Renais Císticas/genética , Doenças Renais Policísticas/embriologia , Doenças Renais Policísticas/genética , Retina/anormalidades , Retina/embriologia , Retinose Pigmentar/embriologia , Retinose Pigmentar/genética , Transdução de Sinais , Proteína GLI1 em Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/genéticaRESUMO
Pathogenic heterozygous variants in PIEZO2 typically cause distal arthrogryposis type 5 (DA5) and the closely related Gordon syndrome (GS). Only one case of PIEZO2-related Marden-Walker syndrome (MWS) has been reported to date. We report the phenotypic features of a Saudi female patient with features consistent with MWS in whom we identified a novel de novo likely pathogenic variant in PIEZO2. Our case lends support to the link between PIEZO2 and MWS.
Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Blefarofimose/genética , Doenças do Tecido Conjuntivo/genética , Contratura/genética , Canais Iônicos/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Adulto , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Aracnodactilia/diagnóstico por imagem , Aracnodactilia/embriologia , Blefarofimose/diagnóstico por imagem , Blefarofimose/embriologia , Criança , Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/embriologia , Pé Torto Equinovaro/genética , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/embriologia , Consanguinidade , Contratura/diagnóstico por imagem , Contratura/embriologia , Síndrome de Dandy-Walker/diagnóstico por imagem , Síndrome de Dandy-Walker/embriologia , Síndrome de Dandy-Walker/genética , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Canais Iônicos/deficiência , Masculino , Linhagem , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Ultrassonografia Pré-NatalRESUMO
The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.
Assuntos
Anormalidades Congênitas/embriologia , Neoplasias/embriologia , Crista Neural/patologia , Síndrome da Deleção 22q11/diagnóstico por imagem , Síndrome da Deleção 22q11/embriologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Síndrome CHARGE/diagnóstico por imagem , Síndrome CHARGE/embriologia , Linhagem da Célula , Movimento Celular , Anormalidades Congênitas/diagnóstico por imagem , Doenças em Gêmeos , Desenvolvimento Embrionário , Síndrome de Goldenhar/diagnóstico por imagem , Síndrome de Goldenhar/embriologia , Doença de Hirschsprung/diagnóstico por imagem , Doença de Hirschsprung/embriologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Disostose Mandibulofacial/diagnóstico por imagem , Disostose Mandibulofacial/embriologia , Neoplasias/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/embriologia , Crista Neural/embriologia , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/embriologia , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/embriologia , Nevo Pigmentado/diagnóstico por imagem , Nevo Pigmentado/embriologia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/embriologia , Tomografia Computadorizada por Raios XRESUMO
El síndrome lumbocostovertebral se define por la presencia de hernia lumbar, hemivértebras y anomalías costales. El objetivo de este trabajo es describir el primer caso reportado en Argentina. El paciente fue comunicado a la Red Nacional de Anomalías Congénitas de Argentina. Se describe el cuadro clínico, los diagnósticos diferenciales y los posibles mecanismos patogénicos involucrados. Se sugiere que esta entidad sea considerada como una asociación. La hernia lumbar en un recién nacido es un hallazgo infrecuente y debe pesquisarse la presencia de otras anomalías asociadas.
Lumbocostovertebral syndrome is defined by the presence of lumbar hernia, hemivertebrae and costal anomalies. Our aim was to describe the first case reported in Argentina. The patient was reported to the National Registry of Congenital Anomalies of Argentina. The clinical picture, differential diagnoses and possible pathogenic mechanisms involved are described. We suggest considering this as a lumbocostovertebral association. Lumbar hernia in a newborn is an infrequent finding and other associated anomalies should be evaluated.
