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Background: The cause of duodenal atresia (DA) is not known. Tandler's "solid cord" hypothesis conflicts with current biological evidence. In humans, a genetic aetiology is supported by the association with Trisomy 21. Interruption of Fgf10 is the strongest genetic link to DA in mice, demonstrating an increased incidence and severity as embryos mature. This project aimed to develop an organoid model to facilitate ex vivo DA research on the FGF10/FGFR2b signalling pathway. We hypothesised that DA morphology represents an evolving spectrum of disease and that Fgf10 knockout organoids would vary in growth pattern compared to wild-type., Methods: Organoids were cultured from the duodenum of E12.5 Fgf10 knockout, heterozygous and wild-type embryos, using an air-liquid interface with Growth Factor reduced Matrigel. Organoids were photographed every 48 h to observe growth. Organoids were isolated and fixed after 14 days, then stained with DAPI, KI-67, and cytokeratin to demonstrate proliferation and differentiation., Results: Wild-type duodenum developed into crypt-forming organoids. Fgf10 heterozygous duodenum failed to progress beyond the development stage of spheroids. Fgf10 knockout duodenum failed to demonstrate any growth. Wholemount staining showed the greatest cell proliferation and differentiation in wild-type tissue., Conclusion: This research presents a novel concept for the growth of embryonic gastrointestinal tissue to inform normal biology. The small sample numbers and restricted culture duration limit longer-term growth analysis. While this model serves as a potential ex vivo setting for future research, that research should consider organoid models with greater standardisation and other gastrointestinal regions., Level of Evidence: Animal/laboratory study., Competing Interests: Conflicts of interest The authors of this paper have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To characterize gastrointestinal bubbles detected since early pregnancy and to describe corresponding diagnoses., Method: A retrospective cohort review of all cases in which gastrointestinal bubbles were detected starting in early prenatal transvaginal scans at 14-17 weeks of gestation between the years 2007 and 2021. Sonographic features and data regarding associated anomalies, genetic abnormalities, and pregnancy outcome were evaluated., Results: Bubbles were detected in 23 of 27 073 early scans and a total of 31 394 scans. Diagnosis was available in 22 cases. Transient bubbles were detected in 10 cases and represented normal peristalsis. Fixed double bubble was detected in nine cases. Double-walled double bubbles represented duodenal duplications (three cases) and esophageal duplications (two cases). Simple cysts represented duodenal atresia (three cases) and a pancreatic cyst (one case). A triple bubble represented duodenal obstruction from Ladd bands in one case. Quadribubble was detected in two cases and represented jejunal atresia., Conclusion: Prenatal detection of gastrointestinal bubbles can accurately diagnose physiological versus pathological upper gastrointestinal conditions. Transient bubbles are physiological. Fixed double bubbles might represent either duodenal atresia or esophageal/duodenal duplications when a double wall is demonstrated. Three or four bubbles might represent more distal intrinsic or extrinsic obstruction., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objective: To assess the value of chromosomal microarray analysis (CMA) for fetal duodenal obstruction (DO)., Methods: Fifty-one fetuses with DO identified by prenatal ultrasound were divided into DO only group and DO with other anomaly group. CMA was carried out on amniotic fluid or umbilical blood samples, and the outcome of pregnancy of all cases were followed up., Results: Eight fetuses (15.7%) were found with genomic abnormalities, which included 3 chromosomal aneuploidies and 5 copy number variations (CNVs), including one 17q12 microduplication syndrome, one 13q21.33q31.1 microdeletion, one 13q21.32q22.3 deletion, one 13q21.2q31.1 deletion and one 1q43q44 duplication. EDNRB from 13q and HNF1B from 17q12 are candidate genes for fetal DO. No significant difference was found in the detection rate of pathogenic CNVs between the DO only and DO with other anomaly groups (9.5% vs.11.1%, P> 0.05). There were 39 live borns, 1 stillbirth, and 11 artificial abortions (8 with abnormal CMA results)., Conclusion: There is a correlation between fetal DO and abnormal copy number of the genome, for which prenatal diagnosis is necessary. CMA not only can detect microdeletions/microduplications, but also identify pathogenic genes, which can facilitate prenatal diagnosis, genetic counseling and prognosis for the fetus.

