Holoprosencephaly (HPE) is the most common developmental defect of the forebrain 
characterized by inadequate or absent midline division of the forebrain into 
cerebral hemispheres, with concomitant midline facial defects in the majority of 
cases. Understanding the pathogenesis of HPE requires knowledge of the 
relationship between the developing brain and the facial structures during 
embryogenesis. A number of signaling pathways control and coordinate the 
development of the brain and face, including Sonic hedgehog, Bone morphogenetic 
protein, Fibroblast growth factor, and Nodal signaling. Mutations in these 
pathways have been identified in animal models of HPE and human patients. 
Because of incomplete penetrance and variable expressivity of HPE, patients 
carrying defined mutations may not manifest the disease at all, or have a 
spectrum of defects. It is currently unknown what drives manifestation of HPE in 
genetically at-risk individuals, but it has been speculated that other gene 
mutations and environmental factors may combine as cumulative insults. HPE can 
be diagnosed in utero by a high-resolution prenatal ultrasound or a fetal 
magnetic resonance imaging, sometimes in combination with molecular testing from 
chorionic villi or amniotic fluid sampling. Currently, there are no effective 
preventive methods for HPE. Better understanding of the mechanisms of 
gene-environment interactions in HPE would provide avenues for such 
interventions.