Prenatal and postnatal peculiarities and consequences of intestinal loop patency disorder with expansive giant cystic abdominal mass in a preterm newborn.

AIM: To analyse the findings in a newborn (36 gestational weeks, birth weight: 4,030 grams, birth length: 48 cm, Apgar score 7/8/8 points) with prenatal suspicion of intestinal obstruction at the duodenum/jejunum level. The patient required urgent surgery on the first day of life. RESULTS: Examination of the abdominal cavity confirmed the presence of a cystic mass with a volume of approximately 800 ml, which was located at the site of jejunal atresia. As part of the surgical solution, the cystic formation and the atretic segment of the intestine were resected with subsequent end-to-end jejuno-jejunal anastomosis and Bishop‒Koop ileostomy. The histological examination of 3 samples collected confirmed the presence of mucous membrane and smooth muscle. CONCLUSION: The cyst anatomically communicated with the aboral section of the jejunum, but the lumen of the jejunum was functionally obturated by solid whitish masses. The histological examination confirmed the diagnostic features of a cyst of intestinal origin. The ileum and colon were patent throughout, but of smaller diameter, so a Bishop-Koop relieving anastomosis was indicated. The condition of the child at the age of 9 months was stabilised and surgical closure of the stoma was carried out (Tab. 1, Fig. 8, Ref. 21). Text in PDF www.elis.sk Keywords: newborn, jejunal atresia, intestinal cyst.

Prominent Follicular Keratosis in Multiple Intestinal Atresia with Combined Immune Deficiency Caused by a TTC7A Homozygous Mutation.

Multiple intestinal atresia with combined immune deficiency (MIA-CID) is an autosomal recessive syndrome due to mutations in the TTC7A gene implicated in the polarization of intestinal and thymic epithelial cells. MIA-CID is lethal in the first year of life in the majority of patients. Dermatological manifestations have been reported in a few cases. We describe a child affected with MIA-CID due to a previously unreported TTC7A homozygous missense mutation. Surgery for bowel occlusion was performed in the first days of life. The patient was totally dependent on parenteral nutrition since birth and presented severe diarrhea and recurrent infections. He underwent hematopoietic stem cell transplantation at 17 months with complete donor engraftment and partial immunity improvement. In the second year of life, he progressively developed diffuse papular follicular keratoses on ichthyosiform skin, nail clubbing, and subungual hyperkeratosis. Histopathology showed hyperkeratosis with follicular plugging and scattered apoptotic keratinocytes, visualized at an ultrastructural examination. Our findings expand the spectrum of dermatological manifestations which can develop in MIA-CID patients. Examination of further patients will allow defining whether keratinocyte apoptosis is also a disease feature.

First multivisceral transplantation in Mitchell-Riley/Martinez-Frias syndrome.

BACKGROUND: MRS/MFS is a rare multisystem disorder with a poor prognosis. The high mortality rate of this syndrome is related to the severity of the associated gastrointestinal, pancreatic, and hepatobiliary conditions, as most of them are not amenable to conventional medical and surgical treatments. METHODS: We report the case of a Romani girl with all the key clinical features of MRS/MFS, and a review of cases reported in the literature. Our patient is a newborn from consanguineous parents who presented duodenal atresia, hypoplastic pancreas, gallbladder agenesis, and neonatal diabetes. Given the clinical suspicion of MRS/MFS, a genetic analysis was performed which revealed the presence of a homozygous variant in the RFX6 gene. During the course of the disease, the patient presented intractable secretory diarrhea and severe intestinal failure. RESULTS: At 2 years of age, she underwent MVT of the stomach, duodenum, small intestine, colon, liver, and pancreas. There were no surgical complications. Histologic evaluation of the small bowel showed extensive patches of gastric heterotopia. After more than 10 years of follow-up, she had presented with normal gastrointestinal, hepatic, and pancreatic function. She has one of the longest survival periods in the literature. CONCLUSIONS: Our experience suggests that multivisceral transplantation may be a promising option in select cases of MRS/MFS.

