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Journal List > J Med Genet > v.38(11); Nov 2001

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J Med Genet. 2001 November; 38(11): 729–739.
doi: 10.1136/jmg.38.11.729.
PMCID: PMC1734759
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Hirschsprung disease, associated syndromes, and genetics: a review
J. Amiel and S. Lyonnet
Département de Génétique, Unité INSERM U-393, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France.
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Abstract
Hirschsprung disease (HSCR, aganglionic megacolon) is the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has dramatically decreased mortality and morbidity, which has allowed the emergence of familial cases. HSCR appeared to be a multifactorial malformation with low, sex dependent penetrance and variable expression according to the length of the aganglionic segment, suggesting the involvement of one or more gene(s) with low penetrance. So far, eight genes have been found to be involved in HSCR. This frequent congenital malformation now stands as a model for genetic disorders with complex patterns of inheritance.


Keywords: Hirschsprung disease; aganglionic megacolon; genetics
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Selected References
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  • Meier-Ruge W, Lutterbeck PM, Herzog B, Morger R, Moser R, Schärli A. Acetylcholinesterase activity in suction biopsies of the rectum in the diagnosis of Hirschsprung's disease. J Pediatr Surg. 1972 Feb;7(1):11–17. [PubMed]
  • Swenson O. Early history of the therapy of Hirschsprung's disease: facts and personal observations over 50 years. J Pediatr Surg. 1996 Aug;31(8):1003–1008. [PubMed]
  • Passarge E. The genetics of Hirschsprung's disease. Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med. 1967 Jan 19;276(3):138–143. [PubMed]
  • Goldberg EL. An epidemiological study of Hirschsprung's disease. Int J Epidemiol. 1984 Dec;13(4):479–485. [PubMed]
  • Garver KL, Law JC, Garver B. Hirschsprung disease: a genetic study. Clin Genet. 1985 Dec;28(6):503–508. [PubMed]
  • Spouge D, Baird PA. Hirschsprung disease in a large birth cohort. Teratology. 1985 Oct;32(2):171–177. [PubMed]
  • Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung disease. Am J Hum Genet. 1990 Mar;46(3):568–580. [PubMed]
  • Taraviras S, Pachnis V. Development of the mammalian enteric nervous system. Curr Opin Genet Dev. 1999 Jun;9(3):321–327. [PubMed]
  • N-Fékété C, Ricour C, Martelli H, Jacob SL, Pellerin D. Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases. J Pediatr Surg. 1986 Mar;21(3):251–254. [PubMed]
  • Neilson IR, Yazbeck S. Ultrashort Hirschsprung's disease: myth or reality. J Pediatr Surg. 1990 Nov;25(11):1135–1138. [PubMed]
  • Parc R, Berrod JL, Tussiot J, Loygue J. Le mégacôlon de l'adulte. A propos de 76 cas. Ann Gastroenterol Hepatol (Paris). 1984 May–Jun;20(3):133–141. [PubMed]
  • Emir H, Akman M, Sarimurat N, Kiliç N, Erdoğan E, Söylet Y. Anorectal manometry during the neonatal period: its specificity in the diagnosis of Hirschsprung's disease. Eur J Pediatr Surg. 1999 Apr;9(2):101–103. [PubMed]
  • López-Alonso M, Ribas J, Hernández A, Anguita FA, Gómez de Terreros I, Martínez-Caro A. Efficiency of the anorectal manometry for the diagnosis of Hirschsprung's disease in the newborn period. Eur J Pediatr Surg. 1995 Jun;5(3):160–163. [PubMed]
  • Kurer MH, Lawson JO, Pambakian H. Suction biopsy in Hirschsprung's disease. Arch Dis Child. 1986 Jan;61(1):83–84. [PubMed]
  • Soave F. Hirschsprung's disease. Technique and results of Soave's operation. Br J Surg. 1966 Dec;53(12):1023–1027. [PubMed]
