Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?

Am J Med Genet. 2002 Feb 15;108(1):51-6. doi: 10.1002/ajmg.10185.


Congenital hydrocephalus associated with aqueductal stenosis and/or agenesis of the corpus callosum has been described in newborn males with mutations in L1CAM, a gene that encodes a neural cell adhesion molecule. These males usually have severe mental retardation and may have spastic paraplegia and adducted thumbs. In contrast, Hirschsprung disease, or absence of ganglion cells in the distal gut, has rarely been described in such individuals. We report a male infant who had severe hydrocephalus identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene revealed a G2254A mutation, resulting in a V752M amino acid substitution. A common polymorphism in RET, but no mutation, was identified. Our patient represents the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. We hypothesize that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Drosophila Proteins*
  • Female
  • Genetic Linkage
  • Hirschsprung Disease / diagnostic imaging
  • Hirschsprung Disease / genetics*
  • Humans
  • Hydrocephalus / diagnostic imaging
  • Hydrocephalus / genetics*
  • Infant, Newborn
  • Leukocyte L1 Antigen Complex
  • Magnetic Resonance Imaging
  • Male
  • Membrane Glycoproteins / genetics*
  • Mutation
  • Mutation, Missense
  • Neural Cell Adhesion Molecules / genetics*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-ret
  • Radiography
  • Receptor Protein-Tyrosine Kinases / genetics
  • Sex Chromosome Disorders / diagnostic imaging
  • Sex Chromosome Disorders / genetics
  • X Chromosome


  • Drosophila Proteins
  • Leukocyte L1 Antigen Complex
  • Membrane Glycoproteins
  • Neural Cell Adhesion Molecules
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila