Intestinal Aganglionosis Research Articles

Dynamic Changes in the Proximal Gut Neural Crest Stem Cell Population Are Associated with Successful Development of the Distal Enteric Nervous System in Rats

Loss of signaling through the endothelin-B receptor (ET(B)) leads to failure of vagal neural crest (NC) cell colonization of the developing gut and causes congenital distal intestinal aganglionosis [Hirschsprung disease (HSCR)] in humans and other mammals. Several studies suggest that cell-cell interactions and the number of NC cells behind the wavefront may play an important role in successful gut colonization. We compared the number and progression of enteric nervous system stem cells in the wild-type (WT) and HSCR rat gut using whole-mount immunohistochemistry for p75, culture and isolation of NC stem cells (NCSCs) by flow cytometry. Isolation and culture demonstrates that NCSCs enter the WT cecum between embryonic day (E) 13.5 and E14.5, and the number of NCSC in the colon significantly increases after E15.5. These findings are consistent with the caudal progression of the NC-cell wavefront by whole-mount staining. During the period of WT colonic colonization of the proximal colon, we found significant differences in the small bowel NCSC pool between WT and HSCR rats. Whereas the proximal gut NCSC pool in WT rats is increasing behind the colonization wavefront, no such change occurs in the proximal NCSC pool in HSCR rats. Dynamic changes in the NCSC pool occur behind the NC colonization wavefront in the gut of WT rats. The absence of these changes in the HSCR rat may contribute to distal aganglionosis.

A morphological study of the pacemaker cells of the aganglionic intestine in Hirschsprung’s disease utilizing ls/ls model mice

Hirschsprung's disease is a congenital aganglionic neural disorder of the segmental distal intestine characterized by unsettled pathogenesis. The relationship between Hirschsprung's disease and pacemaker cells (PMC), which almost corresponds to that of the interstitial cells of Cajal (ICC), was morphologically observed at the level of the intermuscular layer corresponding to Auerbach's plexus using ls/ls mice. These mice are an ideal model because of their large intestinal aganglionosis and gene abnormalities, which are similar to the human form of the disease. Immunostaining using anti-c-kit receptor antibody (ACK2), a marker of PMC, applied to whole-mount muscle-layer specimens, revealed the presence of c-kit immunopositive multipolar cells with many cytoplasmic processes in normal mice. For ls/ls mice, however, there were significantly fewer processes. The average number of processes per positive cell of 2.5 for the aganglionic large intestine was fewer than 3.5 for the large and small intestine of normal mice, indicating the inability to form connections between nerves and PMC in the aganglionic intestine. For normal mice with an Auerbach's plexus, the process attachment of ICC to the Auerbach's plexus was observed by scanning electron microscopy. However, for ls/ls mice no attachment to the intermuscular nerve without Auerbach's plexus was found, although transmission electron microscopy showed no difference in the cell structure and organelles of the c-kit immunopositive cells between the normal and ls/ls mice. These findings suggest that in the aganglionic intestine of Hirschsprung's disease, aplasia of enteric ganglia induces secondary disturbances during the normal development of intestinal PMC.

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.

A Human Yeast Artificial Chromosome Containing the Multiple Endocrine Neoplasia Type 2B Ret Mutation Does Not Induce Medullary Thyroid Carcinoma but Does Support the Growth of Kidneys and Partially Rescues Enteric Nervous System Development in Ret-Deficient Mice

We generated a line of transgenic mice using a yeast artificial chromosome containing the Ret mutation responsible for the multiple endocrine neoplasia type 2B syndrome (MEN 2B). The resulting animals did not develop any of the expected neoplasms associated with MEN 2B. Transgenic animals were then bred with animals lacking murine Ret (Ret(M)) to further evaluate the function of human mutated Ret (Ret(H)(2B)) in the murine context. Whereas mice lacking Ret(M) exhibit intestinal aganglionosis and the absence of kidneys with other genitourinary anomalies, expression of the Ret(H)(2B) transgene in Ret(M)-deficient mice allowed significant renal development with a partial rescue of the enteric nervous system. These Ret(H)(2B)-positive/Ret(M)-deficient mice exhibit normal Ret expression and survive longer than Ret(M)-deficient mice, but still die at 3 to 5 days of age with evidence of enterocolitis. We conclude that the normal expression of a human Ret proto-oncogene with the MEN 2B mutation does not cause any features of MEN 2B in mice. Although the gene is normally expressed in the appropriate target tissues, there is incomplete phenotypic rescue in mice lacking murine Ret. These results suggest important interspecies differences between humans and mice in the function of the Ret oncogene.

