Selective inhibition of pyrimidine or purine biosynthesis has long been used as a therapeutic option to treat various cancers and autoimmune disorders. Leflunomide, a prodrug that is converted in the gastrointestinal tract to the active metabolite, A771726, reduces de novo pyrimidine biosynthesis by selectively inhibiting dihydroorotate dehydrogenase21. In mice, use of leflunomide during pregnancy causes a wide range of limb and craniofacial defects, the most common of which are exencephaly, cleft palate, and “open eye” or failure of eyelid to close25. These phenotypic characteristics recapitulate some of the malformations observed in individuals with Miller syndrome providing further evidence that it is caused by mutations in DHODH .
