title: Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?
abstract: 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.
authors.affiliation: Division of Genetics and Development, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA. mparisi@u.washington.edu
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Parisi
authors.forename: Raj P
authors.initials: RP
authors.lastname: Kapur
authors.forename: Ian
authors.initials: I
authors.lastname: Neilson
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Lynda W
authors.initials: LW
authors.lastname: Holloway
authors.forename: Ron C
authors.initials: RC
authors.lastname: Michaelis
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Leppig
mesh_terms: D029721:Drosophila Proteins; D005260:Female; D008040:Genetic Linkage; D006627:Hirschsprung Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D006849:Hydrocephalus / Q000000981:diagnostic imaging / Q000235:genetics*; D007231:Infant, Newborn; D039841:Leukocyte L1 Antigen Complex; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D019006:Neural Cell Adhesion Molecules / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D011859:Radiography; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D025064:Sex Chromosome Disorders / Q000000981:diagnostic imaging / Q000235:genetics; D014960:X Chromosome
chemical_list: D029721:Drosophila Proteins; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila