Oral-facial-digital syndromes

Robin Godshalk MS MHA

Developmental Malformations

Updated 03.22.2024
Released 02.12.1996
Expires For CME 03.22.2027

Oral-facial-digital syndromes

Author: Robin Godshalk MS MHA

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Editor: Ganeshwaran H Mochida MD

Oral-facial-digital syndromes

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Introduction

Overview

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	Genes
Oral-facial-digital syndrome type I	Polycystic kidney disease Corpus callosum agenesis	OFDI
Oral-facial-digital syndrome type IV	Tibial dysplasia	TCTN3
Oral-facial-digital syndrome type VI	Molar tooth sign	TMEM216 TMEM231 TMEM138 C5orf42 TMEM107 KIAA0753
Classification based on the genotype for other patients	Median cleft of the upper lip	DDX59 NEK1
	Cardiac defects	INTU WDPCP
	Retinopathy	SCLT1 TBC1 D32/C7orf170
	Severe microcephaly	C2CD3
	Chondrodysplasia	IFT57

Clinical manifestations

Presentation and course

At least two genetically distinct variants of oral-facial-digital syndrome exist: (1) oral-facial-digital syndrome type I, which is X-linked dominant and lethal prenatally in males; and (2) oral-facial-digital syndrome type II, which is autosomal recessive. Another X-linked subtype, which is not lethal in males, also has been described and may represent an allelic variant of oral-facial-digital syndrome type I (28). In addition to these genetically distinct variants, additional variants have been proposed based on clinical differences. Such cases appear frequently in the literature (84; 03; 20; 26; 54); however, considerable phenotypic overlap occurs among variants of oral-facial-digital syndrome, and controversy exists as to whether reliable classification can be conducted with phenotypic data alone. With this in mind, some generalizations regarding the phenotypic differences between oral-facial-digital syndrome type I and autosomal recessive forms of oral-facial-digital syndrome follow.

The common findings are oral (cleft palate, hypertrophic frenula, lingual hamartomas, dental anomalies), facial (cleft lip, ocular hypertelorism), and digital (brachydactyly, polydactyly, syndactyly) malformations. The maxillary, mandibular, and lingual frenula are broad and short or atrophic (128). Accessory frenula may be present, although these may be more suggestive of Pallister-Hall syndrome (81). The tongue may be bifid or bound down, lobular, or asymmetric; the alveolar ridges may be cleft. Movement of the tongue is usually restricted, and teeth, particularly incisors, are often missing. This is not always the case, though, for supernumerary incisors have been identified in a case of oral-facial-digital syndrome type I in both primary and permanent dentition (72). Cleft lip and palate is common. Although asymmetric "true" clefts can occur, a midline "pseudocleft" in the inferior vermilion border of the upper lip is more common. The notch created by the latter malformation gives the upper lip a distinctive feline appearance. Midline complete or submucous clefts in the primary or secondary palate are also frequent. Lingual hamartomas exist as one or more nodules in the tongue that histologically are composed of benign muscle, adipose tissue, and salivary glands. Some lesions have a more lipomatous than hamartomatous appearance (42), whereas some may be leiomyomatous (144). The bridge of the nose usually appears broad and flat, and the eyes seem widely separated. The latter feature has been attributed to ocular hypertelorism in some patients and dystopia canthorum in others. Digital manifestations include variable degrees of brachydactyly, polydactyly, and syndactyly of one or more extremity. Almost any digit can be affected, and polydactyly may be preaxial, postaxial, central, or any combination thereof. This constellation of oral, facial, and digital malformations constitutes the salient features for this oral-facial-digital syndrome and is present in most reported cases; however, individual patients or affected family members may not exhibit defects of all three areas: (1) oral region, (2) face, and (3) digits. Significant phenotypic differences have been observed even within families.

Neither the oral nor the facial features of oral-facial-digital syndrome can be used to reliably distinguish X-linked from autosomal recessive variants. At one time, asymmetric limb involvement was attributed to oral-facial-digital syndrome type I and symmetric limb involvement to oral-facial-digital syndrome type II, but numerous exceptions to this claim have been reported. Anneren and colleagues noted that the short tubular bones of patients with oral-facial-digital syndrome type I have an irregular reticular radiographic appearance and proposed that this property might be used to distinguish it from other variants (05). Patients with type I disease may also show dislocated radial heads and cone-shaped distal femoral epiphyses (70). Unfortunately, radiographic data from large numbers of informative patients with different variants have not been compared as yet, so the reliability of particular skeletal findings remains to be tested.

