Featured New InvestigatorThe developmental etiology and pathogenesis of Hirschsprung disease
Section snippets
Gastrointestinal Tract, Enteric Nervous System, and Hirschsprung Disease
The gastrointestinal (GI) tract is an endoderm derived organ system that begins at the mouth and terminates at the anus. The fetal GI tract is divided into 3 segments based on vascular supply. The foregut, supplied by the celiac artery, consists of the esophagus, stomach, part of duodenum, and biliary apparatus. The midgut, supplied by the superior mesenteric artery, comprises the rest of small and large bowel up to the splenic flexure. Lastly, the hindgut consists of the remainder of the large
Clinical Presentation
Histologically, aganglionosis is pathognomonic for HSCR. In 80%-85% of HSCR cases, the aganglionic region is limited to the rectum and sigmoid colon (short segment disease). Long segment disease occurs in up to 20% of cases, and is characterized by aganglionosis extending proximally to the sigmoid colon. Total colonic aganglionosis is rarer, occurring in 3%-8% of patients with HSCR.14 Another rare variant is ultra-short segment disease, affecting only the distal rectum (because this variant has
Diagnosis
The diagnosis of HSCR can be made by a variety of methods. However, the preferred first diagnostic procedure is a contrast enema. This will define the transition zone between normal (dilated) bowel and the narrow aganglionic bowel. This transition zone is seen in 70%-90% of cases.31, 32 The rectosigmoid ratio is used to evaluate the transition zone. A rectosigmoid ratio greater than 1 is normal. A stool-filled proximal bowel will decrease the rectum to sigmoid ratio. Plain radiographs show
Treatment
Currently, the only treatment for HSCR is surgery. Failure to surgically treat HSCR can be fatal due to malnutrition or sepsis following bowel perforation. Although surgery is the routine therapy for HSCR patients, surgical outcomes can vary widely, with a range of long-term consequences, such as constipation, fecal incontinence, and enterocolitis.39, 40 The surgical treatments aim to remove the aganglionic bowel and anastomose the normal bowel to the anus while preserving sphincter function.
Pathogenesis
Proper neural crest cell migration, proliferation, differentiation, survival, and apoptosis all contribute to a functional ENS. Perturbation in any of these processes can lead to a HSCR phenotype. Many genes that play a critical functional role in neural crest cell development have been implicated in HSCR, including the proto-oncogene RET, endothelin signaling genes, and transcription factors.28 Although over a dozen genes have been identified that contribute to the etiology of HSCR, these
Migration
The ENS is derived from migratory neural crest cells that originate at the vagal (somites 1-7) and sacral (caudal to somite 24) regions of the embryonic axis. These subsets contribute to different gut regions.54, 55, 56, 57 Vagal neural crest cells migrate in a rostral to caudal direction and sequentially contribute to the foregut, midgut, and hindgut.2, 55, 58 In contrast, sacral NCCs are thought to contribute to the distal hindgut.59, 60 Migration takes about 6 days in mice, with vagal NCC
Receptor Tyrosine Kinase and Glial Cell Line-Derived Neurotrophic Factor
Many genes contribute to normal enteric neural crest cell migration and the formation of a functional enteric nervous system, and mutations in any of these genes may cause an HSCR phenotype (Table 1). Two of the major contributing gene families responsible for HSCR cases are receptor tyrosine kinase (RET) and glial cell line-derived neurotrophic factor (GDNF). Mutations in the RET pathway account for 15%-35% of patients with sporadic HSCR (HSCR in a single family member) and 50% of familial
Endothelin Pathway
Endothelin signaling is also necessary for normal ENCC migration and may help maintain a permissive NCC environment. Endothelin 3 (EDN3 or ET3) is a secreted peptide expressed by gut mesenchyme97 that binds to the G-protein coupled receptor ENDRB on migrating ENCC. Endothelin converting enzyme 1 (ECE1) post-translationally modifies the immature form of EDN3 into the active form.98, 99 The EDN3-EDNRB signaling pathway is involved in regulating the normal migration of ENCCs and maintains enteric
