Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation

Mutations in the human sonic hedgehog gene (SHH) are the most frequent cause of autosomal dominant inherited holoprosencephaly (HPE), a complex brain malformation resulting from incomplete cleavage of the developing forebrain into two separate hemispheres and ventricles. Here we report the clinical and molecular findings in five unrelated patients with HPE and their relatives with an identified SHH mutation. Three new and one previously reported SHH mutations were identified, a fifth proband was found to carry a reciprocal subtelomeric rearrangement involving the SHH locus in 7q36. An extremely wide intrafamilial phenotypic variability was observed, ranging from the classical phenotype with alobar HPE accompanied by typical severe craniofacial abnormalities to very mild clinical signs of choanal stenosis or solitary median maxillary central incisor (SMMCI) only. Two families were initially ascertained because of microcephaly in combination with developmental delay and/or mental retardation and SMMCI, the latter being a frequent finding in patients with an identified SHH mutation. In other affected family members a delay in speech acquisition and learning disabilities were the leading clinical signs.

Conclusion: mutational analysis of the sonic hedgehog gene should not only be considered in patients presenting with the classical holoprosencephaly phenotype but also in those with two or more clinical signs of the wide phenotypic spectrum of associated abnormalities, especially in combination with a positive family history.