Background: Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of hereditary diabetes, generally caused by one abnormal gene. MODY5 is caused by mutations of the hepatocyte nuclear factor 1 homeobox β gene (HNF1β), always as a part of Chr17q12 deletion, whereas heterozygous mutation in B lymphocyte kinase (BLK) gene is responsible for MODY11., Case Presentation: We report a patient who developed diabetes with a 1.58-Mb Chr17q12 microdeletion and BLK gene c.211G > A mutation using the cytoscan high-density array and whole-exome sequencing analysis. The patient received the surgery at five days after birth for the duodenal atresia and had normal growth postoperatively. Mild elevated liver enzymes were found along with the normal renal function. Quantitative analysis of β-cell function markers, including fasting insulin (< 0.2 mIU/L), fasting C-peptide (0.02 μg/L), postprandial-2 h insulin (< 0.2 mIU/L), and postprandial-2 h C-peptide (0.03 μg/L) suggested a severe loss of insulin secreting capacity. Meanwhile, islet autoantibodies (GADA, IA-2, ICA, and IAA) in the patient's blood appeared negative. Neither dysplasia in other tissues nor abnormality in development and behavior was found., Conclusion: To date, gastrointestinal malformations were extremely rarely reported in patients with MODY. Our clinical report further expands the clinical presentation and variability of MODY5.

Background: The "double bubble" sign is an ultrasonographic finding that commonly represents duodenal atresia and is associated with trisomy 21., Objectives: We sought to evaluate the positive predictive value of a prenatally identified double bubble sign for duodenal atresia and the genetic etiologies associated with it., Methods: We examined a retrospective cohort with prenatal double bubble sign between January 1, 2008, and June 30, 2017. Postnatal diagnoses were determined by review of operative reports and additional postnatal evaluation including cytogenetic analysis, molecular analysis, and/or clinical genetic evaluation., Results: All live births at our institution with a prenatal double bubble sign had confirmed duodenal atresia. Additional anatomic anomalies and/or genetic abnormalities were identified in 62% of cases. Out of 21 cases, 6 had trisomy 21. Of the remaining 15 cases, 8 were nonisolated duodenal atresia, 3 of which had a heterotaxy syndrome. In the 7 isolated cases, 1 likely pathogenic chromosomal microdeletion was identified., Conclusions: Prenatal double bubble sign is a reliable predictor of duodenal atresia. In addition to trisomy 21, heterotaxy may be encountered. ZIC3 mutations as well as microdeletion of 4q22.3 may be underlying genetic etiologies to be considered in the diagnostic evaluation of a prenatal double bubble sign., (© 2019 S. Karger AG, Basel.)

Down syndrome is the most common human chromosomal disorder. Among clinical findings, one constant concern is the high prevalence of gastrointestinal system alterations. The aim of this study was to determine the prevalence of gastrointestinal disorders at a Down syndrome outpatient clinic during a 10-year follow-up period. Data from medical files were retrospectively reviewed from 1,207 patients. Gastrointestinal changes occurred in 612 (50.7%). The most prevalent disorder was chronic intestinal constipation. Intestinal parasite occurred in 22% (mainly giardiasis), gastroesophageal reflux disease in 14%, digestive tract malformations occurred in 5%: 13 cases of duodenal atresia, 8 of imperforate anus, 4 annular pancreases, 2 congenital megacolon, 2 esophageal atresias, 2 esophageal compression by anomalous subclavian and 1 case of duodenal membrane. We had 38/1,207 (3.1%) patients with difficulty in sucking and only three with dysphagia that resolved before the second year of life. Peptic ulcer disease, celiac disease, and biliary lithiasis were less prevalent with 3% each. Awareness of the high prevalence of gastrointestinal disorders promotes outstanding clinical follow-up as well as adequate development and greater quality of life for patients with Down syndrome and their families., (© 2019 Wiley Periodicals, Inc.)