Assuntos
Humanos , Masculino , Recém-Nascido , Costelas/anormalidades , Escoliose/congênito , Hérnia/congênito , Costelas/diagnóstico por imagem , Escoliose/diagnóstico por imagem , Coluna Vertebral/anormalidades , Anormalidades Múltiplas/embriologiaRESUMO
Omphaloceles are ventral abdominal wall defects that are associated with significant other anomalies in up to 80% of cases in some descriptions. Of these abnormalities, Cardiac defects are some of the more common ones, and have the most substantial impact on outcomes and survival. In cases with a severe congenital heart defect (CHD), the omphalocele management changes significantly. This article addresses the common defects seen, and their management issues.
Assuntos
Anormalidades Múltiplas , Cardiopatias Congênitas , Hérnia Umbilical , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/cirurgia , Hérnia Umbilical/diagnóstico , Hérnia Umbilical/embriologia , Hérnia Umbilical/cirurgia , Herniorrafia/métodos , Humanos , Recém-NascidoRESUMO
Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.
Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transporte Vesicular , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologiaRESUMO
PURPOSE: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by impaired epithelial homeostasis. Recently, amniotic fluid stem cells (AFSCs) have been shown to promote growth in hypoplastic lungs of rat fetuses with CDH. Herein, we investigated whether CDH hypoplastic lungs mount an endoplasmic reticulum (ER) stress response and whether AFSCs could re-establish pulmonary epithelial homeostasis. METHODS: Primary epithelial cells were isolated from fetal rat lungs at E14.5 from control and nitrofen-exposed dams at E9.5. Nitrofen-exposed epithelial cells were grown in medium alone or co-cultured with AFSCs. Epithelial cell cultures were compared for apoptosis (TUNEL), cytotoxicity (LIVE/DEAD assay), proliferation (5'EdU), and ER stress (CHOP, Bcl-2) using one-way ANOVA (Dunn's post-test). RESULTS: Compared to control, nitrofen-exposed epithelial cells had increased cytotoxicity and apoptosis, reduced proliferation, and activated ER stress. AFSCs restored apoptosis, proliferation, and ER stress back to control levels, and significantly reduced cytotoxicity. CONCLUSIONS: This study shows for the first time that ER stress-induced apoptosis is activated in the pulmonary epithelium of hypoplastic lungs from fetuses with CDH. AFSC treatment restores epithelial cellular homeostasis by attenuating the ER stress response and apoptosis, by increasing proliferation and migration ability, and by reducing cytotoxicity.
Assuntos
Anormalidades Múltiplas/metabolismo , Líquido Amniótico/citologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Estresse do Retículo Endoplasmático , Hérnias Diafragmáticas Congênitas/metabolismo , Pneumopatias/metabolismo , Pulmão/anormalidades , Prenhez , Células-Tronco/citologia , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/terapia , Animais , Apoptose , Modelos Animais de Doenças , Feminino , Hérnias Diafragmáticas Congênitas/embriologia , Hérnias Diafragmáticas Congênitas/terapia , Pulmão/embriologia , Pulmão/metabolismo , Pneumopatias/embriologia , Pneumopatias/terapia , Éteres Fenílicos/toxicidade , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: To study pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH), investigators have been employing a fetal rat model based on nitrofen administration to dams. Herein, we aimed to: (1) investigate the validity of the model, and (2) synthesize the main biological pathways implicated in the development of PH associated with CDH. METHODS: Using a defined strategy, we conducted a systematic review of the literature searching for studies reporting the incidence of CDH or factors involved in PH development. We also searched for PH factor interactions, relevance to lung development and to human PH. RESULTS: Of 335 full-text articles, 116 reported the incidence of CDH after nitrofen exposure or dysregulated factors in the lungs of nitrofen-exposed rat fetuses. CDH incidence: 54% (27-85%) fetuses developed a diaphragmatic defect, whereas the whole litter had PH in varying degrees. Downregulated signaling pathways included FGF/FGFR, BMP/BMPR, Sonic Hedgehog and retinoid acid signaling pathway, resulting in a delay in early epithelial differentiation, immature distal epithelium and dysfunctional mesenchyme. CONCLUSIONS: The nitrofen model effectively reproduces PH as it disrupts pathways that are critical for lung branching morphogenesis and alveolar differentiation. The low CDH rate confirms that PH is an associated phenomenon rather than the result of mechanical compression alone.
