Test Directory

GLI3 related disorders - Greig cephalopolysyndactyly syndrome (GCPS; MIM 175700), Pallister-Hall syndrome (PHS: MIM 146510), polydactyly, postaxial, type A1 (PAPA1; MIM 174200) and polydactyly, preaxial IV (MIM 174700) are allelic, autosomal dominant disorders caused by mutations in the GLI3 gene. GLI3 encodes a zinc finger transcription factor.

GCPS has variable clinical findings. The primary findings in GCPS include polysyndactyly, macrocephaly and hypertelorism. Polydactyly may occur in any limb with postaxial polydactyly of the hands and preaxial polydactyly of the feet being observed most frequently. Less common findings include inguinal, umbilical or diaphragmatic hernia, craniosynostosis, downslanting palpebral fissures and rare instances of mental retardation and agenesis of the corpus callosum. It has been stressed that not all GCPS patients have the typical findings and that the presentation may be quite subtle. GCPS is caused by loss of function mutations in GLI3. These include rare translocations, small and large deletions, small and large insertions, nonsense, missense and splicing mutations. More than 75% of patients with GCPS are expected to have a definable GLI3 mutation.

PHS is a pleiotropic disorder characterized by hypothalamic hamartoma, mesoaxial (central) polydactyly or postaxial polydactyly and bifid epiglottis. Many additional findings have been reported in PHS including: imperforate anus, nail hypoplasia, genital hypoplasia, dental hypoplasia, developmental delay, kidney dysplasia or dysfunction, hypothyroidism and hormonal abnormalities. Significant inter- and intrafamilial variation is observed in PHS. PHS seems to be caused by truncating mutations in GLI3. These include, small insertions, duplications and deletions, splice site and nonsense mutations. At least 90-95% of PHS patients are expected to have a detectable GLI3 mutation.

PAPA1 includes postaxial, polydactyly type B (PAPB). In PAPA1 the extra digit is well formed and articulates with the fifth or an extra metacarpal. In PAPB the extra digit is not well formed and may be represented by a skin tag. Both PAPA1 and PAPB have been reported in the same pedigrees. Postaxial polydactyly types A1 and B are reported to be about 10 times more common in African Americans than in Caucasians.

Polydactyly, preaxial IV is characterized by mild thumb duplication, variable syndactyly of the 3rd and 4th fingers, partial or complete duplication of the 1st or 2nd toes and syndactyly of all toes. Polydactyly, preaxial IV is probably synonymous with crossed polydactyly type 1. Phenotypic variation has been observed in polydactyly, preaxial pedigrees with defined GLI3 mutations.