Complex pathogenesis of Hirschsprung's disease in a patient with hydrocephalus, vesico-ureteral reflux and a balanced translocation t(3;17)(p12;q11)

Eur J Hum Genet. 2009 Apr;17(4):483-90. doi: 10.1038/ejhg.2008.191. Epub 2008 Oct 29.


Hirschsprung's disease (HSCR), a congenital complex disorder of intestinal innervation, is often associated with other inherited syndromes. Identifying genes involved in syndromic HSCR cases will not only help understanding the specific underlying diseases, but it will also give an insight into the development of the most frequent isolated HSCR. The association between hydrocephalus and HSCR is not surprising as a large number of patients have been reported to show the same clinical association, most of them showing mutations in the L1CAM gene, encoding a neural adhesion molecule often involved in isolated X-linked hydrocephalus. L1 defects are believed to be necessary but not sufficient for the occurrence of the intestinal phenotype in syndromic cases. In this paper, we have carried out the molecular characterization of a patient affected with Hirschsprung's disease and X-linked hydrocephalus, with a de novo reciprocal balanced translocation t(3;17)(p12;q21). In particular, we have taken advantage of this chromosomal defect to gain access to the predisposing background possibly leading to Hirschsprung's disease. Detailed analysis of the RET and L1CAM genes, and molecular characterization of MYO18A and TIAF1, the genes involved in the balanced translocation, allowed us to identify, besides the L1 mutation c.2265delC, different additional factors related to RET-dependent and -independent pathways which may have contributed to the genesis of enteric phenotype in the present patient.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Child
  • Chromosomes, Human, Pair 17 / genetics*
  • Chromosomes, Human, Pair 3 / genetics*
  • Hirschsprung Disease / genetics*
  • Hirschsprung Disease / pathology
  • Humans
  • Hydrocephalus / genetics*
  • Hydrocephalus / pathology
  • Male
  • Molecular Sequence Data
  • Neural Cell Adhesion Molecule L1 / genetics
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • Translocation, Genetic / genetics*
  • Vesico-Ureteral Reflux / genetics*
  • Vesico-Ureteral Reflux / pathology


  • Neural Cell Adhesion Molecule L1
  • Proto-Oncogene Proteins c-ret
  • RET protein, human