Additional phenotypic anomalies that occur relatively frequently in patients with oral-facial-digital syndrome include polycystic (including glomerulocystic) kidneys, fibrocystic disease of the liver and pancreas, cardiac malformations, skeletal dysplasia (particularly mesomelic), cutaneous findings, and central nervous system malformations (56; 117; 18; 58). Some of the more common findings have been advocated as specific variants of oral-facial-digital syndrome (see Table 1). In one patient, penile agenesis and flattened clavicles were variably interpreted as type II, VI, or a new form of oral-facial-digital syndrome (151).

A subset of individuals with oral-facial-digital syndrome is severely handicapped by its extracranial anomalies. Many of them die perinatally because of cardiac defects, pulmonary hypoplasia, or polycystic renal disease (150). The latter can also present in adulthood and can have an incidence as high as 15%. It may be associated with segmental dilatation of intrahepatic bile ducts (Caroli disease), chiefly in females (133). Reported cardiac anomalies include endocardial cushion defects (eg, arteriovenous communis), tetralogy of Fallot, and aortic stenosis.

Involvement of the CNS has been documented in over 60% of patients with oral-facial-digital syndrome (138; 137; 100; 06; 71; 27). Hydrocephaly, agenesis of the corpus callosum, porencephaly, arachnoid or ependymal cysts, heterotopic neuroglial rests, cerebellar dysgenesis (including Dandy-Walker malformation) and hypothalamic hamartomas have all been observed (08). As with other phenotypic features, certain central nervous system anomalies are more characteristic of specific variants of oral-facial-digital syndrome as reflected in the generalizations that follow.

Hydrocephaly. Both communicating and obstructive hydrocephaly have been reported in patients with oral-facial-digital syndrome. In some cases, patients presented with rapid head enlargement. CT or MRI scans usually disclose enlarged, often asymmetric lateral ventricles with various degrees of parenchymal injury. Hydranencephaly has been reported in one case (101). Cystic dilatation of the fourth ventricle has also been observed with and without enlarged lateral ventricles, primarily in the context of cerebellar dysgenesis and autosomal recessive oral-facial-digital syndrome.

Occipital encephalocele. An occipital encephalocele has been reported in at least one fetus with oral-facial-digital syndrome and Dandy-Walker malformation (127), but this encephalocele is not common in such patients.

Agenesis of the corpus callosum. The corpus callosum is missing in some fetuses with oral-facial-digital syndrome type I or other variants. Most of these cases also have other central nervous system anomalies.

Porencephaly. Intrahemispheric (intracerebral) and arachnoid cysts are relatively common, particularly in oral-facial-digital syndrome type I (91). In most cases, the cysts are multiple and asymmetric and involve diverse portions of the cerebral hemisphere. Communication between the cyst and ventricular lumen has been observed; however, more often, the cysts are isolated. A single large cyst may predominate and contribute to macrocephaly.

Ependymal cysts. Interhemispheric or periventricular spaces lined by ciliated columnar epithelium have been reported primarily in patients with oral-facial-digital syndrome type I. The linings of ependymal cysts may contain choroid plexus.

Neuroglial heterotopia. Abnormal accumulations of disorganized neural and glial tissue have been identified in a variety of sites including the meninges, cerebral cortex, basal ganglia, hypothalamus, and brainstem. In some cases, the lining of the ventricular cavity is nodular due to accumulation of these heterotopic rests (55). Focal pachygyria and dramatic asymmetric growth in the brainstem may result as well (138; 137).

Cerebellar anomalies. Cerebellar dysgenesis with associated dilatation or cyst formation in the fourth ventricle has been reported in patients with autosomal recessive and X-linked variants of oral-facial-digital syndrome. In the past, some regarded cerebellar dysgenesis as a relatively specific marker for oral-facial-digital syndrome type VI (Varadi syndrome) (86). The usual malformation is a variant of the Dandy-Walker anomaly in which the inferior vermis is missing or atrophic. The superior vermis is generally intact. The cerebellar hemispheres may be small or show additional evidence of histological disorganization. In keeping with these findings, a large kindred of affected males and asymptomatic carrier females has been identified with Joubert syndrome and OFD1 mutations (22).