Objective: To evaluate the application of noninvasive prenatal testing as an alternative to invasive diagnostic testing in pregnancies with the double bubble sign., Methods: This was a retrospective analysis of 92 pregnancies with fetal double bubble identified by prenatal ultrasound, in which invasive diagnostic testing was performed for genetic investigations using quantitative fluorescence PCR and chromosomal microarray. Noninvasive prenatal testing was assumed to provide to patients for screening for the common aneuploidies., Results: Fetal trisomy 21 was detected in 8 of the 92 patients with prenatal double bubble. No other chromosomal anomalies or microscopic pathogenic copy-number variations (CNV) were found. Noninvasive prenatal testing could theoretically identified the affected pregnancies with trisomy 21 in this group with decreased number of invasive diagnostic testing., Conclusions: Noninvasive prenatal testing could be recommended for genetic evaluation of the etiology of prenatal double bubble after thorough pretest counseling., (© 2018 John Wiley & Sons, Ltd.)

Background: Neonatal diabetes mellitus is a rare condition., Case Characteristics: A small for gestational age male, presented with neonatal onset diabetes mellitus, duodenal atresia, annular pancreas and gall bladder hypoplasia., Observation: Observation: A novel homozygous mutation p.K163R (c.488A>G) in the PDX1 gene was found. Parents were heterozygous for the same., Message: This case highlights the importance of establishing the genetic diagnosis in all cases of neonatal diabetes mellitus.

Deletions of chromosome 17q12 [OMIM 614527] encompass a wide range of phenotypes, including renal cysts, diabetes mellitus, pancreatic structural abnormalities, genital tract anomalies, developmental delay, learning difficulties, and more recently, autism spectrum disorder and schizophrenia. To date, gastrointestinal malformations have not been fully characterized in this syndrome. In this case report, we describe a four-year-old girl with a 17q12 microdeletion who was born with duodenal atresia, bilateral renal cysts, left kidney dysplasia, a midline cystic structure at the conus medullaris, and dysmorphic features. Both the patient and her affected father were found to have a deletion of 17q12, which encompasses the HNF1B (hepatocyte nuclear factor beta). It is hypothesized that HNF1B may play a role in intestinal differentiation and development. Our clinical report further expands the pre-and post-natal presentation of this rare microdeletion syndrome., (© 2014 Wiley Periodicals, Inc.)

The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17∼92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome., (Copyright © 2013 Wiley Periodicals, Inc.)

Familial occurrence of distal foregut atresia (DFA) (Type 1) is rare. Diagnosis is based upon the clinical symptomatology and confirmed by radiological studies, surgery and histology. A number of reports have described families in which several family members have been involved and suggested an autosomal recessive mode of inheritance. Little is known about the underlying genetic causes or indeed the likely pathogenic mechanism. We report a family in which there are five affected cases including three siblings where the DFA appears to be inherited in an autosomal dominant inheritance pattern with reduced penetrance.

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., (Copyright © 2012 Mosby, Inc. All rights reserved.)

The annular pancreas remains an intriguing congenital anomaly. Many theories have sought to explain its embryological basis; however, no consensus has yet been reached regarding the exact mechanism of aberration. More recently, molecular investigations have shed light on some of these theories, confirming the origination of annular tissue from the ventral pancreatic bud. These studies highlight the role of the hedgehog signaling pathway in the development of this anomaly. Overexpression of the ventral-specific gene transmembrane 4 superfamily member 3 (tm4sf3) has also been associated with annular formation. Moreover, isolated case reports of familial annular pancreas have also been documented, suggesting a genetic basis for the development of this anomaly. Annular pancreas can initially present in childhood or adulthood with symptoms of duodenal obstruction and is diagnosed using a variety of imaging modalities. Treatment usually involves surgical correction, with bypass procedures (e.g. duodenoduodenostomy, gastrojejunostomy or duodenojejunostomy) currently favored over annular resection due to complications associated with the latter approach., (Copyright © 2012. Published by Elsevier GmbH.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The occurrence of four gastrointestinal (GIT) anomalies in a single patient is extremely rare. Only one report of four GIT anomalies in a child has been published in the English literature. The current report presents a child with four anomalies and discusses the molecular mechanisms which control the development of the gastrointestinal tract., (© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.)

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.

Feingold syndrome (FS) is a syndromic microcephaly entity for which MYCN is the major disease-causing gene. We studied the expression pattern of MYCN at different stages of human embryonic development and collected a series of 17 FS and 12 isolated oesophageal atresia (IOA) cases. An MYCN gene deletion/mutation was identified in 47% of FS cases exclusively. We hypothesized that mutations or deletions of highly conserved non-coding elements (HCNEs) at the MYCN locus could lead to its misregulation and thereby to FS and/or IOA. We subsequently sequenced five HCNEs at the MYCN locus and designed a high-density tiling path comparative genomic hybridization array of 3.3 Mb at the MYCN locus. We found no mutations or deletions in this region, supporting the hypothesis of genetic heterogeneity in FS.

myc genes are associated with a wide variety of human cancers including most types of nervous system tumors. While the mechanisms by which myc overexpression causes tumorigenesis are multifaceted and have yet to be clearly elucidated, they are at least in part related to endogenous myc function in normal cells. Knockout (KO) of either c-myc or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre impairs mouse brain growth and mutation of N-myc also causes microcephaly in humans in Feingold Syndrome. To further define myc function in NSC and nervous system development, we created a double KO (DKO) for c- and N-myc using nestin-cre. The DKO mice display profoundly impaired overall brain growth associated with decreased cell cycling and migration of NSC, which are strikingly decreased in number. The DKO brain also exhibits specific changes in gene expression including downregulation of genes involved in protein and nucleotide metabolism, mitosis, and chromatin structure as well as upregulation of genes associated with differentiation. Together these data support a model of nervous system tumorigenesis in which excess myc aberrantly locks in a developmentally active chromatin state characterized by overactive cell cycling, and metabolism as well as blocked differentiation.

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.

Duodenal atresia is associated with a wide variety of congenital malformations. Trisomy 21 occurs in approximately one-thirds of infants with duodenal atresia. Congenital heart disease in patients with trisomy 21 and duodenal atresia is well known. However, the frequency and spectrum of congenital heart defects in infants with duodenal atresia and a normal karyotype has not been outlined in the literature. Therefore, we conducted a retrospective chart review to clarify our knowledge about this population. Retrospective review of the medical record was performed on patients with duodenal atresia/stenosis from January 1995 to September 2007. Demographic data included birth weight and gestational age. Variables of interest included cardiac defects and karyotype. Surgical repair for duodenal and cardiac malformations were reviewed. Ninety-four patients with duodenal atresia/stenosis were identified. Average gestational age was 36 weeks and birth weight was 2,536 g. Trisomy 21 was identified in 39 (41%) patients. Overall, 37 patients (39.3%) had a congenital heart defect. Defects were identified in 24 (61.5%) patients with trisomy 21, when compared to 13 (23.6%) patients with a normal karyotype. Of the patients with congenital heart defects and trisomy 21, 11 (28.2%) required operative repair compared to the 6 (10.9%) patients with a defect and normal karyotype. Therefore, in patients with duodenal atresia, the presence of trisomy 21 carries a relative risk of 2.61 for congenital heart defects, and relative risk of 2.59 for open heart surgery. In patients with duodenal atresia, the presence of trisomy 21 carries a 2.5-fold increased risk of cardiac defect and the same increased risk for repairing a cardiac defect.

Umbilical cord ulceration complicated by massive local hemorrhage may be a lethal event in the fetus, and this ulceration has been reported to be associated with upper intestinal atresia. The diagnosis of umbilical cord bleeding is difficult. We present a case of umbilical cord ulceration, hemorrhage, and duodenal atresia which had, in addition, an interstitial deletion of chromosome 13q. A female infant weighing 1,691 g was delivered by cesarean section at 34 weeks of gestation and had resuscitation and laparotomy. Just before the cesarean section, ultrasonography showed a 'double bubble' sign and a linear shadow, suggesting fibrin in the amniotic cavity. This finding may help in the diagnosis of bleeding from the cord., ((c) 2008 S. Karger AG, Basel.)

We report a case of duodenal membranous atresia associated with "apple peel" small bowel in a baby girl. The patient's mother and sibling had also undergone surgery for duodenal atresia. Familial duodenal atresia is sometimes the result of genetic, inherited abnormalities. Fibroblast growth factor (FGF) receptor 2IIIb (Fgfr2b) and Fgf10 are known regulatory molecules relevant to mesenchymal-epithelial interactions. The involvement of the Fgf10/Fgfr2b pathway in the pathogenesis of intestinal atresia are related to tissue-specific transcription factors, which regulate the expression of Fgf10 according to the organ system and the stage of gestation. Furthermore, a spontaneous somatic mutation or a point mutation of Fgf10 early in development would result in a genetic mosaic pattern. Fluorescent in situ hybridization did not show homozygous or heterozygous deletion of the Fgf10 or Fgfr2b gene in this case. It is necessary to study the occurrence of duodenal atresia in posterity and investigate the deletion of the Fgfr2b or Fgf10 genes if possible.

