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).

References

01: Abramowicz I, Carpenter G, Alfieri M, et al. Oral-facial-digital syndrome type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network. Hum Mol Genet 2017;26(1):19-32. PMID 27798113
02: Adly N, Alhashem A, Ammari A, Alkuraya FS. Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. Hum Mutat 2014;35(1):36-40. PMID 24285566
03: Al-Gazali LI, Sztriha L, Punnose J, Shather W, Nork M. Absent pituitary gland and hypoplasia of the cerebellar vermis associated with partial ophthalmoplegia and postaxial polydactyly: a variant of orofaciodigital syndrome VI or a new syndrome. J Med Genet 1999;36:161-6. PMID 10051020
04: Al-Qattan MM, Javed K. Variability of expression of oral-facial-digital syndrome type I in 15 Saudi girls: Why is there a high rate of median cleft lip in the phenotype? Plast Surg (Oakv) 2014;22(4):229-32. PMID 25535458
05: Anneren G, Arvidson B, Gustavson KH, Jorulf H, Carlsson G. Oro-facial-digital syndromes I and II: radiological methods for diagnosis and the clinical variations. Clin Genet 1984;26:178-86. PMID 6478638
06: Anneren G, Gustavson KH, Jozwiak S, Kjartansson S, Stromberg B. Abnormalities of the cerebellum in oro-facio-digital syndrome type II [Mohr syndrome]. Clin Genet 1990;38:69-73. PMID 2387087
07: Atahan Guven M, Ceylaner S, Prefumo F, Uzel M. Prenatal sonographic findings in a case of Varadi-Papp syndrome. Prenat Diagn 2004;24(12):989-91. PMID 15614844
08: Azukizawa T, Yamamoto M, Narumiya S, et al. Oral-facial-digital syndrome type 1 with hypothalamic hamartoma and Dandy-Walker malformation. Pediatr Neurol 2013;48:329-32. PMID 23498571
09: Bayram Y, Aydin H, Gambin T, et al. Exome sequencing identifies a homozygous C5orf42 variant in a Turkish kindred with oral-facial-digital syndrome type VI. Am J Med Genet A 2015;167(9):2132-7. PMID 25846457
10: Bimonte S, De Angelis A, Quagliata L, et al. Ofd1 is required in limb bud patterning and endochondral bone formation. Dev Biol 2011;349:179-91. PMID 20920500
11: Bisschoff IJ, Zeschnigk C, Horn D, et al. Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability. Hum Mutat 2013;34:237-47. PMID 23033313
12: Boer LL, Boek PLJ, van Dam AJ, Oostra RJ. History and highlights of the teratological collection in the Museum Anatomicum of Leiden University, The Netherlands. Am J Med Genet A 2018;176(3):618-37. PMID 29399953
13: Bonnard C, Shboul M, Tonekaboni SH, et al. Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome. Eur J Med Genet 2018. PMID 29605658
14: Boyko OB, Curnes JT, Oakes WJ, Burger PC. Hamartomas of the tuber cinereum: CT, MR, and pathologic findings. AJNR Am J Neuroradiol 1991;12(2):309-14. PMID 1902033
15: Bruel AL, Franco B, Dufford Y, et al. Fifteen years of research on oral-facial-digital syndromes: from 1-16 causal genes. J Med Genet 2017;54(6):371-80. PMID 28289185
16: Bruel AL, Levy J, Elenga N, et al. INTU-related oral-facial-digital syndrome type VI: a confirmatory report. Clin Genet 2018;93(6):1205-9. PMID 29451301
17: Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet 2006;120(2):171-8. PMID 16783569
18: Chetty-John S, Piwnica-Worms K, Bryant J, et al. Fibrocystic disease of liver and pancreas: under-recognized features of the X-linked celiopathy oral-facial-digital syndrome type 1 (OFD I). Am J Med Genet A 2010;152:2640-5. PMID 20818665
19: Chodirker BN, Shah NS, Bunge MK, Reed MH. Another case of Varadi-Papp syndrome with a molar tooth sign. Am J Med Genet A 2005;136:416-7. PMID 15988746
