hirschsprung's disease: etiology and pathophysiology · 2018. 10. 12. · hirschsprung's disease:...

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NORMAL HIRSCHSPRUNG'S DISEASE

Fig. 1. Schematic presentation of the enteric nervous system of the normal (left) and aganglionic (right) bowel wall (E; excitatory fibers, I; inhibitory fibers , NO; nitric oxide)1.

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°l ~ 12:1 : Hirsc h s prung's Disease : Etiology a nd Pathophys iology 45

10. Salmhofer H, Neuhuber WL, Ruth P, Huber A,

Russwurm M, Al lescher HD: Pivotal role of the

interstitial cells of Cajal in the nitric oxide signaling

pathway at small intestine. Morphological evidence. Cell

Tiss Res 305:331-340, 2001

II. Faussone-Pellegrini MS, Gay J, Vannucchi MG, Corsani

L, Fioramonti J: Alterations of neurokinin receptors and

interstitial cells of Cajal during and after jejunal

inflammation induced by Nippostrongylus brasiliensis in

the rat. Neurogstro Mot 14:83-95, 2002

12. Sanders KM, Ordog T, Ward SM: Physiology and

pathophysiology of the interstitial cells of Cajal. .fi·om

bench to bedside. IV Genetic and animal models of GI

motility disorders caused by loss of interstitial cells of

Caja/. Am J Physiol Gastroint Liv Physiol 282:G747-756,

2002

13. Geneste 0, Bidaud D, De Vita G, Hofstra RM,

Tartare-Deckert S, Buys CH, Lenoir GM, Santoro M,

Billaud M: Two distinct mutations of the RET receptor

causing Hirschsprung's disease impair the binding of

signaling effectors to a multifunctional docking site.

Human Mol Genet 8: 1989-1999, 1999

14. Inoue K, Shimotake T, Inoue K, Tokiwa K, Iwai N:

Mutational analysis of the RET proto-oncogene in a

kindred with multiple endocrine neoplasia type 2A and

Hirschsprung's disease. J Pediatr Surg 34: 1552-1554,

1999

15. Cariomagno F, Mellilo RM, Visconti R, Salvatore G,

De Vita G, Lupoli G, Yu Y, Jing S, Vecchio G, Fusco

A, Santoro M: Glial cell line-derived neurotrophic

factor differentially stimulates ret mutants associated

with multiple endocrine neoplasia type 2 syndromes and

Hirschsprung's disease. Endocrinology 139:3613-3619,

1998

16. Puri P: Preface: Hirschsprung's disease and related

disorders-recent progress. Semin Pediatr Surg 7: 137-139,

1998

17. Zhan J, Xiu Y, Gu J, Fang Z, Hu XL: Expression of RET

proto-oncogene and GDNF deficit in Hirschsprung's

disease. J Pediatr Surg 34: 1606-1609, 1999

18. Martucciello G, Favre A, Kakahashi M, V Jasonni:

Immunohistochemical localization of RET protein in

Hirschsprung's disease. J Pediatr Surg 30:433-436, 1995

19. Lyonnet S. Bolino A. Pelet A. Abel L. Nihoul-Fekete C.

Briard ML. Mok-Siu V. Kaariainen H. Martucciello G.

Lerone M: A gene for Hirschsprung disease maps to the

proximal long arm of chromosome 10. Nature Genetics

4:346-350, 1993

20. Romeo G. Ronchetto P. Luo Y. Barone V. Seri M.

Ceccherini I. Pasini B. Bocciardi R. Lerone M. Kaariainen

H: Point mutations affecting the tyrosine kinase domain of

the RET proto-oncogene in Hirschsprung's disease. Nature.

367:377-378, 1994

2 1. Edery P. Lyonnet S. Mulligan LM. Pelet A. Dow E.

Abel L. Holder S. Nihoul-Fekete C. Ponder BA.

Munnich A: Mutations of the RET proto-oncogene in

Hirschsprung's disease. Nature. 367:378-380, 1994

22. Angrist M. Bolk S. Thiel B. Puffenberger EG. Hofstra

RM. Buys CH. Cass DT. Chakravarti A: Mutation

analysis of the RET receptor tyrosine kinase in

Hirschsprung disease. Hum Mol Genet 4:821-30, 1995

23: Attie T. Pelet A. Edery P. Eng C. Mulligan LM. Amiel

J. Boutrand L. Beldjord C. Nihoul-Fekete C. Munnich

A: Diversity of RET proto-oncogene mutations in fami-

lial and sporadic Hirschsprung disease. Hum Mol Genet

4:1381-1386, 1995.

