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  • Updated 03.22.2024
  • Released 02.12.1996
  • Expires For CME 03.22.2027

Oral-facial-digital syndromes



Oral-facial-digital syndrome represents a spectrum of extremely variable congenital conditions whose diversity has engendered considerable discussion. Major changes include hypertrophic frenula, dental anomalies, lingual hamartomas, cleft lip or palate, ocular hypertelorism, brachydactyly, polydactyly, and syndactyly. Other organ systems are affected as well, especially the central nervous system and urinary tract. Mutations in the OFD1 gene have a deleterious effect on primary cilia and alter several signaling pathways during development, thus, accounting for the wide variation in phenotypes and association with Joubert, Meckel-Gruber, and related ciliopathies. Careful physical and genetic workups are, therefore, necessary. As the delineation of syndromes continues, the classification of this complex condition will evolve. There has been a growing list of oral-facial-digital subtypes.

Key points

• Oral-facial-digital syndrome is an extremely variable congenital condition whose diversity has engendered widespread investigation and debate.

• Major changes include hypertrophic frenula, lingual hamartomas, cleft lip or palate, ocular hypertelorism, brachydactyly, polydactyly, and syndactyly.

• The brain may be normal or altered by agenesis of the corpus callosum, cerebral dysgenesis, porencephaly, or midline cerebral and cerebellar defects.

• Research has shown that mutations in the OFD1 gene alter a centrosomal protein in the basal body of primary cilia and influence multiple signalling pathways during development. This accounts for the association of oral-facial-digital syndrome with Joubert, Meckel-Gruber, and related syndromes.

• As the delineation of syndromes and identification of involved genes continue, the classification of this complex condition will evolve.

Historical note and terminology

Papillon-Léage and Psaume are credited with the first description of patients with oral-facial-digital syndrome (94). Another case of oral-facial-digital syndrome has been identified in the Anatomical Museum of the Leiden University Medical Center, Netherlands, and was estimated to be nearly 400 years old (12). Gorlin and colleagues published the first English report of the disorder (45). Since then, several hundred patients have been reported and at least 13 variants have been proposed. The common findings are oral (hypertrophic frenula, lingual hamartomas, cleft palate), facial (cleft lip, ocular hypertelorism), and digital (brachydactyly, polydactyly, syndactyly) malformations. The first reported cases were of females, an observation confirmed in large pedigrees containing fewer liveborn males than expected. These findings were interpreted as evidence for X-linked dominance with prenatal lethality in males.

Rimoin and Edgerton called attention to other families in which males and females were affected; parents of affected individuals were often related, and autosomal recessive inheritance was assumed (102). These authors suggested the existence of two phenotypically similar but genetically distinct, syndromes: (1) oral-facial-digital syndrome type I, which is X-linked dominant; and (2) oral-facial-digital syndrome type II, which is autosomal recessive. Oral-facial-digital syndrome type II has also been referred to as "Mohr syndrome," in deference to a report that may represent the first well-described cases.

The concept of at least two genetically distinct variants of oral-facial-digital syndrome has persisted, and the spectrum of phenotypic features that may be associated with either oral-facial-digital syndrome type I or oral-facial-digital syndrome type II has grown. A number of additional variants of oral-facial-digital syndrome have been suggested based on the recognition of novel and presumed "distinctive" characteristics associated with those typical for oral-facial-digital syndrome (See Table 1). New cases continue to be added (134; 84; 48). Transmission in most (but not all) cases is autosomal recessive.

Table 1. Variants of Oral-facial-digital Syndrome

Oral-facial-digital syndrome I (aka, Papillon-Léage-Psaume syndrome)

• Distinguishing feature: hyperplastic frenula; lobulated tongue; nasal cartilage hypoplasia; cleft lip; cleft palate; digital malformations; cutaneous milia; hypotrichosis; porencephaly; agenesis of corpus callosum; sparse brittle hair
• Inheritance: X-linked dominant, lethal prenatally in males

Oral-facial-digital syndrome II (aka, Mohr syndrome)

• Distinguishing feature: ocular hypertelorism; micrognathia; hydrocephalus
• Inheritance: autosomal recessive

Oral-facial-digital syndrome III (aka, Sugarman syndrome)

• Distinguishing feature: "see-saw" winking
• Inheritance: autosomal recessive

Oral-facial-digital syndrome IV (aka, Baraitser-Burn syndrome)

• Distinguishing feature: skeletal dysplasia
• Inheritance: autosomal recessive

Oral-facial-digital syndrome V (aka, Thurston syndrome)

• Distinguishing feature: cleft lip; postaxial polydactyly; early dental loss; Indian ethnic background
• Inheritance: autosomal recessive

Oral-facial-digital syndrome VI (aka, Varadi syndrome)

• Distinguishing feature: syndactyly and/or bifid toe (13); preaxial or mesoaxial polydactyly (24); lingual and sublingual hamartoma; hypothalamic hamartoma; cerebellar dysgenesis with molar tooth sign; optochiasmatic pilocytic astrocytoma in one patient (110)
• Inheritance: autosomal recessive