Assuntos
Anormalidades Múltiplas/metabolismo , Regulação para Baixo , Hérnias Diafragmáticas Congênitas/metabolismo , Pneumopatias/metabolismo , Pulmão/anormalidades , Pulmão/embriologia , Prenhez , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/embriologia , Animais , Modelos Animais de Doenças , Feminino , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/embriologia , Pulmão/metabolismo , Pneumopatias/induzido quimicamente , Pneumopatias/embriologia , Mesoderma/metabolismo , Organogênese/efeitos dos fármacos , Éteres Fenílicos/toxicidade , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
In mammalian cells TPP1, encoded by the Acd gene, is a key component of the shelterin complex, which is required for telomere length maintenance and telomere protection. In mice, a hypomorphic mutation in Acd causes the adrenocortical dysplasia (acd) phenotype, which includes limb and body axis anomalies, and perinatal lethality. p53 deficiency partially rescues limb and body axis anomalies in acd mutant embryos, but not perinatal lethality, implicating p53-independent mechanisms in the acd phenotype. Loss of function of most shelterin proteins results in early embryonic lethality. Thus, study of the hypomorphic acd allele provides a unique opportunity to understand telomere dysfunction at an organismal level. The aim of this study was to identify transcriptome alterations in acd mutant and acd, p53 double mutant embryos to understand the p53-dependent and -independent factors that contribute to the mutant phenotypes in the context of the whole organism. Genes involved in developmental processes, cell cycle, metabolic pathways, tight junctions, axon guidance and signaling pathways were regulated by p53-driven mechanisms in acd mutant embryos, while genes functioning in immune response, and RNA processing were altered independently of p53 in acd, p53 double mutant embryos. To our best of knowledge, this is the first study revealing detailed transcriptomic alterations, reflecting novel p53-dependent and -independent pathways contributing to the acd phenotype. Our data confirm the importance of cell cycle and DNA repair pathways, and suggest novel links between telomere dysfunction and immune system regulation and the splicing machinery. Given the broad applicability of telomere maintenance in growth, development, and genome stability, our data will also provide a rich resource for others studying telomere maintenance and DNA damage responses in mammalian model systems.
Assuntos
Anormalidades Múltiplas/genética , Córtex Suprarrenal/anormalidades , Perfilação da Expressão Gênica/métodos , Proteínas de Ligação a Telômeros/genética , Proteína Supressora de Tumor p53/genética , Anormalidades Múltiplas/embriologia , Córtex Suprarrenal/embriologia , Animais , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Instabilidade Genômica , Camundongos , Mutação , Fenótipo , Complexo Shelterina , Transdução de SinaisRESUMO
AIM: According to the so far published literature, only one case of endometrial cancer in a patient with unicornuate uterus has been reported. This is a case report study, presenting a rare case of complex atypical endometrial hyperplasia in a woman with unicornuate uterus and multiple genitourinary anomalies. CASE REPORT: A 43-year old G1P1 woman presented with episodes of menometrorrhagia and anemia. She had previous surgical history of laparoscopy due to infertility, in which she was diagnosed with unicornuate uterus with a rudimentary left uterine horn and ipsilateral ectopic ovary in the anatomic place of the left kidney. Dilatation and curettage was performed. Histology showed complex atypical endometrial hyperplasia. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, in an extremely interesting operation due to the multiple genitourinary anomalies. The uterus with a 6-centimeter uterine myoma and the adnexae were removed en block. Great effort was put into dissecting the left fallopian tube which arised from the cervix and via the rudimentary horn led to the left ectopic ovary that was located at the left kidneys' anatomic space. The patient recovered well and final histology was negative for malignancy. DISCUSSION: All necessary imaging examinations have to be scheduled prior to surgical intervention in order to give valuable anatomic information in cases of women diagnosed with Mullerian abnormalities.