  • Newbern WR. Hirschsprung's disease--the Duhamel modification. Am J Gastroenterol. 1967 Jan;47(1):61–68. [PubMed]
  • Hackam DJ, Filler RM, Pearl RH. Enterocolitis after the surgical treatment of Hirschsprung's disease: risk factors and financial impact. J Pediatr Surg. 1998 Jun;33(6):830–833. [PubMed]
  • Yanchar NL, Soucy P. Long-term outcome after Hirschsprung's disease: patients' perspectives. J Pediatr Surg. 1999 Jul;34(7):1152–1160. [PubMed]
  • Moore SW, Albertyn R, Cywes S. Clinical outcome and long-term quality of life after surgical correction of Hirschsprung's disease. J Pediatr Surg. 1996 Nov;31(11):1496–1502. [PubMed]
  • Albanese CT, Jennings RW, Smith B, Bratton B, Harrison MR. Perineal one-stage pull-through for Hirschsprung's disease. J Pediatr Surg. 1999 Mar;34(3):377–380. [PubMed]
  • Jasonni V, Martucciello G. Total colonic aganglionosis. Semin Pediatr Surg. 1998 Aug;7(3):174–180. [PubMed]
  • Tsuji H, Spitz L, Kiely EM, Drake DP, Pierro A. Management and long-term follow-up of infants with total colonic aganglionosis. J Pediatr Surg. 1999 Jan;34(1):158–162. [PubMed]
  • Puffenberger EG, Kauffman ER, Bolk S, Matise TC, Washington SS, Angrist M, Weissenbach J, Garver KL, Mascari M, Ladda R, et al. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet. 1994 Aug;3(8):1217–1225. [PubMed]
  • Salomon R, Attié T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O, Ricour C, Nihoul-Fékété C, Munnich A, Lyonnet S. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nat Genet. 1996 Nov;14(3):345–347. [PubMed]
  • Sakai T, Wakizaka A, Nirasawa Y, Ito Y. Point nucleotidic changes in both the RET proto-oncogene and the endothelin-B receptor gene in a Hirschsprung disease patient associated with Down syndrome. Tohoku J Exp Med. 1999 Jan;187(1):43–47. [PubMed]
  • Fewtrell MS, Tam PK, Thomson AH, Fitchett M, Currie J, Huson SM, Mulligan LM. Hirschsprung's disease associated with a deletion of chromosome 10 (q11.2q21.2): a further link with the neurocristopathies? J Med Genet. 1994 Apr;31(4):325–327. [PubMed]
  • Sparkes RS, Sparkes MC, Kalina RE, Pagon RA, Salk DJ, Disteche CM. Separation of retinoblastoma and esterase D loci in a patient with sporadic retinoblastoma and del(13)(q14.1q22.3). Hum Genet. 1984;68(3):258–259. [PubMed]
  • Lamont MA, Fitchett M, Dennis NR. Interstitial deletion of distal 13q associated with Hirschsprung's disease. J Med Genet. 1989 Feb;26(2):100–104. [PubMed]
  • Bottani A, Xie YG, Binkert F, Schinzel A. A case of Hirschsprung disease with a chromosome 13 microdeletion, del(13)(q32.3q33.2): potential mapping of one disease locus. Hum Genet. 1991 Oct;87(6):748–750. [PubMed]
  • Lurie IW, Supovitz KR, Rosenblum-Vos LS, Wulfsberg EA. Phenotypic variability of del(2) (q22-q23): report of a case with a review of the literature. Genet Couns. 1994;5(1):11–14. [PubMed]
  • Mowat DR, Croaker GD, Cass DT, Kerr BA, Chaitow J, Adès LC, Chia NL, Wilson MJ. Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet. 1998 Aug;35(8):617–623. [PubMed]
  • McMilin KD, Reiss JA, Brown MG, Black MH, Buckmaster DA, Durum CT, Gunter KA, Lawce HJ, Berry TL, Lamb OA, Olson CL, Weeks FF, Yoshitomi MJ, Jacky PB, Olson SB, Magenis RE. Clinical outcomes of four patients with microdeletion in the long arm of chromosome 2. Am J Med Genet. 1998 Jun 16;78(1):36–43. [PubMed]
  • Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H, Kitoh H, Mutoh N, Yamanaka T, Mushiake K, Kato K, Sonta S, Nagaya M. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet. 2001 Apr;27(4):369–370. [PubMed]
  • Hansford JR, Mulligan LM. Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet. 2000 Nov;37(11):817–827. [PubMed]
  • Verdy M, Weber AM, Roy CC, Morin CL, Cadotte M, Brochu P. Hirschsprung's disease in a family with multiple endocrine neoplasia type 2. J Pediatr Gastroenterol Nutr. 1982;1(4):603–607. [PubMed]
