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2.
J Med Genet ; 55(6): 422-429, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29459493

RESUMO

BACKGROUND: Segmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV. PATIENTS AND METHODS: We used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3, MESP2, LFNG, HES7 and TBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients. RESULTS: Ten diagnoses, including four biallelic variants in TBX6, two biallelic variants in LFNG and DLL3, and one in MESP2 and HES7, were made with the gene panel, and two diagnoses, including biallelic variants in FLNB and one variant in MEOX1, were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%). CONCLUSION: After negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.

3.
Eur J Med Genet ; 60(11): 595-604, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28807864

RESUMO

BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.


Assuntos
Exoma , Testes Genéticos/normas , Análise de Sequência de DNA/normas , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos , Fatores de Tempo
4.
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
5.
Am J Hum Genet ; 97(2): 311-8, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166481

RESUMO

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


Assuntos
Proteínas de Ciclo Celular/genética , Transtornos da Motilidade Ciliar/genética , Códon sem Sentido/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Hidrocefalia/genética , Fenótipo , Síndrome de Costela Curta e Polidactilia/genética , Sequência de Bases , Transtornos da Motilidade Ciliar/patologia , Europa Oriental , Evolução Fatal , Efeito Fundador , Humanos , Funções Verossimilhança , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
6.
Prenat Diagn ; 35(7): 675-84, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25754886

RESUMO

OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.


Assuntos
Condrodisplasia Punctata/diagnóstico por imagem , Fenótipo , Índice de Gravidade de Doença , Ultrassonografia Pré-Natal , Condrodisplasia Punctata/genética , Feminino , Marcadores Genéticos , Testes Genéticos , Humanos , Recém-Nascido , Mutação , Gravidez , Segundo Trimestre da Gravidez , Radiografia , Estudos Retrospectivos , Esteroide Isomerases/genética , Inativação do Cromossomo X
7.
Clin Neuropathol ; 34(2): 70-5, 2015 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25492889

RESUMO

AIM: Congenital infantile fibrosarcoma (CIFS) exceptionally occurs in the meninges, with no cases reported before or at birth. We report herein a meningeal CIFS diagnosed in a fetus at 40 weeks of gestation (WG). CASE REPORT: A 24-year-old pregnant woman was referred to the obstetrics department for vaginal bleeding. A severe right hydrocephalus due to a large tumor invading the left hemisphere and ventricles was discovered in the fetus, and medical termination of the pregnancy was achieved. RESULTS: Histological examination revealed a highly cellular spindle or ovoid shaped cell proliferation organized in interlacing bundles; it was diffusely positive for vimentin, and scarcely for SMA (smooth muscle actin). NFs (neurofilaments), NeuN, S100 protein, desmin, GFAP (glial fibrillary acidic protein), Olig2, chromogranin, synaptophysin, CD31, CD34, BCL2, and EMA (epithelial membrane antigen) antibodies were negative. Ki67 antibody labeled 20% of the nuclei. A reverse transcription polymerase chain reaction assay was performed to detect the gene fusion ETV6-NTRK3 transcript. Despite negative results, it was concluded to be a CIFS of the meninges. DISCUSSION: CIFS of the meninges during the fetal period has never been reported. Its diagnosis is based on immunohistochemistry, and, whenever possible, on the detection of the reciprocal translocation t (12;15) resulting in the gene fusion ETV6-NTRK3. Its prognosis depends on rapid growth and local invasiveness leading to cerebral structure damage.


Assuntos
Feto/patologia , Fibrossarcoma/congênito , Neoplasias Meníngeas/congênito , Feminino , Humanos , Gravidez , Diagnóstico Pré-Natal , Adulto Jovem
8.
Am J Reprod Immunol ; 73(1): 79-90, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25263526

RESUMO

PROBLEM: To evaluate the inflammatory pattern in maternal circulation from women with preterm premature rupture of membranes (PPROM) considering the occurrence of histologically confirmed chorioamnionitis (HCA). METHOD OF STUDY: A prospective study was conducted in 121 women with PPROM between 24 and 34 + 0 weeks of gestation. Association between white blood cells (WBC) count, plasma CRP, IL-6, MCP-1 and IP-10 levels, and HCA was assessed. RESULTS: The rate of HCA was 44.7% (54/121). During the 5 days preceding delivery, median CRP, WBC, and IL-6 levels were significantly higher in the HCA than in no-HCA group (P < 0.001). Variations in IL-6, IP-10 levels, during the 24-72 hr before delivery, were predictors of the occurrence of HCA, but the diagnostic accuracy was low [Receiver Operating Characterictic (ROC) curve, area under the curve (AUC) = 0.56]. CONCLUSION: An increase in IL-6, CRP, IP-10 maternal plasma levels was confirmed in PPROM women with HCA. Longitudinal follow-up of these markers did not add valuable information regarding HCA.


