Clinical characteristics: Oral-facial-digital syndrome type I (OFD1) is usually male lethal during gestation and predominantly affects females. OFD1 is characterized by the following: oral features (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities); facial features (widely spaced eyes, telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft of the upper lip, micrognathia); digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe); polycystic kidney disease; brain MRI findings (intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation); and intellectual disability (in approximately 50% of affected individuals).

Diagnosis/testing: The diagnosis of OFD1 is established in a female proband with suggestive findings and a heterozygous OFD1 pathogenic variant identified by molecular genetic testing. The diagnosis of OFD1 is established in a male proband with suggestive findings and a hemizygous pathogenic variant in OFD1 identified by molecular genetic testing.

Management: Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulae, syndactyly, and polydactyly; speech therapy and aggressive treatment of otitis media as needed; removal of accessory teeth; orthodontia for malocclusion; routine treatment for seizures and renal disease; early intervention and individualized education plan as needed; standard treatments for attention-deficit/hyperactivity disorder and/or autistic features; hearing aids and community hearing services as needed.

Surveillance: Annual audiology evaluation and assessment of speech development in children with cleft lip and/or cleft palate; annual dental evaluation or as recommended by the dentist; assessment for new seizures or changes in seizures as recommended by neurologist in those with brain involvement. Annual blood pressure; serum creatinine; and renal, liver, pancreas, and ovarian ultrasound for cystic disease beginning at age ten years. Assess developmental progress, educational needs, and behavioral manifestations at each visit.

Evaluation of relatives at risk: It is appropriate to evaluate the genetic status of apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for renal disease.

Pregnancy management: Careful monitoring of blood pressure and renal function during pregnancy is warranted.

Genetic counseling: OFD1 is inherited in an X-linked manner with, typically, male lethality. The full OFD1 phenotype has not been described in males beyond the perinatal period. Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a de novo pathogenic variant; approximately 25% of females diagnosed with OFD1 have an affected mother (mildly affected females may be diagnosed after the identification of a severely affected individual). If the mother of the proband has an OFD1 pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, most male conceptuses with the OFD1 pathogenic variant miscarry. It is possible for an affected male to be born alive, though this is exceedingly rare. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Once the OFD1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.