20: Chung WY, Chung LP. A case of oral-facial-digital syndrome with overlapping manifestations of type V and type VI: a possible new OFD syndrome. Pediatr Radiol 1999;29:268-71. PMID 10199905
21: Clarren SK, Alvord EC, Hall JG. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly--a new syndrome. Part II: neuropathological considerations. Am J Med Genet 1980;7:75-83. PMID 7211954
22: Coene KL, Roepman R, Doherty D, et al. OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 2009;85(4):465-81. PMID 19800048
23: D’Angelo A, De Angelis A, Avallone B, et al. Ofd1 controls dorso-ventral patterning and axoneme elongation during embryonic brain development. PLoS One 2012;7:e52937. PMID 23300826
24: Darmency-Stamboul V, Burglen L, Lopez E, et al. Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome. Eur J Med Genet 2013;56:301-8. PMID 23523602
25: de Conciliis L, Marchitiello A, Wapenaar MC, et al. Characterization of Cxorf5 (71-71A), a novel human cDNA mapping to Xp22 and encoding a protein containing coiled-coil alpha-helical domains. Genomics 1998;51:243-50. PMID 9722947
26: Degner D, Bleich S, Riegel A, Ruther E. Orofaciodigital syndrome--a new variant? Psychiatric, neurologic and neuroradiological findings. Fortsch Neurol Psychiatr 1999;67(12):525-8. PMID 10683749
27: Del Giudice E, Macca M, Imperati F, et al. CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study. Orphanet J Rare Dis 2014;9:74. PMID 24884629
28: Edwards M, Mulcahy D, Turner G. X-linked recessive inheritance of an orofaciodigital syndrome with partial expression in females and survival of affected males. Clin Genet 1988;34:325-32. PMID 3229001
29: Egger J, Bellman MH, Ross EM, Baraitser M. Joubert-Boltshauser syndrome with polydactyly in siblings. J Neurol Neurosurg Psychiatry 1982;45:737-9. PMID 7131000
30: Erickson RP, Bodensteiner JB. Oro-facial-digital syndrome IX with severe microcephaly: A new variant in a genetically isolated population. Am J Med Genet 2007;143A(24):3309-13. PMID 18000902
31: Feather SA, Woolf AS, Donnai D, Malcolm S, Winter RM. The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3. Hum Mol Genet 1997;6(7):1163-7. PMID 9215688
32: Fenton OM, Watt-Smith SR. The spectrum of the oro-facial digital syndrome. Br J Plast Surg 1985;38:532-9. PMID 4052714
33: Ferrante MI, Barra A, Truong JP, Banfi S, Disteche CM, Franco B. Characterization of the OFD1/Ofd1 genes on the human and mouse sex chromosomes and exclusion of Ofd1 for the Xpl mouse mutant. Genomics 2003;81:560-9. PMID 12782125
34: Ferrante MI, Giorgio G, Feather SA, et al. Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 2001;68:569-76. PMID 11179005
35: Ferrante MI, Romio L, Castro S, et al. Convergent extension movements and ciliary function are mediated by ofd1, a Zebrafish orthologue of the human oral-facial-digital type I syndrome gene. Hum Mol Genet 2009;18:289-303. PMID 18971206
36: Ferrante MI, Zullo A, Barra A, et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 2006;38:112-7. PMID 16311594
37: Field M, Scheffer IE, Gill D, et al. Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations. Eur J Hum Genet 2012;20:806-9. PMID 22353940
38: Figuera LE, Rivas F, Cantu JM. Oral-facial-digital syndrome with fibular aplasia. Clin Genet 1993;44:190-2. PMID 8261648
39: Franco B, Ballabio A. X-inactivation and human disease: X-linked dominant male-lethal disorders. Curr Opin Genet Dev 2006;16:254-9. PMID 16650755
40: Gabrielli O, Ficcadenti A, Fabrizzi G, et al. Child with oral, facial, digital, and skeletal anomalies and psychomotor delay: a new OFDS form. Am J Med Genet 1994;53:290-3. PMID 7531942
