title: Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Gynaecological Endocrinology, Reproductive Medicine and Human Genetics, Hemauerstrasse 1, 93047 Regensburg, Germany. ute.hehr@humangenetik-regensburg.de
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.forename: Claudia
authors.initials: C
authors.lastname: Gross
authors.forename: Uta
authors.initials: U
authors.lastname: Diebold
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wahl
authors.forename: Ulrike
authors.initials: U
authors.lastname: Beudt
authors.forename: Peter
authors.initials: P
authors.lastname: Heidemann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hehr
authors.forename: Dietmar
authors.initials: D
authors.lastname: Mueller
mesh_terms: D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D015534:Trans-Activators