Oral-facial-digital syndrome VII (aka, Whelan syndrome)

• Distinguishing feature: facial asymmetry; hydronephrosis
• Inheritance: autosomal dominant or X-linked dominant

Oral-facial-digital syndrome VIII (aka, Edwards syndrome) (28)

• Distinguishing feature: short tibiae or radii; bilateral preaxial and postaxial polydactyly
• Inheritance: X-linked recessive, not lethal prenatally in either sex

Oral-facial-digital syndrome IX (aka, Gurrieri syndrome) (49; 61; 87; 30; 02)

• Distinguishing feature: retinochoroidal coloboma; severe microcephaly; Dandy-Walker malformation; retrobulbar cysts; short stature
• Inheritance: autosomal recessive

Oral-facial-digital syndrome X (aka, Figuera syndrome) (38)

• Distinguishing feature: fibular aplasia
• Inheritance: autosomal recessive

Oral-facial-digital syndrome XI (aka, Gabrielli syndrome) (40; 51)

• Distinguishing feature: postaxial polydactyly; ventriculomegaly; microcephaly; alar hypoplasia; duplicated vomer; cleft ethmoid; cleft vertebral bodies
• Inheritance: autosomal recessive

Oral-facial-digital syndrome XII (aka, Moran-Barroso syndrome) (84)

• Distinguishing feature: myelomeningocele; stenosis of aqueduct of Sylvius; dysplasia of atrioventricular valves
• Inheritance: autosomal recessive

Oral-facial-digital syndrome XIII (aka, Degner syndrome) (26)

• Distinguishing feature: brachyclinosyndactyly; leukoaraiosis
• Inheritance: autosomal recessive

Efforts to subtype oral-facial-digital syndrome into distinct phenotypic variants have met with criticism from those who believe that many, or perhaps all, of the autosomal recessive variants arise from a single gene mutation (32; 89). This criticism appears justified based on reported individuals or family members with "distinctive" findings characteristic of more than one variant of oral-facial-digital syndrome.

Although detailed neuroanatomic studies were not part of older case reports, the spectrum of neuropathological findings has expanded in parallel with the diverse anatomic findings found in other organ systems. The phenotypic overlap of oral-facial-digital syndrome with Joubert, Meckel-Grüber, and like conditions appears to be a result of altered cilia function although the role of individual proteins remains to be clarified (78). Mutations in OFD1 occur in familial (X-linked) cases of Joubert syndrome type 10 (37) and Simpson-Golabi-Behmel syndrome type 2 (11). Workers have taken different approaches to this association, some developing classifications based on phenotype, for example placing oral-facial-digital syndrome type VI in the category of “Joubert syndrome and related disorders” (97). This viewpoint has gained support from molecular studies. For example, the major gene responsible for oral-facial-digital syndrome type VI (C5orf42 or CPLANE1) is also found in patients with Joubert syndrome (77; 13). Variants of the INTU gene (which encodes a protein necessary for positioning of ciliary basal bodies) have been identified in patients with type VI oral-facial-digital syndrome as well (16). Continuing studies suggest that these mutations may be responsible for polydactyly, hypothalamic hamartoma, and other defects, but not tongue hamartomas (104). Mutations in GLI3 and OFD1 in a subset of 18 patients suggest that impaired sonic hedgehog signaling may play a role in the pathogenesis of hypothalamic hamartoma (108). Others have employed molecular-based classifications, suggesting that these conditions belong to a distinct spectrum characterized by truncating OFD1 mutations (140). Townes and colleagues documented clinical or anatomic evidence of cerebral abnormalities in three patients with oral-facial-digital syndrome and cited 16 other examples among 150 previous case reports (138). Towfighi and colleagues reviewed the neuropathology of oral-facial-digital syndrome type I and found only four other studies in which sufficient neuroanatomic findings were discussed (137). Subsequently, Anneren and colleagues reviewed cerebellar anomalies in oral-facial-digital syndrome type II. In a case report, Leao and Ribeiro-Silva presented a case of oral-facial-digital syndrome type I with severe central nervous system defects as well as a brief discussion of neuropathological literature as it relates to the different variants of oral-facial-digital syndrome (06; 71). The finding of global cerebral dysgenesis in a fetus with oral-facial-digital syndrome (73) may be explained through involvement of the LisH (LIS1 homology) domain described in patients with oral-facial-digital syndrome type 1 (41).

Oral-facial-digital classification can be reduced to three main subtypes and several additional anecdotal cases (15), as seen in Table 2.

Table 2. Novel Classification of Oral-Facial-Digital Syndrome Based on The Association Between Clinical and Molecular Features

Oral-facial-digital subtype

Clinical data


Oral-facial-digital syndrome type I

Polycystic kidney disease
Corpus callosum agenesis


Oral-facial-digital syndrome type IV

Tibial dysplasia


Oral-facial-digital syndrome type VI

Molar tooth sign


Classification based on the genotype for other patients

Median cleft of the upper lip


Cardiac defects




Severe microcephaly




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