41: Gerlitz G, Darhin E, Giorgio G, Franco B, Reiner O. Novel functional features of the Lis-H domain: role in protein dimerization, half-life and cellular localization. Cell Cycle 2005;4:1632-40. PMID 16258276
42: Ghossaini SN, Hadi U, Tawil A. Oral-facial-digital syndrome type II variant associated with congenital tongue lipoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:324-7. PMID 12324787
43: Gleeson JG, Keeler LC, Parisi MA, et al. Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes. Am J Med Genet 2004;125A(2):125-34. PMID 14981712
44: Gonzalez MG, Castro MP, Nieto DV, Bouzan JC. Oral-facial-digital syndrome type I: surgical approach and a case report. J Plast Reconstru Aesthet Surg 2014;67(3):396-8. PMID 23886557
45: Gorlin RJ, Anderson VE, Scott CR. Hypertrophied frenuli, oligophrenia, familial trembling and anomalies of the hand: report of four cases in one family and a forme fruste in another. New Engl J Med 1961;264:486-9. PMID 13707262
46: Grebe TA, Clericuzio C. Autosomal dominant inheritance of hypothalamic hamartoma associated with polysyndactyly: heterogeneity or variable expressivity. Am J Med Genet 1996;66:129-37. PMID 8958318
47: Gunbay S, Zeytinoglu B, Ozkinay F, Ozkinay C, Oncag A. Orofaciodigital syndrome I: a case report. J Clin Pediatr Dent 1996;20:329-32. PMID 9151628
48: Gurrieri F, Franco B, Toriello H, Neri G. Oral-facial-digital syndromes: review and diagnostic guidelines. Am J Med Genet A 2007;143A(24):3314-23. PMID 17963220
49: Gurrieri F, Sammito V, Ricci B, Iossa M, Bellussi A, Neri G. Possible new type of oral-facial-digital syndrome with retinal abnormalities: OFDS type (VIII). Am J Med Genet 1992;42:789-92. PMID 1554016
50: Gustavson KH, Kreuger A, Petersson PO. Syndrome characterized by lingual malformation, polydactyly, tachypnea, and psychomotor retardation (Mohr syndrome). Clin Genet 1971;2(4):261-6. PMID 5146584
51: Guven MA, Ceylaner G, Ceylaner S, Uzel M, Coskun A. Prenatal diagnosis of a case probably with Oral-Facial-Digital Syndrome--Gabrielli type. Genet Couns 2009;20(2):167-72. PMID 19650414
52: Hampl M, Cela P, Szabo-Rogers HL, et al. Role of primary cilia in odontogenesis. J Dent Res 2017;96(9):965-74. PMID 28605602
53: Hannah WB, DeBrosse S, Kinghorn B, et al. The expanding phenotype of OFD1-related disorders: hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia. Mol Genet Genomic Med 2019;7(9):e911. PMID 31373179
54: Hayes LL, Simoneaux SF, Palasis S, Niyazov DM. Laryngeal and tracheal anomalies in an infant with oral-facial-digital syndrome type VI (Váradi-Papp): report of a transitional type. Pediatr Radiol 2008;38(9):994-8. PMID 18478222
55: Hingorani SR, Pagon RA, Shepard TH, Kapur RP. Twin fetuses with abnormalities that overlap with three midline malformation complexes. Am J Med Genet 1991;41:230-5. PMID 1785640
56: Holub M, Bodamer OA, Potocki L. Central nervous system malformations in oral-facial-digital syndrome, type I. Am J Med Genet A 2005;136:218. PMID 15942947
57: Hunkapiller J, Singla V, Seol A, et al. The ciliogenic protein oral-facial-digital 1 regulates the neuronal differentiation of embryonic stem cells. Stem Cells Dev 2011;20:831-41. PMID 20873986
58: Iijima T, Hoshino J, Mise K, et al. Daughter and mother with orofaciodigital syndrome type 1 and glomerulocystic kidney disease. Hum Pathol 2016;55:24-9. PMID 27131853
59: Izzi C, Sottini L, Dallera N, et al. Genetics and nosological classification of renal cystic diseases. G Ital Nefrol 2010;27(Suppl 50):S63-9. PMID 20922698
60: Jacquemart CJ, Trotter TL, Kaplan AM, Beauchamp RF. The oral-facial-digital syndromes reviewed: the role of computerized axial tomography in management. Ariz Med 1980;37:261-4. PMID 7369884
