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1.
Genet Med ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31363182

RESUMO

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

2.
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.

3.
Genet Med ; 21(9): 2015-2024, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739908

RESUMO

PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

4.
Clin Genet ; 95(3): 420-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

5.
Eur J Hum Genet ; 26(2): 287-292, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29255276

RESUMO

CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.

6.
Am J Med Genet C Semin Med Genet ; 175(4): 417-430, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29178447

RESUMO

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Estudos de Coortes , Nervos Cranianos/anormalidades , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , França , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
7.
Hum Genet ; 136(4): 463-479, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283832

RESUMO

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Proteínas Repressoras/genética , Humanos
8.
J Pediatr ; 185: 160-166.e1, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28284480

RESUMO

OBJECTIVE: To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays. RESULTS: In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype. We confirmed that the most common rearrangement in corpus callosum abnormality/intellectual disability is inverted duplication with terminal deletion of the 8p chromosome (3.2%). In addition to the identification of known recurrent CNVs, such as deletions 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26, and 3q26 (including SOX2), our analysis allowed us to refine the 2 known critical regions associated with 8q21.1 deletion and 19p13.1 duplication relevant for corpus callosum abnormality; report a novel 10p12 deletion including ZEB1 recently implicated in corpus callosum abnormality with corneal dystrophy; and) report a novel pathogenic 7q36 duplication encompassing SHH. In addition, 66 variants of unknown significance were identified in 57 patients encompassed candidate genes. CONCLUSIONS: Our results confirm the relevance of using microarray analysis as first line test in patients with corpus callosum abnormality/intellectual disability.


Assuntos
Agenesia do Corpo Caloso/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
9.
J Med Genet ; 54(2): 100-103, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27582083

RESUMO

BACKGROUND: Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. OBJECTIVES: Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. METHODS AND RESULTS: In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. CONCLUSION: Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.


Assuntos
Fibrilina-1/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Patologia Molecular , Alelos , Códon sem Sentido , Feminino , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Masculino , Síndrome de Marfan/patologia , Mutação de Sentido Incorreto/genética , Linhagem
10.
Circ Cardiovasc Genet ; 9(6): 548-558, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27879313

RESUMO

BACKGROUND: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. METHODS AND RESULTS: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. CONCLUSIONS: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.


Assuntos
Aorta Torácica , Doenças da Aorta/genética , Heterozigoto , Mutação , Complicações Cardiovasculares na Gravidez/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/mortalidade , Doenças da Aorta/cirurgia , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/mortalidade , Complicações Cardiovasculares na Gravidez/cirurgia , Prevalência , Modelos de Riscos Proporcionais , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos/epidemiologia , Procedimentos Cirúrgicos Vasculares
11.
Hum Mutat ; 37(12): 1329-1339, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27363716

RESUMO

Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Holoprosencefalia/genética , Mutação , Feminino , Predisposição Genética para Doença , Proteínas Hedgehog/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Análise de Sequência de DNA/métodos , Transdução de Sinais
12.
J Hum Genet ; 61(8): 693-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27193221

RESUMO

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenótipo , Alelos , Substituição de Aminoácidos , Éxons , Facies , Feminino , Filaminas/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA
13.
Genet Med ; 18(1): 49-56, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25790162

RESUMO

PURPOSE: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. METHODS: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. RESULTS: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. CONCLUSION: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Estudos de Associação Genética , Humanos , Masculino , Disostose Mandibulofacial/diagnóstico , Microcefalia/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Deleção de Sequência , Adulto Jovem
14.
Eur Heart J ; 36(32): 2160-6, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25935877

RESUMO

AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving ß-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. ß-Blocker therapy alone should therefore remain the standard first line therapy in these patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Doenças da Aorta/tratamento farmacológico , Losartan/administração & dosagem , Síndrome de Marfan/complicações , Adolescente , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Doenças da Aorta/complicações , Doenças da Aorta/mortalidade , Pressão Sanguínea/efeitos dos fármacos , Dilatação Patológica/complicações , Dilatação Patológica/tratamento farmacológico , Dilatação Patológica/mortalidade , Método Duplo-Cego , Esquema de Medicação , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/prevenção & controle , Masculino , Síndrome de Marfan/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
15.
Am J Med Genet A ; 164A(8): 1965-75, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24782328

RESUMO

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).


