Oral-facial-digital syndrome type I (OFD1) is associated with dysfunction of primary cilia and is characterized by the following abnormalities: oral (lobed tongue, hamartomas or lipomas of the tongue, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia and other dental abnormalities); facial (ocular hypertelorism or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia); digital (brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger; duplicated hallux [great toe]; preaxial or postaxial polydactyly of the hands); brain (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation); and kidney (polycystic kidney disease). As many as 50% of individuals with OFD1 have some degree of intellectual disability, which is usually mild. Almost all affected individuals are female. However, males with OFD1 have been described, mostly as malformed fetuses delivered by women with OFD1.
The diagnosis of OFD1 is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood. Molecular genetic testing of OFD1, the only gene currently known to be associated with oral-facial-digital syndrome type I, is available on a clinical basis.
OFD1 is inherited in an X-linked dominant manner. Approximately 75% of affected individuals are simplex cases (i.e., with no family history of OFD1). A female proband with OFD1 may have the disorder as the result of a de novo gene mutation; the proportion of cases caused by de novo mutations is unknown. The risk that the unaffected mother of an affected female who is a simplex case will give birth to another female with OFD1 is less than 1%. At conception, the risk to the offspring of females with OFD1 of inheriting the disease-causing OFD1 allele is 50%; however, most male conceptuses with the disease-causing allele miscarry. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. Prenatal ultrasound examination may detect structural brain malformations and/or duplication of the hallux.