  • Mulligan LM, Eng C, Attié T, Lyonnet S, Marsh DJ, Hyland VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar A, et al. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994 Dec;3(12):2163–2167. [PubMed]
  • Borst MJ, VanCamp JM, Peacock ML, Decker RA. Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease. Surgery. 1995 Apr;117(4):386–391. [PubMed]
  • Caron P, Attié T, David D, Amiel J, Brousset F, Roger P, Munnich A, Lyonnet S. C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease. J Clin Endocrinol Metab. 1996 Jul;81(7):2731–2733. [PubMed]
  • Peretz H, Luboshitsky R, Baron E, Biton A, Gershoni R, Usher S, Grynberg E, Yakobson E, Graff E, Lapidot M. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting. Hum Mutat. 1997;10(2):155–159. [PubMed]
  • Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998 Jan;7(1):129–134. [PubMed]
  • Romeo G, Ceccherini I, Celli J, Priolo M, Betsos N, Bonardi G, Seri M, Yin L, Lerone M, Jasonni V, Martucciello G. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998 Jun;243(6):515–520. [PubMed]
  • Borrego S, Eng C, Sánchez B, Sáez ME, Navarro E, Antiñolo G. Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. J Clin Endocrinol Metab. 1998 Sep;83(9):3361–3364. [PubMed]
  • WAARDENBURG PJ. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet. 1951 Sep;3(3):195–253. [PubMed]
  • Hageman MJ, Delleman JW. Heterogeneity in Waardenburg syndrome. Am J Hum Genet. 1977 Sep;29(5):468–485. [PubMed]
  • Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravart A. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell. 1994 Dec 30;79(7):1257–1266. [PubMed]
  • Attié T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet. 1995 Dec;4(12):2407–2409. [PubMed]
  • Hofstra RM, Osinga J, Tan-Sindhunata G, Wu Y, Kamsteeg EJ, Stulp RP, van Ravenswaaij-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CH. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet. 1996 Apr;12(4):445–447. [PubMed]
  • Edery P, Attié T, Amiel J, Pelet A, Eng C, Hofstra RM, Martelli H, Bidaud C, Munnich A, Lyonnet S. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet. 1996 Apr;12(4):442–444. [PubMed]
  • Pingault V, Bondurand N, Kuhlbrodt K, Goerich DE, Préhu MO, Puliti A, Herbarth B, Hermans-Borgmeyer I, Legius E, Matthijs G, Amiel J, Lyonnet S, Ceccherini I, Romeo G, Smith JC, Read AP, Wegner M, Goossens M. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet. 1998 Feb;18(2):171–173. [PubMed]
  • Jacobs JM, Wilson J. An unusual demyelinating neuropathy in a patient with Waardenburg's syndrome. Acta Neuropathol. 1992;83(6):670–674. [PubMed]
  • Touraine RL, Attié-Bitach T, Manceau E, Korsch E, Sarda P, Pingault V, Encha-Razavi F, Pelet A, Augé J, Nivelon-Chevallier A, Holschneider AM, Munnes M, Doerfler W, Goossens M, Munnich A, Vekemans M, Lyonnet S. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Am J Hum Genet. 2000 May;66(5):1496–1503. [PubMed]
  • Bondurand N, Kuhlbrodt K, Pingault V, Enderich J, Sajus M, Tommerup N, Warburg M, Hennekam RC, Read AP, Wegner M, Goossens M. A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies. Hum Mol Genet. 1999 Sep;8(9):1785–1789. [PubMed]
  • Gross A, Kunze J, Maier RF, Stoltenburg-Didinger G, Grimmer I, Obladen M. Autosomal-recessive neural crest syndrome with albinism, black lock, cell migration disorder of the neurocytes of the gut, and deafness: ABCD syndrome. Am J Med Genet. 1995 Apr 10;56(3):322–326. [PubMed]
  • Mahakrishnan A, Srinivasan MS. Piebaldness with Hirschsprung's disease. Arch Dermatol. 1980 Oct;116(10):1102–1102. [PubMed]
  • Kaplan P, de Chaderévian JP. Piebaldism-Waardenburg syndrome: histopathologic evidence for a neural crest syndrome. Am J Med Genet. 1988 Nov;31(3):679–688. [PubMed]
