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1.
Am J Hum Genet ; 105(2): 283-301, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353023

RESUMO

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

2.
Int J Gynecol Cancer ; 28(9): 1766-1771, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30365454

RESUMO

OBJECTIVE: This study aimed to assess the outcome of first-line hysterectomy in patients diagnosed as having gestational trophoblastic neoplasia (GTN) whose postoperative imaging showed lung images considered as metastases. METHODS: From 1999 to 2016, patients no longer wishing to conceive, treated by their initial physician by hysterectomy, and whose postoperative imaging workup showed lung images considered as metastasis were identified in the French Trophoblastic Disease Reference Center database. We sought to identify significant predictive factors of requiring salvage chemotherapy. RESULTS: Thirty patients were identified with a maximum number of 2 visible lung nodules and a median largest size of 14 mm on chest x-ray. Nine of these patients had an International Federation of Gynecology and Obstetrics score of higher than 6, and there were no postterm GTN. Twenty-two patients (73.33%; 95% confidence interval, 54.11-87.72; P = 0.0053) normalized their human chorionic gonadotropin (hCG) without salvage chemotherapy, whereas 7 received 1 line of salvage monochemotherapy (8-day methotrexate) and 1 required 2 lines of monochemotherapy (5-day actinomycin D after failure of methotrexate). After a 12.45-month median follow-up (range, 3-48.4 months) since the first normalized hCG, none of these patients died. The median interval between successful hysterectomy and hCG normalization was 3.15 months (range, 1.6-8.7 months). Patients who required salvage chemotherapy had a median size of the largest lung metastasis on chest computed tomography of 4 mm larger than those cured by hysterectomy (P = 0.0455). CONCLUSIONS: For GTN patients no longer wishing to conceive with lung metastases discovered postoperatively, treated by hysterectomy, and whose hCG is decreasing, it is reasonable to expect and to inform patients that approximately 27% will require salvage chemotherapy. However, in patients with lung metastases discovered preoperatively, evidence to recommend first-line hysterectomy is insufficient and these patients should receive first-line chemotherapy.

3.
Pediatr Dev Pathol ; : 1093526618799293, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30193563

RESUMO

We report a male fetus with a 6.8 Mb deletion on chromosome 7p22.1p22.3 at 16 weeks of gestation. The fetus presented a heart-hand syndrome with great artery malposition, bilateral radial ray deficiency, a single pelvic kidney, and growth retardation. This deletion involves a minimal deleted region for cardiac malformation and the RAC1 gene, previously described in limb anomalies in mice. This fetus is the third human case with limb defects and RAC1 deletion.

4.
Gynecol Oncol ; 150(2): 282-287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29887485

RESUMO

BACKGROUND: Low-risk gestational trophoblastic neoplasia (GTN) patients (FIGO score ≤6) are generally treated with single agent chemotherapy (methotrexate or dactinomycin) resulting in a 5-year mortality rate of 0.3%. However, despite these encouraging survival rates, chemotherapy is associated with significant adverse events in most patients. Although it is generally accepted that patients who no longer wish to conceive may be treated by hysterectomy for a hydatidiform mole, the evidence to support this strategy in low-risk GTN patients is lacking. OBJECTIVES: To describe the survival, efficacy, and tolerance associated with first-line hysterectomy in low-risk non-metastatic GTN patients. STUDY DESIGN: Seventy-four of 1072 low-risk GTN patients treated in the French Center underwent first-line hysterectomy. Patients data with successful first-line hysterectomy were retrospectively compared to those requiring further salvage chemotherapy. RESULTS: First-line hysterectomy was followed by hCG normalization in 61 patients (82.4%, 95% confidence interval [CI] 71.8-90.3) without any further salvage chemotherapy, whereas 13 patients required salvage chemotherapy. After multivariate analysis, a FIGO score of 5-6 (exact OR 8.961, 95%CI 1.60-64.96), and the presence of choriocarcinoma (exact OR 14.295, 95%CI 1.78-138.13) were associated with the risk of requiring salvage chemotherapy. CONCLUSION: Hysterectomy as a first-line treatment is effective without salvage chemotherapy in 82.4% of women with low-risk non-metastatic GTN and can be presented as an alternative to single-agent chemotherapy when childbearing considerations have been fulfilled. In young patients, this therapeutic option should not be considered because single-agent chemotherapies are curative in nearly 100% of patients while maintaining fertility.


