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1.
Hum Mutat ; 40(8): 1013-1029, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31021519

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

2.
Am J Hum Genet ; 104(4): 709-720, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905399

RESUMO

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

3.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

4.
Hum Genet ; 2018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29754270

RESUMO

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

6.
Eur J Hum Genet ; 25(10): 1126-1133, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28905882

RESUMO

Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34 bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1Δ) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Δ promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2Δ)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia.


Assuntos
Atresia das Cóanas/genética , Surdez/congênito , Deleção de Genes , Cardiopatias Congênitas/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Atresia das Cóanas/diagnóstico , Surdez/diagnóstico , Surdez/genética , Facies , Feminino , Cardiopatias Congênitas/diagnóstico , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Regiões Promotoras Genéticas
7.
Eur J Endocrinol ; 177(2): 115-125, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28490599

RESUMO

OBJECTIVE: Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations. DESIGN: Retrospective descriptive study. METHODS: Retrospective descriptive study in seven academic centers. RESULTS: We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0-36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423 + 1G > A). CONCLUSIONS: In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.


Assuntos
Mutação em Linhagem Germinativa/genética , Heterozigoto , Fenótipo , Succinato Desidrogenase/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Paraganglioma/diagnóstico , Paraganglioma/epidemiologia , Paraganglioma/genética , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Estudos Retrospectivos , Adulto Jovem
8.
Eur J Hum Genet ; 25(3): 308-314, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28000701

RESUMO

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.


Assuntos
Exoma , Testes Genéticos/estatística & dados numéricos , Perda Auditiva/genética , Análise de Sequência de DNA/estatística & dados numéricos , Conexinas/genética , Variações do Número de Cópias de DNA , Proteínas da Matriz Extracelular/genética , Proteínas Ligadas por GPI/genética , Testes Genéticos/normas , Perda Auditiva/diagnóstico , Perda Auditiva/epidemiologia , Humanos , Proteínas de Membrana/genética , Mutação , Cadeias Pesadas de Miosina/genética , Miosinas/genética , Países Baixos , Análise de Sequência de DNA/normas
9.
Hum Mutat ; 37(8): 732-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27158814

RESUMO

TCF12-related craniosynostosis can be caused by small heterozygous loss-of-function mutations in TCF12. Large intragenic rearrangements, however, have not been described yet. Here, we present the identification of four large rearrangements in TCF12 causing TCF12-related craniosynostosis. Whole-genome sequencing was applied on the DNA of 18 index cases with coronal synostosis and their family members (43 samples in total). The data were analyzed using an autosomal-dominant disease model. Structural variant analysis reported intragenic exon deletions (of sizes 84.9, 8.6, and 5.4 kb) in TCF12 in three different families. The results were confirmed by deletion-specific PCR and dideoxy-sequence analysis. Separately, targeted sequencing of the TCF12 genomic region in a patient with coronal synostosis identified a tandem duplication of 11.3 kb. The pathogenic effect of this duplication was confirmed by cDNA analysis. These findings indicate the importance of screening for larger rearrangements in patients suspected to have TCF12-related craniosynostosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Craniossinostoses/genética , Análise de Sequência de DNA/métodos , Deleção de Sequência , Sequências de Repetição em Tandem , Sequência de Bases , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Linhagem
10.
Nat Biotechnol ; 32(10): 1019-25, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25129690

RESUMO

Despite developments in targeted gene sequencing and whole-genome analysis techniques, the robust detection of all genetic variation, including structural variants, in and around genes of interest and in an allele-specific manner remains a challenge. Here we present targeted locus amplification (TLA), a strategy to selectively amplify and sequence entire genes on the basis of the crosslinking of physically proximal sequences. We show that, unlike other targeted re-sequencing methods, TLA works without detailed prior locus information, as one or a few primer pairs are sufficient for sequencing tens to hundreds of kilobases of surrounding DNA. This enables robust detection of single nucleotide variants, structural variants and gene fusions in clinically relevant genes, including BRCA1 and BRCA2, and enables haplotyping. We show that TLA can also be used to uncover insertion sites and sequences of integrated transgenes and viruses. TLA therefore promises to be a useful method in genetic research and diagnostics when comprehensive or allele-specific genetic information is needed.


