Colonic Aganglionosis Research Articles

Allele-Specific Expression at theRETLocus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease

RET common variants are associated with Hirschsprung disease (HSCR; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well-known HSCR-associated RET haplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level of RET expression when compared with the wild-type counterpart. As allele-specific expression (ASE) contributes to phenotypic variability in health and disease, we investigated whether RET ASE could contribute to the overall reduction of RET mRNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non-HSCR individuals) and peripheral blood mononuclear cells (PBMCs; 16 HSCR and 14 non-HSCR individuals). Analysis of the data generated by SNaPshot and Pyrosequencing revealed that the RET risk haplotype is significantly more expressed in gut than in PBMCs (P = 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of total RET expression levels between gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the RET risk haplotype. Nonrandom RET ASE occurs in ganglionic gut regardless of the disease status. RET ASE should not be excluded as a disease mechanism acting during development.

Are Routine Dilatations Necessary Post Pull-Through Surgery for Hirschsprung Disease?

We aim to compare the anastomotic stricture and enterocolitis rates between groups who either had or did not have anal dilatations (AD or NAD) prescribed routinely post pull-through surgery for Hirschsprung disease (HD); by this means, we will evaluate the benefit of routine dilatations. A retrospective review of the records of all children operated on for HD between 1997 and 2010 was performed. Associated Down syndrome and total colonic aganglionosis were excluded. Two cohorts were identified; those who had anal dilatation prescribed routinely (AD) and those who did not (NAD). In the latter group, if an anastomotic stricture was subsequently diagnosed, anal dilatations were initiated. The anastomotic stricture and enterocolitis rates between groups were compared. Significance was set at p < 0.05. There were 73 children that met the inclusion criteria (30 AD and 43 NAD). The NAD group had the longer mean follow-up period of 91 versus 59 months (p = 0.026); however, follow-up duration was unrelated to the anastomotic stricture rates (p = 0.575) and enterocolitis rates (p = 0.150). The anastomotic stricture rates were 13% (n = 4) versus 14% (n = 6) (p = 1.000) for the AD and NAD groups, respectively (relative risk [95% confidence interval] RR [95% CI], 0.95 [0.29 to 3.09]; p = 0.94). The mean duration between surgery and stricture occurrence was 348 versus 74 days for the AD and NAD groups, respectively. The enterocolitis rates were 23% (n = 7) versus 28% (n = 12) (p = 0.788) for the AD and NAD groups, respectively (RR [95% CI], 0.84 [0.37 to 1.87]; p = 0.66). We have not shown a reduced risk of developing anastomotic strictures or enterocolitis if anal dilatations are prescribed routinely. However, when routine dilatations were prescribed, predominantly late onset strictures of perhaps a different etiology occurred.

Totally Transanal LESS Pull-Through Colectomy: A Novel Approach for Avoiding Abdominal Wall Incision in Children with Long-Segment Intestinal Aganglionosis

Abstract Introduction: Minimally invasive surgery in children with long-segment intestinal aganglionosis aims to reduce the number of abdominal wall incisions. Conventional laparoscopic and laparoendoscopic single-site (LESS) surgeries fulfill this goal. In children, natural orifice translumenal endoscopic surgery (NOTES™; American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and Society for American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) has been limited because of fear of access site complications. We present a novel technique of totally transanal LESS pull-through colectomy (TLPC), avoiding abdominal wall incision, which combines LESS technology and the NOTES approach. Two boys and one girl (2.5 months, 6 months, and 5 years of age, respectively) with sigmoid and transverse colon aganglionosis underwent surgery. The TLPC procedure consisted of an endorectal technique with submucosal dissection starting 1 cm orally from the dentate line to above the peritoneal reflection, where the rectal muscle was divided circumferentially. After ligation of the rectal mucosa, the proximal bowel was replaced into the abdominal cavity, and a TriPort(®) (Olympus Surgical Technologies Europe, Hamburg, Germany) was introduced transanally. Mesenterial resection of the aganglionic bowel was accomplished via transanal LESS until the normoganglionic colon segment was reached and pulled down to the site of anastomosis. After removal of the port, a conventional pull-through procedure was performed. All children displayed normal bowel movements and were complication-free during the follow-up period of up to 7 months. TLPC combines the minimally invasive LESS surgery with the scarless concept of NOTES and allows resection of long-segment aganglionosis without abdominal incision. TLPC is a safe, effective, and feasible surgical procedure in children with long-segment intestinal aganglionosis.

