Oral-facial-digital syndromes By Joseph R Siebert PhD (Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.) Originally released February 12, 1996; last updated July 1, 2017; expires July 1, 2020

Introduction

This article includes discussion of oral-facial-digital syndromes, dysplasia linguofacialis, Mohr syndrome, Mohr- Majewski syndrome, orodigitofacial , orofaciodigital syndrome, oro-facio-digital syndrome, Thurston syndrome, Varadi syndrome, oral-facial-digital syndrome type I, oral-facial-digital syndrome type II, oral-facial-digital syndrome type III, oral-facial-digital syndrome type IV, oral-facial-digital syndrome type IX, oral-facial-digital syndrome type V, oral-facial-digital syndrome type VI, oral-facial-digital syndrome type VII, oral-facial-digital syndrome type VIII, and oral-facial-digital syndrome type X. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Oral-facial-digital syndrome represents a spectrum of extremely variable congenital conditions whose diversity has engendered considerable discussion. Major changes include hypertrophic frenula, lingual hamartomas, cleft lip or palate, ocular hypertelorism, , , and . Other organ systems are affected as well, especially the central and urinary tract. Mutations in the OFD1 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 . Careful physical and genetic workups are, therefore, necessary. As the delineation of syndromes continues, the classification of this complex condition will evolve.

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 , cerebral dysgenesis, porencephaly, or midline cerebral and cerebellar defects. • Research has shown that mutations in the OFD1 gene alter a centrosomal in the 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 continues, 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 (Papillon-Leage and Psaume 1954), although a case of apparent Mohr syndrome appears in the older literature (Case 460 of Otto monstrorum sexcentorum descriptio anatomica, 1841: Beckwith personal communication). Gorlin and colleagues published the first English report of the disorder (Gorlin et al 1961). Since then, several hundred patients have been reported and at least 12 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 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 (Rimoin and Edgerton 1967). These authors suggested the existence of 2 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 2 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 (Toriello 1993; Moran-Barroso et al 1998; Gurrieri et al 2007). 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 ; 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; • 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: central polydactyly (though not a uniform finding) (Darmency-Stamboul et al 2013); lingual and sublingual lumps; hypothalamic hamartoma; cerebellar dysgenesis with molar tooth sign; optochiasmatic pilocytic astrocytoma in 1 patient (Sarma et al 2015) • 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 et al 1988) • 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) (Gurrieri et al 1992; Jamieson and Collins 1993; Nagai et al 1998; Erickson and Bodensteiner 2007; Adly et al 2014) • Distinguishing feature: retinochoroidal coloboma; severe microcephaly; Dandy-Walker malformation; retrobulbar ; short stature • Inheritance: autosomal recessive Oral-facial-digital syndrome X (aka, Figuera syndrome) (Figuera et al 1993) • Distinguishing feature: fibular aplasia • Inheritance: autosomal recessive Oral-facial-digital syndrome XI (aka, Gabrielli syndrome) (Gabrielli et al 1994; Guven et al 2009) • 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) (Moran-Barroso et al 1998) • Distinguishing feature: myelomeningocele; stenosis of aqueduct of Sylvius; dysplasia of atrioventricular valves • Inheritance: autosomal recessive Oral-facial-digital syndrome XIII (aka, Degner syndrome) (Degner et al 1999) • 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 (Fenton and Watt-Smith 1985; Neri et al 1995). 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.

At present, classification is complex, making the process of discerning new types of oral-facial-digital syndrome demanding (Gorlin et al 1990; Gurrieri et al 1992; Camera et al 1994; Toriello et al 1997; Moran-Barroso et al 1998).

Distinction between autosomal recessive oral-facial-digital and other syndromes has also been challenged (Hingorani et al 1991; Lin et al 1991; Muenke et al 1991; Verloes et al 1992; Franceschini et al 1995; Neri et al 1995). In particular, some patients with Beemer-Langer syndrome, Pallister-Hall syndrome, and Majewski short- polydactyly syndrome have phenotypic features indistinguishable from variants 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 remains to be clarified (Macca and Franco 2009). Mutations in OFD1 occur in familial (X-linked) cases of type 10 (Field et al 2012) and Simpson-Golabi-Behmel syndrome type 2 (Bisschoff et al 2013). 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” (Poretti et al 2012). This viewpoint has gained support from molecular studies. For example, the major gene responsible for OFD type VI (C5orf42) is also found in patients with Joubert syndrome (Lopez et al 2014). Continuing studies suggest that these mutations may be responsible for polydactyly, hypothalamic hamartoma, and other defects, but not tongue hamartomas (Romani et al 2015). 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 (Saitsu et al 2016). Others have employed molecular-based classifications, suggesting that these conditions belong to a distinct spectrum characterized by truncating OFD1 mutations (Tsurusaki et al 2013). Townes and colleagues documented clinical or anatomic evidence of cerebral abnormalities in 3 patients with oral- facial-digital syndrome and cited 16 other examples among 150 previous case reports (Townes et al 1976). Towfighi and colleagues reviewed the neuropathology of oral-facial-digital syndrome type I and found only 4 other studies in which sufficient neuroanatomic findings were discussed (Towfighi et al 1985). 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 (Anneren et al 1990; Leao and Ribeiro-Silva 1995). The finding of global cerebral dysgenesis in a fetus with oral-facial-digital syndrome (Lesca et al 2006) may be explained through involvement of the LisH (LIS1 homology) domain described in patients with oral-facial-digital syndrome type 1 (Gerlitz et al 2005).

