Total Intestinal Aganglionosis Research Articles

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.

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.

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.

Concurrent Hirschsprung's disease and anorectal malformation: a systematic review.

Hirschsprung's disease (HSCR) and anorectal malformation (ARM) are often associated with other congenital malformations, but the association of each other is rare. Some studies havereported the incidence of HSCR associated with ARM ranging from 2.0 to 3.4%. The purpose of this study was to update the current epidemiological and therapeutic features of this rare congenital association. A systematic literature search for relevant articles was performed in four databases using acombination of thefollowing terms "association of Hirschsprung's disease and anorectal malformation", "aganglionosis and anorectal malformation" and "congenital megacolon and anorectal malformation" for studies published between 1952 and 2019. Reference lists were screened for additional cases. Forty-three studies met the defined inclusion criteria, reporting a total of 126 patients who were diagnosed with HSCR with ARM. Thirty articles reported 42 single case reports of this association. Twelve articles reported 66 cases of HSCR in case series of 3309 ARM patients, resulting in an incidence of 2% of this association. Associated syndrome was foundin 25 cases (20%): Currarino syndrome in 11, Down syndrome in 8, Cat eye syndrome in 4 and Pallister-Hall syndrome in 2 patients. Extent of aganglionosis was reported in 62 cases: short or rectosigmoid aganglionosis was reportedin 44, long segment aganglionosis in 8, total colonic aganglionosis in 9 and total intestinal aganglionosis in 1 case. Although the association of ARM and HSCR is rare, the incidence of HSCR among ARM cases seems to be higher than inthe general pediatric population. There wasa high incidence of coexistence of ARM and HSCR with severe associated syndromes.

P4.49: Home Parenteral Nutrition: www.Necker-HPN-traveling.com

Introduction: In France, the Hôpital Necker-Enfants Malades Home Parenteral Nutrition (HPN) program is the oldest (certified in 1984) and the largest with ~ 40% of the 380 children currently on HPN. We enrolled > 800 infants and children in our program since 1984. In 2018, it supported 156 children (ages: 3mths-17yrs): short bowel syndrome (SBS) (n=78), congenital enteropathy (CE) (n=28), total intestinal aganglionosis (TIA) (n=22) or chronic intestinal pseudo-obstruction (CIPOS) (n=17); miscell.(n=11). We try to offer the most normal life for the child, parents & siblings: family life, school attendance, physical & cultural activities…, and vacations. In France, holidays are sacred…!!. Moreover, some children have their grand-parents living outside France, especially in North Africa, the French islands (Caribean & Indian Ocean), Turkey, Portugal…. Until recent years, holidays outside of France were like an unreachable dream. Thanks to our experience of vacations within France and with our multidisciplinary approach and mutual trust with families, we crossed progressively the French borders. Nowadays, 23 different countries have been visited by 21 families. Methods: the HPN vacations organization involves nurses, MD, pharmacists, psychologist, social worker…. It requires time and should be anticipated at least 2 months before departure. Contacts are established with airlines companies for transporting material in the aircraft both in the cabin and in the hold. Local medical and nursing contacts are established, while medical recommendations are delivered regarding emergency situations and the management of hot weather conditions. Results: In 2018, 20 children went to foreign countries or French Islands. IF causes: SBS (n=9), CE (n=7), TIA (n=4). Children received PN 3 to 7 nights a week, with bags from the French usual provider, completed if needed by a local hospital pharmacy (n=4). Destinations were: Morocco, Algeria, Turkey, Greece, Tunisia, Caribeans, Portugal, Thailand,…Stay in the country ranged from 1 to 8 weeks. Only one child had an harmful event with a dehydration. Conclusion: According to the very successful and enjoyable experience for the families, we do encourage an increasing number of families to do the same whenever financially possible. We suggest our colleagues and friends in charge of a HPN program to set up a “HPN travel agency”…… for offering families great holidays and happiness.

