Oral-Facial-Digital Syndrome Type I

Excerpt

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 features:

1. Oral (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)

2. Facial (widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia)

3. Digital (brachydactyly, syndactyly, clinodactyly of the fifth finger; duplicated hallux [great toe])

4. Kidney (polycystic kidney disease)

5. Brain (e.g., intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation)

6. Intellectual disability (in ~50% of individuals)

Diagnosis/testing: The diagnosis of OFD1 is established in a proband by identification of an OFD1 pathogenic variant on molecular genetic testing.

Management: Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulae, and syndactyly; removal of accessory teeth and orthodontia for malocclusion; routine treatment for renal disease and seizures. Speech therapy and special education may be warranted.

Surveillance: Annual audiology evaluation and assessment of speech development in children if cleft lip and/or cleft palate is present. Individuals age ten years and older: annual blood pressure examination, serum creatinine, annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease.

Genetic counseling: OFD1 is inherited in an X-linked manner. Approximately 75% of affected individuals represent simplex cases (i.e., with no family history of OFD1). A female proband with OFD1 may have the disorder as the result of a de novo pathogenic variant; the proportion of cases caused by de novo pathogenic variants is unknown. The risk that the unaffected mother of an affected female who is a simplex case will give birth to another female with OFD1 is less than 1%. At conception, the risk to the offspring of females with OFD1 of inheriting the pathogenic variant is 50%; however, most male conceptuses with the pathogenic variant miscarry. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Prenatal ultrasound examination may detect structural brain malformations and/or duplication of the hallux.