Assuntos
Anormalidades Múltiplas/cirurgia , Coristoma/complicações , Endométrio/patologia , Histerectomia/métodos , Rim , Mioma/cirurgia , Ovário , Salpingo-Ooforectomia/métodos , Neoplasias Uterinas/cirurgia , Útero/anormalidades , Anormalidades Múltiplas/embriologia , Adulto , Colo do Útero/anormalidades , Tubas Uterinas/anormalidades , Feminino , Fertilização in vitro , Humanos , Hiperplasia , Infertilidade Feminina/etiologia , Infertilidade Feminina/terapia , Menorragia/etiologia , Metrorragia/etiologia , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/embriologia , Mioma/patologia , Pelve , Neoplasias Uterinas/patologiaRESUMO
BACKGROUND: Phalluses present inside the extrophied bladder of cloacal exstrophy (CE) newborns have been sporadically reported in the literature; this clinical entity has largely unknown origins and may represent an extremely rare anomaly of CE. OBJECTIVE: Along with nearly doubling the number of reported intravesical phalluses in the literature, this study aims to outline the common anatomic features and discuss the implications for theories of CE embryogenesis. STUDY DESIGN: The authors retrospectively identified patients with CE and a potential intravesical phallus between 1997 and 2017 at two high-volume centers. Information was obtained about karyotype, age at closure, neurologic and renal anomalies, diastasis, phallus anatomy, and phallus biopsy pathology. RESULTS: Six genotypic males met the inclusion criteria. Five of six had a diastasis greater than 6 cm. Four of six had paired corporal bodies in the intravesical phallus, one had a single corporal body, and one had a corporal-like structure. Five of six patients had a phallus located midline in the caudal aspect of the bladder; one was located midline in the bladder dome. Phallic biopsies were obtained in three of six patients. Two showed glanular and corporal tissue while the other showed vascular proliferation morphologically similar to that of erectile tissue. DISCUSSION: Previous reports suggested that a superior vesicle fissure configuration, fusion of the corporal bodies, and fused bladder plates were common findings with an intravesical phallus. With the addition of new cases, the only consistent variable between patients is a phallus located anywhere along the bladder plate that can comprise a corporal-like structure, a single corporal body, or fused corporal bodies. These findings have implications for several embryologic theories. Although this is a retrospective review with a limited number of patients, the condition is exceedingly infrequent making it only observable retrospectively over decades at high volume centers. CONCLUSIONS: The study outlined common anatomic features of the intravesical phallus in cloacal exstrophy and discussed the subsequent embryologic implications. In cloacal exstrophy newborns with presumed aphallia, meticulous inspection of the bladder plate and biopsy of any potential phallic structures can prevent resection of phallic tissue.
Assuntos
Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/cirurgia , Extrofia Vesical/embriologia , Extrofia Vesical/cirurgia , Pênis/anormalidades , Pênis/cirurgia , Bexiga Urinária/anormalidades , Bexiga Urinária/cirurgia , Extrofia Vesical/complicações , Pré-Escolar , Humanos , Lactente , Masculino , Pênis/embriologia , Estudos Retrospectivos , Bexiga Urinária/embriologia , Procedimentos Cirúrgicos Urológicos Masculinos/métodosRESUMO
Body-stalk anomaly is a sporadic and rare maldevelopment disorder characterised by large abdominal wall defect, spinal deformity and rudimentary umbilical cord. It is considered a lethal condition as there are only few reports of survival but there was at least one case of long-term survival after neonatal surgery.Differential diagnosis includes isolated omphalocele or gastroschisis, short umbilical cord, amniotic band, limb body-wall complex and other polymalformative syndromes.There are few reports about the expectant prenatal management of the body stalk anomaly as the majority of prenatal diagnosed cases undergo early elective termination. Twin pregnancies discordant for the anomaly represent a challenge to prenatal management as a healthy fetus should also be considered.We describe a case of dichorionic-diamniotic twins discordant for body stalk anomaly which underwent selective feticide of the affected fetus late in pregnancy, in accordance with parents' decision focused on the neonatal well-being of the unaffected twin.