P3.25: INTESTINAL CHOLESTEROL ABSORPTION IS PRESERVED AFTER ISOLATED INTESTINAL TRANSPLANTATION DESPITE INCREASED CHOLESTEROL SYNTHESIS

Introduction. We aimed to investigate cholesterol metabolism in relation to nutritional status and serum lipids after isolated intestinal transplantation (ITX). Methods. Seven patients who had undergone isolated ITX including ascending colon at median age of 17.3 (range, 5.9–52) years due to intestinal failure caused by chronic intestinal pseudo obstruction (n=5) and total intestinal aganglionosis (n=2) were included median 3.5 (IQR, 2.9–7.4) years after ITX. Blood samples were analyzed for fat-soluble vitamins (A, E, D-25-OH), prealbumin, and cholesterol (total, LDL, HDL) and triglyceride levels. In six patients and 14 heathy age- and gender-matched controls, cholesterol metabolism was assessed with serum non-cholesterol sterols. The ratios to cholesterol (102 x µmol/mmol of cholesterol) of the serum cholesterol precursors (cholestenol, desmosterol and lathosterol) reflect cholesterol synthesis, while those of plant sterols (campesterol, sitosterol, and avenasterol) and cholestanol reflect cholesterol absorption efficiency. Lathosterol/cholestanol ratio reflects the balance between cholesterol absorption and synthesis and campesterol/cholestanol ratio reflects the plant sterol intake. Results. Patients were on tacrolimus-based maintenance immunosuppression without current signs of acute or chronic transplant rejection. All patients had weaned off PN median 39 days (IQR 21–215) after ITX and had a median body mass-index of 18.2 (IQR, 16.6–19.1) kg/m2. The levels of fat-soluble vitamins and prealbumin were mostly in normal range while plasma HDL cholesterol was low and triglyceride levels were increased in most patients (Table 1). Cholesterol precursor levels were significantly increased while plant sterols and cholestanol were not significantly different between patients and controls (Table 2). Increased lathosterol/cholestanol-ratio suggest that cholesterol synthesis markedly predominated absorption in patients’ whole body cholesterol homeostasis while the campesterol/cholestanol ratio suggest that the plant sterol intake was decreased in patients compared to controls (Table 2). Conclusion. Following isolated ITX, intestinal cholesterol absorption efficiency is preserved, while cholesterol synthesis increases likely to compensate malabsorption of bile acids. Satisfactory nutritional status, normal fat-soluble vitamin levels and preserved cholesterol absorption suggest that the compensatory increase was sufficient to maintain adequate lipid absorption.

P3.42: Acute dehydration and hypercalcemia in patients with total intestinal aganglionosis on long term parenteral nutrition

P3.42: Acute dehydration and hypercalcemia in patients with total intestinal aganglionosis on long term parenteral nutrition

P1.52: EXTENDED HIRSCHSPRUNG’S DISEASE: OUR EXPERIENCE AND LITERATURE REVIEW

Introduction: Extended Hirschsprung’s disease (EHD) is a rare condition leading to intestinal failure (IF). Its impact in Latin America (LATAM) is unknown. The aim of this study is to review our experience and published evidence. Methods: Case series. Inclusion criteria: patients < 18 ys. with EHD diagnosis, confirmed by full thickness biopsies during laparotomy, between 2009–2018. Residual intestinal length (RIL): measured from ligament of Treitz to enterostomy. Medical records and patients data base review, in addition to PubMed, Cochrane, Embase, Lilacs and Medline research, using “Hirschsprung’s disease”, “intestinal failure” and “total intestinal aganglionosis” as keywords, 1993–2018. Results: N=5. Median age 42.2 m (r:4–108). Mean RIL: 54.6 cm (r:30–80). It took 3.2 surgical procedures (r:2–4) to perform a functional enterostomy. The distal aganglionic bowel was preserved in all cases. 5/5 with IF and mean parenteral nutrition (PN) dependance time of 46 months (r:10–114). All received enteral nutrition by oral feeds and gastroclisis in 2 cases. 3 patients were listed for intestinal transplantation (ITx), 2 have already received an ITx. Follow up: 2.16 years (r: 0.75–4.25). 80% (4/5) overall survival on home PN, 1 death 9 months after ITx due to PTLD (off PN). Literature review: 127 articles. No publications from LATAM. 120 excluded: 6 duplications, 114 do not fulfill inclusion criteria. 7 remaining articles, N 47: 0.49 mo.; mean 4.9 years follow up (r:2.67–7.3); 3.57 procedures (r:1.4–5.75) until reaching an accurate diagnosis; RIL: 44.7 cm (32.2–60); 7 had aganglionic bowel resection; 66% survival; causes of death: 3 after ITx, 1 listed for ITx, 11 due to PN complications. 18/47 patients received an ITx. Discussion: EHD is an uncommon disorder leading to IF, and its prevalence in our continent is unknown. Our outcomes are similar to those published elsewhere. Home PN provides acceptable medium-term survival, although most patients will need an ITx in the long term.

