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2.
Am J Med Genet A ; 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30328679

RESUMO

Trisomy 13 or Patau syndrome (PS) is a well-known aneuploidy characterized by a polymalformative syndrome. We described a large series of fetuses with PS and compared them with cases described in the literature, most of which were live-born. In all, 42 fetuses, aged from 14 to 41 gestational weeks (GW), were examined. The main defects observed were similar to those described in live-born patients: congenital heart defects (76%), holoprosencephaly spectrum anomalies including arhinencephaly and hypotelorism (74%), urinary tract anomalies (71%), ear anomalies (69%), postaxial polydactyly (67%), anogenital anomalies (60%), anophthalmos, and/or microphthalmos (53%), brachycephaly (45%), and oro-facial clefts (45%). A duplication or triplication of at least one distal phalanx of the thumb or hallux was present in 38% of fetuses. This sign has only been reported previously in one patient in the literature. Fetal examination in trisomy 13, is thus, useful to complete the phenotype or to orient diagnosis toward trisomy 13 in the absence of cytogenetic analysis.

3.
Mol Syndromol ; 9(4): 190-196, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30140196

RESUMO

EFEMP2 mutations are known to be responsible for autosomal recessive cutis laxa type 1B (ARCL1B), a rare multisystem disease affecting skin, skeleton, and vascular structures. We report 2 additional related cases of ARCL1B of particular severity leading to termination of pregnancy. Cardinal signs of this connective tissue disease were already seen during the second trimester of pregnancy, then confirmed and clarified at autopsy. Anomalies included cutis laxa, arachnodactyly, clubfoot, wormian bones, moderate bowing of long bones with slender bone trabeculae, rib fractures, undermuscularized diaphragm, hiatal hernia, and arterial tortuosity with thick vascular walls and disorganized elastic fibers. Sequencing of the EFEMP2 gene revealed a novel homozygous nonsense mutation: c.639C>A (p.Cys213*). We performed a thorough histological analysis and discuss differential diagnoses, genotype-phenotype correlations, and the challenge of prenatal diagnosis of this disease.

4.
Cereb Cortex ; 28(7): 2458-2478, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29722804

RESUMO

Neuropathological conditions might affect adult granulogenesis in the adult human dentate gyrus. However, radial glial cells (RGCs) have not been well characterized during human development and aging. We have previously described progenitor and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus from embryonic life until mid-gestation. Here, we describe RGC subtypes in the hippocampus from 13 gestational weeks (GW) to mid-gestation and characterize their evolution and the dynamics of neurogenesis from mid-gestation to adulthood in normal and Alzheimer's disease (AD) subjects. In the pyramidal ventricular zone (VZ), RGC density declined with neurogenesis from mid-gestation until the perinatal period. In the dentate area, morphologic and antigenic differences among RGCs were observed from early ages of development to adulthood. Density and proliferative capacity of dentate RGCs as well as neurogenesis were strongly reduced during childhood until 5 years, few DCX+ cells are seen in adults. The dentate gyrus of both control and AD individuals showed Nestin+ and/or GFAPδ+ cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present in the human hippocampus from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems negligible in the adult.

5.
Am J Med Genet A ; 173(2): 479-486, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27623003

RESUMO

Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.


Assuntos
Hipoplasia Dérmica Focal/diagnóstico , Hipoplasia Dérmica Focal/genética , Aborto Induzido , Aciltransferases/genética , Autopsia , Análise Mutacional de DNA , Feminino , Feto/anormalidades , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Mutação , Fenótipo , Diagnóstico Pré-Natal , Radiografia , Ultrassonografia Pré-Natal
6.
Cereb Cortex ; 27(1): 358-372, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26443441

RESUMO

The molecular mechanisms that orchestrate the development of the human dentate gyrus are not known. In this study, we characterized the formation of human dentate and fimbrial progenitors and postmitotic neurons from 9 gestational weeks (GW9) to GW25. PAX6+ progenitor cells remained proliferative until GW16 in the dentate ventricular zone. By GW11, the secondary dentate matrix had developed in the intermediate zone, surrounding the dentate anlage and streaming toward the subpial layer. This secondary matrix contained proliferating PAX6+ and/or TBR2+ progenitors. In parallel, SOX2+ and PAX6+ fimbrial cells were detected approaching the dentate anlage, representing a possible source of extra-dentate progenitors. By GW16, when the granule cell layer could be delineated, a hilar matrix containing PAX6+ and some TBR2+ progenitors had become identifiable. By GW25, when the 2 limbs of the granule cell layer had formed, the secondary dentate matrix was reduced to a pool of progenitors at the fimbrio-dentate junction. Although human dentate development recapitulates key steps previously described in rodents, differences seemed to emerge in neuron layer markers expression. Further studies are necessary to better elucidate their role in dentate formation and connectivity.