Atresias de intestino delgado. Revisión de la patología y hallazgos radiológicos asociados a distintos casos / Small-bowel atresias: a case series with review of the disease and imaging findings

Las atresias de intestino delgado son una de las causas más frecuentes de obstrucción intestinal en el neonato y habitualmente requieren tratamiento quirúrgico urgente. Las técnicas de imagen conforman una parte muy importante del diagnóstico, aportando la ecografía obstétrica prenatal la sospecha inicial y siendo la radiografía simple de abdomen la prueba que confirma el diagnóstico tras el nacimiento. La ecografía abdominal en el recién nacido está cobrando cada vez mayor importancia, debido a su inocuidad, disponibilidad, bajo coste y alta capacidad de resolución, tanto para la confirmación del diagnóstico como para la detección de las posibles complicaciones asociadas. En este artículo analizamos una serie de casos vistos en nuestro centro y elaboramos un resumen de los diferentes tipos de atresias de intestino delgado, haciendo hincapié en la clínica, los hallazgos radiológicos obtenidos en las diferentes modalidades de imagen, la existencia de patología asociada, su manejo y su evolución.(AU)

Small-bowel atresias are among the most common causes of intestinal obstruction in newborns, and they often require urgent surgical treatment. Imaging techniques play a very important role in their diagnosis, which is often suspected on prenatal obstetric ultrasound and confirmed on postnatal plain-film X-rays. Abdominal ultrasound's lack of ionizing radiation, wide availability, low cost, and high resolution is making this technique increasingly important in confirming atresias and in detecting possible complications in newborns. This review analyzes a series of cases seen at our center. It summarizes the different types of small-bowel atresias, focusing on the clinical presentation, imaging findings on different modalities, presence of associated disease, management, clinical course, and outcomes.(AU)

Gut lumen formation defect can cause intestinal atresia: evidence from histological studies of human embryos and intestinal atresia septum.

Intestinal atresia (IA), a common cause of neonatal intestinal obstruction, is a developmental defect, which disrupts the luminal continuity of the intestine. Here, we investigated (i) the process of lumen formation in human embryos; and (ii) how a defective lumen formation led to IA. We performed histological and histochemical study on 6-10 gestation week human embryos and on IA septal regions. To investigate the topology of embryonic intestine development, we conducted 3D reconstruction. We showed that a 6-7th gestation week embryonic gut has no lumen, but filled with mesenchyme cells and vacuoles of a monolayer of epithelial cells. A narrow gut lumen was formed by gestation week-9, the gut was filled with numerous vacuoles of different sizes, some vacuoles were merging with the developing embryonic gut wall. At gestation week-10, a prominent lumen was developed, only few vacuoles were present and were merging with the intestine wall. At IA septal regions, vacuoles were located in the submucous layer, covered by a single layer of epithelium without glandular structure, and surrounded with fibrous tissue. The mucosal epithelium was developed with lamina propria and basement membrane, but the submucosa and the longitudinal smooth muscle layers were not properly developed. Hence, the vacuoles in IA septum could represent a remnant of vacuoles of embryonic gut. In conclusion, the fusion of vacuoles with the developing intestine wall associates with the disappearance of vacuoles and gut lumen formation in human embryos, and perturbation of these developmental events could lead to IA.

Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6.

Mitchell-Riley syndrome (MRS) is caused by recessive mutations in the regulatory factor X6 gene (RFX6) and is characterised by pancreatic hypoplasia and neonatal diabetes. To determine why individuals with MRS specifically lack pancreatic endocrine cells, we micro-CT imaged a 12-week-old foetus homozygous for the nonsense mutation RFX6 c.1129C>T, which revealed loss of the pancreas body and tail. From this foetus, we derived iPSCs and show that differentiation of these cells in vitro proceeds normally until generation of pancreatic endoderm, which is significantly reduced. We additionally generated an RFX6HA reporter allele by gene targeting in wild-type H9 cells to precisely define RFX6 expression and in parallel performed in situ hybridisation for RFX6 in the dorsal pancreatic bud of a Carnegie stage 14 human embryo. Both in vitro and in vivo, we find that RFX6 specifically labels a subset of PDX1-expressing pancreatic endoderm. In summary, RFX6 is essential for efficient differentiation of pancreatic endoderm, and its absence in individuals with MRS specifically impairs formation of endocrine cells of the pancreas head and tail.

A rare combination of MODY5 and duodenal atresia in a patient: a case report.

