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1.
J Exp Med ; 216(6): 1311-1327, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040185

RESUMO

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

2.
Clin Genet ; 95(3): 384-397, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30614526

RESUMO

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

3.
Afr Health Sci ; 18(1): 147-156, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29977268

RESUMO

Background: Truncus arteriosus communis (TAC) is a congenital heart defect in which the physiologic arterial common trunk was not divided into aorta and pulmonary artery trunk. Objectives: In this paper, we report on three observed cases from which we looked for (in conjunction with literature review) the different causes of TAC many of which have genetic origins. Methods: We collected three clinical files of fetuses having a TAC. Two of them were examinated after a medical termination of pregnancy motivated by severe cardiopathy. The malformation had been diagnosed based on different techniques: echocardiography, skeletal radiography, arteriography, fetal autopsy, karyotype and fluorescence in situ hybridization (FISH). Results: Imaging and fetopathological examination revealed the presence of TAC type 3 and 4 in the Van Praaghs classification. FISH analysis showed a 22q11.2 deletion in one fetus in favour of Digeorge syndrome. The karyotype analysis performed in two cases was normal. Conclusion: Truncus arteriosus is a rare pathology caused by numerous etiologies from which many of them have genetic origin. This malformation can be diagnosed early during prenatal period. Postmortem fetopathological examination allows a better diagnosis approach and eventually a genetic counseling in recurrent cases such as case of consanguinity.


Assuntos
Ecocardiografia/métodos , Feto/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/genética , Hibridização in Situ Fluorescente/métodos , Ultrassonografia Pré-Natal/métodos , Angiografia , Autopsia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Cariotipagem , Masculino
4.
Am J Hum Genet ; 101(6): 985-994, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198724

RESUMO

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.


Assuntos
Proteína Morfogenética Óssea 2/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Nanismo/genética , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Animais , Osso e Ossos/embriologia , Criança , Pré-Escolar , Cromossomos Humanos Par 20/genética , Fissura Palatina/genética , Modelos Animais de Doenças , Feminino , Coração/embriologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Fator de Crescimento Transformador beta/genética
5.
Eur J Med Genet ; 60(11): 605-609, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28811189

RESUMO

Koolen-de Vries syndrome (MIM#610443) is a rare microdeletion syndrome involving the 17q21.31 region, which was first described by Koolen in 2006. Clinical and behavioral characteristics have been extensively reported from more than 100 postnatal cases including infants, children and young adults. The syndrome is highly clinically heterogeneous, but the main features associate characteristic cranio-facial dysmorphism, heart defects, limb, skeletal, genito-urinary anomalies, along with intellectual disability with early childhood epilepsy and behavioral disturbances. Central nervous system malformations usually consist in hydrocephalus and thin corpus callosum. We report herein an early fetal case with an apparently isolated abnormal corpus callosum diagnosed by ultrasonography, for which a medical termination of the pregnancy was achieved at 22 weeks of gestation. Postmortem examination displayed facial dysmorphism consisting of hypertelorism, short philtrum and flat and broad nose, cleft palate and left duplex ureter. Neuropathological examination revealed a mega corpus callosum that has never been reported so far in this syndrome. Array-CGH performed on thymic DNA tissue revealed a 17q21.31 microdeletion, which allowed for the confirmation of early occurring Koolen-de Vries syndrome.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Fenótipo , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Gravidez , Ultrassonografia Pré-Natal
6.
Prenat Diagn ; 36(13): 1270-1275, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27859469

RESUMO

OBJECTIVE: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. METHOD: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. RESULTS: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). CONCLUSION: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/embriologia , Síndrome de Fraser/diagnóstico , Síndrome de Fraser/embriologia , Diagnóstico Pré-Natal/métodos , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/embriologia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/embriologia , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/embriologia , Orelha/anormalidades , Orelha/diagnóstico por imagem , Orelha/embriologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/embriologia , Feminino , Síndrome de Fraser/diagnóstico por imagem , Idade Gestacional , Humanos , Hidropisia Fetal/diagnóstico por imagem , Recém-Nascido , Rim/anormalidades , Rim/diagnóstico por imagem , Rim/embriologia , Oligo-Hidrâmnio/diagnóstico por imagem , Fenótipo , Gravidez , Sindactilia/diagnóstico por imagem , Ultrassonografia Pré-Natal , Anormalidades Urogenitais/diagnóstico
7.
Urology ; 89: 132-3, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26657689

RESUMO

Prenatal testicular torsion is a very rare morbid entity, described in the literature to occur when the testicle is intrascrotal, around the 34th week of gestation. Here we report a case of early testicular necrosis. This male fetus was the product of a medical abortion at 27 weeks. During evisceration, a left testicular nubbin free in the peritoneal cavity was found. Histologically, it was extensively necrotic. Because of the location, the size, and the histological features of this necrotic testicle, we conclude that it was the result of torsion of the pedicle that occurred around the 20th week of pregnancy.


