Intestinal Aganglionosis Research Articles

The Ratio of Remaining to Expected Small Bowel Length Predicts Enteral Autonomy in Pediatric Patients with Short Bowel Syndrome

BackgroundPediatric patients with short bowel syndrome (SBS) often require long-term parenteral nutrition and intravenous fluid support (PN) until enteral autonomy (EA). However, long-term PN accounts for many complications. We aimed to investigate the outcome and predictors of EA in these patients. Material and MethodsThis retrospective observational study was conducted in Children’s Medical Center, Chang Gung Memorial Hospital, a tertiary hospital in Northern Taiwan. Twenty-four patients afflicted with short bowel syndrome between 2002 and 2021 were included. Demographics, operation results, follow-up status, complications, and outcomes were reviewed. ResultsAmong the 24 patients, 14 were males (58%). The median age at bowel resection was 3 days (IQR, 1.3 to 28.8 days). The most common etiologies were total/subtotal intestinal aganglionosis (TIA) (N=6) and malrotation with midgut volvulus (N=6). The median length of the residual small intestine was 25cm (IQR, 7.8 to 71.3cm). Ten (41.7%) had preserved ileocecal valve, and 14 (58.3%) had colon-in-continuity. Intestinal failure-associated liver disease (IFALD) occurred in 14 patients (58.3%), but none had advanced disease. Seven (29.2%) patients achieved enteral autonomy after 10.1±7.3 months. Five patients (21%) expired due to sepsis. Logistic regression and Kaplan-Meier analysis showed the predictors of enteral autonomy were remaining-to-expected small bowel length ratio > 25% and the absence of IFALD. ConclusionsIn this pediatric short bowel syndrome study, enteral autonomy was achieved in 29% after a mean PN duration of 10 months. The remaining-to-expected small bowel length ratio at bowel resection was the most critical predictor of enteral autonomy.

The use of postoperative calibrations in Hirschsprung disease: a practice to reconsider?

Daily postoperative anal dilations after endorectal pull-through for Hirschsprung disease (HD) are still considered a common practice. We analyzed the potential risks of this procedure and its effectiveness compared to a new internal protocol. All infants (< 6months of age) who underwent transanal endorectal pull-through between January 2021 and January 2023 were prospectively enrolled in a new postoperative protocol group without daily anal dilations (Group A) and compared (1:2 fashion) to those previously treated by postoperative anal dilations (Group B). Patients were matched for age and affected colonic tract. Patients with associated syndromes, extended total intestinal aganglionosis, and presence of enterostomy were excluded. Outcomes considered were: anastomotic complications (stenosis, disruption/leakage), incidence of enterocolitis, and constipation. Eleven patients were included in group A and compared to 22 matched patients (group B). There were no significant differences in the occurrence of anastomotic complications between the two groups. We found a lower incidence of enterocolitis and constipation among group A (p = 0.03 and p = 0.02, respectively). A non-dilation strategy after endorectal pull-through could be a feasible alternative and does not significantly increase the risk of postoperative anastomotic complications. Moreover, some preliminary advantages such as lower enterocolitis rate and constipation should be further investigated.

Extended total colonic aganglionosis and total intestinal aganglionosis: Challenging enemies.

Extended total colonic aganglionosis (ETCA) represents uncommon forms of Hirschsprung disease (HD), with aganglionosis extending into the proximal small bowel. ETCA management is challenging and associated with poor outcomes and high mortality. This study compares management and outcomes of ETCA to more common HD forms. A retrospective cohort of HD patients (2012-2023) from two institutions. Three HD forms were compared: short-segment HD (SSHD, n = 19), long-segment HD or total colonic aganglionosis (LS/TCA, n = 9) and ETCA (n = 7). Normally innervated segments in ETCA patients ranged 0-70 cm. Median times to first surgery were; ETCA = 3 days versus TCA = 21 days (p = 0.017) and SSHD = 95 days (p < 0.001), respectively. Median number of surgeries were; ETCA = 4, versus TCA = 2 (p = 0.17) and SSHD = 1 (p = 0.002), respectively. All the patients underwent a definitive pull-through procedure, except four ETCA patients with a permanent jejunostomy and residual aganglionic segment of 57-130 cm. ETCA patients had 92% lower odds of enterocolitis (14%) compared to TCA patients (67%, p = 0.054), and comparable odds to SSHD patients (16%, p = 0.92). ETCA mortality was 14%. Extended total colonic aganglionosis patients require earlier and multiple interventions. Leaving an aganglionic segment may be advantageous, without increasing risk for enterocolitis. Tailored surgical treatment and rehabilitation programmes may prevent mortality and need for transplantation.

