Holoprosencephaly (HPE; MIM #236100) is the most frequent congenital brain malformation (1 in 10,000 live births, 1 in 250 conceptuses). It results from incomplete midline division of the prosencephalon between 18th and 28th day of gestation, affecting both the forebrain and the face. The clinical spectrum is very wide, ranging from severe HPE with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial HPE. Three classic anatomical classes have been described, in decreasing order of severity: alobar, semi-lobar, and lobar HPE. The full spectrum of HPE also includes middle interhemispheric variants (MIH) or syntelencephaly, septopreoptic HPE and microforms characterized by midline defects (e.g., single maxillary median incisor (SMMI) or hypotelorism) without the brain malformations typical of HPE.
GLI2 mutations were initially found in patients with HPE, and those patients were noted to have polydactyly, midfacial and/or pituitary abnormalities as well. Therefore GLI2 mutations were screened in patients with polydactyly and/or pituitary anomalies and it was shown that most often the phenotype includes anterior pituitary anomalies and postaxial polydactyly, although not all individuals with predicted pathogenic mutations have both findings. A common facial phenotype was seen in individuals corresponding to midface hypoplasia, cleft lip/palate and hypotelorism (holoprosencephaly-like features or microform).