Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation
- 24 April 2004
- journal article
- case report
- Published by Springer Science and Business Media LLC in European Journal of Pediatrics
- Vol. 163 (7), 347-352
- https://doi.org/10.1007/s00431-004-1459-0
Abstract
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.Keywords
This publication has 16 references indexed in Scilit:
- Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephalyHuman Genetics, 2001
- Sonic Hedgehog Control of Size and Shape in Midbrain Pattern FormationScience, 2001
- Mutations in holoprosencephalyHuman Mutation, 2000
- Segregation analysis in nonsyndromic holoprosencephalyAmerican Journal of Medical Genetics, 1998
- Mutations in the C-Terminal Domain of Sonic Hedgehog Cause HoloprosencephalyHuman Molecular Genetics, 1997
- Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephalyHuman Genetics, 1997
- Mutations in the human Sonic Hedgehog gene cause holoprosencephalyNature Genetics, 1996
- Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene functionNature, 1996
- Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarityCell, 1993
- Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromologyTeratology, 1989