Assuntos
Torção do Cordão Espermático/embriologia , Feminino , Idade Gestacional , Humanos , Masculino , Gravidez , Terceiro Trimestre da Gravidez
8.
Am J Hum Genet ; 97(2): 311-8, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166481

RESUMO

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.


Assuntos
Proteínas de Ciclo Celular/genética , Transtornos da Motilidade Ciliar/genética , Códon sem Sentido/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Hidrocefalia/genética , Fenótipo , Síndrome de Costela Curta e Polidactilia/genética , Sequência de Bases , Transtornos da Motilidade Ciliar/patologia , Europa Oriental , Evolução Fatal , Efeito Fundador , Humanos , Funções Verossimilhança , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
9.
BMC Pregnancy Childbirth ; 15: 137, 2015 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-26081109

RESUMO

BACKGROUND: Thrombotic thrombocytopenic Purpura (TTP) defined as ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13) activity <10 % is a rare aetiology of thrombocytopenia during pregnancy, although the precise incidence is unknown. During pregnancy, the diagnosis of TTP is crucial as it has high feto-maternal morbidity-mortality and requires urgent plasma exchange. The purpose of this study was to assess the incidence of TTP retrospectively and to describe case presentations and follow-up. METHODS: A monocentric retrospective study (2008-2009) was conducted among pregnant women followed in a tertiary care obstetrical unit who experienced at least one episode of severe thrombocytopenia (platelets ≤75 G/L) during 2008 and 2009. In cases of uncertain aetiology of thrombocytopenia, ADAMTS-13 activity was assessed by the full length technique. RESULTS: Among 8,908 deliveries over the 2 year period, 79 women had a platelet count nadir ≤75 G/L. Eighteen had a known aetiology of thrombocytopenia and 11 were lost to follow-up. Among 50 remaining patients, ADAMTS-13 activity was undetectable (<5 %) in 4, consistent with the diagnosis of TTP. Platelet count spontaneously normalized in 3 patients after delivery. None presented focal cerebral involvement. Three of the four, who were primipara patients, had a sustained severe deficiency in the absence of anti-ADAMTS-13 antibodies, and ADAMTS-13 gene sequencing indicated a constitutive deficiency. The fourth, a multipara patient, had an acquired, auto-immune TTP. Placental pathology in the three primipara patients showed severe and non-specific ischemic lesions. Two patients lost their babies shortly after birth. In subsequent pregnancies in these two patients, prophylactic plasma infusion initiated early with increasing volume throughout pregnancy prevented TTP relapse, improved placental pathology, and led to normal delivery. CONCLUSIONS: The prevalence of TTP among thrombocytopenic pregnant women is high, up to 5 % in a tertiary unit. Platelet count normalization after delivery does not eliminate TTP. Clinicians should be aware of TTP during pregnancy, and, even if assessed retrospectively, ADAMTS-13 assessment is of particular importance for identifying patients with congenital TTP. In these patients, preventive plasma infusion and/or exchange can dramatically improve foetal prognosis, resulting in successful childbirth.


Assuntos
Complicações Hematológicas na Gravidez/epidemiologia , Púrpura Trombocitopênica Trombótica/epidemiologia , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/sangue , Proteína ADAMTS13 , Adulto , Feminino , Humanos , Incidência , Recém-Nascido , Paridade , Morte Perinatal , Placenta/patologia , Plasmaferese , Contagem de Plaquetas , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/terapia , Resultado da Gravidez , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/terapia , Estudos Retrospectivos , Adulto Jovem
10.
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
11.
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
12.
Ann Pathol ; 34(2): 119-23, 2014 Apr.
Artigo em Francês | MEDLINE | ID: mdl-24703021

RESUMO

Of all the gestational trophoblastic tumors, the gestational choriocarcinomas have the worst prognosis and the most uncommon. We report a case diagnosed on a full-term placenta, discovered incidentally. The patient, gravida 2, para 1, delivered a hypotrophic infant at 38 weeks gestation. The placenta was examined in the laboratory to perform anatomo-pathological examination in order to explain the growth retardation. This study revealed the presence of an intraplacental choriocarcinoma. Disease staging was negative for both mother and child, and beta-HCG levels remained at zero. These two factors are rather good prognosis for choriocarcinoma. With this observation, we highlight the added-value of placental examination, which seems essential for any fetal pathology, pathological pregnancy and intrapartum complications. Anatomo-pathological examination must be meticulous and systematized in order to not overlook an intraplacental tumor.


