Cardiac anomalies associated with omphalocele.

Omphaloceles are ventral abdominal wall defects that are associated with significant other anomalies in up to 80% of cases in some descriptions. Of these abnormalities, Cardiac defects are some of the more common ones, and have the most substantial impact on outcomes and survival. In cases with a severe congenital heart defect (CHD), the omphalocele management changes significantly. This article addresses the common defects seen, and their management issues.

Insights into embryology and development of omphalocele.

Congenital abdominal wall defects are one of the most common human birth defects with an incidence of about 1 in 2000 live births. While often discussed together abdominal wall defects consist mainly of two distinct entities namely gastroschisis and omphalocele. There is no clear consensus explaining the precise embryological mechanisms leading to the development of an omphalocele. Many clinicians and embryologists have attempted to explain congenital malformation as a result of failure of progression of normal embryonic development. This review summarizes the mechanisms involved in normal and abnormal development of the ventral abdominal wall.

Gestational Outcomes of Pregnancies with Prenatally Detected Gastroschisis and Omphalocele.

Objective: To evaluate and compare the outcomes of pregnancies with prenatally detected gastroschisis and omphalocele. Materials and Methods: We retrospectively evaluated prenatally detected gastroschisis and omphalocele cases. Cases were compared in terms of maternal demographic and clinical characteristics as well as pregnancy and neonatal outcomes. Results: This study consisted of 17 gastroschisis and 30 omphalocele cases. Only one case with gastroschisis was terminated due to additional severe limb deformities. Seventeen out of 30 cases of omphalocele were terminated for various reasons (56.7%). All patients with gastroschisis had surgical repair, while 8 out of 13 omphalocele cases had surgery. One patient with an omphalocele died after surgery due to sepsis. Six cases of gastroschisis also died in the neonatal period due to various reasons (6/16, 37.5%). Conclusion: Additional genetic disorders are more frequent in those with omphalocele cases, and they are more frequently terminated during gestation that the gastroschisis fetuses.

High prevalence of same-sex twins in patients with cloacal exstrophy: Support for embryological association with monozygotic twinning.

PURPOSE: Previous studies have hypothesized that cloacal exstrophy may be caused by errors early in embryological development related to monozygotic twinning. This study reports the prevalence of twins in a large cohort of patients with cloacal exstrophy. METHODS: Patients with cloacal exstrophy treated 1974-2015 were reviewed for reports of multiple gestation or conjoined twinning. The genetic sex of the patient and their twin, and any mention of anomaly in the twin were recorded. Neither placental exam nor genetic testing results were available to definitively determine zygosity. RESULTS: Of 71 patients, 10 had a live born twin (14%), all of whom were of the same genetic sex as the affected patient. One additional patient's twin suffered intrauterine fetal demise, and another patient had a conjoined heteropagus twin. None of the twins were affected by exstrophy-epispadias complex. The rate of twin birth in this cohort was 4.4-7.7 higher than that reported by the Centers for Disease Control in the general population time period (P<0.001), with a striking preponderance of same-sex pairs. CONCLUSIONS: The highly significant prevalence of same-sex twin pairs within this cohort supports the hypothesis that the embryogenesis of cloacal exstrophy may be related to errors in monozygotic twinning. LEVEL OF EVIDENCE: 2b.

A chicken embryo model for the study of umbilical and supraumbilical body wall malformations.

UNLABELLED: BACKGROUND/PURPOSE; The embryology of ventral body wall malformations is only partially understood, although their incidence is relatively common. As only few experimental data exist on the development of those defects, the aim of our study was to compare the teratogenic effect of trypan blue (TB) and suramin (SA) in their capability to induce umbilical and supraumbilical abdominal wall malformations in a chicken egg model. MATERIALS AND METHODS: A total of 255 fertilized chicken eggs were incubated at 38 °C and 75% relative humidity. Embryos were treated in ovo on incubation day 2.5 (Hamburger/Hamilton (HH) stage 13). The eggshell was windowed, and solutions of TB or SA were injected into the coelomic cavity at the region of the umbilicus. The window was closed and the embryos reincubated until examination on day 8 (HH 34). RESULTS: A total of 60 embryos survived in each group. The largest number of embryos presented with defects in the umbilical and supraumbilical region (25% in the SA group and 40% in the TB group). A combination of both defects (thoracoabdominoschisis) was seen in 20% of the TB and 8.3% of the SA groups, respectively. Associated anomalies found in both groups were head and eye defects, abnormal pelvic configurations, leg deformities, and mild forms of cloacal exstrophies. CONCLUSIONS: TB and SA have both a high potential to induce umbilical and supraumbilical ventral body wall malformations in chicken embryos. This novel animal model might help to establish a more profound understanding of the developmental steps in ventral body wall formation and the embryology for its malformations.