P153 Total intestinal aganglionosis on long-term parenteral nutrition and acute dehydration with hypercalcemia

P153 Total intestinal aganglionosis on long-term parenteral nutrition and acute dehydration with hypercalcemia

Hemophagocytic lymphohistiocytosis presenting in a pediatric patient with near total colonic and small bowel aganglionosis: a case report

BackgroundTotal colonic and small bowel aganglionosis is a rare condition typically requiring intestinal transplant for long-term survival. There have not been any previously reported cases of near total intestinal aganglionosis complicated by concerns for hemophagocytic lymphohistiocytosis and need for both multivisceral organ transplant and hematopoietic stem cell transplant.Case presentationOur patient is a 35-month-old Egyptian boy who presented with bilious emesis and failure to pass meconium shortly after birth. After evaluation, he was found to have near total colonic and small bowel aganglionosis up to the ligament of Treitz. When he was transferred to our tertiary facility, he was already diagnosed as having aganglionosis of total colon and partial small bowel whose case is complicated by the concern for hemophagocytic lymphohistiocytosis. He was not able to absorb any substantial nutrition enterally and was stabilized on long-term total parenteral nutrition which resulted in total parenteral nutrition-induced liver injury. While awaiting evaluation for liver and bowel transplant, he developed concerning symptoms consistent with hemophagocytic lymphohistiocytosis. He presents a complex challenge creating difficulty with management of whether to proceed with bowel transplant as a result of near-total intestinal aganglionosis or hematopoietic stem cell transplant for treatment of hemophagocytic lymphohistiocytosis. In this case, the transplant team proceeded with visceral transplant first, however he did not survive.ConclusionsThis presentation of aganglionosis of total colon and partial small bowel complicated by the concern for hemophagocytic lymphohistiocytosis is unique to medical literature. For many physicians involved it is hard to determine how best to proceed with next steps in care.

Familial Near-Total Intestinal Aganglionosis.

Near total aganglionosis represents the most extreme and rare form of Hirschsprung's disease. It can affect more than one member of family. We report three cases of near total intestinal aganglionosis in a family presenting with intestinal obstruction at birth. All of them were operated and a jejunostomy was performed. Outcome was dismal.

Hirschsprung's disease in twins: a systematic review and meta-analysis.

Hirschsprung's disease (HSCR) is known to occur in families. The reported overall incidence of familial cases is 7.6%, with a higher incidence of 15-21% in total colonic aganglionosis and 50% in the rare total intestinal aganglionosis. HSCR is extremely rare in twins. The aim of this study was to systematically analyse the patterns of HSCR in twins published in the literature. Electronic databases Pubmed and Medline were screened for relevant articles using the keywords "Hirschsprung's disease", "aganglionosis", "twins", "monozygotic", and "dizygotic". Examining reference lists identified further relevant papers. Twelve studies with a total of 18 twin pairs were included in this analysis. 67% twins were discordant. HSCR was found in 24 out of 36 twin subjects (67%), of which 83% affected were male. Rectosigmoid type was reported in 71% of patients, long-segment disease in 21, and 8% presented with a total aganglionosis. Three twin pairs had at least one family member affected with HSCR. HSCR was found in two-thirds of twin subjects with a male predominance. Rectosigmoid aganglionosis was the most common variant. Disease discordance was identified, where environmental insults were postulated to be predisposing factors to disease expression. Future studies investigating the disease-associated mutations in the already identified HSCR genes should provide insights into the genetic basis of HSCR in twins.

