Twin pregnancy complicated by esophageal atresia, duodenal atresia, gastric perforation, and hypoplastic left heart structures in one twin: a case report and review of the literature.

BACKGROUND: The antenatal diagnosis of a combined esophageal atresia without tracheoesophageal fistula and duodenal atresia with or without gastric perforation is a rare occurrence. These diagnoses are difficult and can be suspected on ultrasound by nonspecific findings including a small stomach and polyhydramnios. Fetal magnetic resonance imaging adds significant anatomical detail and can aid in the diagnosis of these complicated cases. Upon an extensive literature review, there are no reports documenting these combined findings in a twin pregnancy. Therefore we believe this is the first case report of an antenatal diagnosis of combined pure esophageal and duodenal atresia in a twin gestation. CASE PRESENTATION: We present a case of a 30-year-old G1P0 white woman at 22-week gestation with a monochorionic-diamniotic twin pregnancy discordant for esophageal atresia, duodenal atresia with gastric perforation, hypoplastic left heart structures, and significant early gestation maternal polyhydramnios. In this case, fetal magnetic resonance imaging was able to depict additional findings including area of gastric wall rupture, hiatal hernia, dilation of the distal esophagus, and area of duodenal obstruction and thus facilitated the proper diagnosis. After extensive counseling at our multidisciplinary team meeting, the parents elected to proceed with radiofrequency ablation of the anomalous twin to maximize the survival of the normal co-twin. The procedure was performed successfully with complete cessation of flow in the umbilical artery and complete cardiac standstill in the anomalous twin with no detrimental effects on the healthy co-twin. CONCLUSIONS: Prenatal diagnosis of complex anomalies in twin pregnancies constitutes a multitude of ethical, religious, and cultural factors that come into play in the management of these cases. Fetal magnetic resonance imaging provides detailed valuable information that can assist in management options including possible prenatal intervention. The combination of a cystic structure with peristalsis-like movement above the diaphragm (for example, "the upper thoracic pouch sign"), polyhydramnios, and progressive distention of the stomach and duodenum should increase suspicion for a combined pure esophageal and duodenal atresia.

Haploinsufficiency of retinaldehyde dehydrogenase 2 decreases the severity and incidence of duodenal atresia in the fibroblast growth factor receptor 2IIIb-/- mouse model.

BACKGROUND: Homozygous null mutation of the fibroblast growth factor receptor 2IIIb (Fgfr2IIIb) gene in mice results in 42% of embryos developing duodenal atresias. Retinaldehyde dehydrogenase 2 (Raldh2, a gene critical for the generation of retinoic acid) is expressed in the mouse duodenum during the temporal window when duodenal atresias form. Raldh2 is critical for the normal development of the pancreatoduodenal region; therefore, we were interested in the effect of a Raldh2 mutation on duodenal atresia formation. To test this, we rendered Fgfr2IIIb(-/-) embryos haploinsufficient for the Raldh2 and examined these embryos for the incidence and severity of duodenal atresia. METHODS: Control embryos, Fgfr2IIIb(-/-) mutants, and Fgfr2IIIb(-/-); Raldh2(+/-) mutants were harvested at embryonic day 18.5, genotyped, and fixed overnight. Intestinal tracts were isolated. The type and severity of duodenal atresia was documented. RESULTS: A total of 97 Fgfr2IIIb(-/-) embryos were studied; 44 had duodenal atresias, and 41 of these presented as type III. In the 70 Fgfr2IIIb(-/-); Raldh2(+/-) embryos studied, a lesser incidence of duodenal atresia was seen (15 of 70; P = .0017; Fisher exact test). Atresia severity was also decreased; there were 12 embryos with type I atresias, 3 with type II atresias, and 0 with type III atresias (P < 2.81E-013; Fisher exact test). CONCLUSION: Haploinsufficiency of Raldh2 decreases the incidence and severity of duodenal atresia in the Fgfr2IIIb(-/-) model. The ability to alter defect severity through manipulation of a single gene in a specific genetic background has potentially important implications for understanding the mechanisms by which intestinal atresias arise.