Hypothalamic hamartomas. A disorganized mass of neuroglial tissue in the hypothalamus has been observed, particularly in patients with autosomal recessive forms of oral-facial-digital syndrome (123). The most dramatic examples are large tumors that radiate into the thalamus and brainstem (121; 55). In some instances, the sella is involved and the anterior pituitary may be affected. At least one child presented with precocious puberty as a consequence of her hypothalamic hamartoma (121). In addition, absent pituitary gland has been reported in patients without hypothalamic hamartomas (113; 03). Conflict exists in the literature as to whether the hypothalamic masses are best termed "hamartomas" or "hamartoblastomas" in deference to variable degrees of histologic immaturity (143). Histologically, these lesions are composed of disordered collections of mature and immature neurons, glial cells, and myelinated fiber tracts (14).

Chorioretinal anomalies. Patients with oral-facial-digital syndrome and chorioretinal and optic nerve colobomata ("lacunae") have been described (49; 61; 90; 124; 118). It has been suggested that this finding distinguishes a unique subtype of autosomal recessive oral-facial-digital syndrome (type IX). Retinal hamartoma, indiscernible from retinoblastoma by preoperative imaging, has been diagnosed in a male with oral-facial-digital syndrome (139). Retinitis pigmentosa and demyelinating optic neuritis have been diagnosed in a 6-year-old boy with an OFD1 mutation (146).

Central nervous system anomalies and neurologic deficits. No single or group of central nervous system findings should be used to differentiate X-linked from autosomal recessive forms of oral-facial-digital syndrome, as large series of different types of patients have not been studied and exceptions to generalizations about specific central nervous system anomalies have been reported (71).

A significant but undefined subset of individuals that survive the perinatal period with any variant of oral-facial-digital syndrome has some neurologic deficits. Psychomotor retardation, developmental delay, seizures, hypotonia, ataxia, deafness, precocious puberty, and failure to thrive have all been reported. The severity of intellectual deficit varies greatly.

The complex of malformations evident in oral-facial-digital syndrome are distinctive from most other conditions; however, specific variants of oral-facial-digital syndrome, in which skeletal dysplasia or central nervous system anomalies coexist, overlap significantly with variants of oral-facial-digital syndrome and other syndromes. The phenotypic similarities between some autosomal recessive variants of oral-facial-digital syndrome and the autosomal recessive skeletal dysplasias, Majewski short-rib polydactyly and Beemer-Langer syndrome represent a spectrum that is so great that their definition as distinct genetic entities has been called into question (32; 119; 55; 89; 93). In each, short mesomelic limb segments, bent tibiae, and polydactyly are characteristic features.

The unusual hypothalamic hamartomas that have been observed in some oral-facial-digital syndrome cases are similar grossly and histologically to masses found in Pallister-Hall and hydrolethalus syndromes (143). Pallister-Hall syndrome is characterized by oral frenulae, palatal defects, median cleft lip, polydactyly, and cerebral malformations (21). Anal atresia is found in most cases of Pallister-Hall syndrome but has only rarely been reported in oral-facial-digital syndrome. Concerns about phenotypic, and possible genotypic, overlap between syndromal forms of hypothalamic hamartoma have led to proposals for novel classification systems of these disorders (55; 143); however, such schemes have not been widely accepted. Hypothalamic hamartomas can also present in isolation as sporadic lesions or as a familial trait with autosomal dominant transmission (46). The genetics of Pallister-Hall syndrome are incompletely understood, but at least one subset of families demonstrates autosomal dominant transmission, which correlates with mutations in the GLI3 gene (69). This pattern of inheritance contrasts with the putative autosomal recessive and X-linked patterns of inheritance ascribed to oral-facial-digital syndrome. The phenotype overlaps with a number of other disorders, including Simpson-Golabi-Behmel syndrome type 2 (22), as well as Goldenhar syndrome (oculo-auriculo-vertebral spectrum) and oculo-auriculo-fronto-nasal syndrome (51).

Partial or complete cerebellar dysgenesis is the primary finding in Joubert-Boltshauser syndrome (64; 29). The latter is an autosomal recessive disorder characterized by partial or complete absence of the cerebellar vermis, hyperpnea, and abnormal eye movements. Hyperpnea and nystagmus (including vertical nystagmus) have been reported in oral-facial-digital syndrome as well (50). Many patients with Joubert-Boltshauser syndrome have polydactyly and one infant had "fleshy tongue nodules" (29). Such cerebellar changes have also been noted on MRI in oral-facial-digital syndrome type VI (Varadi-Papp syndrome), along with abnormal superior cerebellar peduncles and deep interpeduncular fossa, the so-called “molar tooth sign” (43; 19; 96). The presence of these findings in a number of other syndromes (eg, Dekaban-Arima, Senior-Loken, and COACH) suggests some similarities in development. Congenital milia and hypotrichosis appear to distinguish type I from the other forms (88).

