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.
Subject(s)
Drosophila Proteins , Hirschsprung Disease/genetics , Hydrocephalus/genetics , Membrane Glycoproteins/genetics , Neural Cell Adhesion Molecules/genetics , Female , Genetic Linkage , Hirschsprung Disease/diagnostic imaging , Humans , Hydrocephalus/diagnostic imaging , Infant, Newborn , Leukocyte L1 Antigen Complex , Magnetic Resonance Imaging , Male , Mutation , Mutation, Missense , 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 ChromosomeABSTRACT
OBJECTIVE: Discuss the capability for and limitations of prenatal detection of L1 cell adhesion molecule (L1CAM) mutations. METHODS: Haplotype analysis by PCR and PAGE. Mutation detection by SSCP, followed by dideoxy sequencing. Confirmation of sequencing results with PCR and NcoI digestion. RESULTS: A 1-bp deletion was found in exon 2 of L1CAM in all affected males and obligate carriers in the pedigree. Prenatal detection is now possible for subsequent pregnancies. CONCLUSION: In a large gene with widespread mutations such as L1CAM, a mutation must be detected in another family member before direct prenatal mutation testing can be done within the required timeframe. If the proper family members are available, haplotyping offers a fast but indirect test with several limitations.