61: Jamieson R, Collins F. Oral-facial-digital syndrome and retinal abnormalities with autosomal recessive inheritance. Am J Med Genet 1993;47:304-5. PMID 8213926
62: Jerman S, Ward HH, Lee R, et al. OFD1 and flotillins are integral components of a ciliary signaling protein complex organized by polycystins in renal epithelia and odontoblasts. PLoS One 2014;9(9):e106330. PMID 25180832
63: John JR, Kumar P, Sharma RK. Thurston syndrome: an uncommon disorder presenting with common abnormalities. J Craniofac Surg 2013;24:e132-4. PMID 23524810
64: Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. Neurology 1969;19:813-25. PMID 5816874
65: Jugessur A, Skare O, Lie RT, et al. X-linked genes and risk of orofacial clefts: evidence from two population-based studies in Scandinavia. PLoS One 2012;7:e39240. PMID 22723972
66: Kahl P, Heukamp L, Buettner R, Friedrichs N, Roesing B, Knopfle G. Orofaciodigital syndrome type IV (Mohr-Majewski syndrome): report of a family with two affected siblings. Pediatr Dev Pathol 2007;10(3):239-43. PMID 17535085
67: Kang S, Allen J, Graham JM Jr, et al. Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 1997a;34:441-6. PMID 9192261
68: Kang S, Graham JM, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 1997b;15:266-8. PMID 9054938
69: Kang S, Rosenberg M, Ko VD, Biesecker LG. Gene structure and allelic expression assay of the human GLI3 gene. Hum Genet 1997c;101:154-7. PMID 9402960
70: Khalifa O, Rahbeeni Z, Alhashmi N, et al. Oral-facial-digital syndrome type 1: unique radiological findings. Clin Dysmorphol 2012;21:77-9. PMID 22123492
71: Leao MJ, Ribeiro-Silva ML. Orofaciodigital syndrome type I in a patient with severe CNS defects. Pediatr Neurol 1995;13:247-51. PMID 8554663
72: Leonardi R, Gallone M, Sorge G, Greco F. Oral-facial-digital syndrome type I. A case report. Minerva Stomatol 2004;53(4):185-9. PMID 15107776
73: Lesca G, Fallet-Bianco C, Plauchu H, Vitrey D, Verloes A, Attia-Sobol J. Orofaciodigital syndrome with cerebral dysgenesis. Am J Med Genet A 2006;140:757-63. PMID 16502430
74: Li J, Lu D, Liu H, et al. Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signaling. Hum Mol Genet 2017;26(15):2949-60. PMID 28486600
75: Lindeboom JA, Kroon FH, de Vires J, van den Akker HP. Multiple recurrent and de novo odontogenic keratocysts associated with oral-facial-digital syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95(4):458-62. PMID 12686930
76: Lopes CA, Prosser SL, Romio L. Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral-facial-digital syndrome 1. J Cell Sci 2011;124:600-12. PMID 21266464
77: Lopez E, Thauvin-Robinet C, Reversade B, et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet 2014;133(3):367-77. PMID 24178751
78: Macca M, Franco B. The molecular basis of oral-facial-digital syndrome, type 1. Am J Med Genet C Semin Med Genet 2009;151:318-25. PMID 19876934
79: Mascibroda LG, Shboul M, Elrod ND, et al. INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex. Nat Commun 2022;13(1):6054. PMID 36229431
80: McKinnie JE, Abdullah AN, Ramanathan J. Anesthetic considerations in a parturient with oral-facial-digital syndrome and repaired tetralogy of Fallot with left ventricular dysfunction. Int J Obstet Anesth 2014;23(2):182-5. PMID 24631061
81: Mintz SM, Siegel MA, Seider PJ. An overview of oral frena and their association with multiple syndromic and nonsyndromic conditions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99(3):321-4. PMID 15716839
82: Mohr OL. A hereditary sublethal syndrome in man. Skr Norske Vidensk Akad I Mat-Naturv Klasse 1941;14:1-18.
