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PLoS Biology Nov 2022Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model...
Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.
Topics: Animals; N-Myc Proto-Oncogene Protein; Zebrafish; Microcephaly; TOR Serine-Threonine Kinases; Leucine
PubMed: 36318514
DOI: 10.1371/journal.pbio.3001856 -
Orphanet Journal of Rare Diseases Oct 2021Homozygous mutations in the transcription factor RFX6 are the cause of the Mitchell-Riley syndrome (MRS) associating neonatal diabetes, congenital digestive system,...
Determining oncogenic patterns and cancer predisposition through the transcriptomic profile in Mitchell-Riley syndrome with heterotopic gastric mucosa and duodenal atresia: a case report.
BACKGROUND
Homozygous mutations in the transcription factor RFX6 are the cause of the Mitchell-Riley syndrome (MRS) associating neonatal diabetes, congenital digestive system, such as biliary atresia, pancreatic hypoplasia, duodenal and/or jejunal atresia, intestinal malrotation, gallbladder aplasia, cholestasis. A constitutive inactivation of RFX6 leads also to gastric heterotopia. Application of RNA-seq in human diseases may help to better understand pathogenic mechanism of diseases and to predict the risk of developing chronic disorders and personalizing their prevention and treatment. We evaluated oncogenic patterns and cancer predisposition using the transcriptomic profile in a case of MRS with neonatal diabetes, duodenal atresia, and extensive intestinal tract gastric heterotopia.
RESULTS
We signalled the interactors of RFX6 with other up and downregulated genes, that may be interested in severity of diabetic condition, in multi-organs impairment and cancer predisposition. Furthermore, several dysregulated genes are involved in biological processes that can lead to promote cancer including "Evading apoptosis" (BAD, BBC3, EGF, FGFR2, FLT3LG, HMOX1, HRAS, IFNAR2, IGF1R, IL12RB1, IL13RA1, IL15, IL2RB, IL2RG, IL6R, KEAP1, MGST1, PDGFA, PDGFRB, PIK3R3, RALB, RALGDS, RASSF1, SOS1, TGFA, TXNRD3), "Proliferation" (APC, BRAF, CCND2, CCND3, CCNE2, FGFR2, FLT3LG, FZD1, FZD6, HMOX1, HRAS, IGF1R, KEAP1, LRP6, MAPK3, MGST1, PDGFA, PDGFB, PDGFRB, RB1, SOS1, TGFA, TXNRD3, WNT10B), "Sustained angiogenesis" (BRAF, FGFR2, FLT3LG, HRAS, IGF1R, JAG1, MAPK3, NOTCH2, PDGFA, PDGFB, PDGFRB, SOS1, TGFA, TGFB1), "Genomic instability" (BAD, BBC3) and "Insensitivity to anti-growth signals" (SMAD2, TGFB1). We also inspected the signalings and their related genes in cancer, such as "PI3K signaling", "ERK signaling", "JAK-STAT signaling", "Calcium signaling", "Other RAS signaling", "WNT signaling".
CONCLUSIONS
In our MRS patient, we signaled the interactors of RFX6 with other up- and downregulated genes that may be related to severe diabetic condition, multi-organ impairment, and cancer predisposition. Notably, many dysregulated genes may lead to triggering carcinogenesis. The possibility of the patient developing cancer degeneration in heterotopic gastric mucosa and/or additional long-term tumoral sequelae is not excluded. Personalized prevention and treatment strategies should be proposed.
Topics: Carcinogenesis; Diabetes Mellitus; Duodenal Obstruction; Gallbladder Diseases; Gastric Mucosa; Humans; Infant, Newborn; Intestinal Atresia; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Neoplasms; Phosphatidylinositol 3-Kinases; Regulatory Factor X Transcription Factors; Transcriptome
PubMed: 34715892
DOI: 10.1186/s13023-021-02093-9 -
Frontiers in Endocrinology 2022Caused by biallelic mutations of the gene encoding the transcription factor , the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia,...