A meta-analysis of clinical outcome of intestinal transplantation in patients with total intestinal aganglionosis.

Total intestinal aganglionosis (TIA) occurs in less than 1% of patients with Hirschsprung disease (HD), and TIA is the most severe form of HD. Survival has improved with the advent of parenteral nutrition and intestinal transplantation (ITx). The field of ITx has rapidly progressed in the last two decades and has now become an established treatment for patients with intestinal failure. The purpose of this meta-analysis was to determine the clinical outcome of ITx in patients with TIA. A systematic literature search for relevant articles was performed in four databases using the combinations of the following terms: "total intestinal aganglionosis", "intestinal transplantation", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 2003 and 2016. The relevant cohorts of ITx in patients with TIA were systematically searched for clinical outcomes. Thirteen studies met defined inclusion criteria, reporting a total of 63 patients who underwent ITx for TIA. Majority of patients were males (71.0%), and median age of ITx was 4.3 (range 0.25-17.6) years. Isolated ITx was performed in 37% patients and multivisceral ITx in 63%. Mean follow-up period was 40months (range 1-154). Overall survival rate was 66%; the longest survivor was 12.8-year-old after ITx. ITx appears promising in the management of TIA. ITx can be considered a feasible treatment option for patients with TIA who suffer from life-threatening complications of intestinal failure.

RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis.

During the past two decades several genes have been identified that control morphogenesis and differentiation of the enteric neuron system (ENS). These genes, when mutated or deleted, interfere with ENS development. RET gene is the major gene causing Hirschsprung's disease (HD). Mutations in RET gene are responsible for 50% of familial HD cases and 15-20% of sporadic cases. The aim of this meta-analysis was to determine the incidence of RET gene mutations in patients with HD and to correlate RET mutations with the extent of aganglionosis. A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease AND RET Proto-oncogene", "Hirschsprung's disease AND genetic polymorphism" and "RET Gene". The relevant cohorts of HD were systematically searched for reported mutations in the RET gene (RET+). Data on mutation site, phenotype, and familial or sporadic cases were extracted. Combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the different associations. In total, 23 studies concerning RET with 1270 individuals affected with HD were included in this study. 228 (18%) of these HDs were RET+. Of these 228, 96 (42%) presented as rectosigmoid, 81 (36%) long segment, 18 (8%) as TCA, 16 (7%) as total intestinal aganglionosis and 17 (7%) individuals were RET+ but no extent of aganglionosis was not reported. In the rectosigmoid group, no significant association between phenotype and RET mutation could be shown (P = 0.006), whereas a clear association could be shown between long-segment disease, total colonic- and total intestinal aganglionosis and RET mutations (P = 0.0002). Mutations most often occurred in Exon 13 (24) and showed significant association with rectosigmoid disease (P = 0.004). No significance could be shown between RET+ and sporadic cases (P = 0.53), albeit a trend towards RET+ and Familial cases could be observed (P = 0.38). The association with the RET gene and HD is well recognized. This study showed a clear association between RET+ mutations and the long-segment, total colonic- and total intestinal aganglionosis. Exon 13 appears to be a mutational "hot spot" in rectosigmoid disease.