83: Montini E, Andolfi G, Caruso A, et al. Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region. Genomics 1998;51:427-33. PMID 9721213
84: Moran-Barroso V, Valdes Flores M, Garcia-Cavazos R, Kofman-Alfaro S, Saavedra-Ontiveros D. Oral-facial-digital (OFD) syndrome with associated features: a new syndrome or genetic heterogeneity and variability. Clin Dysmorphol 1998;7:55-7. PMID 9546832
85: Morisawa T, Yagi M, Surono A, et al. Novel double-deletion mutations of the OFD1 gene creating multiple novel transcripts. Hum Genet 2004;115(2):97-103. PMID 15221448
86: Munke M, McDonald DM, Cronister A, Stewart JM, Gorlin RJ, Zackai EH. Oral-facial-digital syndrome type VI (Varadi syndrome): further clinical delineation. Am J Med Genet 1990;35:360-9. PMID 2309783
87: Nagai K, Nagao M, Nagao M, et al. Oral-facial-digital syndrome type IX in a patient with Dandy-Walker malformation. J Med Genet 1998;35:342-4. PMID 9598735
88: Nanda A, Sharaf A, Alsaleh QA. Multiple milia in a newborn with congenital malformations: oral-facial-digital syndrome type 1. Pediatr Dermatol 2010;27:669-70. PMID 21510010
89: Neri G, Gurrieri F, Genuardi M. Oral-facial-skeletal syndromes. Am J Med Genet 1995;59:365-8. PMID 8599363
90: Nevin NC, Silvestri J, Kernohan DC, Hutchinson WM. Oral-facial-digital syndrome with retinal abnormalities: OFDS type IX. A further case report. Am J Med Genet 1994;51:228-31. PMID 8074150
91: Odent S, Le Marec B, Toutain A, et al. Central nervous system malformations and early end-stage renal disease in oro-facio-digital syndrome type I: a review. Am J Med Genet 1998;75:389-94. PMID 9482645
92: Ozturk F, Doruk C. Orthodontic treatment of a patient with oral-facial-digital syndrome. Am J Orthod Dentofacial Orthop 2012;141(4 Suppl):S110-8. PMID 22449591
93: Panigrahi I, Das RR, Kulkarni KP, et al. Overlaping phenotypes in OFD type II and OFD type VI: report of two cases. Clin Dysmorphol 2013;22:109-14. PMID 23459408
94: Papillon-Leage M, Psaume J. Une malformation hereditaire de la muqueuse buccale, brides et fret anormaux. Revue Stomatol 1954;55(4):209-27. PMID 15444577
95: Pezzella N, Bove G, Tammaro R, Franco B. OFD1: one gene, several disorders. Am J Med Genet C Semin Med Genet 2022;190(1):57-71. PMID 35112477
96: Poretti A, Brehmer U, Scheer I, Bernet V, Boltshauser E. Prenatal and neonatal MR imaging findings in oral-facial-digital syndrome type VI. AJNR Am J Neuroradiol 2008;29(6):1090-1. PMID 18356465
97: Poretti A, Vitiello G, Hennekam RC, et al. Delineation and diagnostic criteria of Oral-Facial-Digital syndrome type VI. Orphanet J Rare Dis 2012;7:4. PMID 22236771
98: Pradhan M, Manisha, Sankar H. Short humerus: an additional antenatal sonographic feature of OFDS type II. J Clin Ultrasound 2007;35(7):390-4. PMID 17410589
99: Prattichizzo C, Macca M, Novelli V, et al. Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients. Hum Mutat 2008;29(10):1237-46. PMID 18546297
100: Reardon W, Harbord MG, Hall-Craggs MA, Kendall B, Brett EM, Baraitster M. Central nervous system malformations in Mohr's syndrome. J Med Genet 1989;26:659-63. PMID 2555513
