SHH and holoprosencephaly: In agreement with its expression pattern, shh is important in foregut development [32] and critically involved in patterning of the distal elements of the limbs [28,33,34,35], however, mutations in Shh classically lead to defects in midline structures, particularly the face and eyes, and a lack of hemisphere separation of the brain, a disorder termed holoprosencephaly (HPE) [36,37,38,39].