Knockout mouse models of Hirschsprung’s disease

Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cell migration. Rodent animal models of aganglionosis have contributed greatly to our understanding of the genetic basis of HSCR. Several natural or target mutations in specific genes have been reported to produce developmental defects in neural crest migration, differentiation or survival. The aim of this study was to review the currently available knockout models of HSCR to better understand the molecular basis of HSCR. A review of the literature using the keywords "Hirschsprung's disease", "aganglionosis", "megacolon" and "knockout mice model" was performed. Resulting publications were reviewed for relevant mouse models of human aganglionosis. Reference lists were screened for additional relevant studies. 16 gene knockout mouse models were identified as relevant rodent models of human HSCR. Due to the deletion of a specific gene, the phenotypes of these knockout models are diverse and range from small bowel dilatation and muscular hypertrophy to total intestinal aganglionosis. Mouse models of aganglionosis have been instrumental in the discovery of the causative genes of HSCR. Although important advances have been made in understanding the genetic basis of HSCR, animal models of aganglionosis in future should further help to identify the unknown susceptibility genes in HSCR.

Clinical and genetic correlations of familial Hirschsprung’s disease

BackgroundThe risk of familial transmission in Hirschsprung’s disease (HSCR) currently lacks correlation between the clinical phenotype and the underlying genetic factors. The aim of this study was to clinically evaluate familial HSCR transmission and to correlate with the genetic background. MethodsClinical and gene analysis of familial HSCR patients were explored. DNA from 45 patients (35 kindreds) was screened for genetic variations of the RET, and EDNRB genes were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to controls. Main resultsMale:female ratio (3:1) had a female proband in 4 families. Aganglionosis was significantly more frequent with total colonic aganglionosis (TCA) in 40% familial cases (viz: 17/43 (43%) vs. 19 / 342 non-familial patients (5.6%) (p<0.01)). Transmission of S-HSCR was observed in 13 (31%), which was associated with EDNRB variation. RET gene promoter variation correlated with extended aganglionosis in 6/35 kindreds (17%). In 3 kindreds, both significant EDNRB and RET mutations were identified and where present were associated with increased penetrance in succeeding generations. An increased penetrance with succeeding generations occurred in 6 (14%). In a further 3 generation family, extensive variations in exon 6, 13, and 18 affected 3 males with progressive penetration and aganglionic length, including total intestinal aganglionosis in the further offspring. RET and MEN association was noted in 5 kindreds (14.3%) related to RET variations at Cysteine sites. ConclusionsCumulative effects of the RET and EDNRB genes contribute to long-segment and total colonic aganglionosis.

Congenital anomalies of the kidney and urinary tract (CAKUT) associated with Hirschsprung's disease: a systematic review.

Congenital anomalies of the kidney and urinary tract (CAKUT), a term introduced in the late 1990 s accounts for 30-50 % of cases of end-stage renal disease in children. The association of urogenital anomalies and Hirschsprung's disease (HSCR) based on the common genetic background of enteric nervous system and human urinary tract development has been well described in the literature. However, the reported prevalence of HSCR associated with CAKUT seems to be underestimated. The aim of this systematic review was to determine the prevalence of this association and show its relationship to other syndromes. A systematic literature search was conducted for relevant articles published between 1955 and 2014. Two online databases were searched for the terms "Hirschsprung's disease", "congenital anomalies of the kidney and urinary tract", "urogenital anomalies" and "urological anomalies". All published studies containing adequate clinical data were included. Resulting publications were reviewed for epidemiology, genetic testing, operative treatment and morbidity. Reference lists were screened for additional cases. A total of 32 articles reported 222 cases of HSCR associated with either CAKUT, "urological" or "urogenital" anomalies from 1955 to 2014. Gender was reported in a total of 68 cases, with 54 (79 %) males and 14 (21 %) females. Extent of aganglionosis was reported in 67 cases and included classical rectosigmoid disease in 38, long-segment aganglionosis in 12, total colonic aganglionosis in 12 and total intestinal aganglionosis in 5 patients. 18 articles reported 204 cases of either CAKUT, "urological" or "urogenital" anomalies in a case series of 5.693 HSCR patients, resulting in an overall prevalence of 3.6 % of this association. Within this collective of 18 studies only seven were, regardless of the date of publication compatible with CAKUT criteria introduced and published in the late 1990 s. These seven studies reported a total of 72 patients with associated CAKUT among 757 HSCR patients resulting in a prevalence of 9.5 %. After introduction of the CAKUT acronym, only three studies specifically investigated the association of HSCR and CAKUT stating a prevalence of 14.3 % resulting in an almost fivefold increase compared to the reported prevalence of HSCR and associated urological and urogenital anomalies. The remaining 14 publications reported 18 single cases of HSCR patients with associated CAKUT phenotypes. Of these 18 cases, 11 (61 %) cases were associated with other syndromes or syndromatic features or reported chromosomal anomalies. This review confirms that the recognition of CAKUT in HSCR patients has been underestimated in the past. The results suggest that when confronted with HSCR in a patient, a thorough urological investigation may be indicated. The high prevalence of associated syndromes in HSCR with CAKUT may further suggest a syndromic association.

