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1.
Laryngoscope ; 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30734293

RESUMO

OBJECTIVE: To study the histoanatomical structure of laryngeal atresia with a focus on the laryngeal functional components in order to evaluate the functional prognosis of laryngeal atresia repair. METHODS: Twenty-one consecutives cases of laryngeal atresia were diagnosed at our institution between 2009 and 2016. Morphological analysis by macroscopic exam during autopsy was performed in 19 cases. Histological study of the larynx included hematoxylin and eosin staining and protein S100 immunostaining. Our analysis focused on the vocal folds, structures of the lamina propria, cricoarytenoid joints, muscles, and innervation. For each case, associated malformations were classified into two groups: severe and moderate. RESULTS: Antenatal diagnosis was suspected because of congenital high airway obstruction syndrome in nine cases (37%). Associated malformations were present in 19 cases (90%), including severe malformations in 12 cases (57%). Atresia involved the cricoid in all cases, with a residual lumen in only one case and the glottis in 18 cases. Separation between the cricoid and arytenoid cartilages was observed in all cases. Fusion of the vocal process of the arytenoids in the midline was present in 13 cases. According to the gestational age, posterior maculae flavae (MF) were present in 17 of 19 cases, with abnormal structure and median fusion in 13 cases. Anterior MF were present in nine of 18 cases, with fusion on the midline in five cases. Intrinsic abductors and adductors muscles were identifiable in all cases, with fusion of thyroarytenoids muscles in the midline in 18 cases. Both recurrent laryngeal nerves were observed in all cases. CONCLUSION: Laryngeal atresia is generally associated with other malformations, with a high risk of fatal outcomes. We observed that the functional structures of the glottic plane were present in most cases, with the exception of MF, which were frequently abnormal. LEVEL OF EVIDENCE: 4. Laryngoscope, 2019.

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.
Am J Hum Genet ; 104(2): 213-228, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

4.
Eur J Med Genet ; 61(10): 585-595, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29605658

RESUMO

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.

5.
J Pediatr ; 187: 98-104.e3, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28583707

RESUMO

OBJECTIVE: To investigate the association between histologic chorioamnionitis (HCA) and bronchopulmonary dysplasia (BPD) in very preterm infants, both in a general population and for those born after spontaneous preterm labor and after preterm premature rupture of membranes (pPROM). STUDY DESIGN: This study included 2513 live born singletons delivered at 24-31 weeks of gestation from a national prospective population-based cohort of preterm births; 1731 placenta reports were available. HCA was defined as neutrophil infiltrates in the amnion, chorion of the membranes, or chorionic plate, associated or not with funisitis. The main outcome measure was moderate or severe BPD. Analyses involved logistic regressions and multiple imputation for missing data. RESULTS: The incidence of HCA was 28.4% overall: 38% in cases of preterm labor, 64% in cases of pPROM, and less than 5% in cases of vascular disorders. Overall, the risk of BPD after adjustment for gestational age, sex, and antenatal steroids was reduced for infants with HCA (HCA alone: aOR 0.6 [95% CI 0.4-0.9]; associated with funisitis: aOR 0.5 [95% CI 0.3-0.8]). This finding was explained by the high rate of BPD and low rate of chorioamnionitis among children with fetal growth restriction. HCA was not associated with BPD in the preterm labor (13.4% vs 8.5%; aOR 0.9; 95% CI 0.5-1.8) or in the pPROM group (12.9% vs 12.1%; aOR 0.6; 95% CI 0.3-1.3). CONCLUSION: In homogeneous groups of infants born after preterm labor or pPROM, HCA is not associated with BPD.


Assuntos
Displasia Broncopulmonar/epidemiologia , Corioamnionite/epidemiologia , Displasia Broncopulmonar/complicações , Estudos Epidemiológicos , Feminino , Ruptura Prematura de Membranas Fetais , Idade Gestacional , Humanos , Incidência , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Modelos Logísticos , Masculino , Gravidez , Estudos Prospectivos
6.
Prenat Diagn ; 37(4): 323-328, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28152557