Clinical manifestations

Presentation and course

At least 2 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 (Edwards et al 1988). In addition to these genetically distinct variants, additional variants have been proposed based on clinical differences. Such cases appear frequently in the literature (Moran-Barroso et al 1998; Al-Gazali et al 1999; Chung and Chung 1999; Degner et al 1999; Hayes et al 2008); 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), facial (cleft lip, ocular hypertelorism), and digital (brachydactyly, polydactyly, syndactyly) malformations. The maxillary, mandibular, and lingual frenula are broad and short or atrophic (Tagliani et al 2010). Accessory frenula may be present, although these may be more suggestive of Pallister-Hall syndrome (Mintz et al 2005). 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 (Leonardi et al 2004). 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 (Ghossaini et al 2002), whereas some may be leiomyomatous (Wang et al 2013). 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 3 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 (Anneren et al 1984). Patients with type I disease may also show dislocated radial heads and cone-shaped distal femoral epiphyses (Khalifa et al 2012). 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 and , cardiac malformations, skeletal dysplasia (particularly mesomelic), cutaneous findings, and central nervous system malformations (Holub et al 2005; Siebert 2008; Chetty-John et al 2010; Iijima et al 2016). 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 were variably interpreted as type II, VI, or a new form of oral-facial-digital syndrome (Yildirim et al 2002). 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 (Yavuz et al 2014). 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 (), chiefly in females (Toprak et al 2006). 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 (Townes et al 1976; Towfighi et al 1985; Reardon et al 1989; Anneren et al 1990; Leao and Ribeiro-Silva 1995; Del Giudice et al 2014). 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 (Thauvin-Robinet et al 2011; Azukizawa et al 2013). 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-facia- -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 (Reuss et al 1962). 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 . An occipital encephalocele has been reported in at least one fetus with oral-facial-digital syndrome and Dandy-Walker malformation (Suresh et al 1995), 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-facia- -digital syndrome type I (Odent et al 1998). In most cases, the cysts are multiple and asymmetric and involve diverse portions of the cerebral hemisphere. Communication between the and ventricular lumen has been observed; however, more often, the cysts are isolated. A single large cyst may predominate and contribute to .

Ependymal cysts. Interhemispheric or periventricular spaces lined by ciliated columnar 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 (Hingorani et al 1991). Focal and dramatic asymmetric growth in the brainstem may result as well (Townes et al 1976; Towfighi et al 1985).

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) (Munke et al 1990). 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 (Coene et al 2009).

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 (Stephan et al 1994). The most dramatic examples are large tumors that radiate into the thalamus and brainstem (Somer et al 1986; Hingorani et al 1991). 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 (Somer et al 1986). In addition, absent pituitary gland has been reported in patients without hypothalamic hamartomas (Shashi et al 1995; Al-Gazali et al 1999). 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 (Verloes et al 1992). Histologically, these lesions are composed of disordered collections of mature and immature neurons, glial cells, and myelinated fiber tracts (Boyko et al 1991).

Chorioretinal anomalies. Patients with oral-facial-digital syndrome and chorioretinal and optic nerve colobomata ("lacunae") have been described (Gurrieri et al 1992; Jamieson and Collins 1993; Nevin et al 1994; Stevens and Marsh 1994; Sigaudy et al 1996). 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 (Tsai and O'Brien 1999).

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 (Leao and Ribeiro-Silva 1995).

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, , ataxia, deafness, precocious puberty, and failure to thrive have all been reported. The severity of intellectual deficit varies greatly. In an early review of the subject, Reuss and colleagues estimated that "one-third to one-half of patients with oral-facial-digital syndrome are mentally defective," the remainder having "average or better intellectual development" (Reuss et al 1962). A formal comparison of affected and unaffected female family members in a large kindred revealed a range of performance from "average" to "profoundly retarded" in individuals with oral-facial-digital syndrome type I (Doege et al 1968). Comparative studies of large numbers of other variants of oral-facial-digital syndrome have not been reported, but existing case reports suggest the recessive forms of oral-facial-digital syndrome are characterized by a similar wide range of cognitive ability and behavioral changes, including some individuals with normal intelligence (Rimoin and Edgerton 1967; Fenton and Watt-Smith 1985; Del Giudice et al 2014).