Intestinal transplantation for total/near-total aganglionosis and intestinal pseudo-obstruction

Whether from anatomical short gut (such as after resection of extensive intestinal aganglionosis) or from a functional cause (such as intestinal pseudoobstruction), intestinal failure is a devastating disease process with profound morbidity and mortality. These patients require total parenteral nutrition (TPN) and are at risk of developing complications such as liver failure, catheter-related sepsis and loss of venous access. Intestinal transplantation, which has advanced markedly over the last 14 years, is now the accepted standard of care for patients failing TPN. Survival outcomes have improved significantly, infectious complications are better controlled, and new immunosuppressive therapies offer great hope for the future. In particular, the results of intestinal transplantation achieved with the motility disorders are equivalent to those experienced with other causes of intestinal failure. In themselves, the motility disorders present their own set of complicating factors, including determining the extent of the disease process (which may involve any part of the gastrointestinal tract), associated urological anomalies, and the type of organ transplantation required. Extensive workup and careful consideration is required before transplantation is undertaken. However, early referral is desirable once complications arise if these patients are to be offered optimal medical care before the chance of transplantation is lost.

Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis.

The Ret receptor tyrosine kinase mediates physiological signals of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and is essential for postnatal survival in mice. It is implicated in a number of human diseases and developmental abnormalities. Here, we describe our analyses of mice expressing a Ret mutant (RetDN) with diminished kinase activity that inhibits wild-type Ret activity, including its activation of AKT. All RetDN/+ mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The RetDN/+ proximal small intestine also had severe hypoganglionosis and reduction in nerve fiber density, suggesting a potential mechanism for the continued gastric dysmotility in postsurgical HSCR patients. Unlike Ret-null mice, which have abnormalities in the parasympathetic and sympathetic nervous systems, the RetDN/+ mice only had defects in the parasympathetic nervous system. A small proportion of RetDN/+ mice had renal agenesis, and the remainder had hypoplastic kidneys and developed tubulocystic abnormalities postnatally. Postnatal analyses of the testes revealed a decreased number of germ cells, degenerating seminiferous tubules, maturation arrest and apoptosis, indicating a crucial role for Ret in early spermatogenesis.

Gastrointestinal manometric findings in a patient with total intestinal aganglionosis

Background/Purpose The authors studied gastrointestinal motility in a patient with total intestinal aganglionosis (TIA) and the effect of octreotide (OCT) on ileal motility in this patient. Methods The 3200-g girl received ileostomy at 50 cm proximal to the ileocecal site and jejunostomy at 15 cm distal to the ligament of Treitz because of severe ileus owing to TIA. Histology of the intestines, including jejunostomy, showed no ganglion cells. Gastro-duodeno-jejunal and distal ileal manometries were done 8 months after birth. Results In upper gastrointestinal manometry, sporadic contractions and clusters consisting of 3 to 5 contractions were observed in the duodenum and jejunum, but no typical phase 3 was observed during the 3-hour recording period. In ileal manometry, long-lasting repetitive contractions were recorded at 2 distal sites. In the most proximal ileum, the frequency of contractions was less than in the 2 distal sites. OCT administration induced a decrease in the amplitude of contractions during the first 20 minutes. The amplitude increased thereafter and reached a level higher than that before OCT administration. Conclusions In this patient, the predominant manometry finding was the remarkable hypermotility of the ileum. OCT induced a transient decrease in ileal motility and an increase in motility thereafter.