Formation of duodenal atresias in fibroblast growth factor receptor 2IIIb-/- mouse embryos occurs in the absence of an endodermal plug.

PURPOSE: Duodenal atresia in humans has been hypothesized to arise from a failure of the duodenal lumen to recanalize after formation of an endodermal plug. Recently, mutations in the fibroblast growth factor receptor 2 gene (Fgfr2IIIb) have been shown to cause atretic defects of the duodenum in mice. However, work in rats suggests that murine species do not form an endodermal plug during normal duodenal development. These lines of data led us to hypothesize that mice are able to form a duodenal atresia in the absence of an endodermal plug. To test this hypothesis, we examined duodenal development in wild-type and Fgfr2IIIb-/- embryos. METHODS: Paraffin sections were generated for H&E, E-cadherin, or terminal deoxynucleotidyl transferase-mediated X-dUTP nick end labeling staining from Fgfr2IIIb-/- and wild-type embryos between embryonic days (E) 10.5 and E14.5. Sections were photographed and reconstructed into 3-dimensional display using Adobe Photoshop and Amira Visage software. RESULTS: Normal mouse duodenum does not form an endodermal plug, although a plug does form in the pyloric region of the stomach at E14.5. Fgfr2IIIb-/- embryos experience significant apoptosis in the duodenal region at E10.5, followed by the disappearance of the endoderm in the atretic precursor by E11.5. Thereafter, the mesoderm of the atretic precursor involutes over the next 2 days in the absence of further apoptosis. Interestingly, an endodermal plug was not observed at any point during the formation of a duodenal atresia. CONCLUSIONS: These results suggest that duodenal atresia in the Fgfr2IIIb-/- model does not arise from persistence of an epithelial plug. Rather it appears to result from the loss of the endoderm because of apoptosis very early in development.

Retinaldehyde dehydrogenase 2 is down-regulated during duodenal atresia formation in Fgfr2IIIb-/- mice.

BACKGROUND: Homozygous null mutation of fibroblast growth factor receptor 2 (Fgfr2IIIb) or its ligand fibroblast growth factor 10 (Fgf10) results in duodenal atresia in mice. Mutations of either of these genes in humans cause Matthew-Wood syndrome and associated duodenal stenosis. Recently, mutations in the retinol-binding protein receptor gene STRA6 were reported to be implicated in this syndrome as well. This suggests that the retinoic acid (RA) signaling pathway interacts with the Fgf10-Fgfr2IIIb signaling pathway during duodenal development. Accordingly, we hypothesized that Fgfr2IIIb-/- mouse embryos would exhibit disruptions in expression of Raldh2, the gene for the enzyme that regulates the final step in the conversion of vitamin A to the active form RA, during duodenal atresia formation. MATERIALS AND METHODS: Fgfr2III -/- mice were generated from heterozygous breedings. Embryos were harvested between embryonic day (E) 11.0 to E 13.5 and genotyped by polymerase chain reaction (PCR). Duodenums were dissected out, fixed and photographed. Whole mount and section in situs were performed for Raldh2. RESULTS: Fgfr2IIIb-/- embryos demonstrate subtle changes in the duodenal morphology by E11.5 with complete involution of the atretic precursor by E 13.5. Raldh2 appears to be down-regulated as early as E 11.5 in the atretic precursor a full 2 days before this segment disappears. CONCLUSIONS: In Fgfr2IIIb-/- mouse embryos, a reduction of Raldh2 expression is observed within the region that is forming the atresia. This is the first demonstration of such an event in this model. As in humans, these results implicate disruptions between Fgfr2IIIb receptor function and RA signaling in the formation of this defect and indicate that Fgfr2IIIb-/- mouse embryos are a valid model for the study of the atretic spectrum of defects in human duodenal development.

Right-sided congenital diaphragmatic hernia, hepatic pulmonary fusion, duodenal atresia, and imperforate anus in an infant.

