Clinical Description
The diagnosis of oral-facial-digital syndrome type I (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. Almost all affected individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by a female with OFD1.
Oral manifestations. The tongue is lobulated. Tongue nodules, which are usually hamartomas or lipomas, also occur in at least one third of individuals with OFD1. Ankyloglossia attributable to a short lingual frenulum is common. Cleft hard or soft palate, submucous cleft palate, or highly arched palate occurs in more than 50% of affected individuals. Trifurcation of the soft palate has been reported [al-Qattan 1998]. Alveolar clefts and accessory gingival frenulae are common. These fibrous bands are hyperplastic frenulae extending from the buccal mucous membrane to the alveolar ridge, resulting in notching of the alveolar ridges. Dental abnormalities include missing teeth (most common), extra teeth, enamel dysplasia, and malocclusion.
Facial features. Widely spaced eyes or telecanthus occurs in at least 33% of affected individuals. Hypoplasia of the alae nasi, median cleft lip, or pseudocleft upper lip is common. Micrognathia and downslanting palpebral fissures are common.
Digital anomalies. Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger are common. The other fingers, particularly the third (i.e., middle finger) may show variable radial or ulnar deviation. Duplicated hallux (great toe) occurs in fewer than 50% of affected individuals, and if present is usually unilateral. Preaxial or postaxial polydactyly of the hands occurs in 1%-2% of affected individuals.
Radiographs of the hands often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges [al-Qattan & Hassanain 1997].
Milia, small keratinizing cysts, occur in at least 10%, and likely more, most often appearing on the scalp, ear pinnae, face, and dorsa of the hands. Milia are usually present in infancy and then resolve, but can leave pitting scars.
Kidney. Renal cysts can develop from both tubules and glomeruli. The age of onset is most often in adulthood, but renal cysts in children as young as age two years have been described. Although renal cysts have been reported as a prenatal finding [Nishimura et al 1999], the diagnosis is doubtful in these cases. The risk for significant renal disease appears to be higher than 60% after age 18 years [Prattichizzo et al 2008, Saal et al 2010]. End-stage renal disease has been reported in affected girls and women ranging in age from 11 to 70 years.
Intellectual disability. It is estimated that as many as 50% of individuals with OFD1 have some degree of intellectual disability or learning disability. Intellectual disability depends in part on the presence of brain abnormalities, but no consistent correlation exists. When present, intellectual disability is usually mild. Severe intellectual disability in the absence of brain malformations appears to be rare [Del Giudice et al 2014].
Brain malformations. Structural brain abnormalities may occur in as many as 65% of individuals with OFD1 [Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013, Del Giudice et al 2014]. Anomalies most commonly include intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation. Other reported anomalies include type 2 porencephaly (schizencephalic porencephaly), pachygyria and heterotopias, hydrocephalus, cerebral or cerebellar atrophy, hypothalamic hamartomas, and berry aneurysms, each of which has been described in a few affected individuals.
Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy.
Other
Hearing loss from recurrent otitis media, usually associated with cleft palate, has been reported. On occasion, speech and mastication can be affected.
The hair is often described as dry, coarse, and brittle. Alopecia, usually partial, is an occasional finding. Alopecia following the lines of Blaschko has been described [Boente et al 1999].
Liver, pancreatic, and ovarian cysts may be observed, but only in those who have renal cysts as well.
Short stature, choanal atresia, and tibial pseudarthrosis have been reported.
Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [Morleo & Franco 2008].