101: Reuss AL, Pruzansky S, Lis EF, Patau K. The oral-facial-digital syndrome: a multiple congenital condition of females with associated chromosome abnormalities. Pediatrics 1962;29:985-95. PMID 14495129
102: Rimoin D, Edgerton M. Genetic and clinical heterogeneity in the oral-facial-digital syndromes. J Pediatr 1967;71:94-102. PMID 5293864
103: Roberson EC, Dowdle WE, Ozanturk A, et al. TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J Cell Biol 2015;209(1):129-42. PMID 25869670
104: Romani M, Mancini F, Micalizzi A, et al. Oral-facial-digital syndrome type VI: is C5orf42 really the major gene? Hum Genet 2015;134(1):123-26. PMID 25407461
105: Romio L, Fry AM, Winyard PJ, Malcolm S, Woolf AS, Feather SA. OFD1 is a centrosomal/basal body protein expressed during mesenchymal-epithelial transition in human nephrogenesis. J Am Soc Nephrol 2004;15(10):2556-68. PMID 15466260
106: Romio L, Wright V, Price K, et al. OFD1, the gene mutated in oral-facial-digital syndrome type I is expressed in the metanephros and in human embryonic renal mesenchymal cells. J Am Soc Nephrol 2003:14:680-9. PMID 12595504
107: Roosing S, Romani M, Isrie M, et al. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. J Med Genet 2016;53(9):608-15. PMID 27208211
108: Saitsu H, Sonoda M, Higashijima T, et al. Somatic mutations in GLI3 and OFD1 involved in sonic hedgehog signaling cause hypothalamic hamartoma. Ann Clin Transl Neurol 2016;3(5):356-65. PMID 27231705
109: Sakai N, Nakakita N, Yamazaki Y, Ui K, Uchinuma E. Oral-facial-digital syndrome type II (Mohr syndrome): clinical and genetic manifestations. J Craniofac Surg 2002;13:321-6. PMID 12000897
110: Sarma P, Bindu PS, Dwarakanath S, Somanna S. Association of oral-facial-digital syndrome type VI (Varadi-Papp syndrome) with optochiasmatic pilocytic astrocytoma. Childs Nerv Syst 2015;31(5):789-92. PMID 25252823
111: Sattar S, Gleeson JG. The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders. Dev Med Child Neurol 2011;53:793-8. PMID 21679365
112: Shaheen R, Jiang N, Alzahrani F, et al. Bi-allelic mutation in FAM149B1 cause abnormal primary cilium and a range of ciliopathy phenotypes in humans. Am J Hum Genet 2019;104(4):731-7. PMID 30905400
113: Shashi V, Clark P, Rogol AD, Wilson WG. Absent pituitary gland in two brothers with an oral-facial-digital syndrome resembling OFDS II and VI: a new type of OFDS. Am J Med Genet 1995:57:22-6. PMID 7645593
114: Shimojima K, Shimada S, Sugawara M, et al. Challenges in genetic counseling because of intra-familial phenotypic variation of oral-facial-digital syndrome type 1. Congenit Anom (Kyoto) 2013;53(4):155-9. PMID 24712474
115: Shipp TD, Chu GC, Benacerraf B. Prenatal diagnosis of oral-facial-digital syndrome, type I. J Ultrasound Med 2000;19:491-4. PMID 10898304
116: Shotelersuk V, Tifft CJ, Vacha S, Peters KF, Biesecker LG. Discordance of oral-facial-digital syndrome type I in monozygotic twin girls. Am J Med Genet 1999;86:269-73. PMID 10482878
117: Siebert JR. The oral-facial-digital syndromes. In: Malformations of the Nervous System. Series volume - Handbook of Clinical Neurology. Sarnat HB, Curatolo P, editors. Elsevier Publishing Company, 2008;87:341-51.