Assuntos
Doença Trofoblástica Gestacional/cirurgia , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Humanos , Histerectomia/métodos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
5.
Int J Gynecol Cancer ; 28(5): 1038-1044, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29629964

RESUMO

OBJECTIVE: The objective of this study was to evaluate the characteristics and outcomes of patients treated for gestational trophoblastic neoplasia (GTN) with second-line 5-day dactinomycin after failed first-line 8-day methotrexate. METHODS: From 1999 to 2017, patients with methotrexate resistant GTN treated with second line dactinomycin were identified at the French Trophoblastic Disease Reference Center. Using univariate and multivariate analysis, we identified significant predictive factors of second line dactinomycin failure. RESULTS: A total of 877 GTN patients were treated with first-line 8-day methotrexate, of which 103 required second-line 5-day dactinomycin for methotrexate failure. Complete response was observed in 78 patients (75.7% [95% confidence interval, 66.3-83.6]; P < 0.0001), whereas 25 needed third-line treatment, 13 for dactinomycin resistance and 12 for post-dactinomycin relapse. Overall survival of patients treated with dactinomycin was 100%. An interval of greater than or equal to 7 months between antecedent pregnancy termination and methotrexate initiation was a predictive factor significantly associated with second-line dactinomycin failure in multivariate analysis (exact odds ratio, 9.17 [95% confidence interval, 1.98-50.70]; P = 0.0029). No grades 4 and 5 adverse effects were experienced and the most common toxicity being grade 1 nausea (14.6%). CONCLUSION: Given a 75.7% complete response rate in methotrexate failed low-risk GTN patients treated with second-line dactinomycin and an overall survival rate of 100% after third-line treatment, the use of dactinomycin should be favored as second-line, regardless of human chorionic gonadotropin level at the time of dactinomycin initiation. However, an interval between the termination of the antecedent pregnancy and methotrexate initiation longer than 6 months should encourage considering alternative therapeutic strategies.

6.
Clin Chim Acta ; 481: 1-8, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29476731

RESUMO

PURPOSES: Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming. We have developed a next-generation sequencing (NGS) panel to investigate metabolic causes of NIHF, ascites, and polyhydramnios associated to another fetal abnormality. METHODS: The hydrops fetalis (HydFet) panel was designed to cover the coding regions and flanking intronic sequences of 41 genes. A retrospective study of amniotic fluid samples from 40 subjects was conducted. A prospective study was subsequently initiated, and six samples were analyzed using the NGS panel. RESULTS: Five IEM diagnoses were made using the HydFet panel (Niemann-Pick type C (NPC), Barth syndrome, HNF1Β deficiency, GM1 gangliosidosis, and Gaucher disease). This analysis also allowed the identification of 8p sequence triplication in an additional case. CONCLUSION: NGS combined with robust bioinformatics analyses is a useful tool for identifying the causative variants of NIHF. Subsequent functional characterization of the protein encoded by the altered gene and morphological studies may confirm the diagnosis. This paradigm shift allows a significant improvement of IEM diagnosis in NIHF.


Assuntos
Hidropisia Fetal/genética , Hidropisia Fetal/metabolismo , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Adulto , Biologia Computacional , Feminino , Humanos , Hidropisia Fetal/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Gravidez , Estudos Retrospectivos , Análise de Sequência de DNA , Adulto Jovem
7.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Genética , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
8.
Acta Neuropathol Commun ; 5(1): 36, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28460636

RESUMO

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.


