Intestinal Aganglionosis Research Articles

Abnormal Microenvironmental Signals Underlie Intestinal Aganglionosis inDominant megacolonMutant Mice

Dominant megacolon(Dom) is a mutation in an uncharacterized murine gene which is associated with intestinal aganglionosis and the focal absence of melanocytes in heterozygous animals. The phenotype ofDom/+ heterozygotes is similar to thelethal spottedandpiebald lethalmutations, which are due to defects in endothelin-mediated intercellular signals. In this study, theDβH–nlacZtransgenic marker for enteric neural crest cells is used to study the distribution of enteric neurons and their precursors inDom/+ mice and embryos. Vagal neural crest-derived cells in wild-type embryos colonize the gut in a cranial-to-caudal progression. InDom/+ embryos, colonization was retarded from the earliest stages examined (embryonic Day 11.0), including progression through the small intestine. The early onset of this defect contrasts with impaired neural crest colonization associated with thelethal spottedandpiebald lethalmutations which manifest only in the large intestine. Analysis ofDom/+ ←→ +/+ aggregation chimeras indicated that defective colonization is not an autonomous (intrinsic) property ofDom/+ neuroblasts, but likelethal spottedandpiebald lethal,theDominant megacolonmutation directly or indirectly affects microenvironmental signals which influence the migration, proliferation, and/or survival of enteric neural crest cells.

Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts

c-ret encodes a tyrosine kinase receptor that is necessary for normal development of the mammalian enteric nervous system. Germline mutations in c-ret lead to congenital megacolon in humans, while a loss-of-function allele (ret.k-) causes intestinal aganglionosis in mice. Here we examine in detail the function of c-ret during neurogenesis, as well as the lineage relationships among cell populations in the enteric nervous system and the sympathetic nervous system that are dependent on c-ret function. We report that, while the intestine of newborn ret.k- mice is devoid of enteric ganglia, the esophagus and stomach are only partially affected; furthermore, the superior cervical ganglion is absent, while more posterior sympathetic ganglia and the adrenal medulla are unaffected. Analysis of mutant embryos shows that the superior cervical ganglion anlage is present at E10.5, but absent by E12.5, suggesting that c-ret is required for the survival or proliferation of sympathetic neuroblasts. In situ hybridization studies, as well as direct labelling of cells with DiI, indicate that a common pool of neural crest cells derived from the postotic hindbrain normally gives rise to most of the enteric nervous system and the superior cervical ganglion, and is uniquely dependent on c-ret function for normal development. We term this the sympathoenteric lineage. In contrast, a distinct sympathoadrenal lineage derived from trunk neural crest forms the more posterior sympathetic ganglia, and also contributes to the foregut enteric nervous system. Overall, our studies reveal previously unknown complexities of cell lineage and genetic control mechanisms in the developing mammalian peripheral nervous system.

Meconium ileus due to extensive intestinal aganglionosis

Seven full-term infants with aganglionosis extending into the small bowel presented with clinical, radiological, and operative features of meconium ileus. Misdiagnosis resulted in inappropriate treatment. The correct diagnosis was eventually established by rectal suction biopsy, mostly after either recurrent intestinal obstruction or stomal dysfunction, and after cystic fibrosis had been excluded. For two patients, the results of rectal suction biopsies were initially misleading. Two infants died. Extensive intestinal aganglionosis should be considered a rare possibility in all infants with meconium ileus. In such cases, histological examination of the appendix may avoid this potential pitfall.

RET PROTOONCOGENE AND HUMAN-DISEASES - REVIEW

Receptor tyrosine kinases play important roles in the control of normal cell growth and differentiation. Molecular alterations such as point mutations and rearrangements result in activation of these genes as oncogenes. The ret proto-oncogene (proto-ret) encodes a receptor tyrosine kinase that contains a cadherin-related sequence in the extracellular domain. Transcription of the proto-ret gene has been frequently detected in human tumors such as neuroblastoma, pheochromocytoma and thyroid medullary carcinoma, all of which originate from neural crest cells. When expression of the proto-Ret protein was examined immunohistochemically in normal rat tissues, it was observed in some of peripheral ganglion cells. These findings strongly support the view that the proto-ret gene might be involved in the differentiation and proliferation of neural crest cells. The proto-ret gene was assigned to chromosome 10q11.2. Genes for multiple endocrine neoplasia type 2A and type 2B (MEN2A and MEN2B) and Hirschsprung disease have also been mapped to the proximal long arm of chromosome 10 and closely linked to the locus of the proto-ret gene. MEN2A and MEN2B are characterized by the development of pheochromocytoma and thyroid medullary carcinoma and Hirschsprung disease represents a congenital disorder associated with intestinal aganglionosis. Recently, germ line mutations were found to be present in the extracellular domain of the proto-ret gene in most of MEN2A families. These findings suggested the proto-ret gene as a candidate for MEN and Hirschsprung genes. In addition, rearrangement of the proto-ret gene have frequently been detected in thyroid papillary carcinomas.

Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease.

Hirschsprung's disease is a genetic disorder of neural crest development affecting 1 in 5,000 births. It is characterized by the absence of intramural ganglion cells in the hindgut, which often results in partial to complete intestinal obstruction during the first years of life. An autosomal dominant gene causing this disease was recently mapped to chromosome 10q11.2 (refs 1,2), using an interstitial deletion of this region isolated in a cell hybrid. It was subsequently localized to a 250-kilobase interval which contains the RET proto-oncogene. Using flanking intronic sequences as primers to amplify 12 of the 20 exons of RET from genomic DNA of 27 Hirschsprung's disease patients, we have now identified four mutations (one frameshift and three missense) that totally disrupt or partially change the structure of the tyrosine kinase domain of the RET protein (Ret). Mutations in the extracellular cysteine-rich domain of Ret have been identified previously in patients with multiple endocrine neoplasia type 2A, and a targeted mutation in the tyrosine kinase domain of the same gene produces intestinal aganglionosis and kidney agenesis in homozygous transgenic mice. Our results support the hypothesis that RET, in addition to its potential role in tumorigenesis, plays a critical role in the embryogenesis of the mammalian enteric nervous system.

A 3-year survivor of near-total intestinal aganglionosis

A newborn girl had no ganglion cells beyond 2 cm distal to the ligament of Treitz. The proximal jejunum was dilated. A jejunostomy constructed 46 cm distal to the ligament of Treitz functioned. A 28-cm jejunal segment was myectomized to augment enteral feeding. For almost 1 year she has been on enteral feedings only, and her body size has been in the 75th percentile.

Extended Myectomy-Myotomy

That total intestinal aganglionosis (extended Hirschsprung's disease) is uniformly incompatible with life as reported in 1985, is challenged by this series of patients treated over the last 7 years with an alternative therapy, extended myectomy-myotomy of the small bowel. A total of 16 neonates worldwide presented with intestinal obstruction secondary to total (extending to the stomach) or near total (to 40 cm of jejunum) intestinal aganglionosis confirmed at one or more leveling operations. A patient questionnaire was answered by the surgeon of all 16 patients. The sex distribution was eight boys and eight girls. The definitive operation included extending an antimesenteric myectomy-myotomy from the ganglionic-aganglionic transition zone for variable lengths, the operative design being to create sufficient small bowel length to support life (40-cm minimum, total small bowel maximum). The myectomized bowel was terminated as an end-stroma or as an isolated jejuno-ileal segment. Ten of 16 patients have survived (62.5%) whose length of ganglionated bowel varies from 0 to 40 cm (mean, 12.4 cm; median, 6.0 cm). Six patients have died from 1 to 33 months after operation (mean, 9.5 months; median, 5.0 months) of gut-induced infection (n = 5) and respiratory failure (n = 1); their ganglionated bowel length was similar to survivors (range, 0-26 cm; mean, 9.2 cm; median, 8.0 cm). Of the 16 patients, 15 have received enteral nutrients through the myectomized bowel. Of ten survivors, strikingly two are totally gut nourished (2 cm, 7-cm length of ganglionated bowel), six receive from 1/5 to 4/5 of total calories enterally, and one receives minimal enteral feeding. From these patients we have learned that (1) extended myectomy-myotomy relieves the obstruction of extended Hirschsprung's disease; (2) aganglionic bowel after extended myectomy-myotomy acts as a passive conduit for proximally propulsed nutrients; and (3) aganglionic bowel after extended myectomy-myotomy undergoes adaptive change and is capable of absorbing life-supporting nutrients. These data demonstrate extended myectomy-myotomy to be a therapeutic option for otherwise fatal extended Hirschsprung's disease, either as a potentially definitive therapy or as a putative bridge to intestinal transplantation.

Lethal short-bowel syndrome

Infants with short-bowel syndrome are difficult to manage. Despite supportive measures with parenteral nutrition and surgery to lengthen remaining bowel or increase functional absorptive surface area, the outcome for many of these infants is poor. We have reviewed a series of seven infants diagnosed with severe short bowel. Causes included volvulus (3), multiple atresias (2), and total intestinal aganglionosis (2). Survival time ranged from 15 days to 8 months. During the hospital course, each infant underwent one to three operative procedures to diagnose and manage the short bowel and all received total parenteral nutrition (TPN) ranging from 10 days to 6 months. One infant died of liver failure and two others developed significant liver dysfunction secondary to TPN. Most infants remained hospitalized until their death. Death occurred at an average of 9 weeks following the diagnosis of short-bowel syndrome. This review suggests that infants with less than 6 cm of small bowel beyond the Ligament of Treitz will inevitably die of their disease or treatment complications. Until bowel transplant becomes a viable alternative, operative intervention and nutritional support may prolong survival but will not change the outcome of these infants and will only contribute to additional morbidity. A decision to withhold further therapy would be reasonable at the time the diagnosis is established.