Neutrophil Lymphocytes Ratio (NLR) of One-Step and Multi-Step Procedure for Hirschsprung Disease Patients At Arifin Achmad General Hospital

Hirschsprung disease (HD) is a congenital anomaly due to intestinal aganglionosis starting from the internal anal sphincter and spreading to the proximal area with varies extension of the segment. Definitive treatment for this abnormality is to perform surgery to remove the aganglionic bowel and can be carried out in one-step and multi-step procedure. In the process of wound healing after surgery, it involves inflammatory mediators as a marker of whether there is a stress response from the endocrine system such as neutrophil-lymphocyte ratio (NLR). This study aims to compare NLR as an inflammatory biomarker in one-step and multi-step procedure of hirschsprung disease patients at Arifin Achmad Hospital. The design of this study was cross-sectional using medical records and using total sampling for number of samples. Age, gender, and method of surgery were evaluated by univariate and bivariate to determine whether there were statistical differences. Seven HD patient taken from Mei-October at Arifin Achmad Hospital taken for evaluated. The results showed that the most samples were in &amp;lt; 1-month-old (42.9%) and male (71,4%) for gender. The average number of NLR was in 7.33 after one-step procedure and 2.77 for multi-step procedure. This number of NLR both not statistically different neither for the post-operative examination nor the comparison between procedure.

Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis

BackgroundHirschsprung disease is a congenital intestinal motility disorder characterized by an absence of enteric ganglion cells. Total colonic aganglionosis and near total or total intestinal aganglionosis, defined as absence of ganglion cells in the entire colon and with variable length of small bowel involved, are life-threatening conditions which affect less than 10 % of all patients with Hirschsprung disease. The aim of this project was to develop clinical consensus statements within ERNICA, the European Reference Network for rare congenital digestive diseases, on four major topics: Surgical treatment of total colonic aganglionosis, surgical treatment of total intestinal aganglionosis, management of poor bowel function in total colonic and/or intestinal aganglionosis and long-term management in total colonic and or intestinal aganglionosis. MethodsA multidisciplinary panel of representatives from ERNICA centers was invited to participate. Literature was searched, using specified search terms, in Medline (ALL), Embase and Google Scholar. Abstracts were screened and full text publications were selected. The panel was divided in four groups that extracted data from the full text publications and suggested draft statements for each of the major topics. A modified Delphi process was used to refine and agree on the statements. ResultsThe consensus statement was conducted by a multidisciplinary panel of 24 participants from 10 European countries, 45 statements reached consensus after 3 Delphi-rounds. The availability of high-quality clinical evidence was limited, and most statements were based on expert opinion. Another 25 statements did not reach consensus. ConclusionsTotal colonic and total intestinal aganglionosis are rare variants of Hirschsprung disease, with very limited availability of high-quality clinical evidence. This consensus statement provides statements on the surgical treatment, management of poor bowel function and long-term management for these rare patients. The expert panel agreed that patients benefit from multidisciplinary and personalized care, preferably in an expert center. Type of StudyClinical consensus statement. Level of Evidence3a.

Paneth cell proteins DEFA6 and GUCA2A as tissue markers in necrotizing enterocolitis