Factors affected by surgical technique when treating total colonic aganglionosis: laparoscopy-assisted versus open surgery

We compared laparoscopy-assisted Duhamel (Lap-D) with open surgery (Duhamel or Soave=D/S) for treating total colonic aganglionosis (TCA) in children to establish what factors may affect outcome. Fourteen TCA cases treated between 1990 and 2010 were reviewed. Open D/S (O-D/S) through a vertical midline abdominal incision was routine from 1990 to 2005, whereupon Lap-D became routine. Lap-D involves laparoscopic colon resection, ileostomy take-down, and ileum pull-through through an additional Pfannenstiel incision. We compared pre-operative nutrition, operating time, intraoperative blood loss, duration until oral challenge, postoperative analgesic usage, incidence of enterocolitis, early complications that arose within 30days of surgery, and late complications, and wound cosmesis 1year postoperatively (Grade-1: unacceptable, Grade-2: passable, Grade-3: excellent). Six had O-D/S (2D, 4S) and eight had Lap-D. Differences in patient demographics, mean ages/weights at surgery, average length of the aganglionic segment from the terminal ileum, operating time, and time taken for oral challenge were all not significant, full feeding took longer in O-D/S (6.7 vs. 5.9days). Preoperative central vein intravenous hyperalimentation was required for one case in O-D/S and two cases in Lap-D. These three required hospitalization for at least 30days postoperatively and parenteral nutrition after discharge. Although there were no intraoperative complications in either group, there was one case of transient ileus in O-D/S that resolved conservatively. Cosmesis was significantly better in Lap-D (O-D/S=1.2; Lap-D=2.1; p<0.05). Cosmesis was the only factor that was significantly different between Lap-D and O-D/S; all other factors were similar.

Tcof1 acts as a modifier of Pax3 during enteric nervous system development and in the pathogenesis of colonic aganglionosis

Hirschsprung disease (HSCR) is a human congenital disorder, defined by the absence of ganglia from variable lengths of the colon. These ganglia comprise the enteric nervous system (ENS) and are derived from migratory neural crest cells (NCCs). The inheritance of HSCR is complex, often non-Mendelian and characterized by variable penetrance. Although extensive research has identified many key players in the pathogenesis of Hirschsprung disease, a large number of cases remain genetically undefined. Therefore, additional unidentified genes or modifiers must contribute to the etiology and pathogenesis of Hirschsprung disease. We have discovered that Tcof1 may be one such modifier. Haploinsufficiency of Tcof1 in mice results in a reduction of vagal NCCs and their delayed migration along the length of the gut during early development. This alone, however, is not sufficient to cause colonic aganglionosis as alterations in the balance of NCC proliferation and differentiation ensures NCC colonize the entire length of the gut of Tcof1(+/-) mice by E18.5. In contrast, Tcof1 haploinsufficiency is able to sensitize Pax3(+/-) mice to colonic aganglionosis. Although, Pax3 heterozygous mice do not show ENS defects, compound Pax3;Tcof1 heterozygous mice exhibit cumulative apoptosis which severely reduces the NCC population that migrates into the foregut. In addition, the proliferative capacity of these NCC is also diminished. Taken together with the opposing effects of Pax3 and Tcof1 on NCC differentiation, the synergistic haploinsufficiency of Tcof1 and Pax3 results in colonic aganglionosis in mice and may contribute to the pathogenesis of Hirschsprung disease.