Assuntos
Parede Abdominal/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Redução de Gravidez Multifetal , Diagnóstico Pré-Natal , Coluna Vertebral/anormalidades , Cordão Umbilical/anormalidades , Parede Abdominal/diagnóstico por imagem , Parede Abdominal/embriologia , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adulto , Cordocentese , Feminino , Aconselhamento Genético , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Gravidez de Gêmeos , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/embriologia , Cordão Umbilical/diagnóstico por imagem , Cordão Umbilical/embriologiaRESUMO
AIM: The high incidence of cardiac malformations in humans and animal models with congenital diaphragmatic hernia (CDH) is well known. The hypoplasia of left heart is common among fetuses with CDH and has been identified as a poor prognostic factor. However, the precise mechanisms underlying cardiac maldevelopment in CDH are not fully understood. Ras-related C3 botulinum toxin substrate 1 (Rac1) plays a key role in cardiomyocyte polarity and embryonic heart development. Deficiency of Rac1 is reported to impair elongation and cytoskeletal organization of cardiomyocytes, resulting in congenital cardiac defects. We designed this study to test the hypothesis that Rac1 expression is downregulated in the developing hearts of rats with nitrofen-induced CDH. MATERIALS AND METHODS: Following ethical approval (REC1103), time-pregnant Sprague Dawley rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D18 and D21 and divided into CDH and control (CTRL) (n = 6 for each group and time point). Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and confocal-immunofluorescence microscopy were performed to detect cardiac gene and protein expression of Rac1. MAIN RESULTS: qRT-PCR and Western blot analysis revealed that Rac1 expression was significantly decreased in the CDH group compared with controls (p < 0.05). Confocal-immunofluorescence microscopy revealed that Rac1 cardiac expression was markedly decreased in the CDH group compared with controls. CONCLUSION: Decreased cardiac Rac1 expression in the nitrofen-induced CDH suggests that Rac1 deficiency during morphogenesis may impair structural cardiac remodeling, resulting in congenital cardiac defects.
Assuntos
Anormalidades Múltiplas/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/metabolismo , Hérnias Diafragmáticas Congênitas/metabolismo , Miocárdio/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Animais , Biomarcadores/metabolismo , Western Blotting , Imunofluorescência , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/embriologia , Hérnias Diafragmáticas Congênitas/genética , Microscopia Confocal , Éteres Fenílicos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo RealRESUMO
INTRODUCTION: Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major cause of neonatal mortality in newborns with congenital diaphragmatic hernia (CDH). Integrin-mediated cell-matrix interactions play an essential role in the fetal lung mesenchyme by stimulating branching morphogenesis. Mice lacking integrin subunits α3 (Itga3) and α6 (Itga6) exhibit severe PH. Furthermore, Itga8-knockout mice show defective airway branching, suggesting that Itga3, Itga6, and Itga8 are crucial for fetal lung development. We hypothesized that expression of Itga3, Itga6, and Itga8 is decreased in the branching airway mesenchyme of hypoplastic rat lungs in the nitrofen-induced CDH model. MATERIALS AND METHODS: Time-mated rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D15, D18, and D21, and dissected lungs were divided into control and nitrofen-exposed specimens (n = 12 per time-point and group, respectively). Pulmonary gene expression of Itga3, Itga6, and Itga8 was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double-staining for Itga3, Itga6, and Itga8 was combined with the mesenchymal marker Fgf10 to evaluate protein expression and localization in branching airway tissue. RESULTS: Relative mRNA expression of Itga3, Itga6, and Itga8 was significantly decreased in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Itga3, Itga6, and Itga8 mainly in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. CONCLUSION: Decreased expression of Itga3, Itga6, and Itga8 in the pulmonary mesenchyme may lead to disruptions in airway branching morphogenesis, thus contributing to PH in the nitrofen-induced CDH model.