Prognosis and complications

The prognosis for patients with oral-facial-digital syndrome depends on the extent and severity of their congenital malformations and varies considerably (136). A subset of patients dies perinatally due to congenital heart malformations or pulmonary hypoplasia. Other published case histories indicate death at various times during infancy or childhood due to apnea, aspiration, or pneumonia. In general, childhood deaths occur in cases where intellectual deficit is moderate to severe. Patients without life-threatening malformations or neurologic impairment appear to have normal life expectancies. Hypothalamic hamartomas pursue a more indolent course than low-grade gliomas, but they produce morbidity due to their location (122). Precocious puberty has been reported in one child with a hypothalamic hamartoma, and pituitary dysfunction is a potential complication, although patients can respond satisfactorily to hormonal replacement therapy (03). Orthodontia may be necessary (92), and surgery is required to ameliorate midfacial anomalies such as clefts or tumors of the tongue, hypertrophic vestibular frenula, clefts of the upper lip or palate, or hypoplastic nasal cartilages (47; 142). Odontogenic keratocysts, both recurrent and de novo, are another complication (75). Conductive hearing loss has been reported in many patients. Renal insufficiency in one female with oral-facial-digital syndrome type I was treated with transplantation at 19 years; she was well at 23 years (125). The converse has also been reported, ie, the successful transplantation of kidney, lung, liver, and pancreas from a 25-year-old donor with oral-facial-digital syndrome (148). Vaginal atresia has been described in a patient with oral-facial-digital syndrome type I (126).

Biological basis

Etiology and pathogenesis

Mutations in OFD1 (CXORF5) cause oral-facial-digital syndrome type I. Many cases arise sporadically, but others are familial. Involved genes continue to be identified for the diverse forms of the syndrome.

Approximately 75% of cases of oral-facial-digital syndrome type I are sporadic (31); however, at least two genetically distinct forms exist. Oral-facial-digital syndrome type I is X-linked, dominant, and lethal prenatally in males. An X-linked variant of oral-facial-digital syndrome that is not lethal prenatally in males was described and may be allelic with oral-facial-digital syndrome type I (28). Transmission in the remaining cases is most consistent with autosomal recessive inheritance. Differential or skewed X inactivation between mothers and daughters has been offered as an explanation for phenotypic variability within families (39; 129).

New information regarding the genetic heterogeneity of the oral-facial-digital syndromes continues to appear. To date, 19 genes have been identified as causative of the oral-facial-digital syndromes (149). Oral-facial-digital syndrome type I is caused by mutations in OFD1 (CXORF5), which has been mapped to the short arm of the X chromosome (Xp22.2-Xp22.3) (18). A mouse model (X-linked dominant Xp1 mutant), manifesting polydactyly and renal cystic disease, maps to the homologous region on the X chromosome (31). CXORF5, also mapped to Xp22, appears to be a candidate gene for several diseases that include oral-facial-digital syndrome type I, spondyloepiphyseal dysplasia late, craniofrontonasal syndrome, and nonsyndromic sensorineural deafness (25). It has now been shown that CXORF5 (or Cxorf5/71-7a) is the gene responsible for oral-facial-digital syndrome type I. The gene has been renamed OFD1, and at least 90 mutations have been identified in OFD1 (34; 85; 99). In situ RNA studies of the mouse homolog Ofd1 have demonstrated expression of the gene in all of the tissues affected in oral-facial-digital syndrome type I (34). The ofd1 protein in mice is required for cilia formation and left-right axis specification (36). The ofd1 gene protects photoreceptors from oxidative stress and apoptosis, whereas mutations cause retinitis pigmentosa (145). OFD1 localizes to primary cilia and encodes a centrosome or basal body protein that is required for centriole length and the assembly of primary cilia (99; 120; 76). OFD1 contains the epidermal growth factor receptor (EGFR) and flotillin proteins, which are important components of the ciliary signaling complex (62). Deletions in OFD1 lead to centriole hyperelongation and resultant ciliopathies (130). This observation helps explain the extraordinary phenotypic diversity seen in oral-facial-digital syndrome and associated disorders. Cilia are involved in a wide variety of biological processes, including embryonic axis patterning, cell cycle regulation, protein trafficking, and photoreception (111). Further complicating this is the observation that dozens of genes may be responsible for ciliopathies (02). Mutations in some genes affect the regulation of components of cilia. TMEM231 mutations, for example, affect the localization of ciliary membrane proteins and are present in patients with oral-facial-digital syndrome type 3 (103). The OFD1 protein also regulates neuronal differentiation in embryonic stem cells (57) and is required in limb bud patterning and endochondral bone formation (10). Primary cilia are important in tooth development, coordinating signaling pathways critical to ontogenesis. Alterations in ciliary function lead to missing or supernumerary teeth, dentin or enamel hypoplasia, or crowding of teeth (52). The phenotype continues to be expanded. For example, an X-linked recessive syndrome with macrocephaly, intellectual deficit, and ciliary dysfunction has been identified in a family manifesting a frameshift mutation in OFD1 (17). Primary ciliary dyskinesia (situs abnormalities, oto-sino-pulmonary infection, decreased fertility) is now considered part of the OFD1 spectrum (53). OFD1 is conserved in vertebrates and absent in invertebrates (33).