Previous studies suggest that Paneth cells are involved in NEC development. Defensin alpha 6 (DEFA6) and guanylate cyclase activator 2A (GUCA2A) are selective protein markers of Paneth cells. The objective was to explore DEFA6 and GUCA2A expression in intestinal tissue samples from newborn infants with and without NEC. Tissue samples from histologically intact intestine were analyzed from 70 infants: 43 underwent bowel resection due to NEC and 27 controls were operated due to conditions such as intestinal atresia, dysmotility, aganglionosis, pseudo-obstruction or volvulus. Each tissue sample was immunohistochemically stained for DEFA6 and GUCA2A. Semi-automated digital image analysis was performed to determine protein expression. Clinical data and protein expressions were compared between the groups. DEFA6 expression was lower in the NEC group (p = 0.006). Low DEFA6 correlated with risk of developing NEC in a logistic regression analysis, independently of gestational age and birth weight (OR 0.843 [CI 0.732–0.971]; p = 0.018). GUCA2A expression did not differ between the two groups.Conclusion: Lower expression of DEFA6 together with intact GUCA2A expression indicates that NEC patients have well-defined Paneth cells but diminished defensin activity. Our results suggest that DEFA6 could be used as a biomarker for NEC.What is Known:• Previous studies of defensin activity in NEC have been inconsistent, showing that defensin levels may be increased or diminished in NEC. GUCA2A has to our knowledge never been studied in NEC.What is New:• This study benchmarks two specific Paneth cell markers (DEFA6 and GUCA2A) and their activity in individuals with and without NEC.• The key finding is that the NEC group had a lower DEFA6 expression compared to the Controls, while the expression of GUCA2A did not differ between the groups.

A Single RET Mutation in Hirschsprung Disease Induces Intestinal Aganglionosis Via a Dominant-Negative Mechanism

Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of the enteric nervous system (ENS). HSCR potentially involves multiple gene aberrations and displays complex patterns of inheritance. Mutations of the RET gene, encoding the RET receptor tyrosine kinase, play a central role in the pathogenesis of HSCR. Although a wide variety of coding RET mutations have been identified, their pathogenetic significance invivo has remained largely unclear. We introduced a HSCR-associated RET missense mutation, RET(S811F), into the corresponding region (S812) of the mouse Ret gene. Pathogenetic impact of Ret(S812F) was assessed by histologic and functional analyses of the ENS and by biochemical analyses. Interactions of the Ret(S812F) allele with HSCR susceptibility genes, the RET9 allele and the Ednrb gene, were examined by genetic crossing in mice. RetS812F/+ mice displayed intestinal aganglionosis (incidence, 50%) or hypoganglionosis (50%), impaired differentiation of enteric neurons, defecation deficits, and increased lethality. Biochemical analyses revealed that Ret(S811F) protein was not only kinase-deficient but also abrogated function of wild-type RET in trans. Moreover, the Ret(S812F) allele interacted with other HSCR susceptibility genes and caused intestinal aganglionosis with full penetrance. This study demonstrates that a single RET missense mutation alone induces intestinal aganglionosis via a dominant-negative mechanism. The RetS812F/+ mice model HSCR displays dominant inheritance with incomplete penetrance and serves as a valuable platform for better understanding of the pathogenetic mechanism of HSCR caused by coding RET mutations.

A study on the role of matravasti in Hirschsprung disease in children

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by the complete absence of neuronal ganglion cells from a portion of the intestinal tract. Symptoms include constipation, bloating of the belly, and loss of energy and appetite. Diagnosis of the disease includes an abdominal x-ray which shows a bulge in the large intestine caused by stool, barium enema, anorectal manometry, or biopsy of the rectum. In Ayurveda, congenital diseases come under janmabala pravritta vyadhi. It leads to vitiation of the rasavaha, annavaha and malavaha srothas of the fetus, later leading to dusti of vata in pakwashaya and guda. The treatment involves normalization of Vata in the body using a protocol that pacifies the Vata, including Vasti. Considering the age of the patient, Matravasti was done using Sukumaraerandam and a few internal medicines for the mother. It consists of drugs that pacify Vata as well as those which improve digestion.

Novel roles for rRNA and ribosome biogenesis associated factors in neural crest cell colonization of the gut and in the pathogenesis of Hirschsprung disease