AIMS/HYPOTHESIS
Caused by biallelic mutations of the gene encoding the transcription factor , the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the function.
METHODS
Clinical records were analyzed and described in detail. The functional impact of two RFX6 and RFX6 variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function.
RESULTS
All four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6 and RFX6 mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function.
CONCLUSIONS/INTERPRETATION
Multidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.
Topics: Diabetes Mellitus; Duodenal Obstruction; Gallbladder Diseases; Humans; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Intestinal Atresia; Mutation; Regulatory Factor X Transcription Factors
PubMed: 35813646
DOI: 10.3389/fendo.2022.802351 -
World Journal of Surgery Aug 2011Since the initial reports of laparoscopic repair of duodenal atresia in neonates, further reports have been scant. Could this be because of unacceptable rates of...
BACKGROUND
Since the initial reports of laparoscopic repair of duodenal atresia in neonates, further reports have been scant. Could this be because of unacceptable rates of complications, like anastomotic leakage, as mentioned in later reports? In the present study the laparoscopic repair of duodenal atresia in neonates is revisited.
PATIENTS
Group 1 consisted of 22 patients with duodenal obstruction between 2000-2005 until the laparoscopic approach was abandoned. Of these 22 patients, 10 had Down syndrome and 8 had concomitant malformations. In this group 18 patients were operated laparoscopically. Four patients underwent an open procedure. Group 2 consisted of six patients that underwent operation between 2008 and February 2010.
RESULTS
In group 1 there were four conversions. In 14 patients the procedure could be completed laparoscopically. In five patients postoperative leakage occurred. The complication rate was found to be unacceptably high, and the laparoscopic approach was abandoned. After gaining additional experience in intracorporeal suturing and adjusting the technique, the procedure was started up again in 2008. Since then six consecutive neonates have undergone laparoscopic repair of duodenal atresia without complications.
CONCLUSIONS
Laparoscopic repair of duodenal atresia is one of the most demanding pediatric laparoscopic surgical procedures. After initial promising results at the beginning of the twenty-first century a relative "radio silence" followed, apparently caused by unsatisfactory results. Only considerable adjustments in technique and extensive improvement in experience has led to acceptable outcomes more recently. Laparoscopic repair of duodenal atresia should therefore be restricted to pediatric centers with extensive experience in laparoscopic surgery and intracorporeal suturing.
Topics: Anastomotic Leak; Comorbidity; Cross-Sectional Studies; Duodenal Obstruction; Female; Hospitals, Pediatric; Humans; Infant, Newborn; Intestinal Atresia; Laparoscopy; Male; Outcome and Process Assessment, Health Care; Postoperative Complications; Reoperation; Suture Techniques
PubMed: 21604051
DOI: 10.1007/s00268-011-1147-y -
Cureus Sep 2021We present a case of a baby conceived via in vitro fertilization and born prematurely with duodenal atresia. It was later discovered that the patient also had biliary...
We present a case of a baby conceived via in vitro fertilization and born prematurely with duodenal atresia. It was later discovered that the patient also had biliary atresia. Both defects were repaired surgically via duodeno-duodenostomy and Kasai procedures, respectively. Our case presents the rare event of both duodenal and biliary atresia as well as management in this case. Although this dual diagnosis is relatively uncommon, such a possibility should be considered in certain cases. This case also adds to the literature opening up further investigation for a likely link between these two anomalies.
PubMed: 34703705
DOI: 10.7759/cureus.18218 -
Pediatric Surgery International Mar 2023Cardiac anomalies occur frequently in patients with congenital duodenal obstruction (DO). However, the exact occurrence and the type of associated anomalies remain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cardiac anomalies occur frequently in patients with congenital duodenal obstruction (DO). However, the exact occurrence and the type of associated anomalies remain unknown. Therefore, the aim of this systematic review is to aggregate the available literatures on cardiac anomalies in patients with DO.