  • Weinberg AG, Currarino G, Besserman AM. Hirschsprung's disease and congenital deafness. Familial assocation. Hum Genet. 1977 Sep 22;38(2):157–161. [PubMed]
  • Gozal D. Congenital central hypoventilation syndrome: an update. Pediatr Pulmonol. 1998 Oct;26(4):273–282. [PubMed]
  • Chatten J, Voorhess ML. Familial neuroblastoma. Report of a kindred with multiple disorders, including neuroblastomas in four siblings. N Engl J Med. 1967 Dec 7;277(23):1230–1236. [PubMed]
  • Roshkow JE, Haller JO, Berdon WE, Sane SM. Hirschsprung's disease, Ondine's curse, and neuroblastoma--manifestations of neurocristopathy. Pediatr Radiol. 1988;19(1):45–49. [PubMed]
  • Levard G, Boige N, Vitoux C, Aigrain Y, Boureau M, Navarro J. Neurocristopathie. Association "Maladie de Hirschsprung-ganglioneuromes et dysfonctionnement du système nerveux autonome" chez 2 enfants. Arch Fr Pediatr. 1989 Oct;46(8):595–597. [PubMed]
  • Weese-Mayer DE, Silvestri JM, Marazita ML, Hoo JJ. Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome. Am J Med Genet. 1993 Sep 1;47(3):360–367. [PubMed]
  • Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MA, Epstein RA, Mellins RB. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore). 1978 Nov;57(6):517–526. [PubMed]
  • Verloes A, Elmer C, Lacombe D, Heinrichs C, Rebuffat E, Demarquez JL, Moncla A, Adam E. Ondine-Hirschsprung syndrome (Haddad syndrome). Further delineation in two cases and review of the literature. Eur J Pediatr. 1993 Jan;152(1):75–77. [PubMed]
  • Amiel J, Salomon R, Attié T, Pelet A, Trang H, Mokhtari M, Gaultier C, Munnich A, Lyonnet S. Mutations of the RET-GDNF signaling pathway in Ondine's curse. Am J Hum Genet. 1998 Mar;62(3):715–717. [PubMed]
  • Sakai T, Wakizaka A, Matsuda H, Nirasawa Y, Itoh Y. Point mutation in exon 12 of the receptor tyrosine kinase proto-oncogene RET in Ondine-Hirschsprung syndrome. Pediatrics. 1998 May;101(5):924–926. [PubMed]
  • Bolk S, Angrist M, Xie J, Yanagisawa M, Silvestri JM, Weese-Mayer DE, Chakravarti A. Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Nat Genet. 1996 Aug;13(4):395–396. [PubMed]
  • Gaisie G, Oh KS, Young LW. Coexistent neuroblastoma and Hirschsprung's disease--another manifestation of the neurocristopathy? Pediatr Radiol. 1979 Jul 24;8(3):161–163. [PubMed]
  • Michna BA, McWilliams NB, Krummel TM, Hartenberg MA, Salzberg AM. Multifocal ganglioneuroblastoma coexistent with total colonic aganglionosis. J Pediatr Surg. 1988 Jan;23(1 Pt 2):57–59. [PubMed]
  • Merkler RG, Solish SB, Scherzer AL. Meningomyelocele and Hirschprung disease: theoretical and clinical significance. Pediatrics. 1985 Aug;76(2):299–300. [PubMed]
  • Clausen N, Andersson P, Tommerup N. Familial occurrence of neuroblastoma, von Recklinghausen's neurofibromatosis, Hirschsprung's agangliosis and jaw-winking syndrome. Acta Paediatr Scand. 1989 Sep;78(5):736–741. [PubMed]
  • Goldberg RB, Shprintzen RJ. Hirschsprung megacolon and cleft palate in two sibs. J Craniofac Genet Dev Biol. 1981;1(2):185–189. [PubMed]
  • Hurst JA, Markiewicz M, Kumar D, Brett EM. Unknown syndrome: Hirschsprung's disease, microcephaly, and iris coloboma: a new syndrome of defective neuronal migration. J Med Genet. 1988 Jul;25(7):494–497. [PubMed]
  • Halal F, Morel J. The syndrome of Hirschsprung disease, microcephaly, unusual face, and mental retardation. Am J Med Genet. 1990 Sep;37(1):106–108. [PubMed]
  • Santos H, Mateus J, Leal MJ. Hirschsprung disease associated with polydactyly, unilateral renal agenesis, hypertelorism, and congenital deafness: a new autosomal recessive syndrome. J Med Genet. 1988 Mar;25(3):204–205. [PubMed]
