Genetic Factors in the Etiology of Congenital Diaphragmatic Hernia

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

Congenital diaphragmatic hernia and chromosome 15q26: determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization

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

Environmental factors in the etiology of esophageal atresia and congenital diaphragmatic hernia: Results of a case-control study

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% Cl: 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% Cl: 1.65.2). 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. Birth Defects Research (Part A) 82:98-105, 2008. (c) 2008 Wiley-Liss, Inc

The importance of early recognition of Prader-Willi syndrome

Due to its rare nature and subtle dysmorphisms, Prader-Willi syndrome can be challenging to recognize and diagnose in the neonatal period. Feeding difficulties and hypotonia ('floppy infant') are the most striking characteristics. Prader-Willi syndrome requires specific follow-up and treatment, emphasizing the importance of early recognition.We encountered an infant of three months old with severe hypotonia. The hypotonia ameliorated spontaneously over time, although feeding per nasogastric tube was necessary. There were no apparent dysmorphisms. Extensive genetic investigations showed a maternal uniparental disomy of chromosome 15, fitting with Prader-Willi syndrome explaining all symptoms. After excluding contraindications, treatment with growth hormone therapy was started. Parents were educated regarding medical emergencies specific for Prader-Willi syndrome ('medical alerts'). Although Prader-Willi syndrome is rare, it should always be considered in cases of neonatal hypotonia. Early recognition is paramount as specific recommendations and treatment are warranted.</p