Diaphragm development and congenital diaphragmatic hernia

doi:10.1053/j.sempedsurg.2007.01.004

Seminars in Pediatric Surgery

Volume 16, Issue 2, May 2007, Pages 94-100

https://doi.org/10.1053/j.sempedsurg.2007.01.004 Get rights and content

Advances in the understanding of normal diaphragm embryogenesis have provided the necessary foundation for novel insights into the pathogenesis of congenital diaphragmatic hernia (CDH). Although diaphragm formation is still not completely understood, we have identified key structures and periods of development that are clearly abnormal in animal models of CDH. The pleuroperitoneal fold (PPF) is a transient structure which is the target for the neuromuscular component of the diaphragm. The PPF has been shown to be abnormal in multiple animal models of Bochdalek CDH; specifically, a malformation of the nonmuscular component of this tissue is thought to underlie the later defect in the complete diaphragm. Based on data from animal models and the examination of human postmortem tissue, we hypothesize that abnormal PPF development underlies Bochdalek CDH. Further, the understanding of the pathogenesis of rarer subtypes of CDH will be advanced by the study of various new animal models discussed in this review.

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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Diaphragm development and congenital diaphragmatic hernia

Section snippets

Normal embryology of the diaphragm

Abnormal embryology of the diaphragm

Animal models of Bochdalek CDH

Eventration of the diaphragm

Central tendon defects of the diaphragm

Morgagni hernia

Conclusion

Acknowledgments

Semin Perinatol

Mech Dev

J Pediatr Surg

Curr Opin Cell Biol

Am J Pathol

J Surg Res

Paediatr Respir Rev

Toxicology

Am J Pathol

J Pediatr Surg

Am J Pathol

Mech Dev

J Pediatr Surg

Etiology of congenital diaphragmatic hernia: the retinoid hypothesis

Pediatr Res

Development of the human diaphragm and pleural sacs

Contrib Embryol

The developmental anatomy of congenital diaphragmatic hernia

Pediatr Surg Int

Embryology of congenital diaphragmatic hernia

Semin Pediatr Surg

Embryological origins and development of the rat diaphragm

J Comp Neurol

The diaphragm

Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb

Nature

Lbx1 is required for muscle precursor migration along a lateral pathway into the limb

Development