The only relatively common malformation of the diaphragm is congenital diaphragmatic hernia (CDH), which occurs once in every 4000 births (Nordenskjold et al., 1996). CDH results from the malformation or malfusion of the pleuroperitoneal membranes with the other components of the diaphragm, which is supposed to completely separate the pleural and peritoneal cavities (Moore, 1982; Nordenskjold et al., 1996). The defect is a large opening in the posterior or posterolateral region of the diaphragm, near the kidney, and occurring five times more often on the left than on the right because of the earlier closure of the right pleuroperitoneal opening. The fusion of the pleuroperitoneal membranes with other components of the diaphragm is supposed to occur by the end of the sixth week. If it has not fused by the time the intestines return to the abdomen from the extraembryonic coelum and umbilical cord area during the tenth week, the intestines will continue their migration into the thoracic cavity. The stomach and spleen often herniate into the thorax as well. More serious herniation occurs when the liver and kidneys also migrate into the thorax region and displace the heart (pulmonary hypoplasia) and lungs. Sometimes the hole is large enough that the abdominal organs can pass freely back and forth between the abdomen and the thorax, their position dependent on whether the infant is lying down or upright. The mortality rate for CDH is 30-40% if the symptoms are recognized on the first day of life; if symptoms are not recognized until later, the mortality rate is close to 100% (Nordenskjold et al., 1996).
Because abnormalities related to CDH include anencephaly, urogenital abnormalities, cleft palate, and cardiovascular malformations, Nordenskjold et al. (1996) sought to determine whether the WT1 gene, the Wilms' tunmor gene, might be involved. Wilms' tumor is a fast-growing cancerous tumor of the kidney that affects mostly children and is composed of embryonic tissues. WT1 is on chromosome 11, band p13, and has 10 exons. The gene is important in urogenital system formation; it is expressed in the fetal gonad, urogenital ridge, primitive kidney, the mesothelium surrounding the peritoneum, pleura, and pericardium, and in the spleen.
The researchers used knockout mice who had a total absence of the WT1 gene transcript. These mice were born with small hearts and smaller pleural cavities and lungs, and some had defects of the diaphragm that led to the herniation of the lungs into the abdominal cavity. This defect was not exactly like human CDH, but it did suggest a role of the WT1 gene in the deformity. Human infants with CDH were screened for mutations of WT1, but no mutations were found. The knockout mice, however, do suggest that a mesothelial disturbance early in human development is the cause of CDH, especially because the WT1 gene is expressed in the mesotheleum lining the diaphragm's muscle. This study did not rule out the possibility of the involvement of another gene in the WT1 gene pathway being responsible for the defect. The association between urogenital defects and CDH remains important because of the possible WT1 link, which needs further investigation.