Assuntos
Proteínas de Transporte/genética , Epêndima/anormalidades , Doenças Fetais/genética , Hidrocefalia/genética , Mutação com Perda de Função , Adulto , Epêndima/diagnóstico por imagem , Família , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/etiologia , Doenças Fetais/patologia , Homozigoto , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/patologia
9.
Int J Gynecol Cancer ; 27(3): 554-561, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28060141

RESUMO

OBJECTIVE: Recently reported expression of programmed cell death 1 ligand 1 (PD-L1) in gestational trophoblastic diseases (GTDs) suggests that the immune tolerance of pregnancy might be hijacked during neoplastic process. We assessed PD-L1 protein expression in premalignant and malignant GTD lesions and analyzed associations with disease severity and chemotherapy outcomes. METHODS: We included 83 GTD whole-tissue sections from 76 patients in different treatment settings. PD-L1 protein expression was assessed with immunohistochemistry in each trophoblast subtype with the Allred total score (ATS), which combines intensity and proportion expression on a 0- to 8-point scale. Peritumoral immune infiltrate was scored on hematoxylin-eosin-safran-stained slides. RESULTS: PD-L1 expression was ubiquitous and strong in all GTD trophoblast subtypes. For invasive moles, ATS scores were maximal at 8 in 100%, 100%, and 75% of syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast specimens, respectively. For choriocarcinomas, ATS was 8 in 80% of specimens. Immune infiltrates were moderate to severe in 61%, 100%, and 100% of peritumoral zones of choriocarcinoma, epithelioid trophoblastic tumor, and invasive moles, respectively. Because of the homogeneous pathological findings, no significant differences in PD-L1 expression profiles or peritumoral immune infiltrates were found regarding FIGO (International Federation of Gynecology Obstetrics) prognostic score, fatal outcome, or chemosensitivity. CONCLUSIONS: We confirm that PD-L1 is constitutively expressed in all GTD premalignant and malignant trophoblast subtypes, independently from FIGO score, chemoresistance, or fatal outcomes, thereby suggesting a crucial role for PD-L1 in the development and tolerance of GTD. Assessment of anti-PD-L1 drug in GTD patients has been activated.


Assuntos
Antígeno B7-H1/biossíntese , Doença Trofoblástica Gestacional/imunologia , Lesões Pré-Cancerosas/imunologia , Trofoblastos/imunologia , Adulto , Antígeno B7-H1/imunologia , Estudos de Casos e Controles , Feminino , Doença Trofoblástica Gestacional/patologia , Humanos , Lesões Pré-Cancerosas/patologia , Gravidez , Prognóstico , Trofoblastos/patologia
10.
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
11.
Mol Cell Endocrinol ; 434: 69-80, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27302892

RESUMO

Mast cells are present in the human adult adrenal with a potential role in the regulation of aldosterone secretion in both normal cortex and adrenocortical adenomas. We have investigated the human developing adrenal gland for the presence of mast cells in parallel with steroidogenic enzymes profile and serotonin signaling pathway. RT-QPCR and immunohistochemical studies were performed on adrenals at 16-41 weeks of gestation (WG). Tryptase-immunopositive mast cells were found from 18 WG in the adrenal subcapsular layer, close to 3ßHSD- and CYP11B2-immunoreactive cells, firstly detected at 18 and 24 WG, respectively. Tryptophan hydroxylase and serotonin receptor type 4 expression increased at 30 WG before the CYP11B2 expression surge. In addition, HDL and LDL cholesterol receptors were expressed in the subcapsular zone from 24 WG. Altogether, our findings suggest the implication of mast cells and serotonin in the establishment of the mineralocorticoid synthesizing pathway during fetal adrenal development.


