Greig cephalopolysyndactyly syndrome (GCPS)

AD; GLI3 (zinc finger transcription factor in Sonic Hedgehog pathway). Most variants are loss-of-function (truncating mutations or large deletions). Different GLI3 mutations cause:

• Greig cephalopolysyndactyly (GCPS): typically loss-of-function variants in the N- or C-terminus
• Pallister-Hall syndrome (PHS): frameshift/truncating variants in the middle third of GLI3
• Postaxial polydactyly type A: isolated digit anomalies, missense variants

The GLI3 mutational territory determines which syndrome you get.

• Cephalo: macrocephaly, frontal bossing, mild hypertelorism, broad forehead
• Poly: preaxial polydactyly of the feet (duplicated hallux, the most consistent finding) + postaxial polydactyly of the hands
• Syndactyly: soft-tissue webbing, especially between fingers 3-4 and toes 1-2
• Normal intellect (usually); distinguishes from Pallister-Hall
• Corpus callosum agenesis in some

• Clinical (macrocephaly + the polydactyly pattern is highly characteristic)
• GLI3 sequencing + deletion/duplication analysis
• Distinguishing from Pallister-Hall: PHS has hypothalamic hamartoma, central polydactyly, often imperforate anus, more severe cognition

• Pallister-Hall syndrome: same gene, more severe; hypothalamic hamartoma + central polydactyly + bifid epiglottis
• Acrocallosal syndrome: macrocephaly + polydactyly + ACC + intellectual disability; KIF7
• Carpenter syndrome: craniosynostosis + polysyndactyly; RAB23 (AR)

• Hand/foot surgery for polydactyly and syndactyly
• Brain MRI to exclude corpus callosum anomalies
• Developmental monitoring
• Genetic counseling: AD, ~50% recurrence; expressivity variable so parental exam matters