118: Sigaudy S, Philip N, Gire C, Chabrol B. Oral-facial-digital syndrome with retinal abnormalities. Am J Med Genet 1996;61:193-4. PMID 8669453
119: Silengo MC, Bell GL, Biagioli M, Franceschini P. Oro-facial-digital syndrome II. Transitional type between the Mohr and the Majewski syndromes: report of two new cases. Clin Genet 1987;31(5):331-6. PMID 3608220
120: Singla V, Romaguera-Ros M, Garcia-Verdugo JM, et al. Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev Cell 2010;18:410-24. PMID 20230748
121: Somer M, Lindahl E, Perheentupa J. Precocious puberty associated with oral-facial-digital syndrome type I. Acta Pediatr Scand 1986;75:672-5. PMID 3751562
122: Squires LA, Constantini S, Miller DC, Wisoff JH. Hypothalamic hamartoma and the Pallister-Hall syndrome. Pediatr Neurosurg 1995;22(6):303-8. PMID 7577664
123: Stephan MJ, Brooks KL, Moore DC, Coll EJ, Goho C. Hypothalamic hamartoma in oral-facial-digital syndrome type VI (Varadi syndrome). Am J Med Genet 1994;51:131-6. PMID 8092188
124: Stevens JL, Marsh JL. Ocular anomalies in the oral-facial-digital syndrome. J Pediatr Ophthalmol Strabismus 1994;31:397-8. PMID 7714706
125: Stoll C, Sauvage P. Long-term follow-up of a girl with oro-facio-digital syndrome type I due to a mutation in the OFD 1 gene. Ann Genet 2002;45:59-62. PMID 12119212
126: Su WR, Wang PH, Lian JD, Lin MC. Oral-facial-digital syndrome with vaginal atresia, hydronephrosis and congenital cardiac defect. J Pediatr Orthop B 2008;17:179-82. PMID 18525474
127: Suresh S, Rajesh K, Suresh I, Raja V, Gopish D, Gnanasoundari S. Prenatal diagnosis of orofaciodigital syndrome: Mohr type. J Ultrasound Med 1995;14(11):863-6. PMID 8551554
128: Tagliani MM, Gomide MR, Carrara CF. Oral-facial-digital syndrome type 1: oral features in 12 patients submitted to clinical and radiographic examination. Cleft palate Craniofac J 2010;47(2):162-6. PMID 20210637
129: Thauvin-Robinet C, Cossee M, Cormier-Daire V, et al. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J Med Genet 2006;43:54-61. PMID 16397067
130: Thauvin-Robinet C, Lee JS, Lopez E, et al. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation. Nat Genet 2014;46(8):905-11. PMID 24997988
131: Thauvin-Robinet C, Rousseau T, Durand C, et al. Familial orofaciodigital syndrome type I revealed by ultrasound prenatal diagnosis of porencephaly. Prenat Diagn 2001;21:466-70. PMID 11438951
132: Thomas S, Legendre M, Saunier S, et al. TCTN3 mutations cause Mohr-Majewski syndrome. Am J Hum Genet 2012;91:372-8. PMID 22883145
133: Toprak O, Uzum A, Cirit M, et al. Oral-facial-digital syndrome type 1, Caroli’s disease and cystic renal disease. Nephrol Dial Transplant 2006;21:1705-9. PMID 16384823
134: Toriello HV. Review: oral-facial-digital syndromes, 1992. Clin Dysmorphol 1993;2:95-105. PMID 8281288
135: Toriello HV. Are the oral-facial-digital syndromes ciliopathies. Am J Med Genet A 2009;149A:1089-95. PMID 19396822
136: Toriello HV, Carey JC, Suslak E, et al. Six patients with oral-facial-digital syndrome IV: the case for heterogeneity. Am J Med Genet 1997;69:250-60. PMID 9096753
