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Background/aim: Although the mucosectomy-commencing points on transanal endorectal pull-through (TAEPT) differ among reports, the optimal point is unclear. This study assessed the outcomes among different mucosectomy-commencing points., Methods: We conducted a nationwide survey from 2008 to 2012. The data of 1,087 Hirschsprung's disease patients were collected, and data on those who underwent TAEPT were extracted. The patients were divided according to the mucosectomy-commencing points into two groups: in Group A, mucosectomy was started ≥5 mm from the dentate line (DL), and in Group B, mucosectomy was started <5 mm from the DL. The extent of the aganglionic segment and postoperative complications in the month after TAEPT were compared., Results: The data of 327 patients were extracted (Group A, n=155; B, n=172). Aganglionosis extending to the sigmoid colon was the most frequent in both groups. Regarding postoperative complications, the patients of each group experienced enterocolitis (Group A: 8.4%; B: 7.6%) and incontinence (A: 3.9%; B: 2.9%). The incidence of rectal mucosal prolapse was significantly greater in Group B (4.1%); (A: 0%, p=0.02)., Conclusions: Although the outcomes of TAEPT were comparable in both groups, rectal mucosal prolapse was significantly frequent in patients in whom the commencing point was <5 mm from the DL., Type of Study: Retrospective study LEVEL OF EVIDENCE: Level III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Hirschsprung's disease-related short bowel syndrome (HDSBS) is characterized by aganglionosis that extends orally to 75 cm from Treitz's band. The condition is reported be associated with a high mortality rate of 50-80%. This retrospective study aimed to survey the current trends in HDSBS treatment in Japan., Methods: Patient data were extracted from the results of a nationwide survey we conducted, resulting in the retrospective collection of the data of 1087 HD patients from 2008 to 2012 in Japan., Results: A total of 11 (0.9%) cases of HDSBS were noted. All patients underwent jejunostomy as neonates. Radical procedures performed in five patients (A-colon patch method in four, Duhamel's procedure in one). Ziegler's myotomy-myectomy and serial transverse enteroplasty (STEP) were performed in each patient as palliative procedures. No radical operations were performed in 4 of the 11 cases. The mortality rate was 36.4%. Four patients died, 1 patient who underwent STEP and 3 patients who received no radical procedures. The causes of death were sepsis due to enterocolitis or central intravenous catheter infection, and hepatic failure. All patients who underwent radical procedures survived and showed satisfactory outcomes., Conclusion: HDSBS still showed a high mortality rate, although surgical approaches such as the A-colon patch method resulted in satisfactory outcomes.

Three cases of congenital central hypoventilation syndrome (CCHS) associated with Hirschsprung's disease (HSCR) were examined with respect to their genomic DNA on the coding region of the receptor tyrosine kinase (RET) and the endothelin-B receptor (EDNRB). No causative mutations for the disease were detected, but one polymorphism was observed in exon 11 of the RET proto-oncogene. In cases with CCHS, HSCR occurs with a high incidence, and this disease complex has been described as neurocristopathy due to aberrations in neural crest cell proliferation, differentiation or migration during the early fetal period. Both the RET and EDNRB may play important roles in the modulation of neurocristopathies; however, further systemic studies in a large population of patients and control subjects are necessary for elucidating the pathogenesis of this disorder.

To clarify the pathogenesis of excessive proliferation of extrinsic nerve fibers in the aganglionic colon of patients with Hirschsprung's disease (HD), we immunohistochemically determined the role that exocytosis-related proteins play in the regulation of exocytosis using the antibody to HPC-1/syntaxin 1A, an exocytosis-related protein. Localization of exocytosis-related proteins (HPC-1/syntaxin 1A, N-ethylmalemide-sensitive fusion protein (NSF), soluble NSF attachment protein (SNAP), synaptotagmin, synaptobrevin, and synaptosome-associated protein 25 (SNAP-25)) was determined in surgical specimens obtained from normal proximal and aganglionic distal segments of the colon of 7 infant patients with HD. In the normal ganglionic colon, Auerbach's plexus, Meisner's plexus, nerve fibers in the muscle layer, and ganglion cells were immunopositive for all six kinds of antisera. In the aganglionic segments, numerous proliferated nerve fibers and hypertrophied nerve bundles were detected in the submucosal layer and myenteric layer by NSF, SNAP, synaptotagmin, synaptobrevin, and SNAP-25. However, HPC-1/syntaxin 1A was not recognized in the proliferated nerve fibers of the submucosal layer or the hypertrophied nerve bundles of the aganglionic segment. These findings show that immunoreactivity of HPC-1/syntaxin 1A was decreased in the affected bowel segments of patients with HD and may be related to the pathogenesis of extrinsic nerve-fiber proliferation in the aganglionic colon of HD.

