Zonal Aganglionosis Research Articles

Atypical Hirschsprungʼs Disease: Single Zonal Aganglionosis With Positive RAIR and Ganglion Cells Present on Rectal Biopsy: First Case Report

Atypical Hirschsprungʼs Disease: Single Zonal Aganglionosis With Positive RAIR and Ganglion Cells Present on Rectal Biopsy: First Case Report

Immunohistochemical Diagnosis of Hirschsprung’s Disease and Allied Disorders

Summary Introduction. Hirschsprung’s disease accounts for approximately 20% of neonatal bowel obstruction and has a mortality rate of 20 to 25%. As the pathology severely affects a child’s quality of life, quick and precise diagnosis is mandatory. For years, diagnosis relied completely on histopathological analysis of rectal biopsies using haematoxylin-eosin and acetylcholinesterase stains. However, there have been many attempts to find an immunohistochemical marker that would simplify diagnosis of Hirschsprung’s disease. Acceptable markers should be highly sensitive and specific, easy to use and reliable. Aim of the study. The aim is to disclose the full morphological scope of Hirschsprung’s disease and allied disorders by using data available at the Children’s Clinical University Hospital (Riga, Latvia) and to identify the most sensitive and specific immunohistochemical marker for the diagnosis of Hirschsprung’s disease and allied disorders. Material and methods. In a retrospective study, all patients diagnosed with Hirschsprung’s disease and allied disorders at the Pathology Bureau of the Children’s Clinical University Hospital between April 2010 and October 2014 were identified. Immunohistochemical visualisation of calretinin, chromogranin A and synaptophysin was carried out. A conjugated polymer system EnVision was used to detect the bound primary antibodies. The study was controlled by findings in the bowel wall of adults and children lacking aganglionosis. The intensity and pattern of ganglion cell and nerve fibre staining were evaluated semi-quantitatively on a scale of one to three in both submucosal and myenteric plexuses of bowel. The specificity and sensitivity of each immunohistochemical marker were determined with a MedCalc online calculator. Results. During the relevant period, Hirschsprung’s disease (23) and allied disorders (12) were diagnosed in 35 patients. Among these children, 45.7% were diagnosed during the first year of life. Three types of Hirschsprung’s disease were present - short segment disease (73.9%), long segment disease (21.8%) and total colonic aganglionosis (4.3%). Allied Hirschsprung’s disorders were of three different types - hypoganglionosis (75%), zonal aganglionosis (16.7%) and immaturity of ganglion cells (8.3%). After evaluation of the reactivity of immunohistochemical markers, calretinin, synaptophysin and chromogranin showed staining intensity of ganglion cells of 2.47, 0.58 and 0.63, respectively, while nerve plexus staining intensity was 1.84 for calretinin, 2.68 for synaptophysin and 1.79 for chromogranin. Calretinin was characterised by sensitivity/ specificity as high as 90.5%/ 92.9% while these parameters were only 52.4%/ 100.0% for chromogranin A and 33.3%/ 14.3% for synaptophysin. Conclusions. In Latvia, the diagnosis of Hirschsprung’s disease or allied disorder is made later in life than it is in other countries. Hirschsprung’s disease was more frequent than the allied disorders. It can present as short segment disease, long segment disease and total colonic aganglionosis. Calretinin showed the highest reactivity to ganglion cells and proved to be the most specific and sensitive marker for diagnosis of Hirschsprung’s disease and allied disorders. Synaptophysin showed strong staining of myenteric plexuses and can be used for assessment of extrinsic nerve fibres despite its low reactivity to ganglion cells.

Segmental aganglionosis (zonal aganglionosis or “skip” lesions) in Hirschsprungs disease: a report of 2 unusual cases

There is accumulating evidence that "skip" lesions or zonal aganglionosis do occur in HSCR disease, albeit rarely. They are of interest because it may cause confusion in interpreting surgical margins as well as understanding the pathophysiology of HSCR disease. Normally described as "a skip area" of normally ganglionated bowel, surrounded proximally and distally by aganglionosis with variations may occur. We report two cases of infants with unusual types of "skip lesions", identified within the last 5 years. One patient had an area of zonal aganglionosis in the transverse colon and recto-sigmoid, bordered by areas of normally enervated bowel in the right and descending colon. In the second patient, the terminal ileum, transverse, descending and sigmoid colons and rectum were histologically aganglionic, but focal patches of ganglion cells were identified in 21 cm of the right ascending colon and the appendix, suggesting some ENS plasticity and possible incomplete apoptosis. These cases illustrate the point that the presence of ganglion cells at the resection line is not sufficient to guarantee postoperative function and "skip" lesions may uncommonly confuse the picture. In addition, they raise questions as to its pathophysiology and favor an alternate hypothesis of local changes promoting neuroblast apoptosis as the possible cause.