The enteric nervous system regulates the functions of the gastrointestinal system, which include food transportation, digestion, nutrient and liquid absorption and expulsion of waste. The enteric nervous system is comprised of neurons and glia that are primarily derived from a multipotent, migratory population of cells called neural crest cells. Defects in the formation, migration and or differentiation of neural crest cells can lead to incomplete colonization of the gastrointestinal tract and perturbed ENS development resulting in Hirschsprung disease. Hirschsprung disease is a congenital disorder characterized by the absence of ganglia in variable regions of the gastrointestinal tract and ~50% of the known cases of Hirschsprung disease have an unknown genetic diagnosis. This makes it imperative to identify other genes and biological processes that contribute to the etiology and pathogenesis of Hirschsprung disease. We have identified three new genes, Tcof1, Polr1a and Polr1c, and the process of rDNA transcription which is a rate‐limiting step in ribosome biogenesis, as novel regulators of neural crest cell development, enteric nervous system formation and the etiology of Hirschsprung disease. Loss of function mutation of Tcof1, Polr1a and Polr1c in neural crest cells results in total intestinal aganglionosis, the most severe form of Hirschsprung disease in mice. Mechanistically, downregulation of Tcof1, Polr1a and Polr1c results in reduced rRNA synthesis, which leads to increased p53‐dependent NCC apoptosis, and insufficient NCC to colonize the gut. This led us to hypothesize that inhibition of p53 could rescue the Hirschsprung phenotype in the mutants, and we are currently testing this and other and other approaches as potential preventative therapies.

Neural crest cells and their potential therapeutic applications

Neural crest (NC) is a population of cells, formed at the intersection between non-neural ectoderm and neural tube. Neural crest progenitors are multipotent, have capacity to extensive migration and self-renewal. They can be differentiated into various cells types from craniofacial skeletal tissues to components of peripheral nervous system. Influence of signaling molecules and transcription factors, which are expressed at the different stages regulate development of NC. The regulatory network of genes determines the processes of induction, specification, migration and differentiation of neural crest cells (NCC). The purpose of this article is to compare the characteristics of NCC, obtained from tissues of the embryo, fetus and adult; experimental strategies for obtaining NCC from embryonic stem cells, induced pluripotent stem cells, skin fibroblasts; comparison of the potential of different cell types for therapeutic use in a clinical setting. Embryonic stem NCC are differentiated to the trunk, cranial, cardiac, circumpharyngeal and vagal according to the area of their initial migration. Mature stem NCC can be obtained from the dorsal root ganglia, red bone marrow, hair follicle, skin, intestines, carotid body, heart, cornea, iris, dental pulp, hard palate and oral mucosa. Genetic mutations may lead to failure of regulation of NC development, which leads to many congenital human diseases such as cardiovascular defects, craniofacial abnormalities and intestinal aganglionosis, collectively known as neurocristopathies. The identification and isolation of multipotent stem NCC derived from adult tissues, embryonic stem cells, and induced pluripotent stem cells are promising source for regenerative medicine.

Enhanced enteric neurogenesis by Schwann cell precursors in mouse models of Hirschsprung disease.

Hirschsprung disease (HSCR) is characterized by congenital absence of enteric neurons in distal portions of the gut. Although recent studies identified Schwann cell precursors (SCPs) as a novel cellular source of enteric neurons, it is unknown how SCPs contribute to the disease phenotype of HSCR. Using Schwann cell-specific genetic labeling, we investigated SCP-derived neurogenesis in two mouse models of HSCR; Sox10 haploinsufficient mice exhibiting distal colonic aganglionosis and Ednrb knockout mice showing small intestinal aganglionosis. We also examined Ret dependency in SCP-derived neurogenesis using mice displaying intestinal aganglionosis in which Ret expression was conditionally removed in the Schwann cell lineage. SCP-derived neurons were abundant in the transition zone lying between the ganglionated and aganglionic segments, although SCP-derived neurogenesis was scarce in the aganglionic region. In the transition zone, SCPs mainly gave rise to nitrergic neurons that are rarely observed in the SCP-derived neurons under the normal condition. Enhanced SCP-derived neurogenesis was also detected in the transition zone of mice lacking RET expression in the Schwann cell lineage. Increased SCP-derived neurogenesis in the transition zone suggests that reduction in the vagal neural crest-derived enteric neurons promotes SCP-derived neurogenesis. SCPs may adopt a neuronal subtype by responding to changes in the gut environment. Robust SCP-derived neurogenesis can occur in a Ret-independent manner, which suggests that SCPs are a cellular source to compensate for missing enteric neurons in HSCR.

