Pediatric Surgery International

, Volume 21, Issue 12, pp 960–963 | Cite as

Novel mutation of Endothelin-B receptor gene in Waardenburg–Hirschsprung disease

  • Surasak Sangkhathat
  • Piyawan Chiengkriwate
  • Takeshi Kusafuka
  • Sakda Patrapinyokul
  • Masahiro Fukuzawa
Original Article


Homozygous mutations of EDNRB in human have been reported to result in Waardenburg–Hirschsprung disease (WS4), while mutated heterozygotes manifested isolated Hirschsprung disease in lower penetrance. We investigated a case of WS4 together with all members of her nuclear family for the alteration of the EDNRB gene by using PCR–SSCP and direct sequencing technique. The index patient, who was born to a family with no history of Hirschsprung disease, presented total colonic aganglionosis with small bowel extension, sensorineural hearing loss and generalized cutaneous pigmentary defects. Interestingly, both irides were normally black. The study detected a homozygous missense mutation at codon 196 in exon 2 (Ser196Asn), which has not been reported. Both parents and four in six siblings harbored heterozygous mutation without any clinical manifestation. Our findings were consistent with previous observations that full spectrum of WS4 occurred to the mutate homozygotes. Moreover, the non-penetrance of heterozygotes in our pedigree, which differs from other reports, demonstrates the high pleiotropic effect of EDNRB mutations in human.


Waardenburg–Hirschsprung disease Waardenburg–Shah syndrome EDNRB mutation 


  1. 1.
    Shah KN, Dalal SJ, Desai MP et al (1981) White forelock, pigmentary disorder of irides, and long segment Hirshsprung’s disease: possible variant of Waardenburg syndrome. J Pediatr 99:432–435PubMedCrossRefGoogle Scholar
  2. 2.
    Badner JA, Chakravarti A (1990) Waardenburg syndrome and Hirschsprung disease: evidence for pleiotropic effects of a single dominant gene. Am J Med Genet 35:100–104CrossRefPubMedGoogle Scholar
  3. 3.
    Read AP, Newton VE (1997) Waardenburg syndrome. J Med Genet 34:656–665PubMedCrossRefGoogle Scholar
  4. 4.
    Puffenberger EG, Hosoda K, Washington SS et al (1994) A missense mutation of the endothelin-B receptor in multigenic Hirschsprung’s disease. Cell 79:1257–1266CrossRefPubMedGoogle Scholar
  5. 5.
    Attie T, Till M, Pelet A et al (1995) Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet 4:2407–2409PubMedCrossRefGoogle Scholar
  6. 6.
    Broadman JP, Syrris P, Holder SE et al (2001) A novel mutation in the endothelin B receptor gene in a patient with Shah-Waardenberg syndrome and Down syndrome. J Med Genet 38:646–647CrossRefPubMedGoogle Scholar
  7. 7.
    Edery P, Attie T, Amiel J et al (1996) Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 12:442–444CrossRefPubMedGoogle Scholar
  8. 8.
    Hofstra RM, Osinga J, Tan-Sindhunata G et al (1996) A homozygous mutation in the endothelin-3 gene associated with a combined Waardenberg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet 12:445–447CrossRefPubMedGoogle Scholar
  9. 9.
    Pingault V, Bondurand N, Kuhlbrodt K et al (1998) SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet 18:171–173CrossRefPubMedGoogle Scholar
  10. 10.
    Mccallion AS, Chakravarti A (2001) EDNRB/EDN3 and Hirschsprung disease type II. Pigment Cell Res 14:161–169CrossRefPubMedGoogle Scholar
  11. 11.
    Kusafuka T, Wang Y, Puri P (1997) Mutation analysis of the RET, the endothelin-B receptor and the endothelin-3 genes in sporadic cases of Hirschsprung’s disease. J Pediatr Surg 32:501–504CrossRefPubMedGoogle Scholar
  12. 12.
    Inoue M, Hosoda K, Imura K et al (1998) Mutational analysis of the endothelin-B receptor gene in Japanese Hirschsprung’s disease. J Pediatr Surg 33:1206–1208CrossRefPubMedGoogle Scholar
  13. 13.
    Hosoda K, Hammer RE, Richardson JA et al (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79:1267–1276CrossRefPubMedGoogle Scholar
  14. 14.
    Baynash AG, Hosoda K, Giaid A et al (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79:1277–1285CrossRefPubMedGoogle Scholar
  15. 15.
    Kusafuka T, Wang Y, Puri P (1996) Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung’s disease. Hum Mol Genet 5:347–349CrossRefPubMedGoogle Scholar
  16. 16.
    Puffernberger EG, Kauffmann ER, Bolk S et al (1994) Identity-by-descent and association of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet 2:1217–1225CrossRefGoogle Scholar
  17. 17.
    Amiel J, Attie T, Jan D et al (1996) Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 5:355–357CrossRefPubMedGoogle Scholar
  18. 18.
    Syrris P, Carter ND, Patton MA (1999) Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease. Am J Med Genet 87:69–71CrossRefPubMedGoogle Scholar
  19. 19.
    Shanske A, Ferreira JC, Leonard JC et al (2001) Hirschsprung disease in an infant with a contiguous gene syndrome of chromosome 13. Am J Med Genet 102:231–236CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Surasak Sangkhathat
    • 1
    • 2
  • Piyawan Chiengkriwate
    • 2
  • Takeshi Kusafuka
    • 1
  • Sakda Patrapinyokul
    • 2
  • Masahiro Fukuzawa
    • 1
  1. 1.Department of Pediatric SurgeryOsaka University Graduate School of Medicine OsakaJapan
  2. 2.Pediatric Surgery Unit, Department of Surgery, Faculty of MedicinePrince of Songkla UniversityHadyaiThailand

Personalised recommendations