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Universidade Federal de Campina Grande UFCG Centro de Cincias Biolgicas e da Sade CCBS Unidade Acadmica de Medicina Disciplina: Embriologia

ia Professor: Alexandre Marinho

HIRSCHSPRUNGS DISEASE
Discentes: Alexandre Duram de Lima Junior Ana Paula Rodrigues Matos Bibiana Ferreira Gouvea Ramos Felipe Freitas Diniz de Lima Pedro Henrique de Andrade Matos Rafael Bruno da Silveira Alves Rebecca Castelo Branco de Brito Rogger Goncalves Ribeiro Tullyo Lins Almeida Barbosa Victor Hugo dos Santos Sousa

Overview
-Commonest congenital gut mobility disorder
-Absence of enteric nervous system in a variable portion of distal gut -Classical HSCR or short segment disease: aganglionosis restricted to the rectosigmoid region (80% of cases) -Total enteric aganglionosis: high morbity and mortality -Shortly after birth, affected infants present bowel obstruction, which is invariably fatal if left untreated -HSCR can be familial and associated with syndrome conditions -Definitive treatment: resection of aganglionic bowel segment followed by anastomosis of ganglionic gut ( challenges: extensive aganglionosis and repeatedly enterocolitis)

Incidence and associated anomalies


-Incidence: 1 in 5000 in both hemispheres -Undefined interracial differences -Consanguinity in different populations may explain divergences -HSCR-associated mutations have an ethnic compound to them -Stong male bias: the congenital malady affects male patients 2 to 4 times more frenquently than female ones -Associated anomalies: medullary thyroid carcinoma as part of MEN2B (potentially deleterious), Downs syndrome and other neurocristopathies as Shah-Waardenburg

Young boy presenting ShahWaardenburg syndrome

The role of enteric nervous system in determining gut mobility


-Gut motility: SM + ICC (pacemaker cells) +ENS -ICC: Responsible for slow-wave activity. These slow-waves generate some contractility and tendency for craniocaudal propagation -ENS: widespread coordination and modulation of amplitude and frequency of SM contractions -SM contractions: segmentation and peristaltic waves,which require intact myenteric plexus to occur -Colonic motility X small intestinal motility -Distension of rectum, tipically with feces, results in a ENS-dependent reflexive relaxation of the sphincter -HSCRs disease: congenital absence of distal ENS, which makes it impossible to propagate colonic mass movements throught the aganglionic segment. Therefore, the presence of feces in the rectum does not enable relaxation in the aganglionic anal sphincter (Obstruction).

a. Normal colonic biopsy

b.Acetylcholinesterase staining demonstrating aganglionosis and abundance of extrinsic nerve fibers.

Onsent of gut motility in the fetus, normal, and premature neonates.




By late gestational age, fetal swallowing results in ingestion of amniotic fluid that is propagated through the gut. Painstaking antenatal ultrasonographic studies of fetal gut motility demonstrate fetal gastric emptying occurring at 24 weeks and assuming more mature patterns by term. Small intestinal peristalsis is rarely observed before 29 weeks. Subjective observation suggests active waves of small intestinal peristalsis are infrequently seen before 35 weeks of gestation. Ultrasound studies on human fetal internal sphincter development suggest that rhythmic contractions commence in the third trimester In the small intestine of preterm children, disorganized peristalsis is seen before the third trimester, with migrating motor complexes being observed in human small intestine after 33 weeks of gestation.

The authors of recent studies suggest that effective colonic contractions do occur but that these are not mediated by the ENS. Taken together, in both animals and humans although the main components regulating gut motility are present by 14 weeks of gestation, it seems likely that the ENS is relatively quiescent until late in gestation and gut motility is controlled by other factors, such as ICC.

Neural crest origin of the enteric nervous system and the pathogenesis of Hirschsprungs disease


ENS neurons and glia are derived from the vagal segment of the neural crest Vagally derived neural crest cells (NCCs) migrate along the course of the vagus nerves, reach the distal rectum at 12 weeks Discordance between the rate of cell proliferation and elongation by growth of the developing gut may lead to HSCR Spatiotemporal interaction -- migrating cells, developing neurons, and the gut Chains of immature neuroblasts migrate through the developing gut and leave a scaffold that subsequent cells follow may be routed along vasculature Some migrating cells express neuronal markers and these migrate more slowly Cell maturation and neurotransmitter expression are associated with loss of migratory ability

Neural crest origin of the enteric nervous system and the pathogenesis of Hirschsprungs disease
 

Laminin implicated in HSCR pathogenesis Relatively small numbers of neural crest-derived cells can engage in extensive colonization and formation of both neurons and glia These cells may point to a future stem-cell based therapy for HSCR

Hirschsprungs disease and genes


   

HSCR is a complex genetic disease It has low sex-dependent penetrance and variability in the segment aganglionic Failure in the genes responsable for action of NCCs promotes HSCR. It influences of major gene-receptor complexes in determining HSCR susceptibility, such as ret-GDNF and/or endothelin-3/EDNRB. Experiments in mices have shown sex-related differences in endothelin-3 expression and a heterozygous RetDN mutation , may account for the male overrepresentation in HSCR.

Modifying genes and interaction between signaling pathways




The successful colonization of the gut by the ENS precursors depends on the network of interacting molecules
Interaction between pathways requires not only coordination among the pathway members but also with those molecules that mediate their interaction.

Hirschsprungs disease and stem cells




A subset of cells with significant proliferative and differentiative capacity within the migrating wave of NCCs Potentially represent enteric nervous system stem cells (ENSC). Furthermore, long-term studies are necessary to demonstrate the genomic stability of transplanted cells to assess potential tumor risk.

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