Assuntos
Giro Denteado/embriologia , Fórnice/embriologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Biomarcadores/análise , Humanos
7.
Prenat Diagn ; 36(8): 744-51, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27297286

RESUMO

OBJECTIVES: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 ß mutation, their frequency, and genotype/phenotype correlations. METHODS: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists. RESULTS: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%. CONCLUSION: This study underlines the importance of considering hepatocyte nuclear factor-1 ß mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Rim/anormalidades , Pâncreas/anormalidades , Pancreatopatias/congênito , Anormalidades Urogenitais/genética , Autopsia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genética , Anormalidades Congênitas/patologia , Feminino , Genótipo , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Mutação , Pâncreas/diagnóstico por imagem , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/genética , Fenótipo , Gravidez , Ultrassonografia Pré-Natal , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/patologia
8.
Regul Toxicol Pharmacol ; 74: 161-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26627140

RESUMO

Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.


Assuntos
Antibacterianos/toxicidade , Ciprofloxacino/toxicidade , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Articulações/efeitos dos fármacos , Articulações/crescimento & desenvolvimento , Articulações/patologia , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/patologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/patologia , Respiração/efeitos dos fármacos , Medição de Risco , Especificidade da Espécie , Ganho de Peso/efeitos dos fármacos
9.
Eur J Hum Genet ; 24(7): 992-1000, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26626311

RESUMO

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.


Assuntos
Substituição de Aminoácidos , Artrite/genética , Doenças do Colágeno/genética , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Osteocondrodisplasias/genética , Fenótipo , Descolamento Retiniano/genética , Artrite/patologia , Doenças do Colágeno/patologia , Colágeno Tipo II/química , Doenças do Tecido Conjuntivo/patologia , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Osteocondrodisplasias/patologia , Linhagem , Domínios Proteicos , Descolamento Retiniano/patologia
10.
Cereb Cortex ; 26(3): 1255-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25882041

RESUMO

The molecular mechanisms underlying the formation of hippocampus are unknown in humans. To improve our knowledge of molecules that potentially regulate pyramidal neurogenesis and layering in various hippocampal fields, we investigated the expression of progenitor markers and cell fate molecules from gestational week (GW) 9 to GW 20. At GW 9, the progenitor cell compartment of the hippocampal formation mainly consisted of PAX6(+) cells in the ventricular zone. Between GW 9 and 11, a second germinal area, the subventricular zone (SVZ), was formed, as shown by TBR2 labeling. Postmitotic markers (TBR1, CTIP2, SATB2, and CUX1) might reflect the inside-out layering of the plate from GW 11 onwards. TBR1(+) neurons appeared in the deep plate, whereas CTIP2(+), SATB2(+), and CUX1(+) neurons occupied the upper layers. From GW 16, differences in layer segregation were observed between the ammonic and subicular plates. Moreover, an ammonic-to-subicular maturation gradient was observed in germinal/postmitotic areas. Taken together, these findings demonstrate for the first time the presence of an SVZ in the hippocampus of human fetuses and laminar differences in transcription factor expression in the pyramidal layer of the human ammonic and subicular plate, and provide new information to further investigate the connectivity of the hippocampal formation.


Assuntos
Hipocampo/embriologia , Hipocampo/metabolismo , Células-Tronco Neurais/metabolismo , Células Piramidais/metabolismo , Proteínas do Olho/metabolismo , Hipocampo/citologia , Proteínas de Homeodomínio/metabolismo , Imuno-Histoquímica , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Células-Tronco Neurais/citologia , Proteínas Nucleares/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Células Piramidais/citologia , Proteínas Repressoras/metabolismo , Nicho de Células-Tronco/fisiologia , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
11.
Ann Neurol ; 78(3): 387-400, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26018399