RESUMO

OBJECTIVE: The objectives of the study are to describe the obstetric outcomes associated with massive perivillous fibrin deposition (MFD) compared with a control series and to determine if outcome differs according to the extent of fibrin deposition. METHOD: Retrospective case-control study based on placentas analyzed over a consecutive 12-year period. MFD was considered severe if it extended over more than 50% of the placenta and moderate between 25% and 50%. RESULTS: During the study period, MFD was observed on 71 placentas, 39 severe and 32 moderate. Compared with the 142 control women, the 39 women with severe MFD more often had histories of autoimmune disease and intrauterine fetal death. The case women with MFD were associated with elevated levels of maternal alpha-fetoprotein and with a high risk of severe growth restriction and/or intrauterine death. Compared with the infants with moderate MFD, those with severe MFD had also more abnormal umbilical artery Doppler velocimetry findings and more often intrauterine deaths and lower birthweights. CONCLUSION: Regardless of their extent, MFD that covered at least 25% of the placenta was almost always accompanied by severe growth restriction and by a high risk of intrauterine fetal death. Moreover, severe MFD tend to be associated with autoimmune diseases of the mothers, and pregnancies show more often a pathologic Doppler of the umbilical arteries and more often intrauterine fetal death that the moderate form. © 2017 John Wiley & Sons, Ltd.


Assuntos
Vilosidades Coriônicas/metabolismo , Fibrina/metabolismo , Doenças Placentárias/diagnóstico , Doenças Placentárias/epidemiologia , Resultado da Gravidez/epidemiologia , Adulto , Estudos de Casos e Controles , Precipitação Química , Vilosidades Coriônicas/patologia , Feminino , Morte Fetal/etiologia , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/etiologia , Humanos , Doenças Placentárias/metabolismo , Doenças Placentárias/patologia , Gravidez , Prognóstico , Estudos Retrospectivos , Adulto Jovem
7.
Hum Pathol ; 54: 121-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27068524

RESUMO

SALL4 has important functions in embryonic stem cells. The aim of this study was to investigate SALL4 expression in gestational trophoblastic neoplasia. We hypothesized that it could help to distinguish choriocarcinoma, the presumed most primitive form of gestational trophoblastic neoplasia, from placental site trophoblastic tumor and epithelioid trophoblastic tumor, which would be more differentiated variants. This study included 31 gestational trophoblastic neoplasias: 19 choriocarcinomas, 9 placental site trophoblastic tumors, 1 epithelioid trophoblastic tumor, and 2 mixed tumors comprising a placental site trophoblastic tumor and an epithelioid trophoblastic tumor. Unlike usual markers of gestational trophoblastic neoplasia (p63, human chorionic gonadotrophin and human placental lactogen), SALL4 was expressed in 100% of choriocarcinomas and it was not detected in any placental site trophoblastic tumor and epithelioid trophoblastic tumor. However, the proportion of positive cells varied in a wide range, from 10% to 70%, reflecting the fact that SALL4 was specifically present in mononuclear cells consistent with neoplastic cytotrophoblast. So, SALL4 may be helpful in the differential diagnosis of gestational trophoblastic neoplasias.


Assuntos
Biomarcadores Tumorais/análise , Coriocarcinoma/química , Células Epitelioides/química , Doença Trofoblástica Gestacional/química , Fatores de Transcrição/análise , Tumor Trofoblástico de Localização Placentária/química , Trofoblastos/química , Neoplasias Uterinas/química , Coriocarcinoma/patologia , Diagnóstico Diferencial , Células Epitelioides/patologia , Feminino , Doença Trofoblástica Gestacional/patologia , Humanos , Imuno-Histoquímica , Valor Preditivo dos Testes , Gravidez , Tumor Trofoblástico de Localização Placentária/patologia , Trofoblastos/patologia , Neoplasias Uterinas/patologia
8.
PLoS Genet ; 12(3): e1005894, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26967905

RESUMO

Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cílios/genética , Fosfoproteínas/genética , Doenças Renais Policísticas/genética , Proteínas Quinases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Diferenciação Celular/genética , Cílios/patologia , Feminino , Estudos de Associação Genética , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Morfogênese/genética , Mutação , Quinases Relacionadas a NIMA , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Doenças Renais Policísticas/patologia , Porfirinas/administração & dosagem , Transdução de Sinais , Verteporfina , Peixe-Zebra
9.
Ann Pathol ; 35(5): 445-8, 2015 Oct.
Artigo em Francês | MEDLINE | ID: mdl-26372501

RESUMO

We report the case of a 3-year-old child who died from the consequences of a cardio-respiratory arrest despite reanimation procedures. Echocardiography and magnetic resonance imaging (MRI) revealed a mass of the free wall of the left ventricle. Autopsy confirmed the existence of a solitary myocardial tumor, well-circumscribed, firm, with a whitish and trabeculated cut surface. Histologically, the tumor consisted of bundles of spindle-shaped and regular cells mingling with collagen and elastic fibers, insinuating themselves between myocytes in periphery. Calcifications were present. After immunohistochemistry, the cells were highlighted by anti-actin smooth muscle antibody; but they were not highlighted by anti-desmin, anti-ß catenin and anti-Ki67 antibodies. The diagnosis of cardiac fibroma was made. The primary cardiac tumors of child are rare and usually benign. They are essentially represented by rhabdomyoma and fibroma. Cardiac fibroma mostly occurs during the first year of life. It can be revealed by cardiac insufficiency, arrhythmia, chest pain or sudden death.