24. Martucciello G, Thompson H, Mazzola C,A Morando,

M Bertagnon, F Negri, A Brizzolara, L Rocchetti, C

Gambini, V Jasonni: GDNF deficit in Hirschsprung's

disease. J Pediatr Surg 33 :99-102, 1998

25. Langer JC, Betti PA, Blennerhassett MG: Smooth

muscle from aganglionic bowel in Hirschsprung's

disease impairs neuronal development in vitro. Cell Ti-

ssue Res 276:181-186, 1994

26. Kamagata S, Donahoe PK: The feect of fibronectin on

cholinergic differentiation of the fetal colon. J Pediatr

Surg 20:307-314, 1985

27. Pormeranz HD, Rothman TP, Chalazonitis A, Tennyson

VM. Gershon MD: Neural crest-derived cells isolated

from the gut by immunoselection develop neural and

glial phenotypes when cultured on laminin. Develop

BioI 156:341-361, 1993

28. Gershon MD, Chalazonitis A, Rothman TP: From neural

crest to bowel: Development of the enteral nervous

system. J Neurobiol 24:199-214, 1993

29. Fujimoto T, Hata J, Yokoyama S, Mitomi T: A study of

the extracellular matrix protein as the migration pathway

of neural crest cells in the gut: Analysis in human

emblYos with special reference to the pathogenesis of

Hirschsprung's disease. J Pediatr Surg 24:550-556, 1989

30. Chalazonitis A, Rothman TP, Chen Jx, Lamballe F.

Barbacid M. Gershon MD: Neurotrophin-3 induces neural

crest-derived cells from fetal rat gut to develop in vitro as

neurons or glia. J Neurosci 14:6571 -6584, 1994

31. Ohshiro K, Puri P: Reduced glial cell line-derived

neurotrophic factor level in aganglioniC bowel in

Hirschsprung's disease. J Pediatr Surg 33:904-908, 1998

32. Covault J, Sanea JR: distribution of N-CAM in synaptic

and extrasynapticportions of developing and adult skeletal

muscle. J Cell Bioi 102:716-730, 1986

46

33. Gordon L, Whalton J, Moore SE, Walsh FS. Moscoso

JG. Penketh R. Wallwork 1. Taylor KM. Yacoub MH.

Polak JM: Myocardial localization and isoforms of

neural cell adhesion molecules(N-CAM) in the devel-

oping and transplanted human heart. J Clin Invest

86: 1293- 1330, 1990, cited from Puri seminar

34. Romanska HM, Bishop AE, Brereton RJ, Spitz L. Polak

JM: Increased expression of muscular neural cell adhesion

molecule in congenital aganglionosis. Gastroenterology

105:1104-1109, 1993

35. Kobayashi H, O'Briain DS, Puri P: Lack of expression

of NADPH-diaphorase and neural cell adhesion mo-

lecule(NCAM) in colonic muscle of patients with Hir-

schsprung's disease. J Pediatr surg 29:301-304, 1994

36. Ikawa H, Kawano H, Takeda Y, Masuyama H. Watanabe

K. Endo M. Yokoyama J. Kitajima M. Uyemura K.

Kawamura K: Impaired expression of neural cell adhesion

molecule Ll in the extrinsic nerve fibers in Hirschsprung's

disease. J Pediatr Surg 32:542-545, 1997

37. Kamiguchi H, Lemmon V: Neural cell adhesion

moilecule LI: Signaling pathways and growth cone

motility. J Neurosci Res 49: 1-8, 1997

38. Okamoto N, Wada Y, Goto M: Hydrocephalus and

Hirschsprung's disease in a patient with a mutation of

LICAM J Med Genet 34:670-671 , 1997

39. Puri P, Ohshiro K, Wester T: Hirschsprung's disease: A

search for etiology. Semin Pediatr Surg 7:140-1 47, 1998

40. Bardner lA, Chakravarti A: Waardenburg syndrome and

Hirschsprung's disease: Evidence for pleotropic effects of

a single dominant gene. Am J Med Genet 35:100-104,

1990

41. Kusafuka T, Puri P: Genetic aspects of Hirschsprungs

disease. Semin Pediatr Surg 7: 148-155, 1998

42. Pingault V, Bondurand N, Kuhlbrodt K, Georich DE, Prehu

MO, Puliti A, Herbarth B, Hermans-Borgmeyer I, Legius E,

Matthjs G, Amiel J, Lyonnet S, Cecchrini I, Romeo G,

Smith JC, Read AP, Wegner M, Goossens M: SOX10

mutations in patients with Waadenburg-Hirschsprung disease.