Diagnosis of abdominal wall defects in the first trimester.

PURPOSE OF REVIEW: To review prognostic parameters reported recently in the evaluation of abdominal wall defects in the first trimester. RECENT FINDINGS: Evaluation of abdominal wall defects in the first trimester is based principally on associated structural or chromosomal anomalies. In the case of gastroschisis, which is rarely associated with other anomalies, evaluation of prenatal or postnatal outcome is based mainly on the course of pregnancy. In the case of isolated omphalocele in the first trimester, recent studies have evaluated parameters that could help predict prenatal or postnatal outcome. SUMMARY: We review recent studies using new parameters to diagnose abdominal wall defects in the first trimester and to provide early prenatal counselling to parents regarding prenatal and postnatal prognosis.

Repair of umbilical and epigastric hernias.

Umbilical and epigastric hernias are primary midline defects that are present in up to 50% of the population. In the United States, only about 1% of the population carries this specific diagnosis, and only about 11% of these are repaired. Repair is aimed at symptoms relief or prevention, and the patient's goals and expectations should be explicitly identified and aligned with the health care team. This article details some relevant and interesting anatomic issues, reviews existing data, and highlights some common and important surgical techniques. Emphasis is placed on a patient-centered approach to the repair of umbilical and epigastric hernias.

Disturbance of SHH signalling pathway during early embryogenesis in the cadmium-induced omphalocele chick model.

INTRODUCTION: Administration of cadmium (Cd) after 60 h (H) incubation induces ventral body wall defect (VBWD) similar to the omphalocele phenotype in the chick embryo. In this model, the earliest histological changes have been observed in somites commencing at 4-h post-treatment (4H). The molecular mechanism by which Cd acts in this critical period of embryogenesis still remains unclear. Sonic hedgehog (SHH) signalling plays an important role in vertebrate development, including somitogenesis and thus ventral body wall formation. Patched (PTCH), a cell membrane receptor for SHH, is expressed in somites and Patched knockout mice display somite dysfunction. Another transmembrane receptor, Smoothened (SMO), is also expressed in somites and transduces the SHH signal regulated by PTCH. We designed this study to test the hypothesis that SHH signalling is downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model. METHODS: After 60 h of incubation, chicks were exposed to either chick saline or 50 µL of 50 µM cadmium acetate and divided into two groups: control and Cd (n = 24 for each group). Chicks were harvested 1, 4, and 8 h post-treatment. Real-time RT-PCR was performed to evaluate the relative mRNA expression level of SHH, PTCH and SMO. Immunofluorescence confocal microscopy was then performed to evaluate protein expression/distribution of SHH, PTCH and SMO. RESULTS: The relative mRNA expression levels of SHH, PTCH and SMO were significantly downregulated in the Cd group compared to controls at 4H post treatment, whereas, there were no significant differences at the other time points. Immunohistochemistry revealed that the intensity of SHH, PTCH and SMO was markedly diminished at 4 h in Cd-treated embryos compared to controls. CONCLUSION: Disturbance of the SHH signalling pathway as evidenced by SHH, PTCH and SMO downregulation during the narrow window of early embryogenesis may result in somite maldevelopment, contributing to the omphalocele phenotype in the Cd chick model.

Eya1 and Eya2 gene expression is down-regulated during somitic myogenesis in the cadmium-induced omphalocele chick model.

