Oral-facial-digital syndrome type I (OFDSI) is a multiple anomaly syndrome inherited as an X-linked dominant trait.  OFDS1 is caused by defects in the OFD1 gene, which maps to Xp22.2.  Almost all affected individuals are female, since the condition is almost always prenatally lethal in males.  Common manifestations, as the name of the condition implies, affect the face, mouth, and digits.  Facial manifestations include apparent hypertelorism, underdeveloped alae nasi, and micrognathia.   Oral findings include accessory frenulae (webs in the mouth), abnormal lobation or benign tumors of the tongue, cleft palate, and missing or abnormal teeth.  The fingers tend to be short with occasional webbing between some of them, and on rare occasions, there may be polydactyly.  The hallux is often duplicated, often on one foot only.  Other common manifestations include the presence of facial milia (white spots) on the face and/or ears, brain abnormalities, and polycystic kidney disease that develops later in life.

As noted above, mutations in OFD1 are the cause of OFDS1.  Genetic testing is available at several labs, including The University of Chicago Genetic Services.  Most cases are the result of new mutations, although 25% of the time the mutation is inherited from an affected mother.  In 80% of cases the mutation is detectable by sequencing; in another 5% of cases genomic deletions are the cause. 

Although OFD1 is the only gene known to cause OFDS1, two other phenotypes are caused by mutations in OFD1, and a third condition is suspected to be caused by mutation in this gene.    Known allelic conditions are an X-linked recessive intellectual disability syndrome, whose manifestations include macrocephaly, recurrent respiratory infections, and severe intellectual disability.   This condition is also known as the Simpson-Golabi-Behmel syndrome type 2.  The specific mutation described is a 4 bp duplication in exon 16 of the OFD1 gene.  The second condition is an X-linked recessive form of Joubert syndrome, with the phenotype including polydactyly, retinitis pigmentosa, and the presence of a “molar tooth sign” on MRI.   To date, two families have been reported with this condition, and both have mutations in exon 21 of the OFD1 gene.  OFDS VII is suspected to be caused by mutations in OFD1, thought it has only been described in one family.  This disorder is characterized by hydronephrosis and facial asymmetry.

Differential diagnosis includes other oral-facial-digital syndromes, which have been distinguished by clinical manifestations, but not molecular mechanisms as yet.  In general, individuals with these conditions have accessory oral frenulae and/or tongue anomalies, cleft lip/palate, polydactyly of fingers and toes, and distinguishing features such as tibial anomalies in OFDS IV, or cerebellar anomalies and mesoaxial polydactyly (duplicated fingers in the middle of the hand) in OFDS VI.   Most if not all of the other OFD syndromes are likely related to abnormal ciliary function, as is the case with OFDS1.