Assuntos
Coriocarcinoma/patologia , Doenças Placentárias/patologia , Adulto , Feminino , Humanos , Achados Incidentais , Gravidez , Nascimento a Termo
13.
Pediatr Dev Pathol ; 17(2): 102-6, 2014 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24575782

RESUMO

Feto-maternal hemorrhage (FMH) is the cause of late fetal death in 1.6%-11% of cases. In spite of this high frequency, its pathological features have received little attention. The definitive diagnosis of lethal FMH requires confirmation of sufficient fetal blood volume loss. This is determined by tests such as the Kleihauer-Betke test, which may not have been obtained or not have been available before the autopsy. The pathologist may offer a tentative diagnosis of FMH from the autopsy findings. The objective of this study was to better characterize the placental and fetal autopsy findings in lethal FMH. This was a retrospective study of 17 cases of FMH proven by a positive Kleihauer-Betke test. The cases were selected from the autopsy files of the Department of Pathology, Centre Hospitalier Universitaire de Bordeaux. The pathological reports as well as the placental and fetal photographs and the microscopic slides of each case were systematically reviewed. The fetal autopsy findings in FMH are characterized by a eutrophic pale macerated fetus, low liver weight, absent intrathoracic petechiae, increased extramedullary hematopoiesis in the liver and kidney, and increased circulating nucleated red blood cells. The placenta shows an increased frequency of intervillous thrombi. Although nonpathognomonic, some of the pathological features are strongly suggestive of FMH. When the latter is present, a Kleihauer-Betke test should be performed, even some days after the delivery.


Assuntos
Morte Fetal/etiologia , Feto/patologia , Hemorragia/patologia , Placenta/patologia , Adulto , Autopsia/métodos , Feminino , Morte Fetal/metabolismo , Idade Gestacional , Hemorragia/diagnóstico , Humanos , Placenta/irrigação sanguínea , Gravidez
14.
Ann Pathol ; 33(4): 230-6, 2013 Aug.
Artigo em Francês | MEDLINE | ID: mdl-23954115

RESUMO

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.


Assuntos
Doenças Placentárias/patologia , Placenta/patologia , Circulação Placentária , Útero/patologia , Vilosidades Coriônicas/química , Vilosidades Coriônicas/patologia , Amostra da Vilosidade Coriônica , Cistos/patologia , Feminino , Morte Fetal/patologia , Hipóxia Fetal/etiologia , Fibrina/análise , Idade Gestacional , Humanos , Infarto/patologia , Necrose , Tamanho do Órgão , Placenta/irrigação sanguínea , Gravidez , Complicações na Gravidez/fisiopatologia , Trofoblastos/patologia , Útero/irrigação sanguínea
15.
PLoS One ; 8(1): e54013, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23326560

RESUMO

OBJECTIVES: Recent studies have shown that telomere length was significantly reduced in placentas collected at delivery from pregnancies complicated by intrauterine growth restriction secondary to placental insufficiency. Placental telomere length measurement during ongoing pregnancies complicated by intrauterine growth restriction has never been reported. This was the main objective of our study. METHODS: In our center, late chorionic villus samplings were performed between 18 and 37 weeks of amenorrhea in 24 subjects with severe intrauterine growth restriction (cases) and in 28 subjects with other indications for prenatal diagnosis (controls). Placental insufficiency was assessed by histo-pathological examination. Relative measurement of telomere length was carried out prospectively by quantitative Fluorescent In Situ Hybridization using fluorescent Peptide Nucleic Acid probes on interphase nuclei obtained from long-term cultured villi and with an automated epifluorescent microscope. A quantitative Polymerase Chain Reaction technique was performed to confirm the quantitative Fluorescent In Situ Hybridization results. The number of copies of gene loci encoding the RNA template (hTERC) and the catalytic subunit (hTERT) of the enzyme complex telomerase were also estimated in these placentas by Fluorescent In Situ Hybridization. RESULTS: Mean fluorescence intensity of telomere probes estimated by quantitative Fluorescent In Situ Hybridization was significantly less for cases compared to controls (p<0.001). This result indicated that mean telomere length was significantly reduced in placentas during pregnancies complicated by intrauterine growth restriction. Reduced telomere length was confirmed by the quantitative Polymerase Chain Reaction technique. No copy number variation of the hTERC and hTERT loci was noticed for cases, or for controls. CONCLUSION: This study clearly demonstrates a reduction of placental telomere length in ongoing pregnancies (from 18 to 37 weeks of amenorrhea) complicated by severe intrauterine growth restriction secondary to placental insufficiency.