Assuntos
Morte Súbita Cardíaca/etiologia , Fibroma/patologia , Neoplasias Cardíacas/patologia , Calcinose/patologia , Cardiomegalia/etiologia , Pré-Escolar , Diagnóstico Diferencial , Fibroma/complicações , Fibroma/diagnóstico , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/diagnóstico , Humanos , Masculino , Rabdomioma/diagnóstico
10.
Am J Med Genet A ; 167(6): 1252-61, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847481

RESUMO

Tetrasomy 9p is a generic term describing the presence of a supernumerary chromosome incorporating two copies of the 9p arm. Two varieties exist: isodicentric chromosome 9p (i(9p)), where the two 9p arms are linked by a single centromeric region, and pseudodicentric 9p (idic(9p)), where one active and one inactive centromere are linked together by a proximal segment of 9q that may incorporate euchromatic material. In living patients, i(9p) and idic(9p) are usually present in a mosaic state. Fifty-four cases, including fetuses, have been reported, of which only two have been molecularly characterized using array-CGH. Tetrasomy 9p leads to a variable phenotype ranging from multiple congenital anomalies with severe intellectual disability and growth delay to subnormal cognitive and physical developments. Hypertelorism, abnormal ears, microretrognathia and bulbous nose are the most common dysmorphic traits. Microcephaly, growth retardation, joint dislocation, scoliosis, cardiac and renal anomalies were reported in several cases. Those physical anomalies are often, but not universally, accompanied by intellectual disability. The most recurrent breakpoints, defined by conventional cytogenetics, are 9p10, 9q12 and 9q13. We report on 12 new patients with tetrasomy 9p (3 i(9p), 8 idic(9p) and one structurally uncharacterized), including the first case of parental germline mosaicism. All rearrangements have been characterized by DNA microarray. Based on our results and a review of the literature, we further delineate the prenatal and postnatal clinical spectrum of this imbalance. Our results show poor genotype-phenotype correlations and underline the need of precise molecular characterization of the supernumerary marker.


Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Trissomia , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Bandeamento Cromossômico , Cromossomos Humanos Par 9 , Deficiências do Desenvolvimento/patologia , Feminino , Feto , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Deficiência Intelectual/patologia , Cariotipagem , Masculino , Mosaicismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Síndrome
12.
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
13.
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
14.
Hum Genet ; 133(3): 367-77, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24178751

RESUMO

Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders". Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.


Assuntos
Proteínas de Membrana/genética , Síndromes Orofaciodigitais/diagnóstico , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas , Adolescente , Adulto , Alelos , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Cerebelo/anormalidades , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Hamartoma/diagnóstico , Hamartoma/genética , Humanos , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/genética , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Polidactilia/diagnóstico , Polidactilia/genética , Retina/anormalidades , Análise de Sequência de DNA , Adulto Jovem
15.
Acta Neuropathol ; 126(3): 427-42, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23820807

RESUMO

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.


Assuntos
Aqueduto do Mesencéfalo/anormalidades , Aqueduto do Mesencéfalo/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hidrocefalia/patologia , Doenças do Sistema Nervoso/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Feminino , Humanos , Recém-Nascido , Mutação/genética , Doenças do Sistema Nervoso/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Linhagem , Fenótipo , Gravidez
16.
Histopathology ; 63(3): 425-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23822878

RESUMO

AIMS: SALL4 is a marker of germ cell tumours. The aim of this study was to investigate SALL4 expression in blastemal tumours, particularly in hepatoblastoma. METHODS AND RESULTS: The study included 12 hepatoblastomas. Eight hepatoblastomas were pure epithelial tumours, and four were mixed epithelial and mesenchymal tumours. The patients were nine males and three females with a mean age of 14.6 months. Immunohistochemistry was performed with an antibody against SALL4, using an automated immunostainer. Seven of 12 hepatoblastomas showed nuclear staining only in the embryonal component. Fetal and mesenchymal components were negative. CONCLUSIONS: SALL4 is expressed in blastemal tumours, particularly in the embryonal subtype of hepatoblastoma. Pathologists need to be aware of such expression so that misdiagnosis can be avoided.