Additional Genes Regulating Neural Crest Cell Migration
The zinc finger homeobox 1b/SMAL interacting protein (ZFHX1B/SIP1/SMADIP1), is expressed in premigratory and migratory vagal neural crest cells. This transcription factor is involved in neural specification and the epithelial to mesenchymal transition during early NCC development. Zfxh1b-/- mice exhibit complete absence of vagal NCC precursors and die around E9.5 because of cardiovascular and neural defects.118 A human mutation in ZFHX1B is associated with Mowat-Wilson syndrome of which HSCR is
Proliferation, Survival, and Differentiation
Proliferation rates in the developing GI system are equivalent throughout the ENS, with active ENCC proliferation at the wavefront necessary to colonize the gut, and behind the wavefront to fully populate the expanding intestine131 and generate the millions of enteric neurons and glia present in the adult intestine.17 The balance between proliferation and differentiation is necessary to maintain a sufficient progenitor pool of cells necessary to ensure complete ENS colonization.1, 18, 71, 113,
SOX10
Sox10 is expressed in vagal NCCs as they emigrate from the neural tube. Sox10 is used as a marker of ENS progenitors as it is expressed during NCC migration and maintains the ENS progenitor state.100, 145 This transcription factor regulates key genes required for ENS, melanocyte, and glial development,146 such as Ednrb and Ret in ENCCs.147, 148, 149
Mouse and zebrafish Sox10 homozygous mutants display abnormal ENS and melanocyte phenotypes. Sox10Dom mice have a single base pair insertion leading
Vitamin A Metabolism
Of all the human genes and mouse models identified, the RET pathway and its interacting components are the most commonly disrupted genes contributing to the HSCR phenotype. However, the mutations discussed above account for only about 50% of the documented cases of HSCR. Thus, there must be other pathways involved in the pathogenesis of Hirschsprung disease. Recently, a role for retinoid signaling in ENS development and the pathogenesis of colonic aganglionosis has been suggested.160, 161
Retinoid Deficient Mouse Models
Currently, there are a 2 mouse models of depleted retinoid signaling that may phenotypically display some evidence for colonic aganglionosis, Rbp4-/- and Raldh2-/-.160, 161 Rbp4-/- mice are unable to store retinol in their livers, and when subjected to an RA deficient diet during embryogenesis via maternal restriction from E7.5, these mice become fully depleted of Vitamin A and its active form, RA. Subsequently, these Rbp4-/- mice exhibit mild retinoid deficiency, with distal bowel
Discussion
Although more than one-half of the cases associated with HSCR have associated genetic mutations, there is still much more to be learned about this disease. A continued effort is needed to identify responsible genes in experimental models but also to identify relevant mutations in humans. Whole exome and whole genome sequencing of patient samples are an ideal way to identify these genes and mutations. With new genetic models of HSCR and new tools to examine them, new modes of pathogenesis may be
Naomi E. Butler Tjaden is currently pursuing an MD/PhD degree through the University of Kansas Medical Center. Her article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical and Translational Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, on April 2012.
References (168)
Genes and lineages in the formation of the enteric nervous system
Curr Opin Neurobiol
(1997)- et al.
Alterations in neurotrophin and neurotrophin-receptor localization in Hirschsprung’s disease
J Pediatr Surg
(1996) - et al.
The distribution of NCAM in the chick hindlimb during axon outgrowth and synaptogenesis
Dev Biol
(1986) Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases
J Pediatr Surg
(1986)- et al.
Ultrashort Hirschsprung’s disease: myth or reality
J Pediatr Surg
(1990) Practical pathology and genetics of Hirschsprung’s disease
Semin Pediatr Surg
(2009)- et al.
Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development
Dev Biol
(2006) - et al.
Hirschsprung’s disease: associated abnormalities and demography
J Pediatr Surg
(1992) - et al.
Long-term outcome and colonic motility after the Duhamel procedure for Hirschsprung’s disease
J Pediatr Surg
(1999) - et al.
Transanal endorectal pull-through for Hirschsprung’s disease
J Pediatr Surg
(1998)
Perineal one-stage pull-through for Hirschsprung’s disease
J Pediatr Surg
Transanal one-stage soave procedure for infants with Hirschsprung’s disease
J Pediatr Surg
Primary laparoscopic pull-through for Hirschsprung’s disease in infants and children
J Pediatr Surg
Laparoscopic pull-through procedure for Hirschsprung’s disease
Semin Pediatr Surg
A comparative study of laparoscopy-assisted pull-through and open pull-through for Hirschsprung’s disease with special reference to postoperative fecal continence
J Pediatr Surg
Transanal versus open endorectal pull-through for Hirschsprung’s disease
J Pediatr Surg
A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with Hirschsprung’s disease
J Pediatr Surg
Intrasphincteric botulinum toxin decreases the rate of hospitalization for postoperative obstructive symptoms in children with Hirschsprung disease
J Pediatr Surg
Posterior myotomy/myectomy for persistent stooling problems in Hirschsprung’s disease
J Pediatr Surg
Repeat pull-through surgery for complicated Hirschsprung’s disease: indications, techniques, and results
J Pediatr Surg
Reoperative surgery for Hirschsprung’s disease
Semin Pediatr Surg
Sacral neural crest cells colonize aganglionic hindgut in vivo but fail to compensate for lack of enteric ganglia
Dev Biol
A Single rostrocaudal colonization of the rodent intestine by enteric neuron precursors is revealed by the expression of Phox2b, Ret, and p75 and by explants grown under the kidney capsule or in organ culture
Dev Biol
Colonization of the murine hindgut by sacral crest-derived neural precursors: experimental support for an evolutionarily conserved model
Dev Biol
The pattern of neural crest advance in the cecum and colon
Dev Biol
Dynamics of neural crest-derived cell migration in the embryonic mouse gut
Dev Biol
Temporally distinct requirements for endothelin receptor B in the generation and migration of gut neural crest stem cells
Neuron
Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET
Neuron
GFRα-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival
Neuron
Glial cell line-derived neurotrophic factor receptor α1 availability regulates glial cell line-derived neurotrophic factor signaling: evidence from mice carrying one or two mutated alleles
Neuroscience
GDNF is a chemoattractant for enteric neural cells
Dev Biol
GFRα1 is an essential receptor component for GDNF in the developing nervous system and kidney
Neuron
The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung’s Disease
Am J Pathol
The expression pattern of endothelin 3 in the avian embryo
Mech Dev
Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons
Cell
ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1
Cell
Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies
Nat Rev Neurosci
Regional differences in the number of neurons in the myenteric plexus of the guinea pig small intestine and colon: an evaluation of markers used to count neurons
Anat Rec
Interstitial cells of Cajal as pacemakers in the gastrointestinal tract
Ann Rev Physiol
Gut peristalsis is governed by a multitude of cooperating mechanisms
Am J Physiol Gastrointest Liver Physiol
Myenteric plexus in congenital megacolon: study of eleven cases
Arch Int Med
Embryogenesis of the enteric ganglia in normal mice and in mice that develop congenital aganglionic megacolon
J Embryol Exp Morphol
[Colonic nerve network demonstrated by quinacrine]
Bulletin de l'Association des anatomistes
[Distribution of fibronectin and laminin during development of the human myenteric plexus and Hirschsprung’s disease]
Gastroentérologie clinique et biologique
Smooth muscle from aganglionic bowel in Hirschsprung’s disease impairs neuronal development in vitro
Cell Tissue Res
Hirschsprung Disease Overview. 2002
GDNF availability determines enteric neuron number by controlling precursor proliferation
Development
Hirschsprung’s disease: the Australian paediatric surveillance unit’s experience
Pediatr Surg Int
[Megacolon in adults. Apropos of 76 cases]
Annales de gastroentérologie et d'hépatologie
Hirschsprung disease in a large birth cohort
Teratology (Philadelphia)
Cited by (183)
Cinchophen induces RPA1 related DNA damage and apoptosis to impair ENS development of zebrafish
2024, Ecotoxicology and Environmental SafetyThe SNTB1 and ZFHX1B gene have susceptibility in northern Han Chinese populations with high myopia
2023, Experimental Eye ResearchTransition Zone Pull-through in Patients with Hirschsprung Disease: Is Redo Surgery Beneficial for the Long-term Outcomes?
2023, Journal of Pediatric SurgeryNationwide Outcomes of Immediate Versus Staged Surgery for Newborns with Rectosigmoid Hirschsprung Disease
2023, Journal of Pediatric SurgeryHigh incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung’s disease
2024, Pediatric Surgery International
Naomi E. Butler Tjaden is currently pursuing an MD/PhD degree through the University of Kansas Medical Center. Her article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical and Translational Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, on April 2012.
Conflict of interest: None.