Another candidate gene, STK9, has been localized to the same Xp22 region where oral-facial-digital syndrome type I, Nance-Horan syndrome, and nonsyndromic sensorineural deafness map (83).

Oral-facial-digital syndrome type 2 has been associated with distinct variants in the INTS13 gene (79). Depletion of this gene disrupts ciliogenesis and causes dysregulation of other ciliary genes in human cultured cells. This was seen in two unrelated families and was identified in the homozygous state.

The molecular basis for phenotypic similarities between the oral-facial-digital syndromes and other conditions is also becoming understood. Most notable are mutations in the GLI3 gene, which have been identified in many families manifesting autosomal dominant Pallister-Hall syndrome (67; 68; 69). The possibility of postzygotic mutation as a mechanism has also been raised because of the finding of type I oral-facial-digital syndrome in one set of (molecularly proven) monozygotic twins (116). Mutations in TCTN3, the transition zone protein involved in the regulation of the sonic hedgehog signaling pathway, appear to be responsible for the combination of features in oral-facial-digital syndrome type IV and Meckel syndrome (132). Additional evidence for the involvement of sonic hedgehog comes from experimental study of mice with Ofd1 inactivation and forebrain anomalies (23). Mutations in SCLT1, which encodes a centriole distal appendage protein important for cilia formation, have been identified in oral-facial-digital syndrome patients, particularly those with type IX (02; 74). In addition to recognized mutations, it seems that ancestral genetic factors may also play a role in the development of specific phenotypes (04).

Oral-facial-digital syndrome has significant overlap with Joubert syndrome and related disorders. There is even a syndrome (oral-facial-digital syndrome type VI) that results in a hybrid phenotype. The gene that has been identified in families with this phenotype is FAM149B1. Shaheen and colleagues described a family with two siblings with oral-facial-digital features (y shaped metacarpal, lustless hair, and midline cleft) as well as Joubert features (ocular movement abnormality, ptosis, and developmental delay) (112). They demonstrated homozygous truncating alleles in FAM149B1, with a continuum of phenotypic findings consistent with Joubert syndrome but ranging to oral-facial-digital syndrome type VI, in four families.

Although the etiology for oral-facial-digital syndrome is clearly genetic, little information exists concerning pathogenesis of this syndrome. Attention has been called to the predominance of midline malformations in the face, mouth, and brain, and it has been speculated that "midline developmental fields" may be affected. As a result of the strong incidence of prenatal lethality, it appears certain that gene products are important to organogenesis and, ultimately, to survival (31). Alternative splice forms of mRNA (OFD1a and OFD1b) have been identified in the brain, tongue, limb, and metanephros of first trimester human embryos by reverse-transcriptase polymerase chain reaction; it is possible that these mutations result in nonfunctional proteins or unstable transcripts and that OFD1 is involved in the differentiation of metanephric precursor cells (106). The OFD1 protein is a core component of the centrosome and, on this basis, might be expected to be important in a large number of developmental steps. Its expression in the kidney, for example, and contribution to mesenchymal-epithelial transition may help explain the renal cystic anomalies found in some of the oral-facial-digital syndromes (105; 59). The fact that ciliary defects cause anomalies such as those seen in oral-facial-digital syndrome suggests that mutations in ciliary proteins could cause oral-facial-digital syndrome (135). This has received support in both zebrafish and mouse models (35). In addition to ciliary function, OFD1 is associated with chromatin plasticity and DNA repair, which may also contribute to the heterogeneity of malformations (01).