METHODS
In July 2022, a search was performed in PubMed and Embase.com. Studies describing cardiac anomalies in patients with congenital DO were considered eligible. Primary outcome was the pooled percentage of cardiac anomalies in patients with DO. Secondary outcomes were the pooled percentages of the types of cardiac anomalies, type of DO, and trisomy 21. A meta-analysis was performed to pool the reported data.
RESULTS
In total, 99 publications met our eligibility data, representing 6725 patients. The pooled percentage of cardiac anomalies was 29% (95% CI 0.26-0.32). The most common cardiac anomalies were persistent foramen ovale 35% (95% CI 0.20-0.54), ventricular septal defect 33% (95% CI 0.24-0.43), and atrial septal defect 33% (95% CI 0.26-0.41). The most prevalent type of obstruction was type 3 (complete atresias), with a pooled percentage of 54% (95% CI 0.48-0.60). The pooled percentage of Trisomy 21 in patients with DO was 28% (95% CI 0.26-0.31).
CONCLUSION
This review shows cardiac anomalies are found in one-third of the patients with DO regardless of the presence of trisomy 21. Therefore, we recommend that patients with DO should receive preoperative cardiac screening.
LEVEL OF EVIDENCE
II.
Topics: Humans; Child; Down Syndrome; Duodenal Obstruction; Heart Defects, Congenital
PubMed: 36967411
DOI: 10.1007/s00383-023-05449-3 -
Cureus Sep 2021Situs inversus totalis is the mirror image transposition of the abdominal-thoracic viscera. Approximately one in every 5,000 to 20,000 live births has situs inversus...
Situs inversus totalis is the mirror image transposition of the abdominal-thoracic viscera. Approximately one in every 5,000 to 20,000 live births has situs inversus totalis. Most commonly, it is found incidentally and is asymptomatic. A number of malformations, including cardiac, splenic, and gastrointestinal, have been associated with this condition. Coexistence with duodenal atresia is extremely rare, reported in fewer than 30 cases worldwide and one case in Saudi Arabia. We report a preterm neonate who presented with bilious vomiting. Diagnosis of situs inversus totalis with duodenal atresia type III was established and other anomalies were ruled out. The patient was managed surgically by duodenal-duodenostomy and Ladd's procedure. The report emphasizes the importance of identifying this condition and recognizing the "mirror anatomy" before carrying out an operation. Once the diagnosis is confirmed, surgical intervention must be performed as soon as possible to prevent complications.
PubMed: 34659975
DOI: 10.7759/cureus.17764 -
African Journal of Paediatric Surgery :... 2019Intestinal atresia requires multiple surgeries and long hospital stay. We tried managing these cases by primary anastomosis with transanastomotic tube (TAT) for early...
INTRODUCTION
Intestinal atresia requires multiple surgeries and long hospital stay. We tried managing these cases by primary anastomosis with transanastomotic tube (TAT) for early feeding.
AIMS
The aim of the study was to analyse the outcomes in patients of intestinal atresia who underwent primary anastomosis with a TAT.
MATERIALS AND METHODS
The records between June 2014 and November 2017 were analysed. Those with incomplete data or unclear final outcome were excluded. Patients managed by primary anastomosis with TAT (Group A) or without TAT (Group B) were included. The TAT was kept for 6 weeks. Oral feeds were started after 2 weeks in all the cases. P < 0.05 was considered as statistically significant.
RESULTS
Forty-eight cases were included. There were two duodenal atresia, 29 jejunal atresia and 17 ileal atresia. The mean age at surgery was 2 days (range: 1-16 days). There were 42 cases in Group A (with TAT) and six in Group B (without TAT). The average duration of start of feeds was 78 h (range: 72-96 h) in Group A and 402 h (range: 360-504 h) in Group B (P = 0.01). The mean duration of hospital stay was 7 days (range: 5-15 days) and 27 days (range: 19-48 days) in Group A and B, respectively (P = 0.02). The overall survival was 38 (91%) and 3 (50%) in Group A and B, respectively (P = 0.01). Reexploration was required in 2/42 and 2/6 cases in Group A and B, respectively (P = 0.4). Total parental nutrition was required in 2/42 and all cases in Group A and B, respectively.