Ileal atresia, malrotation and Hirschsprung's disease: A case report

Ileal atresia associated with malrotation is rare, but the additional diagnosis of Hirschsprung's disease (HD) in the same patient has not been described in the literature. This case report presents a newborn with a bowel obstruction requiring surgery for ileal atresia and malrotation. The post-operative course was complicated by a distal bowel obstruction. Evaluation of the resected bowel from the original surgery was consistent with total colonic aganglionosis, and a diverting ileostomy was performed. Delay in diagnosis of HD is not uncommon when an initial gastrointestinal anomaly is diagnosed and should be suspected when bowel function fails to return after corrective surgery.

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.

A Triple Threat: Down Syndrome, Congenital Central Hypoventilation Syndrome, and Hirschsprung Disease

Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS. Given the systemic nature of DS-related features, it is natural to attribute neonatal complications to the chromosomal aberration. We describe a biracial male infant with DS who had significantly delayed defecation and required continuous ventilator support, but had no primary cardiac or lung disease. Subsequent evaluations confirmed total colonic aganglionosis. Because we were unable to safely extubate the infant, a diagnosis of congenital central hypoventilation syndrome (CCHS) was considered and confirmed by molecular analysis of the PHOX2B gene, revealing a heterozygous polyalanine repeat-expansion mutation containing 27 repeats (normal gene contains 20 repeats). HSCR coexisting with CCHS is known as Haddad syndrome. This is the first reported case with co-occurrence of DS, CCHS, and HSCR.

Late diagnosis of Hirschsprung disease—patient characteristics and results

PurposeThe aim of the present study was to describe the characteristics and the postoperative results of children diagnosed as having Hirschsprung disease (HD) after the age of 3 years. MethodsAll patients with HD diagnosed after the age of 3 years in our hospital from 1998 to 2011 were included. Patient characteristics and postoperative results were prospectively registered. ResultsEleven children were included. Age at diagnosis was 3.0 to 9.6 years. Ten patients had rectosigmoid disease, whereas 1 had total colonic aganglionosis. Three children were given a diverting ileostomy before the pull-through procedure, and all 3 had ileostomy-related complications. Early postoperative complications were seen in 5 children, of whom 2 had anastomotic leakage. At final follow-up, with a median of 3 years postoperatively, 7 had normal bowel function, 1 had frequent loose stools, and 3 were soiling. ConclusionsEarly postoperative complications, especially anastomotic leakage, occurred frequently in children with late-diagnosed HD. Therefore, a diverting stoma should be considered in these patients. The long-term functional results were comparable with those seen in children operated on as neonates.

Comparative review of functional outcomes post surgery for Hirschsprung’s disease utilizing the paediatric incontinence and constipation scoring system

We aim to analyze differences in functional outcomes in children operated on for Hirschsprung's disease (HD) using the Paediatric incontinence/constipation scoring system (PICSS) validated in a normative group. A retrospective review of the records of all children operated on for HD between 1997 and 2010 was performed. Patients had either a Soave or transanal endorectal pull-through. Children with total colonic aganglionosis and Down's syndrome were excluded. Utilizing the PICSS children who scored below their age-specific lower limit 95 % confidence interval PICSS scores were considered to have incomplete continence or constipation. The rates of incomplete continence and constipation were compared between groups. Significance was set at p < 0.05. PICSS analysis could be completed in 51 (Soave 35, transanal 16). The median age at interview was 71 months (range 6-191 months). The rate of incomplete continence was 75 % (n = 21) and 71 % (n = 10) for the Soave and transanal groups, respectively (p = 1.00). The constipation rate was 34 % (n = 12) and 25 % (n = 4) for the Soave and transanal groups, respectively (p = 0.74). The overall rates of incomplete continence and constipation rates were 74 and 31 %, respectively, compared with 14 and 10 %, respectively, when rates were calculated by review of records. The PICSS is a sensitive tool for assessing functional outcome post HD surgery. The Soave and transanal procedures have similar functional outcomes.