Assuntos
Âmnio/patologia , Corioamnionite/diagnóstico , Trabalho de Parto Prematuro/diagnóstico , Ruptura/diagnóstico , Adulto , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Corioamnionite/imunologia , Citocinas/sangue , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Trabalho de Parto Prematuro/imunologia , Circulação Placentária/imunologia , Valor Preditivo dos Testes , Gravidez , Prognóstico , Estudos Prospectivos , Ruptura/imunologia
9.
Am J Obstet Gynecol ; 210(1): 70.e1-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23994222

RESUMO

OBJECTIVES: To study the influence of pregnancy and labor on the proportion and level of activation of monocyte subpopulations in human pregnancy. STUDY DESIGN: Peripheral blood samples were obtained from healthy nonpregnant women (n = 6); women in the third-trimester of healthy pregnancies (n = 18) and women with preterm premature rupture of membranes (n = 46), just before delivery for the last 2 groups. Monocyte subpopulations were characterized by flow cytometry using CD14, CD16, and activation level using macrophage chemoattractant protein-1 (MCP-1) and CCR2 antibodies. RESULTS: The relative proportion of each monocyte subset in nonpregnant women was similar to that in women with healthy or complicated pregnancies. However, pregnancy was associated with a significant decrease in MCP-1 expressing monocytes (79.5% ± 19.8% vs 9.3% ± 6.8% and 11.9% ± 8.3% for nonpregnant, healthy pregnancy, and preterm premature rupture of membranes (respectively, P < .05). Spontaneous labor was associated with a return to nonpregnant values for the proportion of MCP-1 expressing monocytes in both normal (74.4% ± 16.9) and preterm premature rupture of membranes pregnancy (68.4% ± 35.6), irrespective of the mode of delivery (vaginal or cesarean section). This was not observed in women who delivered without spontaneous labor onset. CCR-2 (MCP-1 receptor) expression was not modified in monocytes at the time of labor, but was significantly increased in granulocytes (3646 ± 1080 vs 7338 ± 2718 for nonlaboring and laboring preterm premature rupture of membranes, respectively, P < .05) CONCLUSION: In light of previous reports of a role for MCP-1 in labor, our results suggest the downregulation of activation levels of monocytes, via MCP-1 expression might be involved in maternofetal immune tolerance. Monocyte reactivation might be associated with labor.


Assuntos
Biomarcadores/sangue , Quimiocina CCL2/sangue , Ruptura Prematura de Membranas Fetais/sangue , Trabalho de Parto/sangue , Receptores de Lipopolissacarídeos/sangue , Monócitos/metabolismo , Trabalho de Parto Prematuro/sangue , Terceiro Trimestre da Gravidez/sangue , Receptores de IgG/sangue , Adolescente , Adulto , Feminino , Citometria de Fluxo , Humanos , Gravidez , Estudos Prospectivos , Adulto Jovem
10.
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
11.
J Med Genet ; 49(11): 713-20, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23125460

RESUMO

BACKGROUND: Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome. METHODS: We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies. RESULTS: Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases. CONCLUSIONS: These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS.


Assuntos
Síndrome Acrocalosal/genética , Cinesina/genética , Mutação , Síndrome Acrocalosal/diagnóstico , Síndrome Acrocalosal/fisiopatologia , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/fisiopatologia , Pré-Escolar , Feminino , Feto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polidactilia/diagnóstico , Polidactilia/fisiopatologia
12.
J Med Genet ; 49(11): 698-707, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23024289

RESUMO

BACKGROUND: CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances. METHOD: Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed. RESULTS: Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype-genotype correlation. CONCLUSIONS: Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.


Assuntos
Síndrome CHARGE , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Mutação , Anormalidades Múltiplas/genética , Adulto , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Síndrome CHARGE/fisiopatologia , Criança , Feminino , Feto , Humanos , Masculino , Fenótipo , Gravidez , Complicações na Gravidez , Estudos Retrospectivos
13.
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
14.
Hum Mutat ; 33(2): 316-26, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22095942

RESUMO

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.


Assuntos
Genes Recessivos , Mutação , Sistema Renina-Angiotensina/genética , Anormalidades Urogenitais/genética , Angiotensinogênio/genética , Animais , Modelos Animais de Doenças , Estudos de Associação Genética , Humanos , Túbulos Renais Proximais/anormalidades , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Renina/genética , Anormalidades Urogenitais/diagnóstico
16.
Eur J Med Genet ; 50(1): 85-91, 2007 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17056308

RESUMO

Casamassima-Morton-Nance syndrome belongs to the heterogeneous group of spondylocostal dysostoses (SCD) represented by a large heterogeneous group in which diverse diagnoses, associations and modes of inheritance are found. Common features include segmentation abnormalities of the vertebrae and ribs. Here, we report on a fetal case with spondylocostal dysostosis, anal and genitourinary malformations and discuss Casamassima-Morton-Nance syndrome.