Assessment and outcome of children with intestinal failure referred for intestinal transplantation

Chronic intestinal failure (CIF) requires long term parenteral nutrition (PN) and, in some patients, intestinal transplantation (ITx). Indications and timing for ITx remain poorly defined. In the present study we aimed to analyze causes and outcome of children with CIF. 118 consecutive patients referred to our institution were assessed by a multidisciplinary team and four different categories were defined retrospectively based on their clinical course: Group 1: patients with reversible intestinal failure; group 2: patients unsuitable for ITx, group 3: patients listed for ITx; group 4: patients stable under PN. Analysis involved comparison between groups for nutritional status, central venous catheter (CVC) related complications, liver disease, and outcome after transplantation by using non parametric tests, Mann-Whitney tests, Kruskal-Wallis, Wilcoxon signed rank tests and chi square distribution for percentage. 118 children (72 boys) with a median age of 15 months at referral (2 months-16 years) were assessed. Etiology of IF was short bowel syndrome [n = 47], intractable diarrhea of infancy [n = 37], total intestinal aganglionosis [n = 18], and chronic intestinal pseudoobstruction [n = 17]. Most patients (89.8%) were totally PN dependent, with 48 children (40.7%) on home-PN prior to admission. Nutritional status was poor with a median body weight at -1.5 z-score (ranges: -5 to +2.5) and median length at -2.0 z-score (ranges: -5.5 to +2.3). The mean number of CVC inserted per patient was 5.2 (range 1-20) and the mean number of CRS per patient was 5.5 (median: 5; range 0-12) Fifty-five patients (46.6%) had thrombosis of ≥2 main venous axis. At admission 34.7% of patients had elevated bilirubin (≥50 μmol/l), and 19.5% had platelets <100,000/ml, and 15% had both. Liver biopsy performed in 79 children was normal (n = 4), or showed F1 or F2 fibrosis (n = 29), bridging fibrosis F3 (n = 20), or cirrhosis (n = 26). Group 1 included 10 children finally weaned from PN (7-years survival: 100%). Group 2 included 12 children with severe liver disease and associated disorders unsuitable for transplantation (7-years survival: 16.6%). Group 3 included 66 patients (56%) who were listed for small bowel or liver-small bowel transplantation, 62/66 have been transplanted (7 years survival: 74.6%). Factors influencing outcome after liver-ITx were body weight (p < .004), length (p < .001), pre-Tx bilirubin plasma level (p < .001) and thrombosis (p < .01) for isolated ITx, Group 4 included 30 children (25.4%) with irreversible IF considered as potential candidates for isolated ITx. Four children were lost from follow up and 3 died within 2 years (survival 88.5%). Among potential candidates, the following parameters improved significantly during the first 12 months of follow up: Body weight (p.0001), length (p < .0001) and bilirubin (p < .0001). many patients had a poor nutritional status with severe complications especially liver disease. PN related complications were the most relevant indication for ITx, but also a negative predictor for outcome. Early patient referral for Tx-assessment might help to identify and separate children with irreversible IF from children with transient IF or uncomplicated long-term PN, allowing to adapt a patient-based treatment strategy including or not ITx.