137: Towfighi J, Berlin CM, Ladda RL, Frauenhofer EE, Lehman RA. Neuropathology of oral-facial-digital syndrome. Arch Pathol Lab Med 1985;109:642-6. PMID 3839363
138: Townes PL, Wood BP, McDonald JV. Further heterogeneity of the oral-facial-digital syndromes. Am J Dis Child 1976;130:548-54. PMID 179315
139: Tsai PS, O’Brien JM. Retinal hamartoma in oral-facial-digital syndrome. Arch Ophthalmol 1999;117:963-5. PMID 10408465
140: Tsurusaki Y, Kosho T, Hatasaki K, et al. Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients. Clin Genet 2013;83(2):135-44. PMID 22548404
141: Varadi V, Szabo L, Papp Z. Syndrome of polydactyly, cleft lip/palate or lingual lump, and psychomotor retardation in endogamic gypsies. J Med Genet 1980;17:119-22. PMID 7381865
142: Velepic MS, Sasso A, Velepic MM, Lustica I, Starcevic R, Komljenovic D. Combined anomalies of the palate in Mohr syndrome: is preoperative electromyography of the palate useful. J Pediatr Surg 2004;39(2):220-2. PMID 14966745
143: Verloes A, Gillerot Y, Langhendries JP, Fryns JP, Koulischer L. Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome. Am J Med Genet 1992;43:669-77. PMID 1621756
144: Wang HL, Chiang FY, Tai CF, Tsai KB, Wang LF. Lingual leiomyomatous hamartoma with bifid tip and ankyloglossia in a patient without oral-facial-digital syndrome: a case report and literature review. World J Surg Oncol 2013;11:230. PMID 24040829
145: Wang J, Chen X, Wang F, et al. OFD1, as a ciliary protein, exhibits neuroprotective function in photoreceptor degeneration models. PLoS One 2016;11(5):e0155860. PMID 27196396
146: Wang X, Zheng C, Liu W, Yang H. Retinitis pigmentosa and bilateral idiopathic demyelinating optic neuritis in a 6-year-old boy with OFD1 gene mutation. Case Rep Ophthalmol Med 2017;2017:5310924. PMID 28191358
147: Wentzensen IM, Johnston JJ, Patton JH, Graham JM, Sapp JC, Biesecker LG. Exome sequencing identifies a mutation in OFD1 in a male with Joubert syndrome, orofaciodigital spectrum anomalies and complex polydactyly. Hum Genome Var 2016;3:15069. PMID 27081566
148: Wiesener A, Knaup KX, Büttner-Herold M, et al. Molecular diagnosis of kidney transplant failure based on urine. Am J Transplant 2020;20(5):1410-6. PMID 31814324
149: Yamada M, Uehara T, Suzuki H, et al. IFT172 as the 19th gene causative of oral-facial-digital syndrome. Am J Med Genet A 2019;179(12):2510-3. PMID 31587445
150: Yavuz YC, Ganidagli SE, Yilmaz T, et al. Orofacial digital syndrome type 1: an underlying cause of chronic renal failure. Ren Fail 2014;36:946-947. PMID 24713104
151: Yildirim S, Akan M, Deviren A, Akoz T. Penile agenesis and clavicular anomaly in a child with an oral facial digital syndrome. Clin Dysmorphol 2002;11:29-32. PMID 11822702

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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Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

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

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

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