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

An unusual combination of syndactylies, macrocephaly, and severe skeletal d ysplasia was observed in a newborn infant. A history of digital anomalies i n 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 typ e II collagen disorder. Molecular analysis confirmed the presence of two do minant mutations in the propositus: a GL13 mutation (E543X), which was pres ent also in the father and grandfather, and a de novo COL2A1 mutation leadi ng to a G973R substitution. Thus, this boy combined the syndactyly-macrocep haly phenotype of Greig cephalosyndactyly syndrome with a severe form of sp ondyloepiphyseal dysplasia caused by the structural defect in type II colla gen. The diagnostic difficulties posed by the combination of two genetic di sorders and the contribution of molecular diagnostics are well illustrated by this case. (C) 2000 Wiley-Liss, Inc.