Duodenal atresia (DA) is not uncommon, either as an isolated anomaly or associated with trisomy 21, malrotation, or cardiac anomalies. It may be diagnosed on antenatal ultrasound by a "double-bubble" sign, which typically persists after birth on a plain abdominal radiograph. DA as a familial association is rare but has been reported with or without other associated anomalies. We report DA in two siblings of nonconsanguineous parents, one case occurring with an annular pancreas in association with gestational diabetes. These two cases suggest possible genetic and environmental components in the aetiology of this anomaly.

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.

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.

The distal foregut comprises the antrum of the stomach and supra-ampullary region of the duodenum. In this part of the gut, intraluminal mucosal diaphragms, webs, membranes (type I), and rarely solid cord (type II) atresias are occasionally seen in clinical practice. Due to increased awareness, the number of reported cases has increased in recent years. These foregut lesions are known to have a strong genetic association. Both antral (AA) and duodenal atresias (DA) may occur as potentially curable sporadic cases or in combination with lethal malformations such as hereditary multiple gastrointestinal atresias affecting the fore-, mid-, and hindgut. The association of AA and junctional epidermolysis bullosa lethalis is well-known. We describe an unusual occurrence of foregut atresias in two consecutive siblings and a pair of monozygous twins. The involvement of four siblings in a single family is extraordinary and as yet unreported. This cluster of cases not only lends a strong support to a genetic origin, but also the mode of transmission, despite the absence of a history of consanguinity. It indicates that atresia of the gastric antrum and supra-ampullary DA are etiologically closely related. It is also possible that the discordant expression in the twins could be a pleiotropic effect of the same genetic factor. Attempts are made to explain the possible pathogenesis of this unusual atresia and relate it to other associated anomalies.

The familial occurrence of duodenal atresia is extremely uncommon. The author reports duodenal atresia occurring in two siblings who underwent successful surgical repair at the Pediatric Surgical Unit, Department of Surgery, Ratchaburi Hospital. To the author's knowledge, this is the first report of familial duodenal atresia in Thailand.

Twenty-nine patients with congenital duodenal obstruction (DO) detected as a "double bubble" (DB) on antenatal ultrasound (US) or diagnosed postnatally were seen at the Women's and Children's Hospital between 1985 and 1994; 24 (83%) had antenatal scans, with 21 (87%) DBs visualised. The 3 fetuses with normal scans who developed DO postnatally had duodenal "windsocks". Five of the 24 scanned patients (21%) were found to have a DB before 20 weeks' gestation: 1 simple duodenal atresia, 2 duodenal atresias with chromosomal abnormalities (1 trisomy 21 and 1 triploidy), 1 biliary atresia with a pre-pyloric vein, and 1 malrotation. Sixteen (67%) cases were detected with scans after 20 weeks (range 28-36 weeks); 12 (75%) of these were done for polyhydramnios. In response to a questionnaire to 9 of the 16 parents whose fetuses underwent a late scan, 5 had had normal early scans elsewhere and 4 did not respond (4 of the remaining 7 had died and 3 were lost to follow-up). Eleven of the 29 patients (38%) had abnormal karyotypes, and 4 (22%) of the 18 with a normal karyotype had associated anomalies. Two sets of familial cases were noted. Early antenatal diagnosis of DO is possible in a minority of cases, and this early diagnosis may be associated with an increased risk of other pathology. Furthermore, early demonstration of a DB at routine US prior to 20 weeks allows appropriate counseling and the option of mid-trimester termination, whereas this is more difficult later in the pregnancy. In all cases detected antenatally, planning of delivery and parent counseling should be achieved.

