That a morphogenetic continuum links the different facial aspects of holoprosencephaly, from cyclopia to the single median incisor malformation, has been suspected for a long time, although no clear explanation has been proposed until now. Each of the morphogenetic steps of holoprosencephaly can actually be seen as a replaying life’s tape experiment, with the same injury occurring at slightly different time points during the formation of the eyes and the nose. Thus, to understand the spectrum of midfacial malformations associated with holoprosencephaly from an evo-devo point of view, one must recall that (1) the eyes develop from a single morphogenetic field which is split into two lateral eye primordia by an evagination of the primitive brain, (2) the first morphologic evidence of the olfactory nose appears later than the eyes, and (3) the nose was first an exclusively olfactory organ, which became also the upper part of the air-breathing system with the secondary formation of a respiratory nose between palate and skull base.
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