Assuntos
Retardo do Crescimento Fetal , Placenta/citologia , Insuficiência Placentária , Homeostase do Telômero/genética , Adulto , Amostra da Vilosidade Coriônica , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Placenta/fisiopatologia , Insuficiência Placentária/genética , Insuficiência Placentária/fisiopatologia , Gravidez , Complicações na Gravidez/fisiopatologia , RNA/genética , Telomerase/genética
16.
Ann Pathol ; 32(3): 217-9, 2012 Jun.
Artigo em Francês | MEDLINE | ID: mdl-22748341

RESUMO

Tamponade is a rare but particularly serious complication of central venous catheters in the newborn. Tamponade can be due to the endocardic aggression caused by the continuous flow of a hyperosmotic solution or by a mechanical injury that can result in perforation of the atrial wall. The risk of tamponade is present whatever is the position of the tip of the catheter, although it has been shown that this risk is increased when this tip is in the right auricle. The originality of our observation is the discovery at the post-mortem examination of an anterior interventricular vein thrombosis, without any lesion of the atrial wall. In the event of the diagnosis of tamponade in living newborn, this etiology must be required because of its therapeutic implications.


Assuntos
Tamponamento Cardíaco/etiologia , Tamponamento Cardíaco/patologia , Cateterismo Venoso Central/efeitos adversos , Doenças em Gêmeos/etiologia , Doenças em Gêmeos/patologia , Trombose Venosa/etiologia , Trombose Venosa/patologia , Evolução Fatal , Feminino , Ventrículos do Coração , Humanos , Recém-Nascido
17.
Brain ; 135(Pt 2): 469-82, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22323514

RESUMO

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).


Assuntos
Encéfalo/patologia , Lissencefalia Cobblestone/genética , Lissencefalia Cobblestone/patologia , Distroglicanas/genética , Encéfalo/metabolismo , Lissencefalia Cobblestone/metabolismo , Distroglicanas/metabolismo , Feminino , Feto , Humanos , Recém-Nascido , Masculino , Manosiltransferases/genética , Manosiltransferases/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Proteínas/genética , Proteínas/metabolismo
18.
Hum Reprod ; 26(10): 2651-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21840909

RESUMO

OBJECTIVE: To evaluate the contribution of referent pathologists (RPs) to the quality of diagnosis of trophoblastic diseases and to study the level of diagnostic agreement between the initial pathologists and the RPs. METHODS: This observational retrospective study was carried between 1 November 1999 and 11 January 2011 using the database of the French Trophoblastic Disease Reference Centre in Lyon. All files for hydatiform moles (HMs), trophoblastic tumours and non-molar pregnancies for which there was an initial suspicion of trophoblastic disease were included, whenever there was rereading of the slides by an RP. A total of 1851 HMs and 150 gestational trophoblastic tumours were analysed. RESULTS: When the initial pathologist diagnosed a complete mole, the RP confirmed the diagnosis in 96% of cases. When the initial pathologist diagnosed a partial mole, the RP confirmed the diagnosis in only 64% of cases. For trophoblastic tumours, when the initial pathologist diagnosed a choriocarcinoma, the RP confirmed the diagnosis in 86% of cases. When the initial anatomopathology suggested an invasive mole, the diagnosis was confirmed in 96% of cases. Finally, when the initial diagnosis was a placental site trophoblastic tumour or an epithelioid trophoblastic tumour, the RP confirmed the diagnosis in 60 and 100% of cases, respectively. CONCLUSION: A systematic policy of rereading of slides for all suspicious moles improves the quality of management of trophoblastic diseases at a national level.


Assuntos
Doença Trofoblástica Gestacional/diagnóstico , Mola Hidatiforme/diagnóstico , Patologia/métodos , Neoplasias Trofoblásticas/diagnóstico , Adolescente , Adulto , Coriocarcinoma/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Mola Hidatiforme Invasiva/diagnóstico , Pessoa de Meia-Idade , Variações Dependentes do Observador , Gravidez , Complicações na Gravidez/diagnóstico , Encaminhamento e Consulta , Reprodutibilidade dos Testes , Estudos Retrospectivos
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