Formation and malformation of the enteric nervous system in mice: An organ culture study

Despite some progress in the treatment of congenital malformations of the enteric nervous system, there is no knowledge about the pathogenesis. The study of the normal formation of the enteric nervous system is hampered by the difficulty of manipulating and culturing mammalian embryos and their organs. Three methods to culture bowel explants of murine embryos, (choriollantoic membrane grafting, organotypic tissue culture, and renal subcapsular space grafting) were compared. The three-dimensional cytoarchitecture of the bowel developed almost normally in the renal subcapsular space cultures. Using this culture system, it was found that neural crest cells colonize the murine bowel in distinct phases. The distal bowel was colonized at the 13th day of development. In a spontaneous mouse mutant model for intestinal aganglionosis, the lethal spotted mouse, the colonization of the distal 2 mm of the bowel did not occur at E13.

Familial Hirschsprung's disease—A report of 22 affected siblings in four families

Twenty-two infants, belonging to four families from Gaza, presenting with typical features of Hirschsprung's disease are reported. Eight patients died at home shortly after birth, prior to 1974, due to low intestinal obstruction. Fourteen patients were referred to Hadassah University Hospital after 1974 and diagnosed, by rectal biopsy, as having Hirschsprung's disease. Thirteen underwent laparotomy and multiple intestinal biopsies. Ten had total intestinal aganglionosis, two had total or near total aganglionosis, and in only one patient was the common rectosigmoid aganglionosis found. One patient died prior to surgery. This unusual familial disease, involving very long aganglionic segments, raises the possibility that these infants suffered from a unique variant of Hirschsprung's disease.

Ondine's curse with Hirschsprung's disease

Hirschsprung's disease can be associated with other congenital abnormalities, some of which are neural in origin. A rare association is with congenital failure of automatic control of respiration--central hypoventilation syndrome, sleep apnoea or Ondine's curse. Patients with this combination tend to have a short life expectancy. Diaphragmatic pacing by electrophrenic stimulation has proven useful in management of patients with central hypoventilation. Three children, two females and one male, with this combination are described. The male child, who had total intestinal aganglionosis, died at the age of one month despite an ileostomy and nocturnal mechanical ventilation. The two females had aganglionosis more typical of Hirschsprung's disease, one requiring colostomy. At the ages of 2 and 6 years, respectively, phrenic nerve stimulators were implanted. Both girls remain independent of nocturnal, mechanical ventilation two and three years after commencement of diaphragm pacing. In patients with Ondine's curse and Hirschsprung's disease in whom the aganglionosis can be effectively managed, diaphragm pacing may lead to independence from mechanical ventilation and prolongation of life of an acceptable quality.

Extensive intestinal aganglionosis.

Extensive aganglionosis very close to the ligament of Treitz and total intestinal aganglionosis are rare forms of Hirschsprung's disease. In these cases, nutrition, fluid, and electrolyte balance are a problem. Although the myectomy-myotomy technique of Ziegler appears hopeful, no effective surgical method has been put into the practice for the treatment of these rare forms of Hirschsprung's disease. We report four cases with extensive intestinal aganglionosis, one of which was total intestinal aganglionosis with involvement of the stomach.

Hirschsprung Disease

Intestinal aganglionosis (Hirschsprung disease) has an incidence of one in 5,000 live births. It is being recognized with greater frequency during the neonatal period when it must be distinguished from other causes of intestinal obstruction. The diagnosis of Hirschsprung disease is most often considered in the infant or child with chronic constipation since birth. A history of delayed passage of meconium may be obtained, and the infant may have no spontaneous evacuation of feces without stimulation. Less commonly, intractable diarrhea secondary to enterocolitis may be the finding.Clinical features suggestive of Hirschsprung disease include increased anal sphincter tone and empty rectum despite the presence of fecal impaction.

Hirschsprung Disease

Intestinal aganglionosis (Hirschsprung disease) has an incidence of one in 5,000 live births. It is being recognized with greater frequency during the neonatal period when it must be distinguished from other causes of intestinal obstruction. The diagnosis of Hirschsprung disease is most often considered in the infant or child with chronic constipation since birth. A history of delayed passage of meconium may be obtained, and the infant may have no spontaneous evacuation of feces without stimulation. Less commonly, intractable diarrhea secondary to enterocolitis may be the finding. Clinical features suggestive of Hirschsprung disease include increased anal sphincter tone and empty rectum despite the presence of fecal impaction.