In a population of close to 2.5 million infants born from 1983 to 1993 registered in the California Birth Defects Monitoring Program, we compared the prevalence of structural birth defects among 2,894 infants with Down syndrome (DS) with that of infants without DS. Among 61 defects uniformly ascertained in affected and unaffected infants, 45 were significantly more common in DS, with atrioventricular canal (risk ratio = 1,009), duodenal atresia (risk ratio = 265), and annular pancreas (risk ratio = 430) being the most common. Most defects of blastogenesis and most midline defects were either nonsignificantly associated or not observed in infants with DS. Theories on the pathogenesis of defects in trisomies must account for the lack of and for the presence of specific defects.

The authors report duodenal atresia occurring in both members of dizygotic twins who showed no signs of Down's syndrome, and both had normal chromosomal constitutions. They both had the two unlinked end type of atresia in the second portion of the duodenum, and direct end-to-end duodenoduodenostomy was carried out. Their postoperative courses were smooth, and both babies were discharged 32 days after birth. Their mother underwent pituitary adenoma removal and partial parathyroidectomy for multiple endocrine neoplasia (MEN-type I). She had been given hormonal supplement therapy after surgery and became pregnant after exogenous gonadotropin therapy. Environmental factors may be responsible for some cases of duodenal atresia.

Junctional epidermolysis bullosa with congenital pyloric or duodenal atresia is a distinct variant within this group of autosomal recessive blistering skin diseases. In this study we demonstrate, for the first time, a homozygous mutation in the alpha6 integrin gene (ITGA6) in a family with three affected individuals. For this purpose, we first determined the genomic organization of ITGA6, and placed the gene on chromosome 2q by high resolution radiation hybrid mapping. Heteroduplex analysis of PCR products containing the individual exons of ITGA6, followed by direct nucleotide sequencing, revealed that the proband was homozygous for a G-to-T transversion in the +1 position of intron 12. This mutation, 1856+1G-->T, affects an invariant base of the 5' donor splice site predicting aberrant splicing involving exon 12. The mutation was verified in the proband's DNA by restriction enzyme digestion which also confirmed that the parents were heterozygous carriers of this mutation. Altered expression of alpha6 integrin, which forms a heterodimer with the beta4 subunit at the dermal-epidermal junction, would explain fragility and blistering as a result of minor trauma to the skin.

We report on two sibs with tetralogy of Fallot (TOF) and duodenal atresia (DA). The first child, a 6-year-old girl, had a right facial palsy in addition to the TOF and DA. Her brother, age 10 months, was born with bilateral microtia without facial palsy. The children are the product of an apparently non-consanguineous union between clinically normal parents. The pertinent family history includes a paternal aunt with TOF and a cleft lip and palate who died in childhood and another paternal aunt with a supernumerary thumb. This family has anomalies found in several syndromes, but does not meet the diagnostic criteria for any of them. The genetic basis for this condition remains unknown, but the pattern of inheritance is likely either autosomal recessive, or autosomal dominant with variable expression and reduced penetrance. The pathogenesis is unknown, but either a disturbance in neural crest cell migration or familial predisposition to vascular disruption might explain this pattern of malformations.

The familial occurrence of duodenal atresia is uncommon. This study evaluated the inheritance patterns, the nature and associations, and the presence of immunologic deficits in duodenal atresia recurring in at least three siblings each in two nonrelated families. In the first family, an association with Fanconi's anemia was observed in three of seven pregnancies (2 boys, 1 girl) suggesting an autosomal recessive mode of transmission. Patients died as a result of overwhelming (fungal) septicemia in association with pancytopenia. In a second family, identical multiple atresias occurred in two female siblings born 18 months apart and a third child with a duodenal stenosis. Overwhelming sepsis and a T-cell dysfunction was seen in the postoperative period, which had partially corrected by follow-up at 5 months. A history of family occurrence of duodenal atresia should alert the physician to the possibility of associated pathology including immune deficiency states.

The sonographic diagnosis of duodenal atresia and associated anomalies was made in a fetus at 15 weeks' gestation. A transient double-bubble sign was observed in three other normal fetuses. Sonographers are cautioned that normal intestinal peristalsis may cause a false image of duodenal atresia.

Chromosomal aberration and micronucleus assays were used to investigate the extent of cytogenetic damage in peripheral blood lymphocytes from four patients in two unrelated families with hereditary megaduodenum. The frequencies of total chromosomal aberrations, which significantly correlated with those of micronuclei, were higher in the patients than in sex- and age-matched controls, with no overlapping between the two groups. The considerable chromosomal fragility in patients with hereditary megaduodenum may be a genotypic marker for preclinical diagnosis predictive of increased cancer risk.