PURPOSE: The molecular mechanisms underlying omphalocele are still largely unknown. Recently, established cadmium (Cd)-induced omphalocele chick model has been used to investigate the pathogenesis of omphalocele. The earliest histologic changes in this model has been observed in somites 4 hours posttreatment, leading us to hypothesize that disruption of migration of somite-derived cells ventrally may cause omphalocele phenotype. Eyes absent (Eya) genes are expressed in the somite (dermomyotome) and play a key role in somitic myogenesis. We designed this study to investigate the hypothesis that Eya1 and Eya2 gene expression is down-regulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model. METHODS: After 60 hours of incubation, chicks were exposed to either chick saline or Cd and divided into control and Cd (n = 24 for each group). Chicks were then harvested 1 hour, 4 hours, and 8 hours posttreatment. Real-time quantitative polymerase chain reaction was performed to evaluate gene expression levels of Eya1 and Eya2 in the chick embryo, and they were statistically analyzed. Immunofluorescence confocal microscopy was also performed to evaluate protein expression and distribution pattern of Eya1 and Eya2. RESULTS: At 4 hours posttreatment, the relative messenger RNA expression levels of Eya1 and Eya2 were significantly down-regulated in the Cd group compared with controls (P < .05). The intensity of Eya1 and Eya2 immunofluorescence was also markedly diminished at 4 hours in the Cd-treated embryos, whereas in control embryos, strong intensity of immunofluorescence of them was expressed in the dermomyotomal cells. CONCLUSION: Down-regulation of Eya genes during the critical period of early embryogenesis may contribute to omphalocele phenotype in the Cd chick model, interfering with migration of embryonic body wall ventrally.

EphB2/B3 gene expression is down-regulated during early embryogenesis in the cadmium-induced omphalocele chick model.

PURPOSE: In the chick embryo, the administration of cadmium (Cd) induces omphalocele phenotype. The earliest histologic change in this model is observed in the somite 4 hours (H) post treatment, postulating that disruption of somite development in embryogenesis may cause omphalocele phenotype. EphB2 and EphB3 are involved in many embryonic developmental processes, including somitogenesis. EphB2(-/-)EphB3(-/-) double knockouts display omphalocele phenotype. We hypothesized that EphB2/B3 genes are down-regulated in the Cd chick model during the critical period of embryogenesis. METHODS: After 60H incubation, chicks were harvested 1H, 4H, and 8H post treatment with saline or Cd and divided into control and Cd groups. Reverse transcriptase-polymerase chain reaction was performed to evaluate gene expression levels of EphB2/B3. Immunofluorescence confocal microscopy was performed to evaluate protein expression/distribution of EphB2/B3. RESULTS: At 4H post treatment, the messenger RNA expression levels of EphB2/B3 were significantly down-regulated in the Cd group compared with controls (P < .05). The intensity of EphB2/B3 immunofluorescence was markedly diminished at 4H in the Cd-treated embryos, whereas strong immunoreactivity was observed in the somite in controls. CONCLUSION: Downregulation of EphB2/B3 during the narrow window of early embryogenesis may interfere with normal somitogenesis, preventing migration of embryonic body wall ventrally and thus causing omphalocele.

Congenital abdominal wall defects and reconstruction in pediatric surgery: gastroschisis and omphalocele.

The embryology, epidemiology, associated anomalies, prenatal course and the neonatal and surgical care of newborns with gastroschisis and omphalocele are reviewed. For gastroschisis temporary intestinal coverage is often done before a more definitive operative closure that may be immediate or delayed. Outcomes in gastroschisis are determined by associated bowel injury. For omphalocele small defects are closed primarily while large defects are treated topically to allow initial skin coverage before a later definitive closure. Outcomes for omphalocele are determined mainly by the presence of associated anomalies.

Presenilin genes are downregulated during somitogenesis in the cadmium-induced omphalocele chick model.