CONCLUSION
Primary repair in intestinal atresia with a TAT is a practical option. The overall outcome is better.
PubMed: 32952137
DOI: 10.4103/ajps.AJPS_101_17 -
American Journal of Obstetrics &... Jan 2021A sonographically large fetal stomach has been associated with gastrointestinal obstruction, per case reports, and is often followed up with serial ultrasound...
BACKGROUND
A sonographically large fetal stomach has been associated with gastrointestinal obstruction, per case reports, and is often followed up with serial ultrasound examinations. The frequency of this phenomenon has not been systematically studied, resulting in challenges in counseling parents about the prognosis and making cost-benefit analysis of serial ultrasound follow-up difficult to assess.
OBJECTIVE
This study aimed to determine the frequency at which an enlarged fetal stomach as the sole abnormality on fetal ultrasound reflects a bowel obstruction to aid in parental counseling and determine the best practice for follow-up.
STUDY DESIGN
We performed a retrospective cohort study of all prenatal sonographic cases in which a large fetal stomach was visualized between January 1, 2002, and June 1, 2016. The inclusion criteria required a fetal diagnosis of a large stomach, defined as an increased measurement in ≥2 dimensions based on a nomogram, that resulted in a liveborn delivery within the Johns Hopkins Health System. We excluded pregnancy loss, pregnancy termination, and cases delivered outside of the Johns Hopkins Health System. Cases were subclassified as isolated or complex based on the absence or presence of additional ultrasound findings at initial presentation of the enlarged stomach. The perinatal outcomes and maternal demographics were determined and compared between isolated and complex cases.
RESULTS
Of 57,346 total cases with ultrasound examinations in the Johns Hopkins Health System within the study time frame, 348 fetuses had enlarged stomachs, with 241 (69.3%) who met the inclusion criteria as follows: 161 (66.8%) isolated and 80 (33.2%) complex. Of the 161 isolated cases, 1 resulted in neonatal small bowel obstruction (0.62%). Of note, 158 of the isolated large stomach cases (98.1%) had no postnatal abnormalities of any kind. Of the 80 complex cases, 18 (22.5%) resulted in neonatal gastrointestinal obstruction (14 cases of duodenal atresia and 4 cases of jejunal atresia). Those with isolated findings were significantly less likely to deliver preterm (n=24 [14.9%] vs n=35 [43.8%]; P<.001), be complicated by polyhydramnios (n=18 [11.2%] vs n=23 [28.8%]; P<.001), have a neonatal intensive care unit admission (n=31 [19.3%] vs n=76 [95.0%]; P<.01), or have a major surgical procedure (n=2 [1.2%] vs n=66 [82.5]; P<.001) compared with complex cases.
CONCLUSION
We found that 0.62% of isolated large fetal stomachs (1 of 161) were associated with neonatal intestinal obstruction. Of the complex cases with an enlarged stomach, 18 of 80 (22.5%) were found to have a gastrointestinal obstruction; by definition, none of these complex cases began as an isolated large stomach as their initial ultrasound finding, but rather had other concurrent sonographic abnormalities, including a double bubble sign and intestinal dilation. With a prevalence of <1% resulting in the development of a small bowel obstruction, our results suggest that, when isolated, a large stomach does not seem to warrant serial prenatal ultrasound follow-up or postnatal imaging and is likely to reflect an incidental finding.
Topics: Duodenal Obstruction; Female; Humans; Infant; Infant, Newborn; Intestinal Atresia; Pregnancy; Retrospective Studies; Stomach; Ultrasonography, Prenatal
PubMed: 33451621
DOI: 10.1016/j.ajogmf.2020.100272 -
Archives of Disease in Childhood Apr 1970
Topics: Consanguinity; Duodenum; Female; Genes, Recessive; Humans; Infant; Infant, Newborn; Intestinal Atresia; Male
PubMed: 5420010
DOI: 10.1136/adc.45.240.281