http://repub.eur.nl/res/aut/12558/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/26997/ 2009-09-01T00:00:00Z Congenital diaphragmatic hernia (CDH) is a severe birth defect characterized by a defect in the diaphragm associated with pulmonary hypoplasia and postnatal pulmonary hypertension. Half of the cases present with other non-pulmonary congenital anomalies (so called non-isolated CDH) and in 5-10% of cases there is a chromosomal etiology. The clinical aspects of CDH are well documented but knowledge on the etiology of CDH is largely lacking. Worldwide many researchers have focused research efforts on CDH. Their findings have led to several hypotheses proposing roles for genetic and environmental factors. In this review we have combined these findings with our own research on the genetics of CDH in results from recent literature and propose a theory on the etiology of CDH. We also propose a protocol for the CDH patient that will help clinicians and researchers to obtain maximal success out of their collaborations that will eventually lead to unravelling the etiology of this intriguing birth defect. http://repub.eur.nl/res/pub/30451/ 2008-03-01T00:00:00Z 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. http://repub.eur.nl/res/pub/10297/ 2007-06-20T00:00:00Z Congenital Diaphragmatic Hernia (CDH) is a relatively common birth defect in which a defect in diaphragm formation is associated with lung hypoplasia and pulmonary hypertension. CDH has a significant mortality of 50-80%, depending on the presence of associated anomalies and on the severity of the pulmonary abnormalities. The etiology of CDH is not known, but it is believed that both environmental and genetic factors contribute to its development. We have collected clinical data of approximately 400 CDH patients. DNA, cell lines and karyotypes are available of ~250 patients. To identify chromosomal regions and genes that play a role in the etiology of CDH we have used complementary molecular (cyto)genetic techniques to identify chromosomal abnormalities. Two of the regions we have identified are the CDH critical region on chromosome 15q26 and a larger region on chromosome 11q23-qter. We have also used high-resolution techniques, such as oligonucleotide-based array-CGH, combined with quantitative PCR, which has proven a fast and reliable method to screen for cryptic chromosomal anomalies in children with non-isolated CDH and which can be used for other congenital anomalies and/or mental retardation as well. The commonly deleted or duplicated regions and their candidate genes identified in patients with non-isolated CDH almost all play a role in retinoic acid metabolism and / or neural crest cell migration. Therefore we propose in the general discussion that both pathways are necessary for normal diaphragm- and lungdevelopment and that disruption at any point in these mechanisms can lead to the development of congenital diaphragmatic hernia. http://repub.eur.nl/res/pub/14013/ 2006-07-15T00:00:00Z Congenital diaphragmatic hernia (CDH) is a relatively common birth defect with a high mortality. Although little is known about its etiology, there is increasing evidence for a strong genetic contribution. Both numerical and structural chromosomal abnormalities have been described in patients with CDH. Partial trisomy 11q and partial trisomy 22 associated with the common t(11;22) has been reported in several cases of CDH. It has been assumed that the diaphragmatic defect seen in these individuals was primarily due to duplication of material from chromosome 22q11. However, in this report we describe a family with a t(11;12) in which one of two brothers with partial trisomy 11q has a left sided posterolateral CDH. This is the second case of CDH in partial trisomy 11q due to an unbalanced translocation other than t(11;22). Using array-based comparative genomic hybridization and fluorescent in situ hybridization, we mapped the breakpoints in both brothers and their mother who is a balanced translocation carrier. Our results suggest that duplication of one or more genes on a approximately 19 Mb region of 11q23.3-qter predisposes to the development of CDH. These effects may be the primary cause of CDH in individuals t(11;22) or may be additive to effects from the duplication of chromosome 22 material. We also conclude that the partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome. http://repub.eur.nl/res/pub/8486/ 2005-01-01T00:00:00Z Congenital diaphragmatic hernia (CDH) has an incidence of 1 in 3,000 births and a high mortality rate (33%-58%). Multifactorial inheritance, teratogenic agents, and genetic abnormalities have all been suggested as possible etiologic factors. To define candidate regions for CDH, we analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. This study focused on the most frequent structural anomaly found: a deletion on chromosome 15q. We analyzed material from three of our patients and from four previously published patients with CDH and a 15q deletion. By using array-based comparative genomic hybridization and fluorescent in situ hybridization to determine the boundaries of the deletions and by including data from two individuals with terminal 15q deletions but without CDH, we were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, one patient with CDH harbored a small interstitial deletion. Together, these findings allowed us to define a minimal deletion region of approximately 5 Mb at chromosome 15q26.1-26.2. The region contains four known genes, of which two--NR2F2 and CHD2--are particularly intriguing gene candidates for CDH.