Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality

J Pediatr Surg. 2002 Aug;37(8):1117-22. doi: 10.1053/jpsu.2002.34455.


Background/purpose: The aim of this report is to describe the pattern of similarities among the patients, exemplifying a newly recognized form of Hirschsprung's disease (HSCR) caused by mutations of ZFHX1B encoding Smad interacting protein-1.

Methods: Fluorescence in situ hybridization (FISH) using several cDNAs and RP11-BAC clones and mutation gene scanning using direct nucleotide sequencing analysis of polymerase chain reaction (PCR) were conducted. Personal records of the patients also were analyzed retrospectively to confirm the clinical features.

Results: All the patients represented isolated cases without any familial tendency. Aganglionic segments were limited to the recto-sigmoid colon in 3 cases and the rectum in one. Chromosomal screening found normal karyotypes in all cases except one, in whom a translocation between chromosomes 2 and 13 was detected. In addition to HSCR, characteristic facial appearance (hypertelorism with strabismus and wide nasal bridge), microcephaly with epilepsy, and severe physical and mental disabilities were found in all the patients. FISH for the patient having the chromosomal abnormality showed that about a 5-Mb cytogenetic deletion flanked at the 2q22 translocation breakpoint. Among 3 genes mapping to this deleted region, 2 nonsense mutations and a 4-base pair deletion were detected in ZFHX1B.

Conclusions: The clinical features of the patients have surprising resemblance and constitute a wide spectrum of neurocristopathies. These findings suggest that the ZFHX1B may be a very important gene for normal embryonic neural crest development. These also indicate that the HSCR can be regarded as a congenital malformation with a background of a multigenetic neurocristopathy. It is of great interest that mutations were located at the same spot (exon 8) of ZFHX1B in 3 of 4 cases, probably accounting for the unique clinical features of this newly recognized form of HSCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Chromosome Mapping
  • Chromosomes, Human, Pair 13
  • Chromosomes, Human, Pair 2
  • Codon, Nonsense*
  • DNA-Binding Proteins / metabolism
  • Female
  • Hirschsprung Disease / diagnosis*
  • Hirschsprung Disease / genetics*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Infant, Newborn
  • Male
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Retrospective Studies
  • Sequence Deletion*
  • Smad Proteins
  • Trans-Activators / metabolism
  • Translocation, Genetic
  • Zinc Finger E-box Binding Homeobox 2


  • Codon, Nonsense
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Repressor Proteins
  • Smad Proteins
  • Trans-Activators
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2