Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
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.
Prenat Diagn ; 38(10): 772-778, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29949202

RESUMO

We report a multiplex family with a GATA1 gene mutation responsible for a massive fetal cerebral hemorrhage occurring at 36 weeks. Two other stillbirth cousins presented with fetal hydrops and congenital hemochromatosis' phenotype at 37 and 12 weeks of gestation. Molecular screening revealed the presence of a c.613G>A pathogenic allelic variation in exon 4 of GATA1 gene in the 3 male siblings and their carrier mothers. The diagnosis of a GATA1 gene mutation may be suspected in cases of male fetuses with intracerebral bleeding, particularly if a history of prior fetal loss(es) and mild maternal thrombocytopenia are also present.

4.
Case Rep Obstet Gynecol ; 2018: 6073204, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670784

RESUMO

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the SMARCB1 gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.

5.
Am J Med Genet A ; 176(7): 1610-1613, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29704304

RESUMO

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT-B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister-Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet-Biedl syndrome to a lethal phenotype.

6.
Int J Rheum Dis ; 21(2): 381-386, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28752595

RESUMO

AIM: The objectives were to determine the frequency of in utero fetal death (IUFD) related to placental disorders and to assess the frequency of antiphospholipid antibodies syndrome (APS) among women referred to the internal medicine department. METHODOLOGY: A retrospective clinical study conducted in Rennes University Hospital, France. From January 2007 to December 2014, 53 women who presented an IUFD at 14 weeks or more of gestational age were included. The main cause for each IUFD was determined by expert agreement. Primary outcome was to analyze the final etiologies diagnosed and the prevalence of IUFD related to placental disorders. Secondary outcomes included the frequency of APS among patients with IUFD of placental origin and the pathological and clinical features associated with APS. RESULTS: IUFD resulted from placental disorders in 36/53 (68%) patients, and remained unexplained in 11 cases (20.8%). Among the 36 patients with placental disorders, APS was diagnosed in five (13.9%) cases, and four (11.1%) patients were considered as having 'non-criteria' APS. History of thrombosis (P = 0.001) and placental infarcts (P = 0.047) were significantly associated with APS. CONCLUSION: Placental disorders were the major cause for IUFD in patients who were referred to internal medicine specialists. Importantly, APS was seldom found in patients with placental disorders. Venous thromboembolism history and placental infarcts were both significantly associated with APS. Further studies are needed in order to deepen our understanding of the physiopathology of placental disorders and its underlying causes among non-APS women, and to determine the best treatment regimen for future pregnancies.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/epidemiologia , Morte Fetal , Infarto/epidemiologia , Medicina Interna , Doenças Placentárias/epidemiologia , Placenta/irrigação sanguínea , Encaminhamento e Consulta , Trombose/epidemiologia , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/imunologia , Biomarcadores/sangue , Feminino , França/epidemiologia , Hospitais Universitários , Humanos , Infarto/diagnóstico , Placenta/patologia , Doenças Placentárias/diagnóstico , Gravidez , Prevalência , Estudos Retrospectivos , Fatores de Risco , Natimorto/epidemiologia , Trombose/diagnóstico , Adulto Jovem
7.
Am J Hum Genet ; 101(6): 1021-1033, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220674

RESUMO

ACTB encodes ß-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, ß-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic ß-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, ß-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Actinas/biossíntese , Adolescente , Adulto , Idoso , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Coloboma/genética , Facies , Feminino , Mutação da Fase de Leitura/genética , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Adulto Jovem
8.
PLoS One ; 12(9): e0184924, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28945767

RESUMO

INTRODUCTION: The objective of this study was to identify prenatal markers of histological chorioamnionitis (HC) during pPROM using fetal computerized cardiotocography (cCTG). MATERIALS AND METHODS: Retrospective review of medical records from pregnant women referred for pPROM between 26 and 34 weeks, in whom placental histology was available, in a tertiary level obstetric service over a 5-year period. Fetal heart rate variability was assessed using cCTG. Patients were included if they were monitored at least six times in the 72 hours preceding delivery. Clinical and biological cCTG parameters during the pPROM latency period were compared between cases with or without HC. RESULTS: In total, 222 pPROM cases were observed, but cCTG data was available in only 23 of these cases (10 with and 13 without HC) after exclusion of co-morbidities which may potentially perturb fetal heart rate variability measures. Groups were comparable for maternal age, parity, gestational age at pPROM, pPROM duration and neonatal characteristics (p>0.1). Baseline fetal heart rate was higher in the HC group [median 147.3 bpm IQR (144.2-149.2) vs. 141.3 bpm (137.1-145.4) in no HC group; p = 0.02]. The number of low variation episodes [6.4, (3.5-15.3) vs. 2.3 (1-5.2); p = 0.04] was also higher in the HC group, whereas short term variations were lower in the HC group [7.1 ms (6-7.4) vs. 8.1 ms (7.4-9); p = 0.01] within 72 hours before delivery. Differences were especially discriminant within 24 hours before delivery, with less short-term variation [5 ms (3.7-5.9) vs. 7.8 ms (5.4-8.7); p = 0.007] and high variation episodes [3.9 (4.9-3.2) vs. 0.8 (1.5-0.2); p < 0.001] in the HC group. CONCLUSION: These results show differences in fetal heart rate variability, suggesting that cCTG could be used clinically to diagnoses chorioamnionitis during the pPROM latency period.


Assuntos
Corioamnionite/etiologia , Ruptura Prematura de Membranas Fetais/fisiopatologia , Frequência Cardíaca Fetal , Adulto , Biomarcadores , Cardiotocografia , Corioamnionite/diagnóstico , Feminino , Humanos , Gravidez , Estudos Retrospectivos
9.
Eur J Med Genet ; 60(7): 395-398, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28455154

RESUMO

Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.


Assuntos
Síndrome de Costello/genética , Doenças Fetais/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Síndrome de Costello/diagnóstico por imagem , Síndrome de Costello/patologia , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/patologia , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal
10.
J Med Genet ; 54(6): 371-380, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28289185

RESUMO

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.


Assuntos
Face/anormalidades , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Doenças Renais Policísticas/genética , Proteínas/genética , Retinite Pigmentosa
11.
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
12.
Prenat Diagn ; 36(8): 744-51, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27297286

RESUMO

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


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Rim/anormalidades , Pâncreas/anormalidades , Pancreatopatias/congênito , Anormalidades Urogenitais/genética , Autopsia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genética , Anormalidades Congênitas/patologia , Feminino , Genótipo , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Mutação , Pâncreas/diagnóstico por imagem , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/genética , Fenótipo , Gravidez , Ultrassonografia Pré-Natal , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/patologia
14.
Nat Genet ; 46(8): 905-11, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997988

RESUMO

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.


Assuntos
Centríolos/genética , Proteínas Associadas aos Microtúbulos/genética , Síndromes Orofaciodigitais/genética , Linhagem Celular , Pré-Escolar , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Microcefalia/genética , Proteínas/genética
15.
Acta Neuropathol Commun ; 2: 69, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-25059107

RESUMO

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).


Assuntos
Encéfalo/anormalidades , Encéfalo/patologia , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico , Malformações do Desenvolvimento Cortical do Grupo I/genética , Mutação/genética , Tubulina (Proteína)/genética , Autopsia , Encéfalo/metabolismo , Análise Mutacional de DNA , Feminino , Feto , Humanos , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/classificação
16.
Prenat Diagn ; 34(1): 90-3, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24382792

RESUMO

OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Rim Displásico Multicístico/genética , Mutação , Pâncreas/anormalidades , Adulto , Pé Torto Equinovaro/genética , Feminino , Idade Gestacional , Heterozigoto , Humanos , Rim Displásico Multicístico/diagnóstico por imagem , Rim Displásico Multicístico/patologia , Oligo-Hidrâmnio/genética , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Fenótipo , Gravidez , Ultrassonografia Pré-Natal
17.
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
18.
Clin J Am Soc Nephrol ; 8(7): 1179-87, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23539225

RESUMO

BACKGROUND AND OBJECTIVES: Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy. RESULTS: This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. CONCLUSIONS: Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Mutação , Fator de Transcrição PAX2/genética , Diagnóstico Pré-Natal , Refluxo Vesicoureteral/diagnóstico , Refluxo Vesicoureteral/genética , Aborto Terapêutico , Autopsia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos , Índice de Gravidade de Doença , Ultrassonografia Pré-Natal , Anormalidades Urogenitais
19.
Eur Radiol ; 23(6): 1711-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23242003

RESUMO

OBJECTIVES: To investigate the contribution of whole-body post-mortem computed tomography (PMCT) in sudden unexpected death in infants and children. METHODS: Forty-seven cases of sudden unexpected death in children investigated with radiographic skeletal survey, whole-body PMCT and autopsy were enrolled. For imaging interpretation, non-specific post-mortem modifications and abnormal findings related to the presumed cause of death were considered separately. All findings were correlated with autopsy findings. RESULTS: There were 31 boys and 16 girls. Of these, 44 children (93.6 %) were younger than 2 years. The cause of death was found at autopsy in 18 cases (38.3 %), with 4 confirmed as child abuse, 12 as infectious diseases, 1 as metabolic disease and 1 as bowel volvulus. PMCT results were in accordance with autopsy in all but three of these 18 cases. Death remains unexplained in 29 cases (61.7 %) and was correlated with no abnormal findings on PMCT in 27 cases. Major discrepancies between PMCT and autopsy findings concerned pulmonary analysis. CONCLUSIONS: Whole-body PMCT may detect relevant findings that can help to explain sudden unexpected death and is essential for detecting non-accidental injuries. We found broad concordance between autopsy and PMCT, except in a few cases of pneumonia. It is a non-invasive technique acceptable to relatives. KEY POINTS: • Whole-body post-mortem computed tomography (PMCT) is an effective non-invasive method. • Whole-body PMCT is essential for detecting child abuse in unexpected death. • There is concordance on cause of death between PMCT and autopsy. • Whole-body PMCT could improve autopsy through dissection and sampling guidance. • PMCT shows findings that may be relevant when parents reject autopsy.


Assuntos
Morte Súbita/etiologia , Tomografia Computadorizada por Raios X/métodos , Autopsia , Causas de Morte , Criança , Maus-Tratos Infantis , Pré-Escolar , Feminino , Cabeça/patologia , Humanos , Lactente , Masculino , Interpretação de Imagem Radiográfica Assistida por Computador , Fatores de Tempo , Imagem Corporal Total/métodos
20.
Am J Hum Genet ; 91(6): 1135-43, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23217329

RESUMO

Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.


Assuntos
Lissencefalia Cobblestone/genética , Proteínas de Membrana/genética , Mutação , Nucleotidiltransferases/genética , Alelos , Lissencefalia Cobblestone/diagnóstico , Consanguinidade , Éxons , Família , Feto/metabolismo , Feto/patologia , Ordem dos Genes , Genótipo , Humanos , Íntrons
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA