hscr disease
TRANSCRIPT
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Universidade Federal de Campina Grande UFCG
Centro de Cincias Biolgicas e da Sade CCBS
Unidade Acadmica de Medicina
Disciplina: EmbriologiaProfessor: Alexandre Marinho
HIRSCHSPRUNGS DISEASE
Discentes:
Alexandre Duram de Lima Junior
Ana Paula Rodrigues Matos
Bibiana Ferreira Gouvea Ramos
Felipe Freitas Diniz de LimaPedro 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
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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 rectosigmoidregion (80% of cases)
-Total enteric aganglionosis: high morbity and mortality
-Shortly after birth, affected infants present bowel obstruction, which is invariably fatalif left untreated
-HSCR can be familial and associated with syndrome conditions
-Definitive treatment: resection of aganglionic bowel segment followed by anastomosisof ganglionic gut ( challenges: extensive aganglionosis and repeatedly enterocolitis)
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Incidence and associated
anomalies-Incidence: 1 in 5000 in both hemispheres
-Undefined interracial differences
-Consanguinity in different populations mayexplain divergences
-HSCR-associated mutations have an ethniccompound to them
-Stong male bias: the congenital malady affectsmale patients 2 to 4 times more frenquently
than female ones
-Associated anomalies: medullary thyroidcarcinoma as part of MEN2B (potentiallydeleterious), Downs syndrome and otherneurocristopathies as Shah-Waardenburg
Young boy presenting Shah-
Waardenburg syndrome
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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).
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a. Normal colonic
biopsy
b.Acetylcholinesterase
staining demonstratingaganglionosis and
abundance of extrinsic
nerve fibers.
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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.
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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 althoughthe 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.
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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 bygrowth 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 alongvasculature
Some migrating cells express neuronal markers and these migrate more
slowly
Cell maturation and neurotransmitter expression are associated with loss
of migratory ability
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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
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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.
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Modifying genes and
interaction between signaling
pathways
The successful colonization of the gut by the ENSprecursors depends on the network of interactingmolecules
Interaction between pathways requires not only coordination amongthe pathway members but also with those molecules that mediatetheir interaction.
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Hirschsprungs disease and
stem cells A subset of cells with significant proliferative and differentiative capacity
within the migrating wave ofNCCs
Potentially represent enteric nervous system stem cells (ENSC).
Furthermore, long-term studies are necessary to demonstrate thegenomic stability of transplanted cells to assess potential tumor risk.