We present a case of a neonate with VACTERL-like association, with the VACTERL association defined as the non-random association of vertebral, anal, cardiac, esophageal, renal/kidney, and limb defects, as manifested by a hemivertebra, imperforate anus, and digit anomalies, in rare association with duodenal atresia and right-sided diaphragmatic hernia. This constellation is previously undescribed and may offer insight into the pathogenesis of VACTERL and associated birth defects.

Double duodenal atresia with perforation: a case report.

Duodenal atresia is a common cause of neonatal bowel obstruction. Double duodenal atresia has been reported as a rare variation of duodenal atresia. This report discusses the importance of an appreciation of unusual anatomy in neonatal duodenal obstruction and highlights the importance of assessing bowel continuity intraoperatively.

Different types of intestinal atresia in identical twins.

The authors present a previously unreported association of different types of intestinal atresia in identical low-birth-weight twins. Both babies were affected by duodenal atresia, associated in the first case with a complete mucosal duodenal membrane and in the second one with an "apple-peel" jejunal atresia. These occurrences may suggest that they were either the consequence of linkage of 2 genes or a pleiotropic expression of a single gene responsible for such rare conditions.

Fibroblast growth factor-10 serves a regulatory role in duodenal development.

PURPOSE: Duodenal obstruction occurs in 1 of 6000 live births and requires urgent surgical intervention. Duodenal atresia previously has been ascribed to a developmental failure of luminal recanalization; however, the cause of duodenal atresia remains incompletely understood. Although familial intestinal atresias have been described and syndromic associations are known, no specific genetic link has been established. Fibroblast growth factor-10 (Fgf10) is a known regulatory molecule relevant to mesenchymal-epithelial interactions, and mice deficient in Fgf10 demonstrate congenital anomalies in several organ systems including the gastrointestinal tract. The authors hypothesized that Fgf10 could serve a regulatory role in establishing normal duodenal development. METHODS: Wild-type mice with beta-galactosidase under the control of the Fgf10 promoter were harvested from timed-pregnancy mothers. The expression of Fgf10 in the duodenum during development was evaluated by developing the embryos in X-Gal solution. Wild-type and mutant Fgf10(-/-) embryos were harvested from timed-pregnancy mothers at 18.5 days postconception (near term) and were analyzed for duodenal morphology (Institutional Animal Care and Use Committee-approved protocol 32-02). Photomicrographs were reviewed. RESULTS: Fibroblast growth factor-10 is active in the duodenum at a late stage of development. The Fgf10(-/-) mutants demonstrate duodenal atresia with a variable phenotype similar to clinical findings. The duodenum fails to develop luminal continuity and has proximal dilation. The phenotype occurs in an autosomal recessive pattern with incomplete penetrance (38%). CONCLUSIONS: Fibroblast growth factor-10 serves as a regulator in normal duodenal growth and development. Its deletion leads to duodenal atresia and challenges traditionally accepted theories of pathogenesis. This novel, genetically mediated duodenal malformation reflects an animal model that will allow further evaluation of the pathogenesis of this surgically correctable disease. By studying the mechanism of Fgf10 function in foregut development, the authors hope to better understand these anomalies and to explore possible therapeutic alternatives.

Fibroblast growth factor receptor 2 IIIb invalidation--a potential cause of familial duodenal atresia.

