HOLOPROSENCEPHALY - FROM HOMER TO HEDGEHOG

Holoprosencephaly (HPE), a common developmental defect affecting the f orebrain and face, is etiologically heterogeneous and exhibits wide ph enotypic variation. Graded degrees of severity of the brain malformati on are also reflected in the highly variable craniofacial malformation s associated with HPE. In addition, Individuals with microforms of HPE , who usually have normal cognition and normal brain imaging, are at r isk for having children with HPE. Some obligate carriers fbr HPE may n ot have any phenotypic abnormalities. Recurrent chromosomal rearrangem ents in individuals with HPE suggest loci containing genes important f or brain development, and abnormalities in these genes may result in H PE, Recently, Sonic Hedgehog (SHH) was the first gene identified as ca using HPE in humans. Proper function of SHH depends on cholesterol mod ification. Other candidate genes that may be involved in HPE include c omponents of the SHH pathway, elements involved in cholesterol metabol ism, and genes expressed in the: developing forebrain.