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Oral-Facial-Digital Syndromes by Joseph R Siebert Phd (Dr

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Oral-Facial-Digital Syndromes by Joseph R Siebert Phd (Dr 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 dysostosis, 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, 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. 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 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 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 (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 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: 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 syndrome) (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 cysts; 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-rib 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 proteins remains to be clarified (Macca and Franco 2009). Mutations in OFD1 occur in familial
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