BACKGROUND/PURPOSE: Duodenal atresia (DA) occurs in 1 in every 6,000 live births and represents a significant surgically correctable cause of intestinal obstruction in the neonate. Familial or congenital DA has been reported, implying that at least some cases of DA are the result of genetic, heritable abnormalities. The genes controlling duodenal development are incompletely understood. Fibroblast growth factor receptor 2IIIb (Fgfr2b) is known to play a critical role in the development of multiple organ systems including other gastrointestinal tract (GIT) structures. This study shows the key role of Fgfr2b in normal duodenal development and the pathogenesis of DA. METHODS: Wild type (Wt) and Fgfr2b-/- embryos were harvested from timed pregnant mothers at stage E18.5 and were analyzed for duodenal phenotype. RESULTS: Inactivation of Fgfr2b results in DA. DA is present in the Fgf2b-/- mutants with a 35% penetrance. The duodenal phenotype of the Fgf2b-/- mutants ranges from normal to a mucosal web, type I, and type III atresia. CONCLUSIONS: Fgfr2b is a critical regulatory gene in the development of the duodenum. Fgfr2b invalidation (Fgfr2b-/- mutant) results in a reproducible, autosomal recessive duodenal atresia phenotype with incomplete penetrance and a variable phenotype.

Fetal duodenal obstructions: increased risk of prenatal sudden death.

OBJECTIVES: The aim of this study was to describe the outcome of fetuses with duodenal obstruction diagnosed prenatally and to compare the outcome with the results of studies of newborns. METHODS: All fetuses with a prenatal diagnosis of duodenal obstruction were registered and evaluated prospectively from January 1985 to December 2000. RESULTS: Duodenal obstruction was found in 29 fetuses at a mean gestational age of 29+2 weeks. Polyhydramnios was found in 24 cases (83%). Six fetuses (21%) had trisomy 21. Associated anomalies, including trisomy 21, were found in 18 cases (62%). Four fetuses with normal karyotype died in utero at 31-35 gestational weeks. Two of them had associated anomalies, but the anomalies could not explain the prenatal deaths and the deaths occurred suddenly and unexpectedly. Three infants died postnatally; all three had associated anomalies. Four infants with normal karyotype had neurological impairment suggesting that they might have had intrauterine asphyxia. CONCLUSIONS: The present study indicates that duodenal obstruction is a more serious condition than previously believed, with an increased risk of prenatal asphyxia and death, even when the karyotype is normal and no associated anomalies are present. We consider the possibility that it could be caused by bradycardia/asystole following vagal overactivity due to distension of the upper gastrointestinal tract.

Apoptosis in murine duodenum during embryonic development.

Duodenum is thought to go through a solid-core stage followed by recanalization during its development. This study investigates the role of apoptosis in normal duodenal development, especially during widening of the lumen, and hence, the possible role of apoptosis in duodenal atresia (DA). Twenty-four time-mated Sprague-Dawley rats were killed from day 13 to day 20 of gestation. Duodenums of 3 fetuses were chosen randomly from each rat and processed. Apoptosis was determined by the terminal deoxytransferase-mediated biotin dUTP nick-end labeling (TUNEL) technique (ApopTag). Apoptosis count and cross-sectional areas were measured with an image analyzer (MetaMorph). The number of apoptotic cells per unit area duodenum peaked on day 15 for the mucosal/submucosal layer and on day 14 for the muscular/mesenchymal layer. The maximal number of apoptotic cells per cross-section of duodenum was between 7 and 8. The cross-sectional areas of the duodenal wall and lumen increased exponentially between day 17 and day 19 while duodenal-wall thickness remained relatively constant throughout duodenal development. The localization, timing, and intensity of apoptosis do not suggest that apoptosis is responsible for the widening of the duodenal lumen; enlargement of the lumen is related to the increase in duodenal circumference. Apoptosis thus may not be involved in the pathogenesis of DA.

Embryogenesis of pancreaticobiliary maljunction inferred from development of duodenal atresia.