Assuntos
Glândulas Suprarrenais/embriologia , Aldosterona/metabolismo , Mastócitos/citologia , Serotonina/metabolismo , Transdução de Sinais , 3-Hidroxiesteroide Desidrogenases/genética , 3-Hidroxiesteroide Desidrogenases/metabolismo , Glândulas Suprarrenais/citologia , Glândulas Suprarrenais/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Mastócitos/metabolismo , Gravidez , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Triptases/genética , Triptases/metabolismo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
12.
Placenta ; 39: 116-24, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26992684

RESUMO

INTRODUCTION: Up to 20% of hydatidiform moles are followed by malignant transformation in gestational trophoblastic neoplasia and require chemotherapy. Syncytin-1 is involved in human placental morphogenesis and is also expressed in various cancers. We assessed the predictive value of the expression of Syncytin-1 and its interactants in the malignant transformation process of hydatidiform moles. METHODS: Syncytin-1 glycoprotein was localized by immunohistochemistry in hydatidiform moles, gestational trophoblastic neoplasia and control placentas. The transcription levels of its locus ERVWE1, its interaction partners (hASCT1, hASCT2, TLR4 and DC-SIGN) and two loci (ERVFRDE1 and ERV3) involved the expression of other placental envelopes were assessed by real-time PCR. RESULTS: Syncytin-1 glycoprotein was expressed in syncytiotrophoblast of hydatidiform moles with an apical enhancement when compared with normal placentas. Moles with further malignant transformation had a higher staining intensity of Syncytin-1 surface unit C-terminus but the transcription level of its locus ERVWE1 was not different from that of moles with further remission and normal placentas. hASCT1 and TLR4, showed lower transcription levels in complete moles when compared to normal placentas. ERVWE1, ERVFRDE1 and ERV3 transcription was down-regulated in hydatidiform moles and gestational trophoblastic neoplasia. CONCLUSIONS: Variations of Syncytin-1 protein localization and down-regulation of hASCT1 and TLR4 transcription are likely to reflect altered functions of Syncytin-1 in the premalignant context of complete moles. The reduced transcription in gestational trophoblastic diseases of ERVWE1, ERVFRDE1 and ERV3, which expression during normal pregnancy is differentially regulated by promoter region methylation, suggest a joint dysregulation mechanism in malignant context.


Assuntos
Transformação Celular Neoplásica/metabolismo , Produtos do Gene env/metabolismo , Mola Hidatiforme/metabolismo , Proteínas da Gravidez/metabolismo , Provírus/metabolismo , Trofoblastos/metabolismo , Neoplasias Uterinas/metabolismo , Transformação Celular Neoplásica/genética , Metilação de DNA , Feminino , Produtos do Gene env/genética , Humanos , Mola Hidatiforme/genética , Mola Hidatiforme/patologia , Gravidez , Proteínas da Gravidez/genética , Regiões Promotoras Genéticas , Provírus/genética , Transcrição Genética , Trofoblastos/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
13.
Eur J Med Genet ; 56(7): 365-70, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23643676

RESUMO

Cartilage-hair-hypoplasia is a rare autosomal recessive metaphyseal dysplasia due to RMRP (the RNA component of the RNase MRP ribonuclease mitochondrial RNA processing complex) gene mutations. So far, about 100 mutations have been reported in the promoter and the transcribed regions. Clinical characteristics include short-limbed short stature, sparse hair and defective cell-mediated immunity. We report herein the antenatal presentation of a female foetus, in whom CHH was suspected from 23 weeks' gestation, leading to a medical termination of the pregnancy at 34 weeks gestation, and thereafter confirmed by morphological and molecular studies. Post-mortem examination confirmed short stature and limbs, and revealed thymic hypoplasia associated with severe CD4 T-cell immunodeficiency along with extensive non caseating epithelioid granulomas in almost all organs, which to our knowledge has been described only in five cases. Molecular studies evidenced on one allele the most frequently reported founder mutation NR_003051: g.70A>G, which is present in 92% of Finnish patients with Cartilage Hair Hypoplasia. On the second allele, a novel mutation consisting of a 10 nucleotide insertion at position -18 of the promoter region of the RMRP gene (M29916.1:g.726_727insCTCACTACTC) was detected. The founder mutation was inherited from the father, and the novel mutation from the mother. To our knowledge, this case report represents the first detailed foetal analysis described in the literature.


