Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual

Am J Med Genet. 2000 Jan 31;90(3):239-42.


An unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia was observed in a newborn infant. A history of digital anomalies in the father and grandfather lead to the diagnosis of dominantly inherited Greig cephalopolysyndactyly syndrome (GCPS, MIM #175700). Having explained the digital findings and macrocephaly, the skeletal changes were thought to fit best congenital spondyloepiphyseal dysplasia (SEDC MIM #183900), a type II collagen disorder. Molecular analysis confirmed the presence of two dominant mutations in the propositus: a GLI3 mutation (E543X), which was present also in the father and grandfather, and a de novo COL2A1 mutation leading to a G973R substitution. Thus, this boy combined the syndactyly-macrocephaly phenotype of Greig cephalosyndactyly syndrome with a severe form of spondyloepiphyseal dysplasia caused by the structural defect in type II collagen. The diagnostic difficulties posed by the combination of two genetic disorders and the contribution of molecular diagnostics are well illustrated by this case.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Collagen / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Genes, Dominant*
  • Humans
  • Infant
  • Kruppel-Like Transcription Factors
  • Lod Score
  • Male
  • Nerve Tissue Proteins*
  • Osteochondrodysplasias / genetics
  • Pedigree
  • Point Mutation*
  • Repressor Proteins*
  • Skull / abnormalities
  • Transcription Factors / genetics*
  • Xenopus Proteins*
  • Zinc Finger Protein Gli3


  • DNA-Binding Proteins
  • GLI3 protein, Xenopus
  • GLI3 protein, human
  • Gli3 protein, mouse
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Repressor Proteins
  • Transcription Factors
  • Xenopus Proteins
  • Zinc Finger Protein Gli3
  • Collagen