A Case of Acquired Zonal Aganglionosis in Adult

A Case of Acquired Zonal Aganglionosis in Adult

Skip segment Hirschsprung’s disease: a systematic review

Hirschsprung's disease is characterised by the congenital absence of ganglion cells beginning in the distal rectum and extending proximally for varying distances. 'Zonal aganglionosis' is a phenomenon involving a zone of aganglionosis occurring within normally innervated intestine. 'Skip segment' Hirschsprung's disease (SSHD) involves a 'skip area' of normally ganglionated intestine, surrounded proximally and distally by aganglionosis. While Hirschsprung's disease is believed to be the result of incomplete craniocaudal migration of neural crest-derived cells, the occurrence of SSHD has no clear embryological explanation. The aim of this study was to perform a systematic review of SSHD, reported in the literature between 1954 and 2009, in order to determine the clinical characteristics of this rare entity and its significance. The first reported case of SSHD was published in 1954. A systematic review of SSHD cases in the literature, from 1954 to 2009, was carried out using the electronic database 'Pubmed'. Detailed information was recorded regarding the age, gender, presenting symptoms and location of the skip segment in each patient. 24 cases of SSHD have been reported in the literature to date. 18/24 (75%) of these cases were males and 6/24 (25%) were females. Of these, 22/24 (92%) were cases of total colonic aganglionosis (TCA), and 2/24 (8%) were rectosigmoid Hirschsprung's disease. Of the 22 TCA cases, 9 (41%) had a skip segment in the transverse colon, 6 (27%) in the ascending colon, 2 (9%) in the caecum and 5 (23%) had multiple skip segments. In both rectosigmoid Hirschsprung's disease cases, the skip segment was in the sigmoid colon. Overall, the length of the skip segment was variable, with the entire transverse colon ganglionated in some cases. SSHD occurs predominantly in patients with TCA. The existence of a skip area of normally innervated colon in TCA may influence surgical management, enabling surgeons to preserve and use the ganglionated skip area during pull-through operations.

Imperforate anus, malrotation, and Hirschsprung's disease with double zonal aganglionosis: an extremely rare combination

The author describes an extremely rare case of coexistence with imperforate anus, malrotation, and double zonal aganglionosis. A colostomy was performed on a 2-day-old male infant at the proximal sigmoid colon, because the finding of an invertgram revealed an intermediate type of imperforate anus. At the age of 1 month, a distal colostogram showed the low type without fistula. An upper gastrointestinal series revealed malrotation. At 4 months of age, Ladd's procedure and an anoplasty were done. The function of the colostomy was not good. At laparotomy, a narrowing terminal ileum was removed for being a suspected intestinal obstruction. Histologic findings of the removed ileum revealed aganglionosis. A rectal suction biopsy showed the positive finding of acetyl cholinesterase staining. Therefore, the patient was diagnosed with extensive aganglionosis. At 9 months of age, a 1-stage ileoendorectal pull-through with a right colon onlay patch was performed. Histologically, a skipped ganglionic bowel segment at the right colon, a double zonal aganglionosis, was found among the extensive aganglionosis. Although the ganglionic right colon was used for the colon patch, which was placed for antiperistaltic movement, postoperatively the bowel function was excellent. The author herein describes an extremely rare case of coexistence of imperforate anus, intestinal malrotation, and double zonal Hirschsprung's disease. A case with this association, to the author's knowledge, has not been reported previously in the literature.

P-136 A case of zonal aganglionosis(Poster Session Hirschsprung and its allied diseases 2,Better Life for Sick Children, Better Future for Pediatric Surgery,the 45th Annual Meeting of Japanese Society of Pediatric Surgeons)

P-136 A case of zonal aganglionosis(Poster Session Hirschsprung and its allied diseases 2,Better Life for Sick Children, Better Future for Pediatric Surgery,the 45th Annual Meeting of Japanese Society of Pediatric Surgeons)

Clinical study of multiple zonal aganglionosis in long segment Hirschsprung's disease

To discuss pathogeny and diagnosis and management of multiple zonal aganglionosis in Hirschsprung's disease. Records of 3 children, aging 5 days, 29 days and 18 months, 3 boys, with multiple zonal aganglionosis in long segment Hirschsprung's disease between 1987-2005 were reviewed retrospectively. Total colectomy and Soave's operations were performed. 3 children were diagnosed HD before surgery, but the convulsive stenosis in distal ileum and proximal ascending colon were detected during surgery. The aganglionic cells in the stenosis gut were confirmed by pathologic diagnosis. The total colon and ileum should be detected carefully during surgery in children with long segment Hirschsprung's disease. It is believed not sound that the neuroblastic cells stop moving from neuroectoderm to gut in early gestation in HD, but it is also believed that some other causes in the course of gestation might interfere the normal growth of the ganglionic cells.