Assuntos
Feto Abortado/patologia , Cabelo/anormalidades , Doença de Hirschsprung/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Osteocondrodisplasias/congênito , RNA Longo não Codificante/genética , Feminino , Granuloma/diagnóstico , Cabelo/embriologia , Doença de Hirschsprung/embriologia , Doença de Hirschsprung/genética , Humanos , Síndromes de Imunodeficiência/embriologia , Síndromes de Imunodeficiência/genética , Inflamação/diagnóstico , Transtornos Leucocíticos/diagnóstico , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/embriologia , Osteocondrodisplasias/genética , Gravidez , Diagnóstico Pré-Natal
14.
Ann Pathol ; 33(1): 57-61, 2013 Feb.
Artigo em Francês | MEDLINE | ID: mdl-23472897

RESUMO

We report on an unusually large teratoma of the umbilical cord associated with multiple fetal anomalies. At 18 WG, an umbilical cord tumour was discovered by ultrasonography in a 38 year-old woman. A 2680 g female neonate (46, XX) was delivered at 37 WG by caesarean section. During surgery for exomphalos, a complete bowel malrotation, ischemic jejunal stenoses and bowel duplication were discovered. The tumor (2515 g) was a teratoma supplied by collaterals of the umbilical vein. Proliferative index calculated by flow cytometry was less than 10%. Tumor karyotype revealed several numerical anomalies with no structural abnormalities using multi-FISH analysis. Immunostaining for CEA and AFP were observed in endodermic derivatives of the duplication and associated with transient high levels of AFP in the blood. To our knowledge, it is the first case to be reported in the literature where karyotype, multi-FISH and FCM studies were available.


Assuntos
Anormalidades Múltiplas/patologia , Teratoma/complicações , Teratoma/patologia , Cordão Umbilical , Feminino , Humanos , Recém-Nascido
15.
Brain ; 135(Pt 2): 469-82, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22323514

RESUMO

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


Assuntos
Encéfalo/patologia , Lissencefalia Cobblestone/genética , Lissencefalia Cobblestone/patologia , Distroglicanas/genética , Encéfalo/metabolismo , Lissencefalia Cobblestone/metabolismo , Distroglicanas/metabolismo , Feminino , Feto , Humanos , Recém-Nascido , Masculino , Manosiltransferases/genética , Manosiltransferases/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Proteínas/genética , Proteínas/metabolismo
16.
Eur J Med Genet ; 55(2): 81-90, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22226660

RESUMO

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS.


Assuntos
Feto/patologia , Fenótipo , Síndrome de Smith-Lemli-Opitz/patologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Observação
17.
Hum Reprod ; 26(10): 2651-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21840909

RESUMO

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


Assuntos
Doença Trofoblástica Gestacional/diagnóstico , Mola Hidatiforme/diagnóstico , Patologia/métodos , Neoplasias Trofoblásticas/diagnóstico , Adolescente , Adulto , Coriocarcinoma/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Mola Hidatiforme Invasiva/diagnóstico , Pessoa de Meia-Idade , Variações Dependentes do Observador , Gravidez , Complicações na Gravidez/diagnóstico , Encaminhamento e Consulta , Reprodutibilidade dos Testes , Estudos Retrospectivos
18.
Nat Genet ; 43(6): 601-6, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21552264

RESUMO

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.


Assuntos
Síndrome Acrocalosal/genética , Cinesina/genética , Síndrome Acrocalosal/patologia , Adolescente , Ventrículos Cerebrais/patologia , Criança , Pré-Escolar , Cílios/genética , Consanguinidade , Feminino , Deformidades Congênitas da Mão/embriologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Proteínas Hedgehog/metabolismo , Humanos , Hidrocefalia/embriologia , Hidrocefalia/genética , Hidrocefalia/patologia , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Linhagem
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