X-linked hydrocephalus (XLH) has an incidence of 1/30,000 male births and is 
characterized by intellectual disability, spastic paraplegia, adducted thumbs, 
and agenesis of corpus callosum, and/or corticospinal tract. The great 
proportion of cases is ascribed to loss of function mutations of L1CAM gene. 
Hirschsprung disease (HSCR) is characterized by the absence of ganglion cells in 
the submucosal and myenteric plexuses along a variable portion of the intestinal 
tract and has incidence of about 1/5,000. Although with several genes involved 
in its pathogenesis, the major HSCR gene is the RET proto-oncogene. To date only 
a few patients have been reported with both phenotypes and mutations in the 
L1CAM gene. In this report, we describe a new patient with concurrent XLH and 
HSCR. L1CAM mutational screening showed the presence of the G698R hemizygous 
mutation, which is a deleterious substitution affecting a key residue necessary 
for the correct folding of the protein. Moreover, the patient also carried the 
transcriptional enhancer RET mutation (c.73 + 9277T > C) in heterozygosis. We 
speculate that both the RET enhancer variant, and the L1CAM mutation may act in 
combination to produce the enteric phenotype, probably with the participation of 
other still unidentified molecular events. While it is obvious that additional 
studies are necessary to further delineate the association between XLH and HSCR 
in the presence of L1CAM mutations, the documentation of this new patient 
reinforces the role of this gene acting either in a direct or indirect way in 
the pathogenesis of Hirschsprung disease.