Genetic aspects of human congenital diaphragmatic hernia

Center for Human Genetics, Massachusetts General Hospital, Boston, MA 02114, USA.
Clinical Genetics (Impact Factor: 3.93). 08/2008; 74(1):1-15. DOI: 10.1111/j.1399-0004.2008.01031.x
Source: PubMed


Congenital diaphragmatic hernia (CDH) is a common major malformation affecting 1/3000-1/4000 births, which continues to be associated with significant perinatal mortality. Much current research is focused on elucidating the genetics and pathophysiology contributing to CDH to develop more effective therapies. The latest data suggest that many cases of CDH are genetically determined and also indicate that CDH is etiologically heterogeneous. The present review will provide a brief summary of diaphragm development and model organism work most relevant to human CDH and will primarily describe important human phenotypes associated with CDH and also provide recommendations for diagnostic evaluation of a fetus or infant with CDH.

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    • "However, a genetic basis is likely since families with recurrence of isolated CDH have been described, following all modes of Mendelian inheritance [Edwards, 1960; Norio et al., 1984; Torfs et al., 1992]. Chromosomal imbalances and monogenic syndromes represent important etiologies for nonisolated CDH [Holder et al., 2007; Pober, 2008; Stoll et al., 2008]. The development of array-CGH allowed the description of small recurrent chromosomal imbalances, leading to the identification of candidate genes. "
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    ABSTRACT: Congenital diaphragmatic hernia (CDH) has an incidence of around 1/3,000 births. The pathogenesis of this developmental anomaly remains largely unknown and the description of small chromosomal imbalances in cases of CDH is of major interest for the identification of candidate genes. We report on a tandem 4q31.23 triplication encompassing the EDNRA gene identified by array-CGH in a male presenting an isolated left postero-lateral CDH. This copy number variation was inherited from the asymptomatic father, carrier of a size-identical duplication. We demonstrate that EDNRA mRNA is over-expressed in the proband in blood tissue. Consistent with the expression of EDNRA in the developing diaphragm and the observation that the endothelin system is up-regulated in human and animal models of CDH, we conclude that the EDNRA triplication may be the cause of CDH in our patient. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1):208-12. DOI:10.1002/ajmg.a.36216 · 2.16 Impact Factor
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    • "Congenital Diaphragmatic Hernia (CDH) is a birth defect that occurs at a frequency of 1 in 2,500 live births (Torfs et al., 1992). This disease manifests as herniation of the abdominal contents into the thoracic cavity, severe pulmonary hypoplasia , and persistent pulmonary hypertension (Ackerman and Pober, 2007; Pober, 2008). Nitrofen is a diphenyl ether herbicide that induces pulmonary hypoplasia associated with CDH in rodents (Acosta et al., 2001a; Costlow and Manson, 1981; Iritani, 1984; Kluth et al., 1990). "
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    ABSTRACT: Nitrofen is a diphenyl ether that induces congenital diaphragmatic hernia (CDH) in rodents. Its mechanism of action has been hypothesized as inhibition of the retinaldehyde dehydrogenase (RALDH) enzymes with consequent reduced retinoic acid signaling. To determine if nitrofen inhibits RALDH enzymes, a reporter gene construct containing a retinoic acid response-element (RARE) was transfected into HEK-293 cells and treated with varying concentrations of nitrofen in the presence of retinaldehyde (retinal). Cell death was characterized by caspace-cleavage microplate assays and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays. Ex vivo analyses of cell viability were characterized in fetal rat lung explants using Live/Dead staining. Cell proliferation and apoptosis were assessed using fluorescent immunohistochemistry with phosphorylated histone and activated caspase antibodies on explant tissues. Nile red staining was used to identify intracellular lipid droplets. Nitrofen-induced dose-dependent declines in RARE-reporter gene expression. However, similar reductions were observed in control-reporter constructs suggesting that nitrofen compromised cell viability. These observed declines in cell viability resulted from increased cell death and were confirmed using two independent assays. Ex vivo analyses showed that mesenchymal cells were particularly susceptible to nitrofen-induced apoptosis while epithelial cell proliferation was dramatically reduced in fetal rat lung explants. Nitrofen treatment of these explants also showed profound lipid redistribution, primarily to phagocytes. The observed declines in nitrofen-associated retinoic acid signaling appear to be independent of RALDH inhibition and likely result from nitrofen induced cell death/apoptosis. These results support a cellular apoptotic mechanism of CDH development, independent of RALDH inhibition.
    Birth Defects Research Part B Developmental and Reproductive Toxicology 06/2010; 89(3):223-32. DOI:10.1002/bdrb.20247 · 0.77 Impact Factor
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    • "Indeed, the diaphragm does prevent movements of the abdominal viscera into the thoracic cavity (see Figs. 7 and 8) (Plagens and JBradbury, 1930). Genetically determined diaphragm defects in animals (posterior defects in mice with Couptf2 and Wtl genes alterations; anterior defects in slit3 knockout mice and Gata4 null carrier mice; muscularization defects in c-Met null mice and Fog2 hypomorphs: see Pober, 2008) and in humans (in the context of congenital diaphragm hernia ) are all associated with an invasion of the thoracic cavity by the liver and abdominal viscera, leading to various degrees of lung hypoplasia and compression that can be lethal (Yuan et al., 2003). Functioning as a visceral organizer and stabilizer may have been instrumental in allowing the concomitance of respiration and locomotion , later optimized to allow rapid, but above all sustained, locomotion. "
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    ABSTRACT: The comparatively low compliance of the mammalian lung results in an evolutionary dilemma: the origin and evolution of this bronchoalveolar lung into a high-performance gas-exchange organ results in a high work of breathing that cannot be achieved without the coupled evolution of a muscular diaphragm. However, despite over 400 years of research into respiratory biology, the origin of this exclusively mammalian structure remains elusive. Here we examine the basic structure of the body wall muscles in vertebrates and discuss the mechanics of costal breathing and functional significance of accessory breathing muscles in non-mammalian amniotes. We then critically examine the mammalian diaphragm and compare hypotheses on its ontogenetic and phylogenetic origin. A closer look at the structure and function across various mammalian groups reveals the evolutionary significance of collateral functions of the diaphragm as a visceral organizer and its role in producing high intra-abdominal pressure.
    Respiratory Physiology & Neurobiology 04/2010; 171(1):1-16. DOI:10.1016/j.resp.2010.01.004 · 1.97 Impact Factor
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