Total intestinal aganglionosis with involvement of the stomach

Total intestinal aganglionosis is the rarest form of Hirschsprung's disease, with absence of ganglia from the duodenum to the rectum. In addition to those cases reported in the literature, a neonate with total intestinal aganglionosis with involvement of the stomach is presented. Diagnosis of this extensive form of Hirschsprung's disease is a major problem. These patients lie beyond the scope of present surgical expertise, and the outcome is universally fatal.

Intestinal aganglionosis: a histologic and acetylcholinesterase histochemical study.

Varying results have been reported with the use of acetylcholinesterase (AchE) staining to diagnose Hirschsprung's disease in rectal suction biopsy. We analyzed the histology and AchE staining of rectal biopsies from 10 patients with documented intestinal aganglionosis and 57 patients with ganglionic bowel. The results show that histologic identification of submucosal ganglion cells is reliable in excluding Hirschsprung's disease and that the absence of ganglion cells in an adequate suction biopsy is highly suggestive of intestinal aganglionosis. Four AchE staining patterns were recognized; the staining patterns overlap in some patients who have and some who lack ganglion cells. The AchE staining pattern did not correlate with sex or age of the patients, or with the length of the aganglionic segment. The acetylcholinesterase stain is not a reliable method of making or excluding a diagnosis of intestinal aganglionosis except when AchE-positive fibers are increased in both the lamina propria and muscularis mucosae. This AchE staining pattern occurred in 6 of our 10 patients with Hirschsprung's disease. In addition, eight segments of aganglionic colon were studied that included 2 cases of total colonic aganglionosis in which hypertrophic, AchE-positive nerve fibers were absent in all layers of bowel wall. This last finding suggests that an abnormality in the preganglionic cholinergic fiber or extrinsic neuron is involved in the pathogenesis of this unusual form of total colonic aganglionosis.

Total intestinal aganglionosis: A new technique for prolonged survival

Total small bowel aganglionosis is uniformly fatal; and prolonged nutritional treatment for the resulting severe short bowel syndrome in the absence of a therapy designed to achieve a functional bowel length has not been warranted. We report an operative technique, long segment small bowel myectomymyotomy, which has produced a functioning length of intestine capable of supporting ever increasing amounts of enteral nutrition. A term female was noted to have neonatal intestinal obstruction, and two laparotomies proved total colonic and near-total small bowel aganglionosis. At 2 months of age reoperation was done and the aganglionosis was proved to extend to 7 cm below the ligament of Treitz. From this transition zone to 10 cm distally, a myectomy was done removing a 1 cm wide length of seromuscular tissue to the level of the submucosa. From the distal end of the myectomy, another 40 cm of bowel received an antimesenteric border myotomy cutting to the submucosal level followed by spreading of the cut surface to a width of 1 cm. This left the patient with 55 to 60 cm of small bowel from the ligament of Treitz to the end of the myotomy at which point an end ostomy was created. The remainder of the small bowel was excised and the colon exteriorized as a mucous fistula. The patient was continued on total parenteral nutrition alone for ten days at which time small volume enteral feeds were introduced. By 5 months of age, 25% of calories were enteral; by 6 months, 33% of calories were enteral; and by 8 months, 45% of intake was enteral.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative Continence After Martin's Operation for Intestinal Aganglionosis

Postoperative Continence After Martin's Operation for Intestinal Aganglionosis

Pathologic explanation for postoperative obstipation in Hirschsprung's disease revealed with monoclonal antibody staining.

Until now, no pathologic explanation could be found for the postoperative obstipation occurring in some patients with intestinal aganglionosis. Twenty-two of 108 infants treated for intestinal aganglionosis suffered from postoperative obstipation. Resected material from these 22 patients and from 17 control subjects was investigated with monoclonal anti-neurofilament antibody staining. An abnormal staining pattern was revealed in 18 of the constipated patients. Consequently, this new immunohistochemical staining technic has revealed a hitherto unsuspected cause for postoperative obstipation in aganglionosis. The monoclonal antibody may provide early warning of such postoperative constipation.

Extensive intestinal aganglionosis including the ileum: A new surgical technique

Extensive aganglionosis including the ileum occurs in less than 5% of children with Hirschsprung's disease; in these cases nutrition, fluid, and electrolyte balance are a problem. The author reports an infant with extensive aganglionosis including the ileum in whom an endorectal pull-through of the Soave type as modified by Boley was performed with a longitudinal side-to-side anastomosis between the aganglionic and normal intestine, preserving terminal ileum and ileocecal valve. At two and one-half years of age the infant is well. He is toilet trained and has 1 to 4 soft bowel movements per day as he is in the 50th percentile for weight. When extensive aganglionosis involves the small intestine, saving the important function of the terminal ileum and the ileocecal valve is possible and highly desirable.