Assuntos
Genômica/métodos , Haplótipos/genética , Modelos Genéticos , Técnicas de Amplificação de Ácido Nucleico/métodos , Análise de Sequência de DNA/métodos , Fusão Gênica/genética , Genes BRCA1 , Genes BRCA2 , Loci Gênicos/genética , Humanos , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética
11.
J Clin Endocrinol Metab ; 96(9): E1472-6, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21752896

RESUMO

CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. OBJECTIVE: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. SETTING: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). METHODS: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. RESULTS: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. CONCLUSIONS: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Complexo II de Transporte de Elétrons/genética , Mutação em Linhagem Germinativa , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Alelos , Análise Mutacional de DNA , Complexo II de Transporte de Elétrons/metabolismo , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Paraganglioma/metabolismo , Feocromocitoma/metabolismo
12.
Mol Cytogenet ; 2: 15, 2009 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-19594915

RESUMO

BACKGROUND: Complex chromosomal rearrangements (CCR) are rare cytogenetic findings that are difficult to karyotype by conventional cytogenetic analysis partially because of the relative low resolution of this technique. High resolution genotyping is necessary in order to identify cryptic imbalances, for instance near the multiple breakpoints, to explain the abnormal phenotype in these patients. We applied several molecular techniques to elucidate the complexity of the CCRs of two adult patients with abnormal phenotypes. RESULTS: Multicolour fluorescence in situ hybridization (M-FISH) showed that in patient 1 the chromosomes 1, 10, 15 and 18 were involved in the rearrangement whereas for patient 2 the chromosomes 5, 9, 11 and 13 were involved. A 250 k Nsp1 SNP-array analysis uncovered a deletion in chromosome region 10p13 for patient 1, harbouring 17 genes, while patient 2 showed no pathogenic gains or losses. Additional FISH analysis with locus specific BAC-probes was performed, leading to the identification of cryptic interstitial structural rearrangements in both patients. CONCLUSION: Application of M-FISH and SNP-array analysis to apparently balanced CCRs is useful to delineate the complex chromosomal rearrangement in detail. However, it does not always identify cryptic imbalances as an explanation for the abnormal phenotype in patients with a CCR.

13.
Curr Opin Obstet Gynecol ; 21(4): 313-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19610175

RESUMO

PURPOSE OF REVIEW: Premature ovarian insufficiency (POI) is a common disorder affecting approximately 1% of women under the age of 40 years. Until now, research aiming to identify genetic causes of POI was mostly based on candidate gene approaches. Recently, several genes have been identified using this approach, and genome-wide searches were conducted. In this review, we discuss these studies and propose future direction for further research in this field. RECENT FINDINGS: Candidate gene approach revealed NOBOX, NR5A1, FIGLA and PGRMC1 as POI-genes. Genome-wide searches (linkage and association studies) are revealing new loci/genes as well. SUMMARY: The role in POI for most reported candidate genes is still under discussion. Because POI families with several affected cases are rare, linkage studies are difficult to conduct; however, the reported loci needs further exploration/replication. In the only genome-wide association studies conducted, the patient cohort used is very small and the reported results are awaiting replication. Unravelling the genetics of POI will need the establishment of a large international consortium.


Assuntos
Ligação Genética , Polimorfismo Genético , Insuficiência Ovariana Primária/genética , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos
14.
Birth Defects Res A Clin Mol Teratol ; 82(2): 98-105, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18172903

RESUMO

BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and congenital diaphragmatic hernia (CDH) are severe congenital anomalies. Their etiologies are mostly unknown and are thought to be multifactorial. No specific environmental factors have consistently been described as risk factors. METHODS: In a study conducted during the years 2000 to 2004 in a pediatric surgical referral center in the Netherlands, parents of children with EA/TEF or with CDH of the Bochdalek type and parents of a group of children without major birth defects filled out a questionnaire about possible exposure to environmental risk factors during the period from 1 month before conception to the end of the first trimester of pregnancy. Children with chromosomal anomalies were excluded. RESULTS: Questionnaires were returned for 47 out of 64 cases (73%) with EA/TEF, for 63 out of 77 cases (82%) with CDH, and for 202 out of 243 controls (83%). In EA/TEF, maternal age was borderline significantly higher than in controls (32.2 vs. 30.6 years, p = .05). Contact with herbicides or insecticides was associated with EA/TEF in univariate analysis (OR 2.0; 95% CI: 1.0-4.1) and in multivariate analysis, although of borderline significance. In univariate analysis, CDH was significantly associated with maternal use of alcohol (OR 2.9; 95% CI: 1.6-5.2). CONCLUSIONS: We found a significant association between maternal alcohol use around the time of conception and CDH. A possible explanation might be the effect of alcohol on the retinoic acid pathway. An association was found between contact with herbicides or insecticides and EA/TEF.