  • Laurence KM, Prosser R, Rocker I, Pearson JF, Richard C. Hirschsprung's disease associated with congenital heart malformation, broad big toes, and ulnar polydactyly in sibs: a case for fetoscopy. J Med Genet. 1975 Dec;12(4):334–338. [PubMed]
  • al-Gazali LI, Donnai D, Mueller RF. Hirschsprung's disease, hypoplastic nails, and minor dysmorphic features: a distinct autosomal recessive syndrome? J Med Genet. 1988 Nov;25(11):758–761. [PubMed]
  • Huang T, Elias ER, Mulliken JB, Kirse DJ, Holmes LB. A new syndrome: heart defects, laryngeal anomalies, preaxial polydactyly, and colonic aganglionosis in sibs. Genet Med. 1999 Mar–Apr;1(3):104–108. [PubMed]
  • Reynolds JF, Barber JC, Alford BA, Chandler JG, Kelly TE. Familial Hirschsprung's disease and type D brachydactyly: a report of four affected males in two generations. Pediatrics. 1983 Feb;71(2):246–249. [PubMed]
  • Reish O, Gorlin RJ, Hordinsky M, Rest EB, Burke B, Berry SA. Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome? Am J Med Genet. 1997 Feb 11;68(4):386–390. [PubMed]
  • Davenport M, Taitz LS, Dickson JA. The Kaufman-McKusick syndrome: another association. J Pediatr Surg. 1989 Nov;24(11):1192–1194. [PubMed]
  • Stone DL, Slavotinek A, Bouffard GG, Banerjee-Basu S, Baxevanis AD, Barr M, Biesecker LG. Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nat Genet. 2000 May;25(1):79–82. [PubMed]
  • Radetti G, Frick R, Pasquino B, Mengarda G, Savage MO. Hypothalamic-pituitary dysfunction and Hirschsprung's disease in the Bardet-Biedl syndrome. Helv Paediatr Acta. 1988 Nov;43(3):249–252. [PubMed]
  • Lorda-Sanchez I, Ayuso C, Ibañez A. Situs inversus and hirschsprung disease: two uncommon manifestations in Bardet-Biedl syndrome. Am J Med Genet. 2000 Jan 3;90(1):80–81. [PubMed]
  • Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green JS, Heon E, Musarella MA, Parfrey PS, Sheffield VC, Biesecker LG. Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet. 2000 Sep;26(1):15–16. [PubMed]
  • Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE, Steiner RD, Porter FD. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998 Jul;63(1):55–62. [PubMed]
  • Waterham HR, Wijburg FA, Hennekam RC, Vreken P, Poll-The BT, Dorland L, Duran M, Jira PE, Smeitink JA, Wevers RA, Wanders RJ. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet. 1998 Aug;63(2):329–338. [PubMed]
  • Patterson K, Toomey KE, Chandra RS. Hirschsprung disease in a 46,XY phenotypic infant girl with Smith-Lemli-Opitz syndrome. J Pediatr. 1983 Sep;103(3):425–427. [PubMed]
  • Mäkitie O, Kaitila I. Cartilage-hair hypoplasia--clinical manifestations in 108 Finnish patients. Eur J Pediatr. 1993 Mar;152(3):211–217. [PubMed]
  • Sulisalo T, Sistonen P, Hästbacka J, Wadelius C, Mäkitie O, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis. Nat Genet. 1993 Apr;3(4):338–341. [PubMed]
  • Mandel H, Brik R, Ludatscher R, Braun J, Berant M. Congenital muscular dystrophy with neurological abnormalities: association with Hirschsprung disease. Am J Med Genet. 1993 Aug 1;47(1):37–40. [PubMed]
  • Kim JJ, Armstrong DD, Fishman MA. Multicore myopathy, microcephaly, aganglionosis, and short stature. J Child Neurol. 1994 Jul;9(3):275–277. [PubMed]
  • Mallory SB, Haynie LS, Williams ML, Hall W. Ichthyosis, deafness, and Hirschsprung's disease. Pediatr Dermatol. 1989 Mar;6(1):24–27. [PubMed]
  • Kaplan P. X linked recessive inheritance of agenesis of the corpus callosum. J Med Genet. 1983 Apr;20(2):122–124. [PubMed]
  • Okamoto N, Wada Y, Goto M. Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM. J Med Genet. 1997 Aug;34(8):670–671. [PubMed]
  • Ikeda K, Goto S. Additional anomalies in Hirschsprung's disease: an analysis based on the nationwide survey in Japan. Z Kinderchir. 1986 Oct;41(5):279–281. [PubMed]