Seizures have been reported in a small number of patients with oral-facial-digital syndrome and were vaguely described as "familial trembling," "rigid spells," or "muscle spasms that might have been convulsions" (Mohr 1941; Papillon-Leage and Psaume 1954; Co-Te et al 1970). Generalized seizures have been rarely observed. Blepharospasm, nystagmus, and "see-saw" eye winking have been observed in patients (Sugarman et al 1971). A specific variant of autosomal recessive oral-facial-digital syndrome (type III) is distinguished by the presence of "see-saw" eye winking (Toriello 1988). Speech impairments are common in all forms of oral-facial-digital syndrome because of the oral manifestations of the disorder. Similarly, digital malformations may affect fine motor movements. Intermittent apnea and hyperpnea have both been reported in multiple patients. Werdnig-Hoffmann disease has been diagnosed in a patient with oral-facial-digital syndrome type I and normal female karyotype (Hashimoto et al 1998). This association was considered incidental because of the patient's normal , but the observation is an important one and bears further watchfulness. Werdnig-Hoffmann disease arises from a deletion in the survival motor neuron (SMN) gene on 5q (Melki et al 1990; Melki et al 1994), and the 5q deletion syndrome shares some phenotypic resemblance with oral-facial-digital syndrome (Kleczkowska et al 1993).

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 (Toriello et al 1997). 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 (Squires et al 1995). 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 (Al-Gazali et al 1999). Orthodontia may be necessary (Ozturk and Doruk 2012), 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 (Gunbay et al 1996; Velepic et al 2004). Odontogenic , both recurrent and de novo, are another complication (Lindeboom et al 2003). Conductive hearing loss has been reported in many patients. Renal insufficiency in one female with oral-facia- -digital syndrome type I was treated with transplantation at 19 years; she was well at 23 years (Stoll and Sauvage 2002). Vaginal atresia has been described in one patient with oral-facial-digital syndrome type I (Su et al 2008).

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 continue to be identified for the diverse forms of the syndrome.

Approximately 75% of cases of oral-facial-digital syndrome type I are sporadic (Feather et al 1997); however, at least 2 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 (Edwards et al 1988). 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 (Franco and Ballabio 2006; Thauvin- Robinet et al 2006).

New information regarding the genetic heterogeneity of the oral-facial-digital syndromes continues to appear. Oral- facial-digital syndrome type I is caused by mutations in OFD1 (CXORF5), which has been mapped to the short of the X (Xp22.2-Xp22.3) (Chetty-John et al 2010). A mouse model (X-linked dominant Xp1 mutant), manifesting polydactyly and renal cystic disease, maps to the homologous region on the (Feather et al 1997). CXORF5, also mapped to Xp22, appears to be a candidate gene for several diseases that include oral-facia- -digital syndrome type I, spondyloepiphyseal dysplasia late, craniofrontonasal syndrome, and nonsyndromic sensorineural deafness (de Conciliis et al 1998). 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 (Ferrante et al 2001; Morisawa et al 2004; Prattichizzo et al 2008). 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 (Ferrante et al 2001). The protein in mice is required for cilia formation and left-right axis specification (Ferrante et al 2006). The ofd1 gene protects photoreceptors from oxidative stress and apoptosis, whereas mutations cause (Wang et al 2016). OFD1 localizes to primary cilia and encodes a or basal body protein that is required for length and the assembly of primary cilia (Prattichizzo et al 2008; Singla et al 2010; Lopes et al 2011). OFD1 contains the epidermal growth factor receptor (EGFR) and flotillin proteins, which are important components of the ciliary signaling complex (Jerman et al 2014). Deletions in OFD1 lead to centriole hyperelongation and resultant ciliopathies (Thauvin-Robinet et al 2014). 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, cycle regulation, protein trafficking, and photoreception (Sattar and Gleeson 2011). Further complicating this is the observation that dozens of genes may be responsible for ciliopathies (Adly et al 2014). 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 (Roberson et al 2015). The OFD1 protein also regulates neuronal differentiation in embryonic stem cells (Hunkapiller et al 2011) and is required in limb bud patterning and endochondral bone formation (Bimonte et al 2011). 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 (Budny et al 2006). OFD1 is conserved in vertebrates and absent in invertebrates (Ferrante et al 2003).

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 (Montini et al 1998).