The authors describe a case of duodenal atresia occurring in two siblings. It is possible that the third sibling also died after complications of the same malformation. This familial occurrence may support the hypothesis that this anomaly is determined by an autosomal-recessive gene.

The case is reported of a baby boy with an interstitial deletion of the long arm of chromosome 13 who, in addition to the described associations of Hirschsprung's disease and intestinal atresia, had umbilical cord ulceration resulting in massive intrapartum haemorrhage. This case provides support for the existence of a previously reported association between umbilical cord ulceration and intestinal atresia, and suggests that it is aetiologically heterogeneous.

This is the report of an infant seen on June 25, 1960 with preampullary total duodenal obstruction caused by a combined annular pancreas and duodenal stenosis above the ampulla. A gastroduodenostomy was performed. In December 1989, he fathered a 1,700-g boy with preampullary duodenal atresia. A duodeno-duodenostomy was performed successfully by the same pediatric surgeon. Second-generation duodenal obstruction is rare; to our knowledge, there are no other cases.

We describe a 37-week gestation female infant who was born with a terminal 2q deletion. Both of her parents had normal chromosomes. This infant had multiple anomalies, including hypertelorism, short palpebral fissures, microphthalmia, cleft lip/cleft palate, and abnormal ears. Autopsy documented Dandy-Walker malformation with severe hydrocephalus, aortopulmonary window, secundum atrial septal defect, duodenal atresia, incomplete rotation of the bowel, gonadal dysgenesis, uterus didelphys, and musculoskeletal defects. Compared with the other 6 children with 2q terminal deletion documented in the literature, this patient is the most severely affected. This patient is also the only one documented to have died and undergone autopsy examination. The findings in this case provide more data for the eventual description of a "terminal 2q deletion syndrome" and suggest that some abnormalities, such as gonadal dysgenesis, may be present in living children with this chromosome abnormality.

Down syndrome (DS) is a major cause of congenital heart and gut disease and mental retardation. DS individuals also have characteristic facies, hands, and dermatoglyphics, in addition to abnormalities of the immune system, an increased risk of leukemia, and an Alzheimer-like dementia. Although their molecular basis is unknown, recent work on patients with DS and partial duplications of chromosome 21 has suggested small chromosomal regions located in band q22 that are likely to contain the genes for some of these features. We now extend these analyses to define molecular markers for the congenital heart disease, the duodenal stenosis, and an "overlap" region for the facial and some of the skeletal features. We report the clinical, cytogenetic, and molecular analysis of two patients. The first is DUP21JS, who carries both a partial duplication of chromosome 21, including the region 21q21.1-q22.13, or proximal q22.2, and DS features including duodenal stenosis. Using quantitative Southern blot dosage analysis and 15 DNA sequences unique to chromosome 21, we have defined the molecular extent of the duplication. This includes the region defined by DNA sequences for APP (amyloid precursor protein), SOD1 (CuZn superoxide dismutase), D21S47, SF57, D21S17, D21S55, D21S3, and D21S15 and excludes the regions defined by DNA sequences for D21S16, D21S46, D21S1, D21S19, BCE I (breast cancer estrogen-inducible gene), D21S39, and D21S44. Using similar techniques, we have also defined the region duplicated in the second case occurring in a family carrying a translocation associated with DS and congenital heart disease. This region includes DNA sequences for D21S55 and D21S3 and excludes DNA sequences for D21S47 and D21S17.(ABSTRACT TRUNCATED AT 250 WORDS)

This report presents a family with two individuals in two successive generations who were affected by annular pancreas and high duodenal obstruction. An argument for autosomal dominant transmission and implications for appropriate team management are discussed.

We report on a 19-month-old girl with ring chromosome 4 and a multiple congenital anomaly syndrome. The clinical and cytogenetic findings are compared with those of previous cases in whom the breakpoints in ring chromosome 4 are known.

Two siblings with extrinsic duodenal obstruction caused by congenital peritoneal bands are reported. Attention is drawn to the unusual physical sign of halitosis as a presenting feature. It is suggested that this physical sign may be an indication for barium studies.