Comparison between Tran abdominal and trans anal one stage pull through in Hirschsprung disease

Background: Hirschsprung’s disease (HD) is one of the commonly studied diseases among pediatric surgeons and researchers. It is also known as intestinal aganglionosis, which is a kind of birth defects mainly expressed as partial or complete absence of ganglion cells of the intestinal tract. Objective: The aim of the current work was to evaluate the management of children with Hirschsprung's disease by one stage pull-through Soave procedures (transanal and trans-abdominal one stage pull-through) concerning perioperative, short term outcomes and complications. Patients and methods: This randomized controlled trial study included a total of 32 patients subjected to transanal and transabdominal one stage pull-through procedures for management of Hirschsprung’s disease. Patients were recruited from the Inpatient Clinic, Pediatrics Surgical Department, Assiut University Hospitals. This study was conducted between April 2015 to March 2019 and followed up at our clinics. Results: Comparison of the rates of late post-operative complications among the studied groups revealed that regarding post-operative incontinence, group A had statistically insignificant (p = 0.723) lower rates (50%) compared with group B (56%). Likewise, rates of adhesive intestinal obstruction were insignificantly (p = 0.310) higher (6.2%) in comparison with group B (0%). There was statistically significant (p = 0.001) longer duration of hospital stay among patients in group A (11.1 ± 6.4days) compared with patients in group B (5.0 ± 1.4 days). Conclusion: It could be concluded that the advantages of TERPT include a good cosmetic effect, short hospital stays, safe, and less surgical site infection compared to transabdominal procedures.

Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system.

Retinoic acid (RA) signaling is essential for enteric nervous system (ENS) development, since vitamin A deficiency or mutations in RA signaling profoundly reduce bowel colonization by ENS precursors. These RA effects could occur because of RA activity within the ENS lineage or via RA activity in other cell types. To define cell-autonomous roles for retinoid signaling within the ENS lineage at distinct developmental time points, we activated a potent floxed dominant-negative RA receptor α (RarαDN) in the ENS using diverse CRE recombinase–expressing mouse lines. This strategy enabled us to block RA signaling at premigratory, migratory, and postmigratory stages for ENS precursors. We found that cell-autonomous loss of RA receptor (RAR) signaling dramatically affected ENS development. CRE activation of RarαDN expression at premigratory or migratory stages caused severe intestinal aganglionosis, but at later stages, RarαDN induced a broad range of phenotypes including hypoganglionosis, submucosal plexus loss, and abnormal neural differentiation. RNA sequencing highlighted distinct RA-regulated gene sets at different developmental stages. These studies show complicated context-dependent RA-mediated regulation of ENS development.

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells.

Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb-/- mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb+/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb-/- mice generated functional neurons with similar calcium responses to Ednrb+/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb-/- recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice.

Mutations of the gene encoding the RET tyrosine kinase causes Hirschsprung’s disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the RET gene have adverse effects on ENS development in vivo. We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients. Although Ret51(C618F)/51(C618F)mice displayed hyperganglionosis of the ENS, Ret51(C618F)/- mice exhibited severe intestinal aganglionosis because of premature neuronal differentiation. Reduced levels of glial cell-derived neurotrophic factor (GDNF), a RET-activating neurotrophic factor, ameliorated the ENS phenotype of Ret51(C618F)/- mice, demonstrating that GDNF-mediated activation of RET51(C618F) is responsible for severe aganglionic phenotype. The RET51(C618F) allele showed genetic interaction with Ednrb gene, one of modifier genes for HSCR. These data reveal that proliferation and differentiation of ENS precursors are exquisitely controlled by both the activation levels and total dose of RET. Increased RET activity coupled with a decreased gene dosage can cause intestinal aganglionosis, a finding that provides novel insight into HSCR pathogenesis.

Genetic mutation in Hirschsprungs/congenital central hypoventilation syndrome

Abstract Background Congenital central hypoventilation syndrome (CCHS) is a disorder of respiratory and autonomic regulation which presents with hypoventilation. In some patients, CCHS is associated with Hirschsprung disease and as such known as Haddad syndrome. Case presentation A preterm was referred to our intensive care unit due to suspicion of meconium ileus after loop-ileostomy at the age of 8 days. The patient presented with recurrent apnea, did not respond to caffeine citrate, and was dependent on ventilation. Furthermore, the patient was unable to pass stool spontaneously. In the course of clinical deterioration, fluoroscopy showed a perforation next to the ileostomy and resection of ileum was conducted. An ileostomy was performed, and several biopsies of the intestines were taken. Neither in the biopsies nor in the resected segment were ganglion cells identified histopathologically. Considering the poor prognosis, life support was withdrawn. Autopsy and histology verified total aganglionosis of the intestines. Genetic testing confirmed a rare pathogenic deletion in the alanine-repeat region in the PHOX2B (c.722-759del; p.Ala241Glyfs*106). Conclusion CCHS and intestinal aganglionosis are hints for Haddad syndrome. To confirm the diagnosis, biopsies of the intestines and genetic testing for mutations in the PHOX2B gene should be performed.

