Alx3 −/− embryos from diabetic pregnancies showed an even higher proportion of craniofacial malformations (Table 2, superscript b). These malformations were considerably more severe than those observed in Alx3 +/− embryos, generating clearly dysmorphic embryos (Fig. 2G,H). In contrast, the proportion of caudal malformations was not significantly different from those found in heterozygote or wild type embryos from diabetic mothers (Table 2). When compared with non-diabetic pregnancies, maternal diabetes significantly increased the number of Alx3 −/− embryos with severe craniofacial malformations (Table 2, superscript c). Remarkably, the proportion of craniofacial malformations in Alx3 +/− or Alx3 −/− embryos from diabetic pregnancies was considerably higher than expected if the effects of diabetes and Alx3 deficiency were additive (Table 2, superscripts d and e, respectively). A similar result was obtained when the proportion of total malformations (craniofacial and caudal together) was considered for each genotype (Table 2, superscripts f and g). In summary, craniofacial malformations due to Alx3 inactivation or haploinsufficiency increase considerably in diabetic gestations. This synergistic increase indicates that Alx3 deficiency renders the embryos more vulnerable to the teratogenic effects of hyperglycaemia.