Assuntos
Biomarcadores Tumorais/metabolismo , Hepatoblastoma/metabolismo , Hepatoblastoma/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fatores de Transcrição/metabolismo , Estudos de Casos e Controles , Pré-Escolar , Feminino , Feto/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Fígado/embriologia , Fígado/metabolismo , Masculino
18.
Insights Imaging ; 4(4): 417-29, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23686748

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI), commonly called "brittle bone disease", is a genetic disorder characterised by increased bone fragility and decreased bone density due to quantitative and/or qualitative abnormalities of type I collagen. Different types of OI exist, from mild to severe; they may lead to death, multiple bone fractures, skeletal deformity and short stature. METHODS: Severe cases are usually diagnosed before birth and may incite the parents to choose therapeutic abortion, whereas milder cases are much more difficult to diagnose and may be sometimes confused with non-accidental injury (NAI) ("child abuse") in young children. Whatever the degree of severity, conventional radiography still remains the mainstay in diagnosing OI. RESULTS: The prognosis of this disorder has changed in the last few years thanks to biphosphonate therapy. CONCLUSION: The aim of this pictorial review is to illustrate the radiographic manifestations of OI, including in children receiving biphosphonates, and to outline specific patterns that help differentiate OI from NAI when necessary. KEY POINTS: • The main radiographic features of OI are osteopenia, bone fractures and bone deformities. • Some radiographic features depend on the type of OI or may be encountered with biphosphonates.

19.
Am J Med Genet A ; 161A(3): 572-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23401077

RESUMO

Silver-Russell syndrome (SRS) is characterized by pre- and post-natal growth restriction that spares head growth, feeding difficulties, and variable dysmorphic facial features without major malformations. Hypomethylation of the paternal 11p15 imprinting control region 1 (ICR1) and maternal uniparental disomy of chromosome 7 are found in 50-60% and in 5-10% of SRS patients, respectively. We report on the pre- and post-natal features of three unrelated SRS patients with unusual congenital heart defects (CHDs). Two patients born prematurely had total anomalous pulmonary venous return and died shortly after birth, and a third patient, now 4 years old, had cor triatriatum sinistrum, which was surgically corrected. In all three patients, the underlying molecular defect was 11p15 ICR1 hypomethylation. Based on a large cohort with molecularly proven SRS, the prevalence of CHD in SRS is estimated at 5.5%. We suggest that the occurrence of CHD in SRS with 11p15 ICR1 hypomethylation is not coincidental, but specific to this genotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos Par 11/genética , Cardiopatias Congênitas/diagnóstico , Síndrome de Silver-Russell/diagnóstico , Anormalidades Múltiplas/genética , Pré-Escolar , Metilação de DNA , Evolução Fatal , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Masculino , Síndrome de Silver-Russell/genética
20.
Int J Gynaecol Obstet ; 120(2): 165-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23200099

RESUMO

OBJECTIVE: To investigate gross and microscopic placental lesions associated with pre-eclampsia and to determine which lesions are most strongly linked to serious pregnancy complications. METHODS: A retrospective case-control study of 173 placentas from women with pre-eclampsia and 173 placentas from healthy normotensive women was conducted. RESULTS: The mean placental weight in the pre-eclampsia group was lower than that recorded for the control group (280 g vs 360 g; P<0.001). Infarcts (65.9% vs 13.2%; P<0.001) and placental abruption (P<0.001) were most frequent among women with pre-eclampsia. Microscopic findings showed the following lesions to be associated with pre-eclampsia: hypermature villi, defined by absence of intermediate villi (72% vs 16%; P<0.001), excessive syncytial knots (90% vs 9%; P<0.001), decidual vasculopathy (51% vs 8%; P<0.001), villous fibrosis (6% vs 0%; P<0.001), erythroblastosis (11% vs 4%; P<0.01), and avascular terminal villi (9% vs 3%; P<0.05). Increased syncytial knots, infarcts, basal decidual vasculopathy, hypermature villi, and placental erythroblastosis were still associated with pre-eclampsia after logistic regression modeling. CONCLUSION: Placental lesions most strongly associated with pre-eclampsia were all causes or expressions of placental hypoxia or ischemia, which appears as the primary mechanism of pre-eclampsia.


Assuntos
Placenta/patologia , Pré-Eclâmpsia/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Infarto/patologia , Modelos Logísticos , Análise Multivariada , Tamanho do Órgão , Placenta/irrigação sanguínea , Gravidez , Estudos Retrospectivos , Adulto Jovem
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