Unlabelled: We report on mutation analysis of five genes involved in the receptor tyrosine kinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese patients with Hirschsprung disease. Analysis of DNA obtained from peripheral blood cells revealed six mutations in the RET proto-oncogene, four of which were disease-causing mutations in exon 9 (D584G), the splice donor site of intron 10 (+2T to A), exon 11 (A654T), and exon 12 (T706A). A heterozygous A to G transition was found in 47 bases upstream from the 5' end of exon 2 in two HD patients but was also seen in one control subject (2/28; 1/24). A silent 2307T to G transversion was observed in exon 13. Two disease-causing mutations were detected in the endothelin receptor (EDNRB) gene, in the non-coding region of exon 1 (-26 G to A) and in exon 4 (A301T); the latter mutation was a novel one. One silent mutation was observed in exon 4 (codon 277). One heterozygous T to C mutation was found in the glial cell line-derived neurotrophic factor gene in 25 bases upstream of the coding region in exon 1. No nucleotide changes were detected in either the endothelin-3 or neurturin genes. Disease-causing mutation rates in the RET proto-oncogene and the EDNRB gene were estimated at 14.3% (4/28) and 10.7% (3/28), respectively. In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease. Further systematic studies of genetic variation in a large series of patients and controls are necessary for elucidating the pathogenesis of this disorder., Conclusion: This study provides further gene alterations as disease-causing mutations in Japanese cases of sporadic Hirschsprung disease. However, the low mutation rate of the susceptibility genes may indicate that Hirschsprung disease arises from a combination of genetic and environmental factors.

A short-segment Hirschsprung disease (HSCR) patient associated with 21 trisomy showing point nucleotidic changes in both the receptor tyrosine kinase (RET) proto-oncogene and the endothelin-B receptor (EDNRB) gene is reported. A T to A heterozygous transition at the splicing donor site of the intron 10 in the RET proto-oncogene, and a G to A heterozygous substitution in non-coding region in the exon 1 of the EDNRB gene were observed. The familial analysis with these genes revealed that the origin of the former mutation was de novo and the latter one was maternal. No patient has been reported with two points mutations in different pathogenetically susceptible loci for HSCR. There is genetic evidence that the RET and EDNRB genes may interact in their susceptibility leading to HSCR.

A 5-year-old girl with congenital central hypoventilation syndrome associated with Hirschsprung's disease (Ondine-Hirschsprung syndrome) representing a missense mutation in exon 12 of the receptor tyrosine kinase (RET) proto-oncogene is reported. Using a direct sequencing technique, genomic DNA obtained from the patient's peripheral leukocytes was analyzed for its nucleotide sequences in all 20 exons of the RET proto-oncogene, seven regions of the 1st to the 7th exon of the endothelin-B receptor gene and endothelin 3 gene, including sequences corresponding to proteolytic cleavage sites. The analysis revealed that adenine at the 2116th base in the 12th exon in the RET proto-oncogene was substituted by guanine, supposedly resulting in a mutation of Thr 706 to Ala. No other mutational change was observed in the gene examined in this case. Mutation analysis has not been described previously on the gene in this disease complex. Mutation in this case might impair the maturation of the tyrosine kinase protein and subsequently cause neurocristopathy supposedly originating from the neural crest.

In order to assess abnormalities in the adrenergic mechanism in the intestine of Hirschsprung's disease, catecholamine concentrations, alpha-adrenoceptors, and the effect of electrical field stimulation were examined in aganglionic segments of colon or rectum. The aganglionic segment had a higher concentration of norepinephrine, assayed with high performance liquid chromatography with an electrochemical detector, whereas concentrations of epinephrine or dopamine were similar in normal and pathological segments. In four patients with extensive aganglionosis, the norepinephrine concentration in aganglionic colon segments decreased progressively in descending, transverse, and ascending colon. The tissue content of alpha-adrenoceptors and their affinity assayed from the specific binding of [3H]dihydro-alpha-ergocryptine appeared similar in normal and aganglionic segments of the rectosigmoidal colon. Electrical field stimulation of normal rectosigmoidal colon segments caused relaxation at low frequencies and contraction at a very high frequency. Relaxation was not abolished by blocking concentrations of propranolol or phentolamine. In aganglionic segments, the predominant response to electrical field stimulation was contraction, which was inhibited by either atropine or tetrodotoxin. These results indicate that an alpha-adrenergic system and cholinergic innervation apparently exist in aganglionic colon segments and that dysfunction of the colon appears to result from lack of a nonadrenergic inhibitory system.