Patients with oral-facial-digital syndrome, type 1 (OFD1) have oral (lobed tongue, cleft palate, hamartomas or lipomas of tongue or dental abnormalities), facial (cleft lip, hypertelorism, telecanthus, hypoplastic alae nasi, or micrognathia) and digital (brachydactyly, syndactyly, radial/ulnar deviation or polydactyly) abnormalities. As many as 40% of individuals have structural brain abnormalities including agenesis of the corpus callosum and Dandy-Walker malformation. Approximately 50% of individuals have mental retardation, usually mild. Less than 50% of individuals have polycystic kidney disease. Prattichizzo, et al. (2008) detected OFD1 mutations in 81 of 100 patients with characteristic facial features of OFD1.
Two families have been described with a severe form of Simpson-Golabi-Behmel syndrome (SGBS2). Males in these families have renal cysts, dysmorphic features, macrocephaly, developmental delay and respiratory problems. Most males died very early in life. Females appear unaffected. Budny, et al. (2006) described one family with SGBS2 males and unaffected females with a truncating mutation in OFD1. Another family with SGBS2 was mapped to the region surrounding OFD1.
Patients with Joubert syndrome (JS) have a specific hindbrain formation described on brain MRI as the “molar tooth sign”. Other features of the classic form of this condition include hypotonia, cerebellar ataxia, dysregulated breathing patterns, and developmental delay. Retinal, renal, or liver abnormalities, colobomas and orofacial or digital signs have been described in patients within the JS spectrum. Coene, et al. (2009) described one family and an isolated male with JS and two different truncating mutations in OFD1.
OFD1 testing is reasonable for:
- females with adult-onset polycystic kidney disease without evidence of involvement of male relatives
- females with at least 2 of the following: lingual anomalies, facial milia, oral frenula, brain malformations
- males with macrocephaly, delays, severe respiratory problems, and family history consistent with XL inheritance
- males with molar tooth sign and family history consistent with XL inheritance
Deletions and/or duplications of the OFD1 gene as causative of disease have been reported.