Association of Hirschsprung’s disease and anorectal malformation: a systematic review

The association of Hirschsprung's disease (HD) and anorectal malformation (ARM) is rare. The exact incidence of this association is not known but HD coexisting with ARM has been reported in 2.3 to 3.4% of ARM cases. Most of the reported cases in the literature have been single case reports. The aim of this systematic review was to determine the incidence of HD associated with ARM and its relationship to other syndromes. A systematic review of the literature was performed for the keywords "association of Hirschsprung's disease and anorectal malformation", "aganglionosis and anorectal malformation" as well as "congenital megacolon and anorectal malformation". Resulting publications were reviewed for epidemiology, operative treatment and morbidity. Reference lists were screened for additional cases. A total of 38 articles reported 90 cases of HD coexisting with ARM from 1952 to 2013. Twenty eight articles reported 40 single case reports of this association. Ten articles reported 50 cases of HD in case series of 2,465 ARM patients, resulting in an incidence of 2% of this association. Gender was reported in 63 cases, with 30 males (48%) and 33 females (52%). Associated syndromes were reported in 23 patients: Currarino syndrome in 11, Down syndrome in 8, Cat eye syndrome in 3 and Pallister-Hall syndrome in one case. Extent of aganglionosis was reported in 49 cases and included classical rectosigmoid disease in 36, long segment aganglionosis in 5, total colonic aganglionosis in 7 and total intestinal aganglionosis in one patient. In 35% of the patients stoma was created in the aganglionotic region and failed to work. There was a median delay of 8 months for the diagnosis of HD from initial diagnosis of ARM. Various surgical techniques were employed for the pull-through operation for HD. The review confirms that the recognition of HD is often delayed because of the initial diagnosis of ARM and the fact that the dysfunctional colostomy is usually proximal to the affected aganglionotic bowel. There is a high incidence of associated syndromes when HD coexists with ARM.

Correlation between multiple RET mutations and severity of Hirschsprung’s disease

The enteric nervous system (ENS), comprising neurons and glial cells, organized as interconnected ganglia within the gut wall, controls peristalsis and the production of secretions. The RET receptor tyrosine kinase is expressed throughout enteric neurogenesis and is required for normal ENS development. Humans with mutations in the RET locus have Hirschsprung's disease (HSCR), and mice lacking RET exhibit total intestinal aganglionosis. Although a number of mutations with the potential for causing HSCR have been reported, their precise correlation with phenotype and symptom severity in HSCR is not clearly understood. Our study investigates the correlation between mutations in the RET locus and symptom severity in HSCR. We performed a comprehensive nucleotide analysis of the RET coding region in 18 HSCR patients and 87 controls, performed cellular biological analysis by Western blotting using the expression vector, and analyzed cell proliferation with anti-Ki67 antibody under immunofluorescence confocal microscopy (ICM). We identified three novel mutations, D489N, L769L, and V778D in the RET coding region in our HSCR patients. In the allelic distribution of D489N and L769L, the difference between HSCR patients and controls reached statistical significance (p=0.0373 and p=0.0004, respectively), whereas no statistical difference was observed in the allelic distribution of V778D (p=0.1073). One HSCR patient who died from total colonic aganglionosis had a combination of homozygous mutation of D489N, L769L, and heterozygous mutation of V778D. Western blotting of full mutant RET from this patient showed significantly increased 150kD-band, which corresponds to the immature form compared with wild-type and single mutant RET. ICM showed that overexpression of full mutant RET significantly reduced cellular proliferation in comparison with wild-type and single mutant RET. A combination of mutations in the RET locus may correlate with symptom severity in HSCR as a consequence of reduced cellular proliferation secondary to altered maturation of RET.