SHH and holoprosencephaly: Particular attention may be given to Shh-associated congenital malformations, including OFCs, holoprosencephaly, and hypospadias, that are often etiologically complex and difficult to model in in vitro systems (Murray, 2002; Carmichael et al., 2012; Krauss and Hong, 2016; Beames and Lipinski, 2020).