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).

Epidemiology

An incidence of one case per 250,000 live births has been calculated. The frequency of this syndrome among patients with cleft lip or palate is significantly greater, 8 to 16 per 1000 (60). Multiple cases of oral-facial-digital syndrome type VI (Varadi syndrome), which is characterized by cerebellar dysgenesis and central polydactyly, were first described in a large pedigree of European gypsies (141); however, cases have been observed in other ethnic groups as well (86). Oral-facial-digital syndrome type V (Thurston syndrome) has only been ascribed to persons of Indian background, though a child with findings overlapping with types V and VI has been reported from China (20). The prevalence of oral-facial-digital syndrome and association with other anomalies varies, even among populations with seemingly related genotypes, for example Danes and Norwegians (65).

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).

Management

Management has to be tailored to each patient individually because the type and severity of anomalies vary so greatly. The extensive spectrum of clinical manifestations is an example of the paradigm of the complexity of genetic disease (95). In patients with lethal anomalies (eg, severe pulmonary hypoplasia, congenital heart defects, or devastating brain anomalies), minimal supportive care may be the most appropriate management. Most other patients require one or more surgical procedures to remove extra digits or ameliorate oral anomalies, such as clefts, frenula, and lingual tumors (109). Surgeons need to be alert to possible syndromic diagnoses as they treat these myriad problems, and they need to realize that the presence of oral anomalies may complicate the repair of facial clefts (63; 44). In addition, some type of ventricular shunt may be required for hydrocephalus. Many patients benefit from gastrostomy tube placement to ameliorate feeding difficulties and failure to thrive. All affected individuals should have comprehensive auditory and visual examinations. Genetic counseling for patients and their families is important and may be complex given the degree of patient variability (114; 107).

Special considerations

Pregnancy

Insufficient information exists concerning reproductive function in patients with oral-facial-digital syndrome. Early spontaneous abortion of affected male embryos is common with the X-linked dominant form of oral-facial-digital syndrome (oral-facial-digital syndrome type I); however, patients with oral-facial-digital syndrome type I are clearly fertile, for the disorder is transmitted in families as an X-linked dominant condition. As the hypothalamic-pituitary axis is disrupted in most patients with hypothalamic hamartomas, a variety of endocrine dysfunctions including reproductive problems might be expected. No information regarding reproduction by patients with hamartomatous lesions exists.

Anesthesia

Because of the anomalies that involve the oral cavity, anesthesia can be challenging (80).