Total colonic aganglionosis in Hirschsprung disease

Total colonic aganglionosis (TCA) is a relatively uncommon form of Hirschsprung disease (HSCR), occurring in approximately 2%-13% of cases. It can probably be classified as TCA (defined as aganglionosis extending from the anus to at least the ileocecal valve, but not >50 cm proximal to the ileocecal valve) and total colonic and small bowel aganglionosis, which may involve a very long segment of aganglionosis. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are many differences between TCA and other forms of HSCR, which require explanation if its ubiquitous clinical features are to be understood. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties that may be experienced in diagnosis, suggesting a different pathophysiology from the more common forms of HSCR. There is also some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms. This study, in addition to reviewing current understanding and differences between TCA and the more frequently encountered rectosigmoid (or short-segment) expression, correlates them with what is currently known about the genetic and molecular biological background. Moreover, it reviews current outcomes to find consensus on management.

Total colonic aganglionosis: a systematic review and meta-analysis of long-term clinical outcome

Total colonic aganglionosis (TCA) is a severe form of Hirschsprung's disease (HD), occurring in less than 10% of the cases. It is a challenging surgical condition and outcomes of pull-through (PT) surgery are reported to be inferior to those in patients with recto-sigmoid HD. As even large centres only see a few patients with TCA, there is little information on the long-term outcome of patients after PT operation for TCA. The aim of this meta-analysis was to investigate the long-term clinical outcome in patients with TCA. MEDLINE(®) and EMBASE(®) databases were searched for relevant articles that reported the outcomes of patients with TCA published between 1980 and 2011. The search terms were "Hirschsprung's disease", "Total colonic aganglionosis" AND "Outcome". All published studies containing adequate clinical data for a mean follow-up period of not less than 4years were included. Reference lists of retrieved articles were reviewed for additional cases. Detailed records of morbidity and mortality were extracted and analysed. This search yielded 225 articles reporting on outcomes in TCA. Of these, 189 were excluded for having too short a follow-up period, small or single case series, inadequate clinical data and duplicated patient groups. Ultimately, 36 articles from 37 centres containing useful clinical information on the outcomes of TCA in 969 patients were identified. There were 152 early deaths prior to PT (15.7%). Of 817 survivors, 739 underwent PT. The mortality rate for TCA post-PT was 5.7%. The most frequently reported post-operative complication was enterocolitis in 42% of the cases. 17.5% of patients underwent subsequent major surgery including redo PT, stoma reformation or other laparotomy. Long-term follow-up data were available in 396 patients. Satisfactory or normal bowel control was reported in 60% of the patients. Soiling, faecal incontinence or other poor outcome was reported in 33.5% of the cases and 6.5% of the patients had undergone conversion to a permanent ileostomy for post-operative complications. This meta-analysis reveals that a large number of patients with TCA have long-term problems with bowel control.

Total Colonic Aganglionosis—A Diagnostic Intricacy

Total colonic aganglionosis (TCA) is an unusual variety of aganglionosis. Although appearing to be an extension of Hirschprung's disease (HD), it may differ from it in many ways and thus is difficult to diagnose on the basis of features applied for HD. The aim of this case report is to discuss the difficulties encountered in recognition of TCA and identification of features which can help in early diagnosis.

Clinical Impacts of Delayed Diagnosis of Hirschsprung’s Disease in Newborn Infants