The embryogenesis of pancreaticobiliary maljunction is inferred from the embryogenesis of duodenal atresia. The epithelial cells of the duodenum begin to proliferate and completely plug the lumen, but a process of vacuolation recanalizes the duodenum. Recanalization of the common duct frequently appears with two lumina and openings into the duodenum with two orifices. These two major canals create a narrow segment of the duodenum and this narrow zone is the area in the duodenum that is most prone to faulty recanalization and atresia formation. A bifid biliary system inserts at blind upper and lower pouches of the duodenum, and the common bile duct inserts in a Y fashion. The common bile duct inserts at the stenotic segment, and the end result is a T-shaped formation in patients with duodenal stenosis. During the development of the bile duct, abnormal fusion may occur between the bile duct and branches of the right ventral pancreatic duct. The site in the bile duct where a branch of the pancreatic duct joins is likely to develop atresia due to disturbance of the recanalization process, as seen in duodenal atresia. Severe impairment of vacuolation causes divided atretic bile duct at the site where the pancreatic duct inserts in a Y-fashion into the upper and lower bile duct. Moderate impairment of vacuolation causes a stenosis at the site where the pancreatic duct inserts in a T-shape, with a moderate dilatation of the bile duct.

Murine duodenum does not go through a "solid core" stage in its embryological development.

Embryological development of duodenum is believed to go through a "solid core" stage which subsequently vacuolizes. Failure of vacuolization is thought to be the cause of duodenal atresia. This study examines the embryological development of rat duodenum. Thirty-six time-mated Sprague-Dawley rats were studied. Six fetal duodenal specimens were obtained for each gestational day from day 9 to day 20. These specimens were fixed with formalin, sectioned, stained with haematoxylin and eosin and examined under microscope. The duodenal diameters and the lumen diameters at each gestational date were measured. The foregut started to form at the gestation stage of day 10. The lumen was narrowest on days 12 and 13, but the duodenum did not become a "solid core". No vacuolization was detected through out the development of the duodenum. Embryological development of rat duodenum did not go through a "solid core" stage.

[Embryological premises for the emergence of congenital obstruction of the duodenum in man]. / Embriologicheskie predposylki vozniknoveniia vrozhdennoi neprokhodimosti dvenadtsatiperstnoi kishki u cheloveka.

There is no unity in views on the causes of the congenital "internal" duodenal obstruction occurring in the human being. The investigation makes it possible to conclude that the embryological premises for this pathology are: 1) death of epitheliocytes in the process of recanalization; 2) spiralization, resulting in narrowing the organ's flexure and in deformity of blood vessels. Morphogenesis of the duodenal papillae and of the intestinal villi contributes to stenosis of the intestinal canal. Spiralization and death of epitheliocytes--are normal processes of the embryonal organogenesis. But their abundance under influence of some external factors can stipulate disorders in the normal organogenesis.

Combination of annular pancreas and partial situs inversus: a multiple organ malrotation syndrome associated with duodenal obstruction.

A combination of annular pancreas and partial situs inversus has been encountered in three babies who presented as duodenal obstruction. All the abnormalities can be explained on the basis of multiple organ malrotation involving the duodenum, pancreas, liver, stomach, and indirectly, the spleen; hence, the term multiple organ malrotation syndrome (MOMS). The heart maintains its normal left side location in this condition. Similarly the remaining small bowel, large bowel, and appendix are normally located. It is proposed that the triad of intestinal obstruction as suggested by vomiting and visible peristalsis, left-sided liver in the presence of laevocardia, and radiographic appearance of reversed double bubble, be considered as indicating MOMS.

Pancreas annulare in human embryos.

2 cases of pancreas annulare with duodenal stenosis were found among 3,307 induced abortuses of 5-12 weeks where the pancreatoduodenal area was available for examination. This corresponds to a 0.06% incidence, greatly exceeds the occurrence of the anomaly in neonates and suggests partial prenatal elimination of embryos with pancreas annulare and duodenal stenosis. Microscopic examination of serialed embryonic sections gives evidence of (1) the origin of the ring from the ventral anlage; (2) the underdevelopment of the ring material, which later may cause fibrosis of the annulus, usually observed in neonates; (3) the origin of duodenal stenosis in case of pancreas annulare till 8 weeks of fetal life; (4) the development of such stenosis not only due to atrophy of duodenal segment, resulted from compression by the pancreatic ring, but also due to anomalous differentiation of intestinal segment, the cause of which may be the disturbance of morphogenetic correlations.