Irreversible Intestinal Failure

ABSTRACTIntestinal failure (IF) can be defined as the reduction of functional gut mass below the minimal amount necessary for digestion and absorption adequate to satisfy the nutrient and fluid requirements for maintenance in adults or growth in children. In developed countries, IF mainly includes individuals with the congenital or early onset of conditions requiring protracted or indefinite parenteral nutrition (PN). Short bowel syndrome was the first commonly recognized cause of protracted IF. The normal physiologic process of intestinal adaptation after extensive resection usually allows for recovery of sufficient intestinal function within weeks to months. During this time, patients can be sustained on parenteral nutrition. Only a few children have permanent intestinal insufficiency and life‐long dependency on PN. Non‐transplant surgery including small bowel tapering and lengthening may allow weaning from PN in some cases. Hormonal therapy with recombinant human growth hormone has produced poor results while therapy with glucagon‐like peptide‐2 holds promise. Congenital diseases of enterocyte development such as microvillus inclusion disease or intestinal epithelial dysplasia cause permanent IF for which no curative medical treatment is currently available. Severe and extensive motility disorders such as total or subtotal intestinal aganglionosis (long segment Hirschsprung disease) or chronic intestinal pseudo‐obstruction syndrome may also cause permanent IF. PN and home‐PN remain are the mainstays of therapy regardless of the cause of IF. Some patients develop complications while receiving long‐term PN for IF especially catheter related complications (thrombosis, sepsis) and liver disease. These patients may be candidates for intestinal transplantation. This review discusses the causes of irreversible IF and emphasizes the specific medico‐surgical strategies for prevention and treatment of these conditions at several stages of IF.

Irreversible intestinal failure.

Intestinal failure (IF) can be defined as the reduction of functional gut mass below the minimal amount necessary for digestion and absorption adequate to satisfy the nutrient and fluid requirements for maintenance in adults or growth in children. In developed countries, IF mainly includes individuals with the congenital or early onset of conditions requiring protracted or indefinite parenteral nutrition (PN). Short bowel syndrome was the first commonly recognized cause of protracted IF. The normal physiologic process of intestinal adaptation after extensive resection usually allows for recovery of sufficient intestinal function within weeks to months. During this time, patients can be sustained on parenteral nutrition. Only a few children have permanent intestinal insufficiency and life-long dependency on PN. Non-transplant surgery including small bowel tapering and lengthening may allow weaning from PN in some cases. Hormonal therapy with recombinant human growth hormone has produced poor results while therapy with glucagon-like peptide-2 holds promise. Congenital diseases of enterocyte development such as microvillus inclusion disease or intestinal epithelial dysplasia cause permanent IF for which no curative medical treatment is currently available. Severe and extensive motility disorders such as total or subtotal intestinal aganglionosis (long segment Hirschsprung disease) or chronic intestinal pseudo-obstruction syndrome may also cause permanent IF. PN and home-PN remain are the mainstays of therapy regardless of the cause of IF. Some patients develop complications while receiving long-term PN for IF especially catheter related complications (thrombosis, sepsis) and liver disease. These patients may be candidates for intestinal transplantation. This review discusses the causes of irreversible IF and emphasizes the specific medico-surgical strategies for prevention and treatment of these conditions at several stages of IF.

Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation.

SOX10 is a member of the SOX gene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the RET promoter; and Sox10 binding sites identified in the P0 promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the SOX10 mutants appeared to correlate with the intestinal and/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET transcription may lead to intestinal aganglionosis, overexpression of genes coding for structural myelin proteins such as P0 due to mutant SOX10 may explain the dysmyelination phenotype observed in the patients with an additional neurological disorder.

Histopathological differences between recto-sigmoid Hirschsprung's disease and total colonic aganglionosis.

Total colonic aganglionosis (TCA) is a severe form of ultra long Hirschsprung's disease with an incidence of 2 to 14% among all forms of intestinal aganglionosis. C-kit positive interstitial cells of Cajal (ICCs) are pacemaker cells that play a key role in the motility function of the bowel. The aim of this study was to compare the innervation and ICCs distribution in total colonic and recto-sigmoid HD. Full thickness colonic specimens were obtained from four children with TCA, ten with recto-sigmoid HD and four controls. Single immunohistochemistry using peripherin, neuronal nitric oxide synthase (nNOS) and c-kit antibody was performed and analysed in light microscopy. Additionally, whole-mount preparations were stained using anti c-kit immunohistochemistry and NADPH-diaphorase. In the ganglionic bowel of TCA, recto-sigmoid HD and control patients there was a strong nNOS and peripherin immunoreactivity (IR) in ganglia of myenteric and submucous plexus and in thin nerve fibres in the muscle layers. In the TCA there was weak or lack of nNOS IR in the sparse, short nerve trunks of the myenteric and submucous plexuses and muscle layers, whereas nNOS weakly positive nerve trunks were observed in the recto-sigmoid HD bowel. Peripherin IR was markedly reduced in the TCA specimens compared to recto-sigmoid HD. In the TCA specimens there was a lack of ICCs-MY in the smooth muscle layer in all the specimens, whereas in the recto-sigmoid aganglionic bowel ICCs-MY were markedly reduced. Whole-mount preparations showed lack of ICCs-MY and a markedly reduced number of NADPH-positive nerve trunks in TCA. Our findings demonstrate clear histopathological differences between rectosigmoid Hirschsprung's disease and total colonic aganglionosis.

Intestinal transplantation for gut failure

In recent years, we have witnessed increasing clinical experience with intestinal transplantation at selected centers. Although early results with this therapy were poor, several important advances have led to improved outcomes. These improvements prompted the Centers for Medicare and Medicaid Services to issue a memorandum on October 4, 2000, according federal reimbursement for intestinal transplantation at selected centers and for selected indications.1 The Centers for Medicare and Medicaid Services stipulated that, to qualify for transplantation, patients must meet a specific definition of intestinal failure and have experienced failure of parenteral nutrition (Table 1). In addition, the Centers for Medicare and Medicaid Services set forth centerspecific criteria for reimbursement, including 1-year patient survival rates of at least 65% and minimum center volume of at least 10 transplants performed per year. Only 4 centers in the United States currently meet these criteria (Mount Sinai Medical Center, University of Pittsburgh Medical Center, University of Miami, and University of Nebraska Medical Center). Thus, intestinal transplantation is currently at a crossroads, transitioning from its historical status as an experimental therapy to standard care for patients with appropriate indications. Presently, appropriate indications, timing of referral, and outcomes of intestinal transplantation are not well recognized among physicians caring for patients who may be candidates for this therapy. Definitions of terms such as “intestinal failure” and “failure of parenteral nutrition” are not standard, and there is no accepted algorithm for integrating parenteral nutrition, intestinal rehabilitation, and transplantation for patients with intestinal failure. Herein we review (1) the applicability of intestinal transplantation for patients with intestinal failure, (2) the current state of medical practice in intestinal transplantation with an emphasis on recent improvements, and (3) current results of this therapy. We also offer for the general gastroenterologist or gastrointestinal surgeon a rational approach to managing intestinal failure and integrating intestinal rehabilitation, parenteral nutrition, and transplantation.2 Brief History

Discrepancy between macroscopic and microscopic transitional zones in Hirschsprung's disease with reference to the type of RET/GDNF/SOX10 gene mutation

Background/Purpose: Recent studies have found that Hirschsrung's disease is caused by diverse genomic abnormalities. To clarifiy whether these pathogenic variations influence the distribution and function of enteric ganglia, the authors studied the morphology of the macroscopic and microscopic transitional zone in Hirschsprung's disease with reference to the type of genetic mutation. Methods: In 120 patients with Hirschsprung's disease, the location and morphology of the gut caliber change were recorded, and the enteric nervous system was investigated histologically using biopsy specimens. The DNA sequences of all the RET/GDNF/NTN and SOX10 coding regions were determined using the direct DyeDeoxy Terminator Cycle method. Results: In RET mutation carriers, the gut caliber change was almost identical to the histologic transition in cases of short segment aganglionosis, whereas these were markedly dissociated in cases exhibiting extensive aganglionosis. In contrast, SOX10 mutation carriers had a very long histologic transition and exhibited no caliber change. Conclusions: The type of genetic mutation responsible for Hirschsprung's disease influences the postnatal distribution and function of enteric ganglia. The data on discrepancy between macroscopic and microscopic transitions may enable us to concentrate the sites of the leveling biopsy more accurately especially in cases of long type intestinal aganglionosis carrying RET gene mutation. J Pediatr Surg 38:698-701. © 2003 Elsevier Inc. All rights reserved.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 51

