The diaphragm, a shelf of muscle that separates the chest cavity from the abdominal cavity, is critical to sustaining life. A life-threatening birth defect known as congenital diaphragmatic hernia (CDH), results from failure of normal diaphragm formation which in turn allows abdominal organs to migrate into the chest cavity. Abnormal lung development, so-called pulmonary hypoplasia, frequently co-occurs with CDH, and in fact is the major predictor of morbidity and mortality. This appears to arise from combined primary developmental defects of the lung, as well as mechanical compression from the displaced abdominal contents. CDH affects as many as 1 in 3,000 newborns and continues to have a mortality rate as high as 50 percent. Scientists have come to understand that it is not limited to a single or specific defect in the diaphragm and is often accompanied by other major malformations, usually relating to the lungs or cardiovascular development. There is also increasing evidence that genetic mutations in important developmental pathways contribute to CDH.
Four new reviews shed light on CHD by describing the diversity of the condition, exploring potential ways of treating it, using animal models to discover which genes play a role in diaphragm development, and examining its connection to cardiovascular malformations. The studies were published in May 2007 in a special issue of the American Journal of Medical Genetics Part C that examines the biology and genetics of CHD and is available online via Wiley InterScience at (http://www.interscience.wiley.com/journal/ajmgc).
In an introduction by Kate G. Ackerman and Barbara R. Pober of Harvard Medical School and several of the affiliated Harvard hospitals authors note that it is not known how many different types of diaphragm defects occur in humans or which types are developmentally related. They present a schematic developed to capture the full range of diaphragm defects which is currently in use by pediatric surgeons and pathologists at several institutions. "We anticipate that widespread use of a standard approach to CDH classification will improve the quality of information in the medical literature, and ultimately will be used to develop genotype-phenotype correlations," they state.
In the womb, fetal lung growth and maturation are strongly affected by the extent to which developing lungs are stretched by liquid that fills future airspaces. In the article by Paul A. Khan, Marc Cloutier, and Bruno Piedboeuf of the Centre de Recherche du Centre hospitalier de L'Universite Laval data are presented from examination of sheep, rabbit, rat and mice models of tracheal occlusion (TO). TO, a surgery that is performed in utero helps stimulate fetal lung growth and remedy pulmonary hypoplasia by closing the trachea, thus preventing fluid from leaving the lungs and causing them to be stretched. "TO not only promotes development of an increased gas exchange surface area, but also markedly remodels pulmonary vasculature and stimulates endothelial cell proliferation," the authors state. In all of the models they note that TO eliminates the thickening of fine blood vessels that afflicts CDH patients. "With future technical refinement and improved post-surgical care, TO may well become a more reliable and effective means of clinical intervention," they conclude.
Advances in understanding diaphragm development from the evaluation of genetic mouse models were discussed in an article by Ackerman and John J. Greer of the University of Alberta. They note that there are genes that are now known to play a role in diaphragm development, and that many of these genes are also important for cardiac and lung development. They describe the role of the transcription factor Fog2: "Fog2 is the first gene recognized to be necessary for both primary lung development and primary diaphragm development providing evidence for the hypothesis that diaphragmatic defects may be associated with primary lung defects." They note that other genes that are predicted to interact with Fog2, COUP-TFII and Gata4, are also necessary for diaphragm, cardiac, and lung development. Other mouse models of mutations linked to anterior or central diaphragm defects are also discussed, in particular the Slit genes, but a genetic association between Slit mutations and human diaphragm defects has not yet been found. The authors conclude: "Since humans with CDH often have lung, cardiac, and other defects, the discovery of genetic pathways controlling development independently in the thoracic and upper abdominal regions of the embryo or fetus will result in a better understanding of the disease."
The connection between CDH and cardiovascular malformations (CVMs) is the subject of another paper led by Angela E. Lin of Harvard Medical School and MassGeneral Hospital for Children in Boston, MA. The authors found that the frequency of CVMs co-occurring with CDH ranged from 10-50% depending on inclusion or exclusion of cases with genetic syndromes. Furthermore, they note that the most common types of CVMs were proportional to the frequency found in the general population. The combination of CVM and CDH results in a poorer prognosis than would be expected with either malformation alone. "However, the impact on these survival data from patients with a malformation syndrome or other genetic etiology has not been consistently evaluated, and we encourage researchers to re-analyze existing series and ensure that future studies distinguish CDH which is isolated from that which is associated with other malformations, especially as part of genetic syndromes," the authors state. In addition, they suggest that left ventricular "hypoplasia," commonly seen in prenatally diagnosed cases with CDH (in which the enlarged right ventricle compresses the left ventricle) is often reversible, unlike true hypoplasia in which the heart is underdeveloped. Accordingly, the diagnosis of hypoplastic left heart syndrome should be made with caution in fetuses with CDH.