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 ß gene (HNF1ß), 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 ß-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.

Expanding the phenotype and the genotype of Stromme syndrome: A novel variant of the CENPF gene and literature review.

This report describes siblings with Stromme syndrome, a rare genetic condition that primarily presents with a triad of intestinal atresia, cranial and ocular malformations, and other organ systems could be involved. This clinical triad was initially named after the first person to describe it in 1993. Here, we report a family with two siblings who presented with unusual intestinal atresia and ocular and CNS abnormalities. The first patient is a 6-year-old-boy with apple peel duodeno-jejunal atresia, unilateral microphthalmia and microcephaly. The second patient, a younger brother, presented with intestinal atresia, corneal opacity and alobar holoprosencephaly and passed away at the age of 3 months. Exome sequencing showed a novel homozygous variant in the CENPF gene, NM_016343.3: c.1195-2 A > G that was detected in both of the affected siblings. This is a report and literature review of CENPF-related ciliopathy, which may result in Stromme syndrome. As this is the fourth report linking the CENPF gene variant with Stromme syndrome and first reported case presented with holoprosencephaly, it will expand the current knowledge on the genotype and the phenotype of Stromme syndrome.

Clinicopathological study of intestinal smooth muscles, interstitial cells of Cajal, and enteric neurons in neonatal jejuno-ileal atresia with special reference to muscle morphometry.

PURPOSE: To assess the thickness of the intestinal smooth muscle layer and analyze the distribution and density of interstitial cells of Cajal (ICC) and enteric neurons in the proximal and distal segments of neonatal jejuno-ileal atresia. METHODS: This is an observational study done over a period of one year in which fifteen cases of jejuno-ileal atresia were included. All the cases underwent laparotomy and resection of the atretic segment with variable portions of the dilated proximal segment and distal segment. Histopathological analysis was done on the sections taken from proximal segments (at 3 cm, 5 cm & 8 cm) and the distal segment (at 2 cm) from the atretic portion. The mean thickness of the inner circular muscle layer (ICML) and outer longitudinal muscle layer (OLML) was assessed in the above segments using image morphometry. In addition, we also analyzed the distribution and density of the ICCs and enteric neurons in the different segments using immunohistochemistry for c-kit and S-100, respectively. Controls included normal jejuno-ileal segments resected from postmortem cases (n=7) and other nonrelated surgeries (n=3). The findings were then compared with each-other and with normal controls. RESULTS: Mean thickness of ICML and OLML of the proximal segments at 8 cm was significantly lower than at 3 cm and 5 cm of ileal and jejunal atresias (p≪ 0.5). The mean thickness of ICML and OLML of distal segments at 2 cm was similar to the controls in all the atretic cases (p≫ 0.5). The mean ICML thickness at proximal 8 cm segment was similar to the distal segment of both ileal & jejunal atresias (p= 0.06 & 0.37 respectively). The mean thickness of the OLML of the proximal 8 cm segments was significantly more than that at the distal segment (p=0.008) in ileal atresias but was similar in cases of jejunal atresias (p=0.07). Both the proximal and distal segments of ileal as well as jejunal atresias showed reduction in distribution and density of ICCs, as compared to normal controls. The density of ICCs in proximal segments at 3 cm and 5 cm was similar in both ileal (p=0.33) and jejunal segments (p=0.41) but was significantly lower than the proximal 8 cm segments (p≪0.05).The distribution of ICCs in the proximal segment at 8 cm was similar to the distal segments (p≪0.05). S-100 staining showed dense expression of neurons and glial cells with presence of submucosal giant ganglia within the proximal dilated segments as compared to the distal segments and the controls, which were more marked at 3 cm and 5 cm levels than at 8 cm level. CONCLUSION: Muscle morphometry using image analysis is a simple technique to assess the thickness of the intestinal smooth muscle layers. There is significant smooth muscle hypertrophy along with marked alteration in density and distribution of ICCs and ENS in the dilated proximal segments up to 5 cm, and relatively milder changes at 8 cm levels, as compared to the distal segments and the controls. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level II.

Gastrointestinal disorders in Down syndrome.

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.

LncRNA-MEG3 protects against ganglion cell dysplasia in congenital intestinal atresia through directly regulating miR-211-5p/GDNF axis.