We report a case of peripheral both demyelinating and axonal polyneuropathy in a patient affected from intestinal aganglionosis with high dose intermittent metronidazole therapy. Intestinal aganglionosis is a myenteric plexus disorder with lack of innervation concerning the whole digestive tract from the rectum to the esophagus. The familial incidence of this condition seems to be high and a recessive autosomal transmission is likely. In the pathogenesis of this disorder aberrant neural crest migration seems to be implicated: indeed frequent neurologic signs resembling dysautonomic ones, deafness and rare peripheral demyelinating or axonal neuropathies are associated. The patient was a 12 years old female child affected by intestinal aganglionosis and underwent to chronic intermittent Metronidazole treatment, with daily doses of 500 mg for 15 day every month. She was admitted to our Hospital for inability to walk, dysesthesias and pain at lower limbs, acutely started and progressively worsening. At the admission neurological examination showed ataxic gait with bilateral foot drop, severe distal weakness, bilateral tibialis anterior muscle atrophy, absent deep tendon reflexes, rapidly worsening. CSF was normal. Antibodies against to peripheral nerve (antigangliosides, sulfatide, MAG, glycosaminoglycans) resulted negative. Spinal cord MRI revealed increased roots size and increased epidural space. EMG showed denervation spontaneous activity with neurogenic MUAP modification on distal muscles. Nerve conduction study showed severe slowing of motor velocity on right and left peroneal nerves with reduced amplitude of CMAP. Sensory conduction was mild slowing on both sural nerves with reduced amplitude of SAP. Metronidazole therapy was discontinued; desametazone, high dose vitamin and intravenous immunoglobulin therapy was established in addition to rehydration and parenteral nutrition. Clinical conditions progressively improved and at two months follow up the girl was able to walk with mild ataxia. The authors emphasize in described case the difficulty to differentiate toxic or vitamin deficiency or autoimmune pathogenesis.

Improved quality of life by combined transplantation in Hirschsprung's disease with a very long aganglionic segment

Background/Purpose: The treatment of children with Hirschsprung's disease beginning in the proximal jejunum remains a challenge for the pediatric surgeon. These patients need a definitive parenteral nutrition, which could lead to a liver impairment. The goal of this work is to assess the quality of life after combined liver, intestine, and right colon transplantation. Methods: This is a retrospective study of 3 patients. Data regarding symptomatology, radiographic and operating findings, postoperating recovery, and quality of life were analyzed and compared with the quality of life before the transplantation. Results: The suspicion of a very long intestinal aganglionosis should be derived from the intestinal biopsies. Three combined liver, intestine, and right colon transplantation operations have been performed. The immunosuppression included steroids, tacrolimus, and azathioprine. An abdominal pull-trough (Duhamel procedure 2, Swenson procedure 1) was performed from 6 to 24 months after the transplantation. The follow-up after the transplantation ranges from 2 to 6 years. These 3 patients are completely off total parenteral nutrition with bowel movements 2 to 3 times a day. Two patients are continent day and night, and one is continent during the day only. Conclusions: Intestinal transplantation is feasible with good results even when a liver impairment needs a combined intestine and liver transplantation. The right colon transplantation, in our experience, does not impair the results. The quality of life after the transplantation is better than before. J Pediatr Surg 38:422-424. Copyright 2003, Elsevier Science (USA). All rights reserved.

Mutation analysis of the RET gene in total intestinal aganglionosis by wave DNA fragment analysis system

Background/Purpose: Total intestinal aganglionosis (TIA) extending from the duodenum to the rectum is the most rare form of Hirschprung's disease (HSCR) and usually is fatal. RET is the major gene associated with HSCR, and germline mutations of this gene account for up 50% of familial and up to 15 to 20% of sporadic cases in HSCR. The aim of this study was to investigate DNA variants in the RET gene in TIA patients using the WAVE DNA Fragment Analysis System. Methods: Genomic DNA was extracted from whole blood samples from 6 patients with TIA. Polymerase chain reaction (PCR) amplification of the 21 exons of RET was performed using published oligonucleotide primers. Heteroduplexes were followed by the WAVE DNA Fragment Analysis System with the DNASep cartridge. Results: WAVE system technology detected 16 variants in the RET gene in the 6 patients with TIA. Three patients had a significant mutation in exon 8, 11, and 15, respectively. Thirteen RET polymorphic variants also were detected in the 6 patients, with L746L variant in exon 13 occurring in 4 patients. Conclusions: WAVE system technology is an efficient method for the detection of DNA sequence variants. Our findings suggest that not only RET mutations but also RET polymorphic variants may contribute to the occurrence of TIA. J Pediatr Surg 38:497-501. Copyright 2003, Elsevier Science (USA). All rights reserved.