PURPOSE: Although the precise pathogenesis of ventral body wall (VBW) defects is not clearly understood, it has recently postulated that disruption of somite development during early embryogenesis may cause failure of proper VBW formation. The administration of cadmium (Cd) after 60 h of incubation induces omphalocele spectrum in the chick embryo. Previous studies have shown that one of the earliest histological changes seen in this model is abnormal cell death in the somite, occurring at 4 h post treatment (4H). However, the molecular mechanism by which Cd acts in this critical period of embryogenesis still remains unclear. Presenilins are expressed in somites and play an important role in vertebrate development, including somitogenesis and thus VBW formation. We designed this study to test the hypothesis that gene expression levels of presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele in the chick model. METHODS: After 60 h of incubation, chick embryos were exposed to either saline or 50 µM cadmium and divided into two groups: control and Cd (n = 8 at each time point for each group). Real-time RT-PCR was performed to evaluate the relative mRNA expression levels of PSEN1 and PSEN2 in the Cd-induced omphalocele chick model. Differences between two groups at each time point were analysed statistically and the significance was accepted at p < 0.05. Immunofluorescence confocal microscopy was performed to evaluate the protein expression/distribution of presenilins in the somite of chick embryo. RESULTS: The relative mRNA expression levels of PSEN1 and PSEN2 were significantly downregulated in the Cd group at 4H compared with controls (p < 0.005) (Table). However, there were no significant differences at the other time points. At 4H, immunofluorescence of presenilins (green) was markedly diminished in the Cd-treated embryos, whereas strong immunofluorescence of them was seen in the somite (dermomyotome) in controls (Fig. 1). 1 Immunofluorescence Confocal Microscopy for PSEN1 and PSEN2 in the dermomyotome of the somite in the trunk level of chick embryo 4H post treatment. Intensity of PSEN1 immunofluorescence (green) was markedly diminished in Cd-treated embryos, whereas strong PSEN1 expression was seen in the dermomyotome in controls. PSEN2 immunofluorescence was also decreased in the Cd-treated embryos, whereas strong PSEN2 immunofluorescence (green) was observed predominantly in the dermomyotome in controls. Immunofluorescence in orange is DNA counter staining by DAPI CONCLUSION: We provide evidence, for the first time, that gene expression of presenilins is downregulated during the narrow window of very early embryogenesis in the Cd chick model. Decreased expression of presenilins may contribute to omphalocele phenotype in Cd chick model, by disrupting somite development.

Alteration of gene expression of IQGAP1 and Rho-family GTPases in the cadmium-induced ventral body wall defects in the chick model.

Cadmium (Cd) induces ventral body wall defects (VBWD) in the chick embryo, with adherens junctions (AJs) breakdown at 4h post treatment (4H). Signalling by which Cd disrupts AJs in this model remains unclear. IQGAP1 regulates AJs via binding to Cdc42 and Rac1, Rho-family GTPases. Activation of IQGAP1-Cdc42 interaction regulates AJs positively, whereas Rac1 activation inhibits AJs. We hypothesised that IQGAP1 and Cdc42 are downregulated and Rac1 is upregulated during embryogenesis in the Cd chick model. Chick embryos were explanted and treated with saline or Cd after 60 h incubation. Chicks were harvested at 1H, 4H and 8H post treatment and RT-PCR and immunohistochemistry were performed. Gene expression levels of IQGAP1 and Cdc42 were significantly downregulated and Rac1 was upregulated in Cd group compared to controls only at 4H. Immunoreactivity of IQGAP1 and Cdc42 was also markedly decreased, whereas Rac1 was increased in Cd group compared to controls at 4H. Alteration of IQGAP and Rho-family GTPases may cause VBWD in Cd chick model by inducing the dissociation of cadherin-mediated AJs.

Spectrum of cloacal exstrophy.

Cloacal exstrophy, one of the most severe congenital anomalies compatible with life, occurs in up to 1 in 200,000 lives births. The condition affects nearly every major organ system with severe neurologic, skeletal, gastrointestinal, and genitourinary ramifications. With increased understanding of the anatomy and embryology combined with refinements in prenatal diagnosis and postnatal care, there is now near-universal survival of patients with cloacal exstrophy. Functional and cosmetic outcomes have improved with modifications in surgical technique. However, debate continues regarding the issue of gender identity, and long-term data are still accruing with respect to the best strategy for management. Despite the extensive malformations noted, many patients have gone on to live fruitful lives.

BMPR1A-mediated BMP1 signalling is disrupted in the cadmium-induced omphalocele in the chick model.

PURPOSE: In the chick embryo, administration of cadmium (Cd) induces omphalocele phenotype. The earliest histological changes in this model are observed commencing at 4-h post treatment (4H). The molecular mechanisms by which Cd acts during the critical period of embryogenesis remain unclear. Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) regulate many fundamental biological processes and are involved in various embryonic morphogenesis, including ventral body wall (VBW) formation. Homozygous BMP1 mutant mice cause VBW defects. It has been reported that BMPR1A conditional knockouts also exhibit omphalocele phenotype. We designed this study to test the hypothesis that gene expression levels of BMP1 and BMPR1A are downregulated during the critical period of embryogenesis in the Cd chick model. METHODS: After 60-h incubation, chick embryos were exposed to either Cd or saline and then harvested 1H, 4H and 8H. Chicks were divided into control (n = 24) and Cd (n = 24). RT-PCR was performed and differences between the two groups were tested statistically (significance was accepted at p < 0.05). Immunohistochemical study was also performed to evaluate those proteins expression/distribution. RESULTS: The gene expression levels of BMP1 and BMPR1A at 4H were significantly downregulated in Cd group compared to controls. Immunoreactivity of BMP1 and BMPR1A was also markedly decreased in Cd-treated embryos compared to controls. CONCLUSION: Disruption of BMPR1A-mediated BMP1 signalling during the narrow window of early embryogenesis may interfere with normal VBW formation, causing omphalocele phenotype in the Cd chick model.

