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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.