  • Ryan ET, Ecker JL, Christakis NA, Folkman J. Hirschsprung's disease: associated abnormalities and demography. J Pediatr Surg. 1992 Jan;27(1):76–81. [PubMed]
  • Russell MB, Russell CA, Niebuhr E. An epidemiological study of Hirschsprung's disease and additional anomalies. Acta Paediatr. 1994 Jan;83(1):68–71. [PubMed]
  • Sarioglu A, Tanyel FC, Büyükpamukçu N, Hiçsönmez A. Hirschsprung-associated congenital anomalies. Eur J Pediatr Surg. 1997 Dec;7(6):331–337. [PubMed]
  • Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994 Jan 27;367(6461):380–383. [PubMed]
  • Whalen TV, Jr, Asch MJ. Report of two patients with hypertrophic pyloric stenosis and Hirschsprung's disease. Coincident or common etiology? Am Surg. 1985 Aug;51(8):480–481. [PubMed]
  • Sayed M, al-Alaiyan S. Agenesis of corpus callosum, hypertrophic pyloric stenosis and Hirschsprung disease: coincidence or common etiology? Neuropediatrics. 1996 Aug;27(4):204–206. [PubMed]
  • Janik JP, Wayne ER, Janik JS, Price MR. Ileal atresia with total colonic aganglionosis. J Pediatr Surg. 1997 Oct;32(10):1502–1503. [PubMed]
  • Lyonnet S, Bolino A, Pelet A, Abel L, Nihoul-Fékété C, Briard ML, Mok-Siu V, Kaariainen H, Martucciello G, Lerone M, et al. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nat Genet. 1993 Aug;4(4):346–350. [PubMed]
  • Angrist M, Kauffman E, Slaugenhaupt SA, Matise TC, Puffenberger EG, Washington SS, Lipson A, Cass DT, Reyna T, Weeks DE, et al. A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10. Nat Genet. 1993 Aug;4(4):351–356. [PubMed]
  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458–460. [PubMed]
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA., Jr Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851–856. [PubMed]
  • Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fékété C, Ponder BA, Munnich A. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994 Jan 27;367(6461):378–380. [PubMed]
  • Romeo G, Ronchetto P, Luo Y, Barone V, Seri M, Ceccherini I, Pasini B, Bocciardi R, Lerone M, Kääriäinen H, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994 Jan 27;367(6461):377–378. [PubMed]
  • Ceccherini I, Bocciardi R, Luo Y, Pasini B, Hofstra R, Takahashi M, Romeo G. Exon structure and flanking intronic sequences of the human RET proto-oncogene. Biochem Biophys Res Commun. 1993 Nov 15;196(3):1288–1295. [PubMed]
  • Attié T, Pelet A, Edery P, Eng C, Mulligan LM, Amiel J, Boutrand L, Beldjord C, Nihoul-Fékété C, Munnich A, et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995 Aug;4(8):1381–1386. [PubMed]
  • 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. 1995 May;4(5):821–830. [PubMed]
  • Seri M, Yin L, Barone V, Bolino A, Celli I, Bocciardi R, Pasini B, Ceccherini I, Lerone M, Kristoffersson U, Larsson LT, Casasa JM, Cass DT, Abramowicz MJ, Vanderwinden JM, Kravcenkiene I, Baric I, Silengo M, Martucciello G, Romeo G. Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat. 1997;9(3):243–249. [PubMed]
  • Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994 Feb;3(2):237–241. [PubMed]
  • Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JW, van Amstel HK, Romeo G, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994 Jan 27;367(6461):375–376. [PubMed]
  • Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA, Jr, Goodfellow PJ, Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1579–1583. [PubMed]
  • Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381–383. [PubMed]
  • Pasini B, Borrello MG, Greco A, Bongarzone I, Luo Y, Mondellini P, Alberti L, Miranda C, Arighi E, Bocciardi R, et al. Loss of function effect of RET mutations causing Hirschsprung disease. Nat Genet. 1995 May;10(1):35–40. [PubMed]