Altered PITX2 and LEF1 gene expression in the cadmium-induced omphalocele in the chick model.

PURPOSE: Although, recent studies have suggested that disruption of somitogenesis may be involved in ventral body wall (VBW) defects; the molecular mechanisms of VBW defects remain unclear. In the chick embryo, the administration of cadmium (Cd) induces VBW defects similar to the human omphalocele. In this model, the earliest histological change in the somite occurs commencing at 4 h post-Cd treatment (4 h). PITX2 is expressed in somites, and PITX2 mutants have been shown to display VBW defects. PITX2 interacts with lymphoid enhancer factor-1 (LEF1) to regulate somite myogenesis. We designed this study to investigate the hypothesis that PITX2 and LEF1 genes are downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model. MATERIALS AND METHODS: Chick embryos were exposed to Cd or saline after 60 h incubation and harvested at 1, 4, and 8 h posttreatment. Chicks were then divided into two groups: control (n = 24), and Cd (n = 24). RT-PCR was performed and analyzed statistically (significant difference was accepted at p < 0.05). Immunohistochemistry was also performed to evaluate expression/distribution of those proteins. RESULTS: The mRNA expression levels of PITX2 and LEF1 at 4 h were significantly decreased in the Cd group compared with controls, whereas there were no differences at the other time points. Immunoreactivity of those proteins at 4 h was also markedly decreased in somites in the Cd-treated embryos compared with controls. CONCLUSIONS: Downregulation of PITX2 and LEF1 genes may interfere with ventral body wall formation in Cd chick model causing omphalocele by disrupting somite myogenesis.

Conditional mutation of fibroblast growth factor receptors 1 and 2 results in an omphalocele in mice associated with disruptions in ventral body wall muscle formation.

BACKGROUND/PURPOSE: We observed that fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) are expressed during abdominal wall development in mice and hypothesized that conditional mutation of these genes would result in abdominal wall defects. METHODS: Section in situ hybridizations were performed for Fgfr1 and Fgfr2 on wild-type embryos at embryonic day (E) 11.5 and E13.5. Conditional mutation of Fgfr1and Fgfr2 was achieved with a tamoxifen inducible Cre at E8.5. Litters were harvested at E17.5, whole mount photographs were taken, and paraffin sections were generated and stained with hematoxylin and eosin. RESULTS: Fgfr1 was expressed in ectoderm, lateral plate mesoderm, and myoblasts, whereas Fgfr2 was expressed almost exclusively in the early dermis and ectoderm of the abdominal wall. Conditional mutation of both Fgfr2 alleles and one Fgfr1 allele resulted in omphalocele in 38.7% of mutants. Histologic examination in mutants demonstrated disruptions in dermal and muscle development. CONCLUSIONS: Mutant embryos with omphalocele arising from mutation in Fgfr1 and Fgfr2 exhibit disruptions in the development of the secondary abdominal wall structures. These findings are consistent with a model of ventral abdominal wall development in which organization of the muscles and connective tissue (secondary abdominal wall structures) is influenced by positional information emanating from the primary abdominal wall.

Disruption of GLI3-ZIC3 interaction in the cadmium-induced omphalocele chick model.

