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Estimated annual incidence of 1/250,000 to 1/50,000 live births has been reported. Almost all patients are female. Exceptional cases of affected males have been described.

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.

Diagnosis is often made at birth on the basis of characteristic oral, facial, and digital anomalies. In other affected individuals, diagnosis is suspected only in later childhood or adulthood after polycystic kidney disease is found. Diagnostic methods include direct sequencing of OFD1 and dosage analysis in negative cases to detect genomic rearrangements not identifiable by direct sequencing due to the presence of the wild-type allele.

Differential diagnoses include other OFD syndromes and disorders (OFD2, 3, 4, 5, 6, 8 and 9), and familial cystic renal disease (see these terms). Meckel and Joubert syndromes (see these terms) should also be considered.

Prenatal diagnosis and preimplantation genetic diagnosis are recommended for at-risk pregnancies and require identification of the disease-causing mutation in the family.

OFD1 follows an X-linked dominant pattern of inheritance. The gene mutations commonly occur de novo. About 75% of affected female cases involve a single family member. Carrier testing for at-risk relatives is recommended.

Treatment involves cosmetic or reconstructive surgery for cleft lip and/or palate, tongue nodules, and accessory frenulae, removal of accessory teeth, orthodontia for malocclusion, surgery to repair syndactyly, as well as routine management of kidney disease and seizures. Management requires special educational evaluation for learning disabilities.

Male mortality usually occurs in the first or second trimester of pregnancy. The prognosis in affected females is variable and depends on the associated malformations and/or visceral involvement, severity, treatment, and the course of the disease.

Last update: September 2012 - Expert reviewer(s): Pr Brunella FRANCO