  • Carlomagno F, De Vita G, Berlingieri MT, de Franciscis V, Melillo RM, Colantuoni V, Kraus MH, Di Fiore PP, Fusco A, Santoro M. Molecular heterogeneity of RET loss of function in Hirschsprung's disease. EMBO J. 1996 Jun 3;15(11):2717–2725. [PubMed]
  • Pelet A, Geneste O, 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. 1998 Mar 15;101(6):1415–1423. [PubMed]
  • Bolk S, Pelet A, Hofstra RM, Angrist M, Salomon R, Croaker D, Buys CH, Lyonnet S, Chakravarti A. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):268–273. [PubMed]
  • Borrego S, Sáez ME, Ruiz A, Gimm O, López-Alonso M, Antiñolo G, Eng C. Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. J Med Genet. 1999 Oct;36(10):771–774. [PubMed]
  • Borrego S, Ruiz A, Saez ME, Gimm O, Gao X, López-Alonso M, Hernández A, Wright FA, Antiñolo G, Eng C. RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease. J Med Genet. 2000 Aug;37(8):572–578. [PubMed]
  • Moore MW, Klein RD, Fariñas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver-Moore K, Rosenthal A. Renal and neuronal abnormalities in mice lacking GDNF. Nature. 1996 Jul 4;382(6586):76–79. [PubMed]
  • Sánchez MP, Silos-Santiago I, Frisén J, He B, Lira SA, Barbacid M. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature. 1996 Jul 4;382(6586):70–73. [PubMed]
  • Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, Westphal H. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996 Jul 4;382(6586):73–76. [PubMed]
  • Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M, et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature. 1996 Jun 27;381(6585):789–793. [PubMed]
  • Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell. 1996 Jun 28;85(7):1113–1124. [PubMed]
  • Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock RA, Hefti F, Phillips HS, Goddard A, Moore MW, Buj-Bello A, Davies AM, Asai N, Takahashi M, Vandlen R, Henderson CE, Rosenthal A. Characterization of a multicomponent receptor for GDNF. Nature. 1996 Jul 4;382(6586):80–83. [PubMed]
  • Rosenthal A. The GDNF protein family: gene ablation studies reveal what they really do and how. Neuron. 1999 Feb;22(2):201–203. [PubMed]
  • Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson EM, Jr, Milbrandt J. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature. 1996 Dec 5;384(6608):467–470. [PubMed]
  • Milbrandt J, de Sauvage FJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG, Lampe PA, Heuckeroth RO, Kotzbauer PT, Simburger KS, Golden JP, Davies JA, Vejsada R, Kato AC, Hynes M, Sherman D, Nishimura M, Wang LC, Vandlen R, Moffat B, Klein RD, Poulsen K, Gray C, Garces A, Johnson EM, Jr, et al. Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron. 1998 Feb;20(2):245–253. [PubMed]
  • Baloh RH, Tansey MG, Lampe PA, Fahrner TJ, Enomoto H, Simburger KS, Leitner ML, Araki T, Johnson EM, Jr, Milbrandt J. Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. Neuron. 1998 Dec;21(6):1291–1302. [PubMed]
  • Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996 Nov;14(3):341–344. [PubMed]
  • Ivanchuk SM, Myers SM, Eng C, Mulligan LM. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Hum Mol Genet. 1996 Dec;5(12):2023–2026. [PubMed]
  • Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attié T, Bachy B, Munnich A, Lyonnet S. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998 Sep;7(9):1449–1452. [PubMed]
  • Cacalano G, Fariñas I, Wang LC, Hagler K, Forgie A, Moore M, Armanini M, Phillips H, Ryan AM, Reichardt LF, Hynes M, Davies A, Rosenthal A. GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron. 1998 Jul;21(1):53–62. [PubMed]
  • Enomoto H, Araki T, Jackman A, Heuckeroth RO, Snider WD, Johnson EM, Jr, Milbrandt J. GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron. 1998 Aug;21(2):317–324. [PubMed]
  • Angrist M, Jing S, Bolk S, Bentley K, Nallasamy S, Halushka M, Fox GM, Chakravarti A. Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics. 1998 Mar 15;48(3):354–362. [PubMed]