Asian infants are at a higher risk of having Hirschsprung's disease (HD). Although HD is surgically correctable, serious and even lethal complications such as Hirschsprung's-associated enterocolitis (HAEC) can still occur. The aim of this study was to investigate the risk factors of HAEC, and the clinical impacts of delayed diagnosis of HD in newborn infants. By review of medical charts in a medical center in Taiwan, 51 cases of neonates with HD between 2002 and 2009 were collected. Patients were divided into two groups based on the time of initial diagnosis: Group I, diagnosis made within 1 week after birth, and Group II after 1 week. Clinical features including demographic distribution, presenting features of HD, short-term and long-term complications related to HD were compared between the two groups of patients. There were 25 patients in Group I and 19 in Group II. Group II patients had more severe clinical signs and symptoms of HAEC than Group I patients. The incidence of preoperative HAEC was 12% in Group I and 63% in Group II (adjusted odds ratio = 12.81, confidence interval = 2.60-62.97). Patients with preoperative HAEC were more likely to develop adhesive bowel obstruction after operation (33% vs. 3%, p = 0.013) and failure to thrive (33% vs. 3%, p = 0.013). Also, patients with long-segment or total colonic aganglionosis were at risk of developing both postoperative HAEC (85% vs. 29%, p = 0.001) and failure to thrive (39% vs. 3%, p = 0.002). In our study, we found that delayed diagnosis of HD beyond 1 week after birth significantly increases the risk of serious complications in neonatal patients. Patients with long-segment or total colonic aganglionosis have higher risk of postoperative HAEC and failure to thrive. Patients with preoperative HAEC are more likely to have adhesive bowel obstruction and failure to thrive.

Total colonic aganglionosis with skip lesions: report of a rare case and management

We present an unusual case of total colonic aganglionosis with well-documented skip lesions and discuss our staged approach for diagnosis and surgical management. To date, there have been few reported cases of total colonic aganglionosis with skip areas. This type of presentation challenges the accepted theory regarding the etiology of colonic aganglionosis. Although skip lesions in Hirschsprung disease are extremely rare, their existence must be appreciated especially when a patient's clinical and pathologic findings do not support classic Hirschsprung disease. If not considered, additional areas of aganglionosis can be missed at initial presentation, leading to a delay in definitive treatment. This case illustrates how careful mapping of bowel via multiple biopsies can identify and thereby preserve intervening segments of bowel with normal ganglions cells to yield the maximal amount of bowel possible.

Intronic RET gene variants in Down syndrome–associated Hirschsprung disease in an African population

BackgroundClinical association between Hirschsprung disease (HD) and Down syndrome (DS) is well established. RET promoter and intron 1 variations have been shown to interfere with RET function, increasing the risk of HD pathogenesis. The intronic single-nucleotide polymorphism 2 (SNP2 [rs2435357]) has been associated with DS-associated HD (DS-HD). This study focuses on variations of specific RET intron, 1 SNPs (viz, SNP1 [rs2506004] and SNP2 [rs2435357]) in DS-HD. Patients and MethodsDNA was extracted from paraffin-embedded tissue samples and whole blood in 14 patients with DS with histologically proven HD. Polymerase chain reaction products of RET intron 1 were screened for genetic variation and matched to DS and controls from the general population. ResultsThirty-seven blood and/or tissue from 14 patients with DS-HD were investigated. RET intronic variations (SNP1 [rs2506004] or SNP2 [rs2435357]) were detected in all patients. SNP1 was detected in all patients, was heterozygous in 9, and homozygous in 5 samples (all aganglionic and 1 total colonic aganglionosis). SNP2 was absent in 6 patients, heterozygous in 6, and homozygous in 3. Three DS controls had a heterozygous SNP1. Homozygous intronic SNP RET variations were related to aganglionic tissue but not normally ganglionated or transitional zone from the same individual. ConclusionsPotential disease-related RET mutations were identified in the intron region in 80% of patients with DS-HD investigated, suggesting a causal relationship. The presence of a homozygous form in the aganglionic tissue probably represents a somatic mutation, which suggests local microenvironmental factors in HD pathogenesis.