RESUMO

OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant expression of the transcription factor DUX4. However, it is still difficult to correlate these genotypes with the phenotypes observed in patients. Because we have recently shown that mice with disrupted Fat1 functions exhibit FSHD-like phenotypes, we have investigated the expression of the human FAT1 gene in FSHD. METHODS: We first analyzed FAT1 expression in FSHD adult muscles and determined whether FAT1 expression was driven by DUX4. We next determined FAT1 expression levels in 64 muscles isolated from 16 control fetuses. These data were further complemented with analysis of Fat1 expression in developing mouse embryos. RESULTS: We demonstrated that FAT1 expression is independent of DUX4. Moreover, we observed that (1) in control fetal human biopsies or in developing mouse embryos, FAT1 is expressed at lower levels in muscles that are affected at early stages of FSHD progression than in muscles that are affected later or are nonaffected; and (2) in adult muscle biopsies, FAT1 expression is lower in FSHD muscles compared to control muscles. INTERPRETATION: We propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset, whereas DUX4 may worsen the muscle phenotype.


Assuntos
Caderinas/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/metabolismo , Músculo Quadríceps/metabolismo , Músculo Quadríceps/patologia , Adulto , Animais , Células Cultivadas , Feminino , Feto , Humanos , Masculino , Camundongos , Músculo Esquelético/embriologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Quadríceps/embriologia
12.
Prenat Diagn ; 35(7): 675-84, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25754886

RESUMO

OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.


Assuntos
Condrodisplasia Punctata/diagnóstico por imagem , Fenótipo , Índice de Gravidade de Doença , Ultrassonografia Pré-Natal , Condrodisplasia Punctata/genética , Feminino , Marcadores Genéticos , Testes Genéticos , Humanos , Recém-Nascido , Mutação , Gravidez , Segundo Trimestre da Gravidez , Radiografia , Estudos Retrospectivos , Esteroide Isomerases/genética , Inativação do Cromossomo X
13.
Prenat Diagn ; 35(3): 214-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25346315

RESUMO

OBJECTIVE: The aim of this study is to analyze the contribution of biochemistry and cytology of fetal ascites fluid to the etiological diagnosis of ascites after ultrasonographic scan, maternal blood sampling, and fetal karyotyping. METHOD: This is a retrospective study of 100 consecutive cases of nonimmune fetal ascites in which ascites fluid was sampled. All women underwent referral ultrasound scan and fetal karyotyping. All cases of fetal ascites were studied by biochemistry (total protein, ß2 -microglobulin, IgM, gamma-glutamyl transpeptidase, aspartate aminotransferase, aminopeptidase M, and intestinal isoform of alkaline phosphatase) and cytology (lymphocyte count and vacuolated cells). RESULTS: The etiology of ascites was diagnosed at ultrasound scan in only 50% of cases. We observed significantly (P < 0.001) low levels of total protein in ascites of urinary origin, high levels of digestive enzymes in ascites of digestive origin, and high ß2 -microglobulin in infectious ascites. Vacuolated cells were observed in all ten storage metabolic diseases. CONCLUSION: Sampling of fetal ascites fluid for biochemical and cytological examination provides important additional information. We propose a two-step management: (1) detailed ultrasound scan examination, maternal blood analysis, and fetal karyotyping and (2) biochemical and cytological analyses. On the basis of such an approach, 63% and 96% of etiologies would have been identified in our series after the first and second steps, respectively. © 2014 John Wiley & Sons, Ltd.


Assuntos
Anemia/complicações , Ascite/etiologia , Líquido Ascítico/química , Doenças do Sistema Digestório/complicações , Doenças Fetais/etiologia , Cardiopatias Congênitas/complicações , Doenças Urológicas/complicações , Viroses/complicações , Fosfatase Alcalina/metabolismo , Anemia/diagnóstico , Anemia/metabolismo , Aneuploidia , Ascite/diagnóstico por imagem , Ascite/metabolismo , Líquido Ascítico/citologia , Aspartato Aminotransferases/metabolismo , Antígenos CD13/metabolismo , Ascite Quilosa/diagnóstico , Ascite Quilosa/metabolismo , Estudos de Coortes , Doenças do Sistema Digestório/diagnóstico , Doenças do Sistema Digestório/metabolismo , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/metabolismo , Proteínas Ligadas por GPI/metabolismo , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/metabolismo , Humanos , Imunoglobulina M/metabolismo , Contagem de Linfócitos , Gravidez , Proteínas/metabolismo , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Doenças Urológicas/diagnóstico , Doenças Urológicas/metabolismo , Vacúolos , Viroses/diagnóstico , Viroses/metabolismo , Microglobulina beta-2/metabolismo , gama-Glutamiltransferase/metabolismo
14.
Eur J Hum Genet ; 23(1): 92-102, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24736735

RESUMO

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.