  • Myers SM, Salomon R, Goessling A, Pelet A, Eng C, von Deimling A, Lyonnet S, Mulligan LM. Investigation of germline GFR alpha-1 mutations in Hirschsprung disease. J Med Genet. 1999 Mar;36(3):217–220. [PubMed]
  • Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2863–2867. [PubMed]
  • Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Trends Pharmacol Sci. 1992 Mar;13(3):103–108. [PubMed]
  • Cohen IT, Gadd MA. Hirschsprung's disease in a kindred: a possible clue to the genetics of the disease. J Pediatr Surg. 1982 Oct;17(5):632–634. [PubMed]
  • Van Camp G, Van Thienen MN, Handig I, Van Roy B, Rao VS, Milunsky A, Read AP, Baldwin CT, Farrer LA, Bonduelle M, et al. Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q. J Med Genet. 1995 Jul;32(7):531–536. [PubMed]
  • Kiss P, Osztovics M. Association of 13q deletion and Hirschsprung's disease. J Med Genet. 1989 Dec;26(12):793–794. [PubMed]
  • Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, 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. 1994 Dec 30;79(7):1267–1276. [PubMed]
  • Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell. 1994 Dec 30;79(7):1277–1285. [PubMed]
  • Bidaud C, Salomon R, Van Camp G, Pelet A, Attié T, Eng C, Bonduelle M, Amiel J, Nihoul-Fékété C, Willems PJ, Munnich A, Lyonnet S. Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease. Eur J Hum Genet. 1997 Jul–Aug;5(4):247–251. [PubMed]
  • Chakravarti A. Endothelin receptor-mediated signaling in hirschsprung disease. Hum Mol Genet. 1996 Mar;5(3):303–307. [PubMed]
  • Amiel J, Attié T, Jan D, Pelet A, Edery P, Bidaud C, Lacombe D, Tam P, Simeoni J, Flori E, Nihoul-Fékété C, Munnich A, Lyonnet S. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet. 1996 Mar;5(3):355–357. [PubMed]
  • Kusafuka T, Wang Y, Puri P. Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease. Hum Mol Genet. 1996 Mar;5(3):347–349. [PubMed]
  • Auricchio A, Casari G, Staiano A, Ballabio A. Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Hum Mol Genet. 1996 Mar;5(3):351–354. [PubMed]
  • Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, de Wit D, Emoto N, Hammer RE. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development. 1998 Mar;125(5):825–836. [PubMed]
  • Hofstra RM, Valdenaire O, Arch E, Osinga J, Kroes H, Löffler BM, Hamosh A, Meijers C, Buys CH. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am J Hum Genet. 1999 Jan;64(1):304–308. [PubMed]
  • Lane PW, Liu HM. Association of megacolon with a new dominant spotting gene (Dom) in the mouse. J Hered. 1984 Nov–Dec;75(6):435–439. [PubMed]
  • Herbarth B, Pingault V, Bondurand N, Kuhlbrodt K, Hermans-Borgmeyer I, Puliti A, Lemort N, Goossens M, Wegner M. Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5161–5165. [PubMed]
  • Southard-Smith EM, Angrist M, Ellison JS, Agarwala R, Baxevanis AD, Chakravarti A, Pavan WJ. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res. 1999 Mar;9(3):215–225. [PubMed]
  • Auricchio A, Griseri P, Carpentieri ML, Betsos N, Staiano A, Tozzi A, Priolo M, Thompson H, Bocciardi R, Romeo G, Ballabio A, Ceccherini I. Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. Am J Hum Genet. 1999 Apr;64(4):1216–1221. [PubMed]
  • Potterf SB, Furumura M, Dunn KJ, Arnheiter H, Pavan WJ. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Hum Genet. 2000 Jul;107(1):1–6. [PubMed]
  • Southard-Smith EM, Kos L, Pavan WJ. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet. 1998 Jan;18(1):60–64. [PubMed]
  • Hall CM. Werner's mesomelic dysplasia with ventricular septal defect and Hirschsprung's disease. Pediatr Radiol. 1981;10(4):247–249. [PubMed]
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