Duhamel pull-through for Hirschsprung disease: a comparison of open and laparoscopic techniques

PurposeVarious pull-through techniques, both open and laparoscopic, have been performed for Hirschsprung disease. Our study compares open and laparoscopic Duhamel pull-through. MethodsAfter ethical approval, we reviewed all children (n = 181) with Hirschsprung disease admitted to our institution between 1999 and 2009. We excluded total colonic aganglionosis (n = 14), previous pull-through done elsewhere (n = 33), or follow-up performed abroad (n = 58). Open and laparoscopic pull-through were done in the same period according to surgeon preference. Data were analyzed using χ2 or Mann-Whitney U test. ResultsSeventy-six children had a Duhamel pull-through for rectosigmoid aganglionosis. Operative time, time to full feeds, and length of hospital stay were similar in each group. Open (n = 41)Fifteen children (37%) required 33 further procedures. Fourteen had procedures for persistent constipation, including redo Duhamel (n = 2), stoma formation (n = 2), spur division (n = 2), and dilatation/stretch/Botox/rectal biopsy/manual evacuation (n = 23). Three children had other procedures (adhesiolysis [n = 2] and incisional hernia repair [n = 1]). Laparoscopic (n = 35)Fourteen children (40%) required 30 further procedures. Eleven had procedures for persistent constipation, including redo Duhamel (n = 1), stoma formation (n = 4), spur division (n = 9), and dilatation/stretch/rectal biopsy (n = 8). Three children had other procedures (adhesiolysis [n = 1] and incisional hernia repair [n = 2]). There were 4 conversions. ConclusionOpen and laparoscopic Duhamel pull-through have similar outcomes. We show that the techniques have comparable operative times and hospital stay.

Balancing neural crest cell intrinsic processes with those of the microenvironment in Tcof1 haploinsufficient mice enables complete enteric nervous system formation

The enteric nervous system (ENS) comprises a complex neuronal network that regulates peristalsis of the gut wall and secretions into the lumen. The ENS is formed from a multipotent progenitor cell population called the neural crest, which is derived from the neuroepithelium. Neural crest cells (NCCs) migrate over incredible distances to colonize the entire length of the gut and during their migration they must survive, proliferate and ultimately differentiate. The absence of an ENS from variable lengths of the colon results in Hirschsprung's disease (HSCR) or colonic aganglionosis. Mutations in about 12 different genes have been identified in HSCR patients but the complex pattern of inheritance and variable penetrance suggests that additional genes or modifiers must be involved in the etiology and pathogenesis of this disease. We discovered that Tcof1 haploinsufficiency in mice models many of the early features of HSCR. Neuroepithelial apoptosis diminished the size of the neural stem cell pool resulting in reduced NCC numbers and their delayed migration along the gut from E10.5 to E14.5. Surprisingly however, we observe continued and complete colonization of the entire colon throughout E14.5-E18.5, a period in which the gut is considered to be non- or less-permissive to NCC. Thus, we reveal for the first time that reduced NCC progenitor numbers and delayed migration do not unequivocally equate with a predisposition for the pathogenesis of HSCR. In fact, these deficiencies can be overcome by balancing NCC intrinsic processes of proliferation and differentiation with extrinsic influences of the gut microenvironment.

‘Hop the skip’ with extended segment intestinal biopsy in Hirschsprung's disease

INTRODUCTIONSkip segment Hirschsprung's is an extremely rare condition, with only 25 reported cases in the English language literature. Diagnosis of skip segment Hirschsprung's may be missed as it is rarely suspected at initial surgery. PRESENTATION OF CASEA case report of an infant with total colonic aganglionosis and a skip segment Hirschsprung's in the cecum is presented. A review of literature on current surgical practice is presented along with our suggested modification to the diagnostic and therapeutic algorithm of this rare condition. DISCUSSIONIn our patient the initial leveling colostomy was incorrectly sited at the level of the first detected ganglionated segment. Subsequent recurrent episodes of enterocolitis led to a diagnosis of a long skip segment involving the ascending colon, cecum and terminal ileum. Correct leveling colostomy and a subsequent Duhamel procedure led to a good outcome. CONCLUSIONDetermination of the transition zone in Hirschsprung's may be incorrect if intestinal biopsies are terminated at the first evidence of ganglion cells. Extended segment intestinal biopsies should be included in the algorithm for management of long segment Hirschsprung's disease and will enable the surgeon to correctly detect rare manifestations such as skip segment disease at the initial procedure.

RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients

Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5′ untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.