Assuntos
Estudos de Associação Genética , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Acrocefalossindactilia/diagnóstico , Acrocefalossindactilia/genética , Estudos de Coortes , Análise Mutacional de DNA , Família , Expressão Gênica , Rearranjo Gênico , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Fenótipo , Proteína Gli3 com Dedos de Zinco
15.
Eur J Hum Genet ; 23(8): 1010-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25351778

RESUMO

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Obesidade/genética , Penetrância , Síndrome de Prader-Willi/genética , Proteínas Repressoras/genética , Feto Abortado , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Obesidade/complicações , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/patologia , Gravidez
16.
Am J Med Genet A ; 164A(11): 2724-31, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25111715

RESUMO

The 22q11 deletion syndrome is one of the most common human microdeletion syndromes, with a wide spectrum of abnormalities. The fetal phenotype associated with the 22q11 deletion is poorly described in the literature. A national retrospective study was performed from 74 feto-pathological examinations. The objectives were to evaluate the circumstances of the 22q11 deletion diagnosis and to describe fetal anomalies. Post mortem examinations were performed after 66 terminations of pregnancy and eight fetal deaths. The series included nine fetuses from the first trimester, 55 from the second trimester, and ten from the third trimester. A 22q11 FISH analysis was recommended for 57 fetuses after multidisciplinary prenatal diagnostic counseling and for 17 fetuses by a fetal pathologist. Conotruncal heart defects were the most common anomalies (65 fetuses), followed by thymus defects (62 fetuses), and malformations of the urinary tract (25 fetuses). This study identified several unusual and severe features rarely described in the literature. Neurological abnormalities were described in ten fetuses, with seven neural tube defects and five arhinencephalies. This series also included lethal malformations: two hypoplastic left heart syndromes, two bilateral renal agenesis, and one tracheal agenesis. Genetic analysis for a 22q11 deletion is usually indicated when a congenital conotruncal heart and/or thymus defect is detected, but might also be useful in case of other lethal or severe malformations that initially led to the termination of pregnancy.


Assuntos
Síndrome da Deleção 22q11/diagnóstico , Síndrome da Deleção 22q11/genética , Feto , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Feminino , Estudos de Associação Genética , Aconselhamento Genético , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos
17.
Am J Med Genet A ; 164A(10): 2504-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24975584

RESUMO

Inversion duplication and terminal deletion of the long arm of chromosome 13 (inv dup del 13q) is a rare chromosomal rearrangement: only five patients have been reported, mostly involving a ring chromosome 13. We report on additional three fetuses with pure inv dup del 13q: Patient 1 had macrosomia, enlarged kidneys, hypersegmented lungs, unilateral moderate ventriculomegaly, and a mild form of hand and feet preaxial polydactyly; Patient 2 had intrauterine growth retardation, widely spaced eyes, left microphthalmia, right anophthalmia, short nose, bilateral absent thumbs, cutaneous syndactyly of toes 4 and 5, bifid third metacarpal, a small left kidney, hyposegmented lungs, and partial agenesis of the corpus callosum; Patient 3 had widely spaced eyes, long and smooth philtrum, low-set ears, median notch in the upper alveolar ridge, bifid tongue, cutaneous syndactyly of toes 2 and 3, enlarged kidneys and pancreas, arhinencephaly, and partial agenesis of the corpus callosum. We compared the phenotypes of these patients to those previously reported for ring chromosome 13, pure 13q deletions and duplications. We narrowed some critical regions previously reported for lung, kidney and fetal growth, and for thumb, cerebral, and eye anomalies.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Inversão Cromossômica/genética , Feto/patologia , Duplicação Gênica/genética , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fenótipo , Cromossomos em Anel
18.
J Neuropathol Exp Neurol ; 73(2): 143-58, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24423639