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 (Kang et al 1997a; Kang et al 1997b; Kang et al 1997c). The possibility of postzygotic mutation as a mechanism has also been raised because of the finding of type I oral-facia- -digital syndrome in one set of (molecularly proven) monozygotic twins (Shotelersuk et al 1999). 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 OFD IV and Meckel syndrome (Thomas et al 2012). Additional evidence for the involvement of sonic hedgehog comes from experimental study of mice with Ofd1 inactivation and forebrain anomalies (D'Angelo et al 2012). 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 (Adly et al 2014; Li et al 2017). In addition to recognized mutations, it seems that ancestral genetic factors may also play a role in the development of specific phenotypes (Al-Qattan and Javed 2014).

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 (Feather et al 1997). 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 (Romio et al 2003). 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 , for example, and contribution to mesenchymal-epithelial transition may help explain the renal cystic anomalies found in some of the oral-facial-digital syndromes (Romio et al 2004; Izzi et al 2010). 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 (Toriello 2009). This has received support in both zebrafish and mouse models (Ferrante et al 2009). In addition to ciliary function, OFD1 is associated with chromatin plasticity and DNA repair, which may also contribute to the heterogeneity of malformations (Abramowicz et al 2017).

Epidemiology"

An incidence of 1 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 (Jacquemart et al 1980). Multiple cases of oral-facia- -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 (Varadi et al 1980); however, cases have been observed in other ethnic groups as well (Munke et al 1990). 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 (Chung and Chung 1999). 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 (Jugessur et al 2012).

Differential diagnosis

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 (Fenton and Watt-Smith 1985; Silengo et al 1987; Hingorani et al 1991; Neri et al 1995; Panigrahi et al 2013). 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 (Verloes et al 1992). Pallister- Hall syndrome is characterized by oral frenulae, palatal defects, median cleft lip, polydactyly, and cerebral malformations (Clarren et al 1980). 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 (Hingorani et al 1991; Verloes et al 1992); 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 (Grebe and Clericuzio 1996). 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 (Kang et al 1997c). 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 (Coene et al 2009), as well as Goldenhar syndrome (oculo-auriculo-vertebral spectrum) and oculo-auriculo-fronto-nasal syndrome (Guven et al 2009).

Partial or complete cerebellar dysgenesis is the primary finding in Joubert-Boltshauser syndrome (Joubert et al 1969; Egger et al 1982). The latter is an autosomal recessive disorder characterized by partial or complete absence of the , hyperpnea, and abnormal eye movements. Hyperpnea and nystagmus (including vertical nystagmus) have been reported in oral-facial-digital syndrome as well (Gustavson et al 1971). Many patients with Joubert-Boltshauser syndrome have polydactyly and one infant had "fleshy tongue nodules" (Egger et al 1982). 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” (Gleeson et al 2004; Chodirker et al 2005; Poretti et al 2008). 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 (Nanda et al 2010).

Diagnostic workup

Prenatal diagnosis of type I oral-facial-digital syndrome is possible and most often relies on findings, which can be enhanced by fetal autopsy in nonsurvivors (Shipp et al 2000; Thauvin-Robinet et al 2001). However, because the changes in the oral-facial-digital syndromes are so variable and can be minimal, ultrasound diagnosis is not at all straightforward (Atahan et al 2004). Prenatal MRI may augment ultrasound, eg, molar tooth sign and hypothalamic hamartoma in oral-facial-digital syndrome type VI (Poretti et al 2008). Researchers have suggested that the shortened humerus is a marker for oral-facial-digital syndrome type II (Pradhan et al 2007) and that the shortened ulna may be indicative of oral-facial-digital syndrome type IV (Kahl et al 2007). 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 x- rays should be obtained to screen for missing teeth. The digits must be carefully inspected for subtle malformations such as brachydactyly, , 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 (Roosing et al 2016). Exome sequencing is finding increasing use in identifying mutations in patients (Bayram et al 2015; Wentzensen et al 2016).

Management

Management has to be tailored to each patient individually because the type and severity of anomalies vary so greatly. 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 (Sakai et al 2002). 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 (John et al 2013; Gonzalez et al 2014). 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 (Shimojima et al 2013; Roosing et al 2016).

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 by patients with hamartomatous lesions exists.

Anesthesia

Because of the anomalies that involve the oral cavity, anesthesia can be challenging (McKinnie et al 2014).

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**References especially recommended by the author or editor for general reading.

Former authors

Raj P Kapur MD PhD (original author)

ICD and OMIM codes

ICD codes

ICD-9: Oral-facial-digital syndrome: 759.87

ICD-10: Oro-facial-digital syndrome: Q87.0

OMIM numbers

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

Profile

Age range of presentation

0-01 month

Sex preponderance female>male, >1:1

Family history family history may be obtained

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

Differential diagnosis list

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

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

Other topics to consider

Cephaloceles Ependymal cysts Dandy-Walker syndrome Joubert syndrome Myelomeningocele

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