Background LncRNAs are known to take part in normal brain functions and nervous system diseases. Little evidence has pointed to the dysregulation of lncRNAs in congenital intestinal atresia. We aimed to investigate the underlying molecular mechanism of congenital intestinal atresia that involves in lncRNA-MEG3. Materials and methods The expressions of LncRNA-MEG3, miR-211-5p and GDNF were determined by the qRT-PCR and Western blot assay when appropriate. The results were verified in intestinal atresia Wistar rat model and bone marrow derived stem cell (BMSCs)-derived into intestinal ganglion cells. RNA immunoprecipitation and RNA pull-down assays were performed to analyze the regulatory mechanism between MEG3 and miR-211-5p. The effects of MEG3 on the cell proliferation and apoptosis of isolated intestinal ganglion cells were detected with an MTT assay and flow cytometry, respectively. Results The expression of MEG3 was detected to be declined in congenital intestinal atresia tissues at clinic and animal levels. MEG3 promoted the differentiation of BMSCs into intestinal ganglion cells and regulated GDNF expression in retinal ganglion cells (RGC-5 cells) via targeting miR-211-5p. Hypoxia induced the apoptosis of intestinal ganglion cells via MEG3/miR-211-5p/GDNF axis. Conclusion MEG3 promoted the differentiation of BMSCs into intestinal ganglion cells and inhibited the apoptosis of intestinal ganglion cells under the exposure of hypoxia to protect against CIA injury via directly regulating miR-211-5p/GDNF axis.

Characterization and origin of heme precursors in amniotic fluid: lessons from normal and pathological pregnancies.

BACKGROUND: Heme is the prosthetic group of numerous proteins involved in vital processes such as oxygen transport, oxidative stress, and energetic mitochondrial metabolism. Free heme also plays a significant role at early stages of development and in cell differentiation processes. The metabolism of heme by the fetal placenta unit is not well-established in humans. METHODS: In a retrospective study, we measured heme precursors in the amniotic fluid (AF) of 51 healthy women, and 10 AF samples from pregnancies with either upper or lower intestinal atresia or ileus were also analyzed. RESULTS: We showed that the porphyrin precursors aminolevulinic acid, porphobilinogen, and protoporphyrin IX are present at the limit of detection in the AF. Total porphyrin levels decreased progressively from week 13 to week 33 (p < 0.01). Interestingly, uroporphyrin, initially detected as traces, increased with maturation, in contrast to coproporphyrin. Uro- and coproporphyrins were type I immature isomers (>90%), suggesting a lack of maturity in the fetal compartment of the heme pathway. Finally, the differential analysis of AF from normal and pathological pregnancies demonstrated the predominant hepatic origin of fetal porphyrins excreted in the AF. CONCLUSION: This study gives the first insight into heme metabolism in the AF during normal and pathological pregnancies.

Retrospective study of umbilical cord ulceration related to congenital intestinal atresia: A single-center report.

AIM: Umbilical cord ulceration (UCU) is a disease in which an ulcer forms in the umbilical cord in the pregnant uterus and is accompanied by hemorrhaging from the same site. UCU occurs in fetuses with congenital upper-intestinal atresia (CUIA); however, its onset mechanism remains unclear. Here, we report our investigation of cases of UCU in our hospital. METHODS: Among the 9825 deliveries performed between 2007 and 2016 at this hospital, 20 fetuses were diagnosed with CUIA, 4 (20%) of which had UCU. There was no difference in the backgrounds of the fetuses with UCU (UCU group: 4 fetuses) and those without (non-UCU group: 16 fetuses). RESULTS: There was no intergroup difference in gestational age at delivery. Four cases in the UCU group had maternal age 35 weeks (26-39), weeks of delivery 35 weeks (35-36) and weight 2178.5 g (1600-2640); three out of four fetuses were female; and the location of gastrointestinal obstruction was in the duodenum in one case and in the jejunum in three cases. Death occurred in three of four fetuses in the UCU group versus none in the non-UCU group. CONCLUSION: We performed a retrospective statistical investigation on the risk of UCU onset in cases from this hospital; however, we could not identify any prognostic factors for its onset. We investigated a total of 27 past reported UCU cases and the 4 cases in this study. Mean gestational age at onset was 33.3 ± 2.7 for all 27 cases. Various methods for the early discovery of UCU have been reported in the past; however, there is currently no gold standard. Based on this report and a review of past papers, for CUIA, it is desirable to perform in-hospital management from gestational week 30 onward and decide proper delivery timing on a case-by-case basis.

Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE) syndrome in a patient with very-early onset inflammatory bowel disease.

Tricho-hepato-enteric syndrome (SD/THE) and Multiple intestinal atresia with combined immune deficiency (MIA-CID) are autosomal recessive disorders that present immunological and gastrointestinal features. There are two different phenotypes of patients with TTC7A mutations: the severe form, caused by null mutations and leading to the classical MIA-CID; and the mild form, caused by missense mutations and leading to predominant features of VEO-IBD, less severe immunological involvement and hair abnormalities. We expand the knowledge about TTC7A deficiency, describing a patient with the mild phenotype of TTC7A deficiency but presenting overlapping features of SD/THE and MIA-CID: intestinal atresia and inflammatory bowel disease evocative of MIA-CID, but also dental abnormalities, huge forehead, liver abnormalities, autoimmune thyroiditis and hypogammaglobulinemia, evocative of SD/THE.

Delayed presentation of jejunal atresia.

Type I intestinal atresias (webs) are rare causes of gastrointestinal obstruction in infants, the most common site being the second portion of the duodenum. According to the Louw and Barnard classification, type 1 atresia has been defined as an intra-luminal web which results in either complete (web with no perforation) or incomplete (web with central perforation) intestinal obstruction. The jejunum is a rare site of such webs. Diagnosis of an incompletely obstructing web due to central perforation is usually difficult and challenging. We present two cases of jejunal web with a central perforation in which the presentation was delayed. Both were managed by excision of the web.

Jejunal Occlusion Caused by Heterotopic Gastric and Duodenal Mucosa: A Late Complication of a Complex Intestinal Malformation.

We report a rare case of late complication of a complex intestinal malformation. At day 1 of life, a baby girl underwent resection of an atretic jejunal segment, associated with an enteric duplication harboring foci of gastric and duodenal heterotopia. After an asymptomatic period of 19 years, the patient presented with acute bowel obstruction. Recurrence of the jejunal occlusion at the previous anastomotic site was caused by mucosa hyperplasia in association with heterotopic gastric and duodenal tissue. A Wnt/ß-catenin pathway deregulation was hypothesized but not confirmed by CTNNB1 exon 3 mutation analysis. This case illustrates a rare association of 3 pathologies-namely, intestinal atresia, enteric duplication, and heterotopia, with a late-occurring acute complication.

Immunoregulation effects of different γδT cells and toll-like receptor signaling pathways in neonatal necrotizing enterocolitis.

The aim of the study was to observe cytokine and T-cell-related toll-like-receptor (TLR) changes in intestinal samples of neonatal necrotizing enterocolitis patients.Four necrotic bowels were collected from neonatal NEC patients with gestational ages of 28 to 29 weeks in our hospital, whereas 4 neonatal patients who underwent intestinal atresia surgery served as the controls. Intestinal flora was examined and IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and IL-17 expressions in resected intestine samples, as well as in isolated gamma delta T (γδT) cells, were analyzed immunohistochemically and via quantitative RT-PCR. γδT cells were isolated from the intestinal intraepithelial lymphocytes (IELs) and their TLR4/TLR9 distribution in the intestinal tissues was determined by flow cytometry.The bacterial flora of the neonatal NEC patients' contained significantly higher amounts of Gram-negative Enterobacteriaceae, Klebsiella, and Bacteroides but anaerobic Gram-positive Bifidobacteria occurred significantly less in the NEC than the control group. IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and IL-17 expressions in the resected intestine samples and in isolated γδT cells were enhanced in NEC samples compared to the controls. γδT cells were less prevalent in NEC-derived intestinal tissues, but their TLR4/TLR9 expressions were significantly enhanced.The changed bacterial flora in preterm neonatal NEC patients led to an obvious inflammation of the intestines, which was accompanied by reductions of γδT cell localizations to the intestine and a shift of their surface expressions to TLR4 and TLR9.