RESUMO

Neurologic morbidity associated with congenital cytomegalovirus (CMV) infection is a major public health concern. The pathogenesis of cerebral lesions remains unclear. We report the neuropathologic substrates, the immune response, and the cellular targets of CMV in 16 infected human fetal brains aged 23 to 28.5 gestational weeks. Nine cases were microcephalic, 10 had extensive cortical lesions, 8 had hippocampal abnormalities, and 5 cases showed infection of the olfactory bulb. The density of CMV-immunolabeled cells correlated with the presence of microcephaly and the extent of brain abnormalities. Innate and adaptive immune responses were present but did not react against all CMV-infected cells. Cytomegalovirus infected all cell types but showed higher tropism for stem cells/radial glial cells. The results indicate that 2 main factors influence the neuropathologic outcome at this stage: the density of CMV-positive cells and the tropism of CMV for stem/progenitor cells. This suggests that the large spectrum of CMV-induced brain abnormalities is caused not only by tissue destruction but also by the particular vulnerability of stem cells during early brain development. Florid infection of the hippocampus and the olfactory bulb may expose these patients to the risk of neurocognitive and sensorineural handicap even in cases of infection at late stages of gestation.


Assuntos
Encéfalo/embriologia , Encéfalo/patologia , Infecções por Citomegalovirus/patologia , Citomegalovirus/patogenicidade , Encéfalo/metabolismo , Encéfalo/virologia , Estudos de Casos e Controles , Feto , Idade Gestacional , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Antígeno Ki-67/metabolismo
19.
Birth Defects Res A Clin Mol Teratol ; 97(12): 770-3, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24254654

RESUMO

BACKGROUND: Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facial syndrome (FHUFS) is a rare disorder, which has been more frequently described in females. Only a few cases diagnosed prenatally have been reported so far in the literature. FFS is characterized by femoral hypoplasia and various facial abnormalities, which can be associated with a variety of other malformations CASES: In this report, we present two male fetuses which were diagnosed with FFS after detection of short femora, micrognathia, and other anomalies by ultrasonography at the age of 14 and 16 weeks, respectively. The sonographic findings were confirmed at autopsy. The differential diagnosis of FFS with other disorders characterized by hypoplastic femora is discussed CONCLUSION: FFS represents a severe condition; hence, the importance of an early prenatal diagnosis, especially in light of offering counseling for affected parents.


Assuntos
Face/anormalidades , Fêmur/anormalidades , Doenças Fetais/diagnóstico , Feto/anormalidades , Síndrome de Pierre Robin/diagnóstico , Ultrassonografia Pré-Natal , Face/diagnóstico por imagem , Feminino , Fêmur/diagnóstico por imagem , Doenças Fetais/diagnóstico por imagem , Humanos , Masculino , Síndrome de Pierre Robin/diagnóstico por imagem , Gravidez
20.
Prenat Diagn ; 33(12): 1167-72, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23943585

RESUMO

OBJECTIVE: The aim of this research was to evaluate the outcome and prognostic value of fetal serum ß2-microglobulin in case of prenatal diagnosis of severe bilateral renal hypoplasia. METHODS: Cases of hypoplastic kidneys were detected on ultrasound and referred to our laboratory for determination of fetal blood ß2-microglobulin, over a 12-year period. Prenatal prognostic assessment was based upon amniotic fluid volume and fetal serum ß2-microglobulin (cut-off: 5 mg/L). Outcome measures were postnatal renal function or renal pathological features when termination of pregnancy (TOP) and genetic studies were performed. RESULTS: A total of 34 cases were identified; 13 (38%) were liveborn and 21 (62%) underwent TOP. Renal hypoplasia was confirmed postnatally in all cases. Oligohydramnios/anhydramnios was observed in 30/34 (88%) cases. Associated genetic or anatomical anomalies were found in 8/34 (24%) cases. Renal function of liveborn infants was normal in 4/13 cases. Renal lesions were observed in all TOPs (21/21 cases). Overall, 30/34 (88.2%) cases had a poor outcome. ß2-microglobulin accurately predicts poor renal outcome in 27/31 (87.1%) cases. ß2-microglobulin was not interpretable in three cases due to amniotic fluid contamination. The prognostic value of ß2-microglobulin was similar to that of amniotic fluid volume assessment. CONCLUSION: Hypoplastic kidneys complicated by oligohydramnios/anhydramnios are associated with poor outcome. Fetal serum ß2-microglobulin and oligohydramnios both predicted poor outcome.


Assuntos
Sangue Fetal/química , Rim/anormalidades , Diagnóstico Pré-Natal , Microglobulina beta-2/sangue , Aborto Induzido , Líquido Amniótico , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Oligo-Hidrâmnio , Gravidez , Prognóstico , Insuficiência Renal/etiologia , Ultrassonografia Pré-Natal
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