PURPOSE: Administration of heavy metal cadmium (Cd) after 60-h incubation induces omphalocele spectrum in the chick embryo. Although previous studies have shown that the earliest detectable histological changes in the chick Cd model occurs commencing at 4-h post-treatment (4H). However, the molecular mechanism by which Cd acts in the critical period of early embryogenesis still remains unclear. Zic3, a Gli superfamily transcription factor, is expressed in somites and plays an important role in vertebrate development, including somitogenesis and thus ventral body wall formation. Gli3 is also expressed in somites and interacts with Zic3 physically and functionally. It has been reported that Gli3 homozygous double mutants display omphalocele. Zic3 mutant mice have also been known to result in omphalocele phenotype. We designed this study to test the hypothesis that Gli3 and Zic3 gene expression is downregulated during the critical period of very early embryogenesis in the Cd-induced omphalocele in the chick model. METHODS: After 60-h incubation, chick embryos were exposed to either saline or 50 µM cadmium and divided into two groups: control and Cd (n = 24 for each group). Real-time reverse transcription polymerase chain reaction was performed to evaluate the relative mRNA expression levels of Gli3 and Zic3 in the Cd-induced omphalocele chick model. Differences between the two groups at each time point were analyzed statistically and the significance was accepted at p < 0.05. Immunohistochemistry was also performed to evaluate the expression/distribution of those proteins in chick embryo. RESULTS: The relative mRNA expression level of Gli3 and Zic3 was significantly decreased in the Cd group at 4H when compared with controls (p < 0.05). However, there were no significant differences at the other time points. At 4H, immunoreactivity of GLI3 and ZIC3 was also markedly decreased in Cd-treated embryos, whereas strong expression of them was seen in the somite in controls. CONCLUSION: We provide evidence, for the first time, that Gli3 and Zic3 gene expression is downregulated during the narrow window of very early embryogenesis in Cd chick model. Disruption of Gli3-Zic3 interaction in the critical period for ventral body wall formation may contribute to omphalocele phenotype in Cd chick model.

Disruption of noncanonical Wnt/CA2+ pathway in the cadmium-induced omphalocele in the chick model.

PURPOSE: Cadmium (Cd) has been found to cause ventral body wall defects (VBWDs) in the chick embryo similar to human omphalocele. The earliest detectable histologic changes in Cd-induced VBWD chick model have been observed 4 hours posttreatment. The exact mechanism by which Cd acts in the early embryogenesis remains unclear. Wnt proteins play a key role during embryogenesis, and altered Wnt signaling has been linked to developmental defects. Noncanonical Wnt/Ca(2+) pathway has been implicated in regulating embryogenesis by controlling cell movement and adhesion. Wnt11 can activate protein kinase C (PKC) and calcium/calmodulin-dependent kinase II (CaMKII) in the Wnt/Ca(2+) pathway. We hypothesized that the Wnt11, PKCalpha, and CaMKII gene expression is downregulated in the Cd-induced VBWD during early embryogenesis. METHODS: After 60 hours of incubation, chick embryos were harvested 1 hour (1H), 4H, and 8H after treatment of saline or cadmium and divided into 2 groups: control and Cd (n = 8 at each time-point, respectively). Real-time polymerase chain reaction was performed to evaluate the messenger RNA (mRNA) expression of Wnt11, PKCalpha, and CaMKII in the Cd-induced VBWD chick model. RESULTS: The mRNA expression levels of Wnt11, PKCalpha, and CaMKII were significantly decreased at 1H in Cd group compared to controls (P < .05). However, there were no significant differences in the other time-points. CONCLUSION: Downregulation of Wnt11, PKCalpha, and CaMKII gene expression during the narrow window of early embryogenesis may cause VBWD, interfering with cell movement and adhesion, disrupting Wnt/Ca(2+) pathway.

The embryologic origin of ventral body wall defects.

Ventral body wall defects include ectopia cordis, bladder exstrophy, and the abdominal wall malformations gastroschisis and omphalocele. The etiology of ectopia cordis, gastroschisis, and bladder exstrophy is not known, but they may be linked to abnormalities in the lateral body wall folds responsible for closing the thoracic, abdominal, and pelvic portions of the ventral body wall. These folds form in the fourth week (postfertilization) of development as a combination of the parietal layer of lateral plate mesoderm and overlying ectoderm and must move ventrally to meet in the midline. There are differential rates of cell proliferation in the folds and asymmetries in their movement that may be involved in teratogenic effects of toxic factors. Also, the fusion process between the folds is complex, involving cell-to-cell adhesion, cell migration, and cell reorganization and all of these phenomena may be targets for disruption, leading to malformations. In this regard, closure of the ventral body wall is likened to neural tube closure and involves similar processes. It also encompasses a similar time frame during development, such that most neural tube and ventral body wall defects have their origins during the fourth week of development. Omphalocele is a separate entity whose etiology is known. This defect is attributed to a failure of gut loops to return to the body cavity after their normal physiological herniation into the umbilical cord from the 6th to 10th week of development. Thus, the origin of this defect is completely different from that of the ventral body wall malformations.