Assuntos
Obesidade/diagnóstico , Obesidade/genética , Fenótipo , Locos de Características Quantitativas , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Lactente , Masculino , Síndrome
16.
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
17.
Mol Genet Metab ; 110(1-2): 90-7, 2013 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23920044

RESUMO

Congenital deletions at the 3q13.31 locus have been recently described as a novel microdeletion syndrome characterized by developmental delay, postnatal overgrowth, hypoplastic male genitalia and characteristic facial features. A common critical region of overlapping of 580kb was delineated including two strong candidate genes for developmental delay: DRD3 and ZBTB20. In this report, we describe a new case of 3q13.31 microdeletion identified by array-CGH in a 16year-old girl sharing clinical features commonly observed in the 3q13.31 microdeletion syndrome. This girl had a microdeletion of 7.39Mb spanning the common critical region of overlapping. More interestingly, we report for the first time the existence of a microduplication reciprocal to the microdeletion syndrome. This familial 2.76Mb microduplication identified by array-CGH was carried by two brothers and their father. The phenotype shared by the brothers resembled the phenotype related to the 3q13.31 microdeletion syndrome including especially severe intellectual disability, developmental delay, behavioral abnormalities and obesity. This microduplication involves three strong candidate genes for the developmental delay ZBTB20, LSAMP and GAP43. Further molecular characterization showed that DRD3, another strong candidate gene for developmental delay, was not included in the duplicated region. However, a dosage alteration of this gene cannot be completely excluded as the duplication was inverted at proximity of this gene, as revealed by FISH analysis. Finally, we hypothesized that the phenotype shared by the two brothers could be related to a gene dosage imbalance even if gene expression could not be measured in relevant tissues such as brain or adipocytes.


Assuntos
Deficiências do Desenvolvimento/genética , Deleção de Genes , Genes Duplicados , Obesidade/genética , Adolescente , Moléculas de Adesão Celular Neuronais/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Feminino , Proteína GAP-43/genética , Proteínas Ligadas por GPI/genética , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteínas do Tecido Nervoso/genética , Obesidade/patologia , Receptores de Dopamina D3/genética , Fatores de Transcrição/genética
18.
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
19.
Ann Pathol ; 29(5): 424-7, 2009 Oct.
Artigo em Francês | MEDLINE | ID: mdl-20004848

RESUMO

A case of maze-like angiomatoid anomaly in villi obtained by chorionic villous sampling (CVS) is described. This feature is pathognomonic of partial mole (triploid syndrome) and it was later confirmed by chromosomal analysis. Maze-like angiomatoid anomaly was previously described on specimen submitted after spontaneous or induced abortions, but it was never reported on CVS. This report emphasized that microscopic investigation of CVS cannot be conclusive for cytogenetic anomaly in almost all cases excepted for partial mole where diagnosis criteria are usually characteristic.


Assuntos
Amostra da Vilosidade Coriônica , Mola Hidatiforme/patologia , Neoplasias Uterinas/patologia , Adulto , Feminino , Humanos , Gravidez
20.
J Autism Dev Disord ; 39(9): 1252-60, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19350377

RESUMO

Research regarding the behavioral aspects of children with Rubinstein-Taybi syndrome (RTS) has suggested some possible behavioral patterns including autistic features. Caregivers of 39 children (mean age = 8.4 years) with RTS (49% showing abnormality in CREBBP gene) and 39 children (mean age = 8.6 years) matched on developmental level, age and gender were administered the Child Behavior Checklist and the Children's Social Behavior Questionnaire. Children with RTS did not exhibit higher internalizing (affective and anxiety symptoms) or externalizing (disruptive symptoms) behavioral problems than expected for their age/developmental range. However, they displayed some specific behaviors: short attention span, motor stereotypies, poor coordination, and overweight. The presence of an identified CREBBP gene abnormality was possibly related to the motor difficulties through impaired motor skills learning.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Proteína de Ligação a CREB/genética , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/genética , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Comportamento Social , Adolescente , Transtorno Autístico/psicologia , Criança , Transtornos do Comportamento Infantil/psicologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Sobrepeso/diagnóstico , Sobrepeso/genética , Sobrepeso/psicologia , Determinação da Personalidade/estatística & dados numéricos , Fenótipo , Psicometria , Transtornos Psicomotores/psicologia , Síndrome de Rubinstein-Taybi/psicologia , Comportamento Estereotipado
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