Nat Genet 18:171-1 73, 1998

43. Moore SW, Johnson AG: Hirschsprung's disease: genetic

and fUnctional associations of Down's and Waardenburg

syndromes. Semin Pediatr Surg 7:156-161, 1998

44. Sakai T, Wakizaka A, Matsuda H, Nirasawa Y, Hoh Y:

Point mutation in exon 12 of the receptor tyrosine

kinase proto-oncogene RET in Ondine-Hirschsprung

syndrome. Pediatrics 101 :924-926, 1998

45. Urushihara N, Nakagawa Y, Tanaka N, Uemura N,

Yoshida A: Ordine's curse and Hirschsprung's disease;

neurocristopathic syndrome. J Pediatr Surg 9:430-432,

1999

46. Luo Y. Ceccherini l. Pasini B. Matera I. Bicocchi MP.

Barone V. Bocciardi R. Kaariainen H. Weber D. Devoto

M : Close linkage with the RET protooncogene and

boundaries of deletion mutations in autosomal dominant

Hirschsprung's disease. Hum Mol Genet 2: 1803-1808,

1993

47. Oosma M.P, Cardone M, Cariomagno F, Coiantuoni V:

Mutations in the extracellular domain cause RET loss of

function by a dominant negative mechanism. Molec Cell

Bioi 18:3321-3329, 1998

48. Pelet A, Geneste 0, Edery P, Pasini A, Chappuis S, Atti

T, Munnich A, Lenoir G, Lyonnet S, Billaud M: Various

mechanisms cause RET-mediated signaling defects in

Hirschsprung's disease. J Clin Invest 101:1415-1423, 1998

49. Sancandi M, Ceccherini I, Costa M, Fava M, Chen B,

Wu Y, Hofstra R, Laurie T, Griffihs M, Burge D, Tam

PK: Incidence of RET mutations in patients with

Hirschsprung's disease. J Pediatr surg 35 :139-142, 2000

50. Martucciello G, Thompson H, Mazzola C, Morando A,

Bertagnon M, Negri F, Brizzolara A, Rocchetti L,

Gambini C, Jasonni V: GDNF deficit in Hirschsprung's

disease. J Pediatr Surg 33 :99-102, 1998

51. Hosoda K. Hammer RE. Richardson JA. Baynash AG.

Cheung Je. Giaid A. Yanagisawa M: Targeted and natural (piebald-lethal) mutations of endothelin-B

receptor gene produce megacolon associated with

spotted coat color in mice. Cell 79: 1267-76, 1994

52. Tanaka H, Moroi K, Iwai J, Takahashi H, Ohnuma N,

Hori S, Takimoto M, Nishiyama M, Masaki T,

Yanagisawa M, Sekiya S, Kimura S: Novel mutations of

the endothelin B receptor gene in patients with

Hirschsprung's disease and their characterization. 1 Bioi

Chern 273:11378-11383,1998

53 . Oue T, Puri P: Altered endothelin-3 and endothelin-B

receptor mRNA expression in Hirschsprung's disease. J

Pediatr Surg 34:1257-1260, 1999

54. Woodward MN, Kenny SE, Vaillant C, Lloyd DA, Edgar

DH: Time-dependent effects of endothelin-3 on enteric

nervous system development in an organ culture model of

Hirschsprung's disease. J Pediatr Surg 35:25-29, 2000

55. Yanagisawa M: Endothelins in development of neural

crest derived tissue. Presented at the 2nd Intematinal

Meeting: Hirschsprung's and related neurocristopathies.

Cleveland, OH, October 1995, cited from KusafUka T,

Puri P: Genetic aspects of Hirschsprungs disease.

Semin Pediatr Surg 7:148-155, 1998

56. Pingault V. Puliti A. Prehu MO. Samadi A. Bondurand

N. Goossens M: Human homology and candidate genes

for the Dominant megacolon locus, a mouse model of

Hirschsprung's disease. Genomics. 39:86-9, 1997

01 qJ 12] : Hirsc hsp run g's D isease Etio logy and P aLhop h ysiology 47

57. Kuroda T, Doody DP, Donahoe PK: Aberrant colonic

expression of MHC class If antigens in Hirschsprung's

disease. Aust NZ J Surg 61 :373-179, 199 1

58. Hirobe S. Doody DP. Ryan DP. Kim SH. Donahoe PK:

Ectopic class If major histocompatibility antigens in

Hirschsprung's disease and neuronal intestinal dysplasia.

J Pedialr Surg 27:357-62; 1992

59. Kobayashi H, Hirakawa H, Puri P: Overexpression of

intercellular adhesion molecule-l(ICAM-I) and MIle class

II antigen on hypertrophic nerve trunks suggests an

immunopathologic response in Hirschsprung's disease. J

Pediatr Surg 30: 1680-1683, 1995