Diagnostic workup

Prenatal diagnosis of type I oral-facial-digital syndrome is possible and most often relies on ultrasound findings, which can be enhanced by fetal autopsy in nonsurvivors (115; 131). However, because the changes in the oral-facial-digital syndromes are so variable and can be minimal, ultrasound diagnosis is not at all straightforward (07). Prenatal MRI may augment ultrasound, eg, molar tooth sign and hypothalamic hamartoma in oral-facial-digital syndrome type VI (96). Researchers have suggested that the shortened humerus is a marker for oral-facial-digital syndrome type II (98) and that the shortened ulna may be indicative of oral-facial-digital syndrome type IV (66). In the postnatal period, a detailed family history and examination of parents and siblings is essential. The history should include information about recurrent pregnancy losses, as males with oral-facial-digital syndrome type I die prenatally. A comprehensive physical examination should include oral and ocular evaluation, body measurements, and tests of olfactory function. At appropriate ages, dental radiographs should be obtained to screen for missing or supernumerary teeth, hypoplastic dentin or enamel, and spacing defects. The digits must be carefully inspected for subtle malformations such as brachydactyly, clinodactyly, or partial syndactyly. Radiographs of hands and feet should be obtained even when polydactyly is not evident to exclude bifid metacarpals, abnormal ossification of short tubular bones, or other skeletal anomalies. Radiographs of the long bones should be obtained from unusually short or disproportionately short individuals. Additional studies should include renal ultrasound examination (polycystic kidneys), cranial imaging studies (preferably CT or MRI), echocardiography, and possibly endocrine evaluation of pituitary function. Some families may elect to bank DNA, making it available for future testing or even for preimplantation testing of embryos. Genotype-phenotype correlations are unclear, making genetic workup essential (107). Exome sequencing is finding increasing use in identifying mutations in patients (09; 147).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Robin Godshalk MS MHA

Dr. Godshalk of Fragile X Center at Atlantic Health System in Morristown, New Jersey has no relevant financial relationships to disclose.
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Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
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Former Authors

Raj Kapur MD
Joseph R Siebert PhD

Patient Profile

Age range of presentation: 0-01 month
Sex preponderance: female>male, >1:1
Heredity: heredity typical

heredity may be a factor

autosomal recessive

X-linked dominant

X-linked recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Oral-facial-digital syndrome: 759.87
ICD-10: Oro-facial-digital syndrome: Q87.0
OMIM: Oral-facial-digital syndrome type I: #311200

Oral-facial-digital syndrome type II: %252100

Oral-facial-digital syndrome type III: %258850

Oral-facial-digital syndrome type IV: #258860

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Oral-facial-digital syndromes

Associated Disorders

Arrhinencephaly
Beemer-Langer syndrome
Cardiac malformations
Cerebellar dysgenesis
Dandy-Walker malformation
- Deafness
- Holoprosencephaly
- Hydrolethalis syndrome
- Hypertelorism
- Hypothalamic hamartoma
- Joubert syndrome
- Joubert-Boltshauser syndrome
- Lingual hamartoma
- Meckel-Grüber syndrome
- Midline cleft lip
- Oral frenula
- Pallister-Hall syndrome
- Polydactyly
- Porencephaly
- Simpson-Golabi-Behmel syndrome, type 2
- Skeletal dysplasia

Differential Diagnosis

Majewski short-rib polydactyly
Beemer-Langer syndrome
Pallister-Hall syndrome
Joubert-Boltshauser syndrome
Simpson-Golabi-Behmel syndrome type 2
- Goldenhar syndrome (oculo-auriculo-vertebral spectrum)
- Oculo-auriculo-fronto-nasal syndrome

Also Relevant

Cephaloceles
Dandy-Walker syndrome
Ependymal cysts
Joubert syndrome
Myelomeningocele

Clinical Categories

Developmental Malformations

Patient Handouts

Oral-facial-digital syndrome

Web References

Testing

Oral-Facial-Digital Syndrome Type I

Oral-facial-digital syndromes

Oral-facial-digital syndromes

Introduction

Overview

Key points

Historical note and terminology

Table 1. Variants of Oral-facial-digital Syndrome

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

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Norrie disease

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

Oral-facial-digital syndromes

Introduction

Overview

Key points

Historical note and terminology

Table 1. Variants of Oral-facial-digital Syndrome

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

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Norrie disease

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

This is an article preview.
Start a Free Account
to access the full version.