Lumbo‐sacral neural crest contributes to the avian enteric nervous system independently of vagal neural crest

Most of the avian enteric nervous system is derived from the vagal neural crest, but a minority of the neural cells in the hindgut, and to an even lesser extent in the midgut, are of lumbo-sacral crest origin. Since the lumbo-sacral contribution was not detected or deemed negligible in the absence of vagal cells, it had been hypothesised that lumbo-sacral neural crest cells require vagal crest cells to contribute to the enteric nervous system. In contrast, zonal aganglionosis, a rare congenital human bowel disease led to the opposite suggestion, that lumbo-sacral cells could compensate for the absence of vagal cells to construct a complete enteric nervous system. To test these notions, we combined E4 chick midgut and hindgut, isolated prior to arrival of neural precursors, with E1.7 chick vagal and/or E2.7 quail lumbo-sacral neural tube as crest donors, and grafted these to the chorio-allantoic membrane of E9 chick hosts. Double and triple immuno-labelling for quail cells (QCPNA), neural crest cells (HNK-1), neurons and neurites (neurofilament) and glial cells (GFAP) indicated that vagal crest cells produced neurons and glia in large ganglia throughout the entire intestinal tissues. Lumbo-sacral crest contributed small numbers of neurons and glial cells in the presence or absence of vagal cells, chiefly in colorectum, but not in nearby small intestinal tissue. Thus for production of enteric neural cells the avian lumbo-sacral neural crest neither requires the vagal neural crest, nor significantly compensates for its lack. However, enteric neurogenesis of lumbo-sacral cells requires the hindgut microenvironment, whereas that of vagal cells is not restricted to a particular intestinal region. Dev Dyn 2000;218:525–530. © 2000 Wiley-Liss, Inc.

Lumbo-sacral neural crest contributes to the avian enteric nervous system independently of vagal neural crest.

Most of the avian enteric nervous system is derived from the vagal neural crest, but a minority of the neural cells in the hindgut, and to an even lesser extent in the midgut, are of lumbo-sacral crest origin. Since the lumbo-sacral contribution was not detected or deemed negligible in the absence of vagal cells, it had been hypothesised that lumbo-sacral neural crest cells require vagal crest cells to contribute to the enteric nervous system. In contrast, zonal aganglionosis, a rare congenital human bowel disease led to the opposite suggestion, that lumbo-sacral cells could compensate for the absence of vagal cells to construct a complete enteric nervous system. To test these notions, we combined E4 chick midgut and hindgut, isolated prior to arrival of neural precursors, with E1. 7 chick vagal and/or E2.7 quail lumbo-sacral neural tube as crest donors, and grafted these to the chorio-allantoic membrane of E9 chick hosts. Double and triple immuno-labelling for quail cells (QCPNA), neural crest cells (HNK-1), neurons and neurites (neurofilament) and glial cells (GFAP) indicated that vagal crest cells produced neurons and glia in large ganglia throughout the entire intestinal tissues. Lumbo-sacral crest contributed small numbers of neurons and glial cells in the presence or absence of vagal cells, chiefly in colorectum, but not in nearby small intestinal tissue. Thus for production of enteric neural cells the avian lumbo-sacral neural crest neither requires the vagal neural crest, nor significantly compensates for its lack. However, enteric neurogenesis of lumbo-sacral cells requires the hindgut microenvironment, whereas that of vagal cells is not restricted to a particular intestinal region.

Hirschprung's disease.

Current evidence on the pathogenesis of Hirschprung's disease, then, favours the 'abnormal microenvironment' hypothesis wherein the developing and migrating normal neural crest cells confront a segmentally abnormal and hostile microenvironment in the colon. This hypothesis would account both for the congenital absence of ganglion cells in the wall of colon and also for the range of enteric neuronal abnormalities encountered including neuronal dysplasia, hypoganglionosis, and zonal aganglionosis. The abnormal constitution of the mesenchymal and basement membrane extracellular matrix in the affected segment of colon is presumably genetically determined and further understanding of the pathogenesis of this disorder will emerge as molecular geneticists characterise the specific genes and gene products associated with Hirschprung's disease. Advances in this field should permit gene probes to be developed to facilitate prenatal and postnatal diagnosis.

Double zonal aganglionosis in long segment Hirschsprung's disease with a “skip area” in transverse colon

The case of an infant with Hirschsprung's disease involving the rectum, entire colon, cecum, appendix, terminal ileum and sparing the midtransverse colon is described. The purpose of the report is to submit an additional illustration of this rarely documented aspect of intestinal aganglionosis.