New perspective for the management of near-total or total intestinal aganglionosis in infants

Background Purpose: Extensive intestinal aganglionosis is rare. The diagnosis and treatment are known to be difficult and it had been considered to be fatal. The aim of this study was to review our experience with children with extensive intestinal aganglionosis. Methods: Retrospective analysis was conducted in patients referred to the intestinal transplantation unit since 1993. Presentation and outcome were analysed looking at 2 groups who had either undergone previous subtotal intestinal resection (group I) or no or limited resection (group II). Results. Eight children were selected (3 patients in group I and 5 in group II). Group I was remarkable in that patients all were referred early in age with progressing liver failure. Parents of one patient refused to accept transplantation as treatment, and he died one month later. Two noncirrhotic patients were maintained in the parenteral nutrition programme and currently progress well with enteral feedings. The other 5 patients underwent transplant, and 4 of 5 are alive after transplantation with a mean follow-up of 22.2 months (range 0.4 to 63.6). Conclusions: Subtotal resection of intestine at the time of diagnosis must be avoided. Conservative management with parenteral nutrition may be associated with long-term good outcome. Small bowel transplant may open new perspective in the management of patients with end-stage liver disease. J Pediatr Surg 38:25-28. Copyright 2003, Elsevier Science (USA). All rights reserved.

Hirschsprung, RET-SOX and beyond: The challenge of examining non-mendelian traits (Review)

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a common hereditary disorder causing intestinal obstruction, thereby showing considerable phenotypic variation in conjunction with complex inheritance. Moreover, phenotypic assessment of the disease has been complicated since a subset of the observed mutations is also associated with several additional syndromic anomalies. Coding sequence mutations in e.g. RET, GDNF, EDNRB, EDN3, and SOX10 lead to long-segment (L-HSCR) as well as syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). Furthermore, mutations in the RET gene are responsible for approximately half of the familial and some sporadic cases, strongly suggesting, on the one hand, the importance of non-coding variations and, on the other hand, that additional genes involved in the development of the enteric nervous system still await their discovery. For almost all of the identified HSCR genes incomplete penetrance of the HSCR phenotype has been reported, probably due to modifier loci. Therefore, HSCR has become a model for a complex oligo-/polygenic disorder in which the relationship between different genes creating a non-mendelian inheritance pattern still remains to be elucidated.

Diagnosis and surgical management of colic in the foal: Literature review and a retrospective study

Foals can develop many of the same types of colics as adult horses, but appear to be relatively more prone to surgical colics. Therefore, it is critical to have a greater suspicion for a surgical lesion earlier in the disease course in a foal than one would for an adult horse. A so-called “watch and wait” or “medical treatment first” approach can carry as much risk as exploratory surgery in foals. Radiography and ultrasonography can replace rectal palpation and can facilitate diagnosis of gastroduodenal obstructions, necrotizing enterocolitis, enteritis, impactions, displacements, intussusceptions, ruptured viscus, intestinal aganglionosis, aplasias and atresias, diaphragmatic and inguinal hernias, and pneumoperitoneum. Of the 83 foals that underwent abdominal surgery in this study, 59% were discharged from the clinic and 25% had to be euthanatized intraoperatively. Therefore, survival rate for foals that were allowed to recover from surgery was 79%. Survival rate for foals with small intestinal strangulation was poor (46%), compared with foals with large intestinal lesions (80%) and foals with genitourinary tract problems (89%). With advances in anesthesia, surgery, diagnostic procedures, and medical care, surgery for acute colic in the foal has become increasingly more common and carries a good prognosis.

Proximal jejunostomy with or without myectomy-myotomy modification in five infants with total intestinal aganglionosis: An experience with surgical treatments in a single institution

Background: Total intestinal aganglionosis is characterized by the absence of intramural ganglion cells, in which the disease's involvement extends from the stomach to the anorectum. This disease was suggested previously to be incompatible with life, but recently an extended small bowel myectomy-myotomy has achieved some prolonged survivors. Methods: Five patients with total intestinal aganglionosis underwent laparotomy at 1 to 5 days of age. Surgery was performed as a simple jejunostomy 60 to 70 cm below the ligament of Treitz in the initial 2, jejunustomy 30 cm below the ligament of Treitz in 1, and jejunostomy with myectomy-myotomy modification 30 to 35 cm below the ligament of Treitz in the remaining 2 infants. Results: The initial 2 patients died of sepsis, possibly derived from frequent enteritis and bacterial translocation at 7 and 8 months of age. Another patient had prolonged survival but died of hepatic failure at 1 year, 4 months. The remaining 2 children have survived beyond 2 years of age without any liver dysfunction, receiving a combination of enteral and parenteral nutrition. Conclusions: The more proximal site (30 to 35 cm below the ligament of Treitz) of jejunostomy with myectomy-myotomy modification appeared to be preferable for prolonged survival in these 5 patients with total intestinal aganglionosis. J Pediatr Surg 37:835-839. Copyright 2002, Elsevier Science (USA). All rights reserved.