ChIP-Seq-Based Approach in Mouse Enteric Precursor Cells Reveals New Potential Genes with a Role in Enteric Nervous System Development and Hirschsprung Disease.

Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex gene regulatory system. Several genes have been associated with HSCR, but many aspects still remain poorly understood. The present study is focused on deciphering the PAX6 interaction network during enteric nervous system (ENS) formation. A combined experimental and computational approach was performed to identify PAX6 direct targets, as well as gene networks shared among such targets as potential susceptibility factors for HSCR. As a result, genes related to PAX6 either directly (RABGGTB and BRD3) or indirectly (TGFB1, HRAS, and GRB2) were identified as putative genes associated with HSCR. Interestingly, GRB2 is involved in the RET/GDNF/GFRA1 signaling pathway, one of the main pathways implicated in the disease. Our findings represent a new contribution to advance in the knowledge of the genetic basis of HSCR. The investigation of the role of these genes could help to elucidate their implication in HSCR onset.

Double barrel enteroplasty for the management of short bowel syndrome in children.

Currently, there are two well-established methods of bowel lengthening in patients with short bowel syndrome (SBS)-longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP) [1-4]. Both procedures may carry a high reported morbidity and mortality of 30.2% and 14.4%, respectively [5]. We report the outcomes of a novel technique: double barrel enteroplasty (DBE) for autologous intestinal reconstruction. We performed a retrospective review of all ten patients who underwent DBE at our institution since 2011. All patients have SBS and were dependent on parenteral nutrition (PN) at the time of surgery. Etiologies were gastroschisis (n = 4), bowel atresia (n = 3), necrotising enterocolitis (n = 1), volvulus (n = 1), and near-total intestinal aganglionosis (n = 1). Patient survival, complications, and subsequent enteral autonomy were evaluated. All patients are alive with normal liver function. Five children achieved enteral autonomy, while the remaining are on weaning PN. There was no bleeding, anastomotic leak, perforation, infective complications, or intestinal necrosis. No patient has required a liver and/or intestinal transplant. Double barrel enteroplasty is technically feasible and safe. It has similar efficacy and may have fewer complications when compared with other methods of autologous intestinal reconstruction.

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease.

Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology.

New Insights Into the Indications for Intestinal Transplantation: Consensus in the Year 2019.

In 2001, a Statement was published that described indications for intestinal transplantation in patients with intestinal failure expected to require parenteral nutrition indefinitely. Since 2001, advances in the management of intestinal failure including transplantation and patient survival, both on extended parenteral nutrition and after transplantation, have improved, leading to a reduction in the number of intestinal transplants worldwide from a peak of 270 per year in 2008 to 149 per year in 2017. These changes suggest that the original 2001 Statement requires reassessment. All patients with permanent intestinal failure should be managed by dedicated multidisciplinary intestinal rehabilitation teams. Under care of these teams, patients should be considered for intestinal transplantation in the event of progressive intestinal failure-associated liver disease, progressive loss of central vein access, and repeated life-threatening central venous catheter-associated infections requiring critical care. Additional indications for transplantation include large desmoid tumors and other intra-abdominal tumors with reasonable expectation of posttransplant cure, extensive mesenteric vein thrombosis and intestinal infarction, total intestinal aganglionosis, and nonrecoverable congenital secretory diarrhea. Quality of life typically improves after successful intestinal transplantation and may support the decision to proceed with transplantation when other indications are present. However, the requirement for life-long immunosuppression and its associated side effects preclude intestinal transplantation if motivated only by an expectation of improved quality of life. Increasing experience with intestinal transplantation and critical appraisal of transplant outcomes including graft survival and patient quality of life together with potential advances in immunosuppression can be expected to influence transplant practices in the future.