OFD1 is associated with prenatal male lethality in almost all cases. In female patients, there is a very high degree of phenotypic variability ranging from multiple severe malformations and visceral involvement to only renal cysts or dysmorphic features. Manifestations include oral malformations in >95% (lobed tongue, tongue hamartomas or lipomas, ankyloglossia, cleft or highly arched palate, accessory gingival frenulae, missing (hypodontia, see this term) or extra teeth, enamel dysplasia, and malocclusion), craniofacial abnormalities in about 87% including facial dysmorphism (ocular hypertelorism or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia, downslanting palpebral fissures), abnormal hair/alopecia, evanescent facial milia, digital malformations in about 88% (brachydactyly, syndactyly, 5th finger clinodactyly, duplicated hallux/broad thumb, preaxial or postaxial polydactyly), involvement of the CNS in about 50% including brain abnormalities (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation) and mild to moderate intellectual deficit. Visceral involvement includes polycystic kidney disease (at least 50%), and hepatic and pancreatic cystic disease. Hearing problems have also been described in about 6%.
OFD1 is caused by mutations in the OFD1 gene (Xp22) encoding a protein localized in the centrosome and basal body of primary cilia, which play an important role in development. A fraction of cases displays genomic deletions. High penetrance has been reported but expression is highly variable.