Assuntos
Atresia Esofágica/etiologia , Hérnia Diafragmática/etiologia , Hérnias Diafragmáticas Congênitas , Adulto , Estudos de Casos e Controles , Meio Ambiente , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Inquéritos e Questionários
15.
Artigo em Inglês | MEDLINE | ID: mdl-18186125

RESUMO

BACKGROUND: The VACTERL association is the nonrandom co-occurrence of Vertebral anomalies, Anal atresia, Cardiovascular malformations, Tracheo-esophageal fistula (TEF) and/or Esophageal atresia (EA), Renal anomalies, and/or Limb-anomalies. The full phenotype of patients with EA/TEF and other anomalies of the VACTERL spectrum of defects association is not well described in the literature. METHODS: Data on patients with EA/TEF seen in two pediatric surgical centers in the Netherlands between January 1988 and August 2006 were evaluated for defects of the VACTERL spectrum as well as non-VACTERL-type defects. The presence of two or more defects of the VACTERL spectrum in addition to EA/TEF was the criterion for inclusion in this study. A detailed description was made of all defects. RESULTS: Of 463 patients with EA and/or TEF, 107 (23.1%) fulfilled the inclusion criterion, of which seventeen cases had a recognized etiology and were excluded, leaving 90 cases (19.4%) for analysis. Other than the esophagus and the trachea, the vertebrae/ribs and the cardiovascular system were most commonly affected (68.9 and 65.6%, respectively). Interestingly, 70% of cases had additional non-VACTERL-type defects, with high occurrences for single umbilical artery (20%), genital defects (23.3%), and respiratory tract anomalies (13.3%). CONCLUSIONS: Many patients with EA/TEF and at least two other defects of the VACTERL spectrum also display non-VACTERL-type congenital anomalies.


Assuntos
Anormalidades Múltiplas/epidemiologia , Atresia Esofágica/diagnóstico , Fístula Traqueoesofágica/diagnóstico , Anormalidades Múltiplas/etiologia , Adulto , Aberrações Cromossômicas , Atresia Esofágica/etiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Recém-Nascido , Cariotipagem , Deformidades Congênitas dos Membros/epidemiologia , Gravidez , Fístula Traqueoesofágica/etiologia
16.
Pediatr Dev Pathol ; 7(5): 459-67, 2004 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15547770

RESUMO

Congenital diaphragmatic hernia (CDH) is a severe life-threatening disease, with an incidence of 3 per 10,000 births, that can occur as an isolated defect or in combination with other congenital anomalies. We reviewed the clinical and autopsy reports of 39 subjects with CDH that were autopsied between 1988 and 2001 to determine whether autopsy had an additional value in the detection of malformations in patients with CDH. We compared the clinical data (including echographic results in some patients) concerning congenital anomalies with the autopsy results. Before autopsy, 6 structural cardiac defects, 3 anomalies of the urogenital system, and 3 anomalies of the digestive tract were observed in 10 patients (clinical and echographic results). However, with postmortem examination, only 4 structural cardiac defects were confirmed, 2 cases showed another cardiac anomaly, and 7 new cardiac defects were found. In the urogenital system, 1 anomaly was confirmed, 1 was not confirmed, and 1 showed another malformation. In addition, in 7 patients new urogenital malformations were found after autopsy. In the digestive tract, all 3 malformations were confirmed, but we found 3 new malformations after postmortem examination. All clinically established dysmorphic features and anomalies of the skeletal system and central nervous system were confirmed by autopsy, and no additional malformations were found. We concluded that postmortem examination has an important additional role in the detection of structural cardiac defects and malformations of the urogenital system and digestive tract in children with CDH.


Assuntos
Anormalidades Múltiplas/patologia , Autopsia , Hérnia Diafragmática/patologia , Hérnias Diafragmáticas Congênitas , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos
18.
Birth Defects Res A Clin Mol Teratol ; 67(8): 578-84, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-14632307

RESUMO

BACKGROUND: The pathogenesis of congenital diaphragmatic hernia (CDH), a severe birth defect, is not well understood; however, both developmental genes and environmental factors have been suggested to be involved. CDH is frequently associated with malformations of other structures, such as limbs, whose embryogenesis is better understood. An examination of the co-occurrence of developmental defects may provide clues as to the origin and timing of the insult to the diaphragm and limbs. Our focus was on CDH-associated limb-reduction defects (LRDs). METHODS: For this descriptive study, we reviewed the medical records of infants with a posterolateral (Bochdalek) CDH and an associated LRD among 146 patients from the Sophia Children's Hospital, and among 810 infants and 36 stillbirths from the California Birth Defects Monitoring Program (CBDMP). RESULTS: In the hospital group, 14 patients (10%) had an associated limb defect, of which about one-third were LRDs (of these, most were of a nonsevere type, such as hypoplasia of fingers). In the registry group, a limb defect was found in 162 cases (18.5%), 18 of which were mostly severe LRD (usually of the upper extremities). Additional congenital anomalies were observed in all CDH-LRD cases in both groups. CONCLUSIONS: In the registry group, 77.8% of LRDs were either bilateral or ipsilateral, and were mostly preaxial, suggesting an early embryological insult affecting both precursor anlages. These results, from large numbers of cases, support the notion of a developmental association between CDH and LRD, as has been observed in several knockout mice. Future analyses of candidate genes from patients with CDH and LRD may elucidate this developmental association in humans.


Assuntos
Hérnias Diafragmáticas Congênitas , Deformidades Congênitas dos Membros , Feminino , Dedos/anormalidades , Hérnia Diafragmática/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Registros Médicos
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