Oral-facial-digital syndrome type 1 (OFD1)
Log in to starLast updated 12d ago
A girl has a lobulated tongue with small tongue nodules, a cleft of the soft palate, and widely spaced eyes with a broad nasal root. Her hands show clinodactyly of the fifth finger. Renal ultrasound in her 20s reveals bilateral polycystic kidneys. There is no history of an affected father, and no affected males in the family.
XLD; male lethal; OFD1 (encodes a centriolar/ciliary basal body protein; a ciliopathy)
- Essentially all affected individuals are female; hemizygous males do not survive gestation
- About 75% of cases are simplex with a de novo variant; about 25% have an affected mother
Oral, facial, and digital anomalies plus variable systemic ciliopathy features:
- Oral: Lobulated tongue with hamartomatous nodules, hyperplastic frenula, cleft of the hard and/or soft palate, pseudocleft or cleft of the upper lip, hypodontia
- Facial: Hypertelorism, broad/hypoplastic nasal alae, milia on the face and ears
- Digital: Brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe
- Renal: Polycystic kidney disease, usually developing later in childhood or adulthood (over half of affected individuals)
- CNS: Intellectual disability (about half); brain malformations (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation) in about two-thirds
- Suggestive oral, facial, and digital findings in a female, especially the lobulated tongue with nodules
- Molecular confirmation of a heterozygous (female) or hemizygous (rare surviving mosaic male) pathogenic OFD1 variant; sequence analysis detects about 80%, with deletion/duplication analysis for the remainder
- Renal ultrasound at diagnosis and periodically thereafter, since polycystic kidney disease often develops later
- Brain MRI to evaluate for structural malformations
- Joubert syndrome (AR, multiple ciliopathy genes): molar tooth sign on brain MRI is the defining feature, distinguishing it from OFD1; some genetic overlap exists (OFD1 variants can also cause a Joubert-spectrum ciliopathy in males, "OFD1-related Joubert syndrome")
- Bardet-Biedl syndrome (AR, >20 BBS genes): rod-cone dystrophy and postaxial polydactyly, without the characteristic oral/tongue findings
- Meckel-Gruber syndrome (AR, ciliopathy genes): occipital encephalocele and enlarged cystic kidneys, lethal, and not X-linked
- Multidisciplinary craniofacial/cleft team care; surgical repair of cleft palate and excision of tongue nodules as needed
- Speech therapy and dental/orthodontic management of hypodontia
- Serial renal ultrasound and function monitoring for polycystic kidney disease, with nephrology follow-up
- Developmental evaluation and early intervention; neuroimaging-directed management of any structural brain anomaly
- Genetic counseling for X-linked dominant inheritance with male lethality: an affected mother has a 50% recurrence risk in daughters and no risk of an affected son
"FeeDBacK" (FDBK): the four systems involved, Face, Digits, Brain, Kidney.
OFD is an "Only Female Disorder": essentially only females are affected. Hemizygous males do not survive gestation, so there is no affected father and no affected son.
"Lobulated tongue, lobulated kidneys": the same nodular, lobed pattern shows up twice, on the tongue at birth and, later, as polycystic kidneys.