Assuntos
Anormalidades Múltiplas/metabolismo , Hérnias Diafragmáticas Congênitas/complicações , Cadeias alfa de Integrinas/metabolismo , Integrina alfa3/metabolismo , Integrina alfa6/metabolismo , Pneumopatias/metabolismo , Pulmão/anormalidades , Pulmão/metabolismo , Mesoderma/metabolismo , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/embriologia , Animais , Biomarcadores/metabolismo , Imunofluorescência , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/embriologia , Pulmão/embriologia , Pneumopatias/induzido quimicamente , Pneumopatias/embriologia , Mesoderma/embriologia , Microscopia Confocal , Éteres Fenílicos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Congenital portosystemic venous shunts are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation and have been divided into extra- and intrahepatic shunts. They occur during liver and systemic venous vascular embryogenesis and are associated with other congenital abnormalities. They carry a higher risk of benign and malignant liver tumors and, if left untreated, can result in significant medical complications including systemic encephalopathy and pulmonary hypertension. CONCLUSION: This article reviews the various types of congenital portosystemic shunts and their anatomy, pathogenesis, symptomatology, and timing and options of treatment. What is Known: ⢠The natural history and basic management of this rare congenital anomaly are presented. What is New: ⢠This paper is a comprehensive review; highlights important topics in pathogenesis, clinical symptomatology, and treatment options; and proposes an algorithm in the management of congenital portosystemic shunt disease in order to provide a clear idea to a pediatrician. An effort has been made to emphasize the indications for treatment in the children population and link to the adult group by discussing the consequences of lack of treatment or delayed diagnosis.
Assuntos
Veia Porta/anormalidades , Malformações Vasculares , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/terapia , Procedimentos Endovasculares , Hepatectomia , Humanos , Ligadura , Transplante de Fígado , Veia Porta/embriologia , Malformações Vasculares/diagnóstico , Malformações Vasculares/embriologia , Malformações Vasculares/terapiaRESUMO
A number of textbooks, review articles, and case reports highlight the potential comorbidity of choanal atresia in craniosynostosis patients. However, the lack of a precise definition of choanal atresia within the current craniosynostosis literature and widely varying methods of detection and diagnosis have produced uncertainty regarding the true coincidence of these conditions. The authors review the anatomy and embryologic basis of the human choanae, provide an overview of choanal atresia, and analyze the available literature that links choanal atresia and craniosynostosis. Review of over 50 case reports that describe patients diagnosed with both conditions reveals inconsistent descriptions of choanal atresia and limited use of definitive diagnostic methodologies. The authors further present preliminary analysis of three-dimensional medical head computed tomographic scans of children diagnosed with craniosynostosis syndromes (e.g., Apert, Pfeiffer, Muenke, and Crouzon) and typically developing children and, although finding no evidence of choanal atresia, report the potentially reduced nasal airway volumes in children diagnosed with Apert and Pfeiffer syndromes. A recent study of the Fgfr2c Crouzon/Pfeiffer syndrome mouse model similarly found a significant reduction in nasal airway volumes in littermates carrying this FGFR2 mutation relative to unaffected littermates, without detection of choanal atresia. The significant correlation between specific craniosynostosis syndromes and reduced nasal airway volume in mouse models for craniosynostosis and human pediatric patients indicates comorbidity of choanal and nasopharyngeal dysmorphologies and craniosynostosis conditions. Genetic, developmental, and epidemiologic sources of these interactions are areas particularly worthy of further research.