Assuntos
Anormalidades Múltiplas/genética , Canal Anal/anormalidades , Disostoses/patologia , Anormalidades Urogenitais/genética , Disostoses/genética , Feto/anormalidades , Humanos , Costelas/anormalidades , Coluna Vertebral/anormalidades , Síndrome
17.
Am J Hum Genet ; 80(1): 186-94, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17160906

RESUMO

Joubert syndrome (JS) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in two genes, AHI1 and CEP290, identified to date. In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly. Occipital encephalocele and/or polydactyly have occasionally been reported in some patients with JS, and these phenotypic features can also be observed in Meckel-Gruber syndrome (MKS). MKS is a rare, autosomal recessive lethal condition characterized by central nervous system malformations (typically, occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. Since there is obvious phenotypic overlap between JS and MKS, we hypothesized that mutations in the recently identified MKS genes, MKS1 on chromosome 17q and MKS3 on 8q, may be a cause of JS. After mutation analysis of MKS1 and MKS3 in a series of patients with JS (n=22), we identified MKS3 mutations in four patients with JS, thus defining MKS3 as the sixth JS locus (JBTS6). No MKS1 mutations were identified in this series, suggesting that the allelism is restricted to MKS3.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Membrana/genética , Adolescente , Encéfalo/anormalidades , Cerebelo/patologia , Criança , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Feminino , Feto/anormalidades , Humanos , Rim/anormalidades , Fígado/anormalidades , Masculino , Mutação , Gravidez , Proteínas/genética , Síndrome
18.
Eur J Med Genet ; 50(1): 48-53, 2007 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17067864

RESUMO

Here we describe the clinical, histopathological and molecular studies of a female proband that died at 2 months of age in the context of a syndromic polymicrogyria. There was no significant family history. Clinical and radiological features included poor contact, cleft palate, facial dysmorphic features with frontal bossing, down-slanting and small palpebral fissures, inferior epicanthic folds, low-set and malformed ears, flat nose, retrognathism and short neck, minor limb anomalies, polymicrogyria that appear more severe in the perisylvian regions and cerebellar vermis hypoplasia. Autopsy findings revealed a patent foramen ovale with persistent left superior vena cava, left renal hypoplasia and microphthalmia. This description does not fit with any of the known syndromes with polymicrogyria and cytogenetic analyses including standard and high resolution chromosome analyses, telomeric FISH studies and array-CGH were normal. Consequently, the reported features in this child are unique and are likely to represent a new syndrome.


Assuntos
Cerebelo/anormalidades , Fissura Palatina/patologia , Ossos Faciais/anormalidades , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome
19.
Prenat Diagn ; 26(12): 1151-5, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17009344

RESUMO

BACKGROUND: We report a 19-week gestation female foetus with a new syndrome characterised by increased nuchal translucency and severe micromelia with campomelia evident from the early second trimester. METHODS AND RESULTS: Cytogenetic studies performed on amniocytes revealed a normal female karyotype. Autopsy after termination of pregnancy showed facial dysmorphism, cleft palate, bowed, shortened limbs, hypoplasia of the preaxial elements in all four limbs with accompanying accessory ossification centres in the feet, and severe calvarial underossification. A diagnosis of otopalatodigital syndrome type 2, associated with mutations in FLNA, a gene encoding the cytoskeletal protein filamin A, was considered but discarded due to the severity of micromelia, early lethality, and the presence of generalised osteopenia instead of hyperostosis. The degree of undermodelling and campomelia was reminiscent of another group of conditions that include atelosteogenesis types 1 and 3, caused by mutations in FLNB. Sequencing analysis did not reveal any pathogenic mutation in the three paralogous filamin genes: FLNA, FLNB and FLNC. CONCLUSION: Clinical, radiological and cytogenetic findings suggest that this phenotype is a new entity whose aetiopathogenesis may be functionally related to the filaminopathies.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Face/anormalidades , Osteocondrodisplasias/diagnóstico por imagem , Polidactilia/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Aborto Induzido , Adulto , Autopsia , Doenças Ósseas Metabólicas/patologia , Fissura Palatina/diagnóstico por imagem , Proteínas Contráteis/genética , Análise Citogenética , Feminino , Doenças Fetais/diagnóstico por imagem , Filaminas , Humanos , Proteínas dos Microfilamentos/genética , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Polidactilia/patologia , Gravidez , Ultrassonografia
20.
J Am Soc Nephrol ; 17(8): 2253-63, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16790508

RESUMO

Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.


Assuntos
Genes Recessivos , Túbulos Renais/anormalidades , Oligo-Hidrâmnio , Sistema Renina-Angiotensina/fisiologia , Anuria/etiologia , Feminino , Morte Fetal/etiologia , Homozigoto , Humanos , Imuno-Histoquímica , Recém-Nascido , Túbulos Renais/patologia , Masculino , Gravidez , Crânio/patologia
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