Diaphragm development and congenital diaphragmatic hernia
Section snippets
Normal embryology of the diaphragm
The basic structure of the diaphragm is established early in gestation and is intimately linked with the formation of the body cavities. The process can be broken down into several steps which are outlined below. All of the gestational ages referred to are given for rat development unless otherwise specified.
Abnormal embryology of the diaphragm
CDH can be phenotypically characterized into several subtypes depending on the location of the defect or its nature. The most common type of CDH, and the primary focus of this review, is the posterolateral diaphragm defect. Clinically referred to as a Bochdalek hernia, it accounts for greater than 95% of cases and is typically synonymous with the diagnosis of CDH.15, 16 We will also briefly discuss three rarer types of CDH, including eventration of the diaphragm, defects of the central tendon,
Animal models of Bochdalek CDH
In the 1970s, toxicological studies of the herbicide nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) showed that, although relatively harmless to adult rodents, nitrofen induced developmental anomalies in the lungs, hearts, diaphragms, and skeletal tissues of fetuses exposed in utero.23, 24 Further study showed that diaphragm defects could be induced by administering a single 100-mg dose of nitrofen to pregnant rats, typically between E8 and 11; and most significantly, the defects produced
Eventration of the diaphragm
Diaphragmatic eventration is a relatively uncommon class of CDH. It is characterized by incomplete muscularization of the diaphragm, allowing the abdominal contents to protrude into the thoracic cavity in the areas where no muscle has formed, and the diaphragm is subsequently weaker. The pathogenesis has not been thoroughly studied; however, the recent characterization of mice expressing a mutant form of Fog2, which have a phenotype consistent with diaphragmatic eventration as seen in humans,
Central tendon defects of the diaphragm
Central tendon defects are characterized by congenital herniation of abdominal contents through the central tendon of the diaphragm. The embryogenesis of this defect is poorly understood; failure to form, rupture, or stretching of the central tendon due to an underlying weakness have all been suggested to explain this defect.8 Mice with a null mutation in the Slit3 gene have central tendon defects similar to those seen in humans, shedding light on the etiology of this defect and providing a
Morgagni hernia
This rare anterior defect of the diaphragm is variably referred to as Morgagni, retrosternal, or parasternal hernia. It accounts for only ∼5% of all CDH cases. Interestingly, the incidence among children with Down’s syndrome may be as high as 1:1000.41 It is characterized by herniation of abdominal contents through the foramen of Morgagni; small triangular areas of the diaphragm adjacent to the lower end of the sternum. Embryologically, this area is considered congenitally weak and that this is
Conclusion
The improved understanding of diaphragm formation in normal and pathological circumstances has allowed us to construct a hypothetical model describing the origin of Bochdalek CDH (Figure 3). Central to this hypothesis is the PPF, a transient structure which forms early in diaphragm development and is the target for migratory muscle precursor cells and the phrenic nerve. Evidence from animal models suggests that it is a malformation of the nonmuscular component of the PPF that underlies the
Acknowledgments
This work is supported by Canadian Institute for Health Research, March of Dimes. JJG and RDC are scientist and studentship recipients from Alberta Heritage Foundation for Medical Research, respectively.
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