Otodental Dysplasia
A number sign (#) is used with this entry because of evidence that otodental dysplasia is caused by contiguous gene microdeletion at chromosome 11q13 in a region containing the FGF3 gene (164950).
Otodental dysplasia and coloboma is associated with microdeletion at chromosome 11q13 involving haploinsufficiency of multiple genes, including FGF3 and the FADD gene (602457).
DescriptionOtodental syndrome is an autosomal dominant condition characterized by grossly enlarged canine and molar teeth (globodontia), associated with sensorineural hearing loss. Ocular coloboma segregating with otodental syndrome has been reported (summary by Gregory-Evans et al., 2007).
Clinical FeaturesLevin et al. (1975) and Levin and Jorgenson (1972, 1974) described a syndrome of sensorineural hearing loss and dental anomalies in a 6-generation kindred of Italian ancestry. A high frequency hearing loss varied in onset from early childhood to middle age. The maxillary deciduous canines and the deciduous and permanent molars were large and bulbous, but the incisors were normal. Premolars were congenitally missing in half of affected persons. On dental radiographs, the deciduous molars frequently appeared to have 2 separate pulp chambers. Taurodontia and pulp stones were also noted. Additional families with the disorder were described by Jorgenson et al. (1975) and Witkop et al. (1976). Cook et al. (1981) reported audiologic follow-up of the family originally studied by Jorgenson et al. (1975), and noted flat, severe, bilaterally symmetrical sensorineural losses in their cases.
Santos-Pinto et al. (1998) examined an affected mother, son, and daughter from a 3-generation Brazilian family, originally reported by de Toledo et al. (1971), in which multiple members had globodontia. All 3 examined individuals had deformed maxillary arches, large and bulbous canines, globe-shaped molars, delayed eruption of teeth of about 1 year, and multiple missing primary and/or permanent teeth. The mother did not have hearing loss, the son had partial hearing loss in adolescence, and the daughter had lost hearing in early childhood, following frequent ear abscesses. None of the patients had coloboma. The son and daughter had long facies with 'strong mentalis activity,' and the daughter had a full-cheek appearance. The authors noted that Witkop et al. (1976) had observed that patients with otodental syndrome had long facies, anteverted nostrils, long philtrum and a full-cheek appearance.
Van Doorne et al. (1998) described a 12-year-old Belgian boy who had characteristic features of otodental syndrome, including a symmetric dolichofacial appearance, high-frequency sensorineural hearing loss, and abnormalities of deciduous and permanent dentition with bulbous canines and globe-shaped posterior teeth. Previously unreported findings in this patient included generalized macrodontia, the combination of hypodontia and hyperdontia, with maxillary agenesis of premolars as well as presence of supplementary canines, and significant delay in mineralization of the premolars. Investigation of the family revealed that the patient's father had sensorineural hearing loss since childhood, bulbous cuspids, and globodontic morphology of 2 remaining mandibular molars, with normal appearance of the 4 mandibular incisors. The patient had an older brother who was unaffected except for the presence of a lateral incisor that was fused with a supplementary tooth; his grandmother, great-grandmother, as well as other sibs were reported to have had dental abnormalities and hearing problems, suggestive of autosomal dominant inheritance.
Sedano et al. (2001) reported a 5-year-old boy who had normal maxillary and mandibular incisors but markedly macrodontic, globular teeth in the premolar and molar areas of all quadrants as well as the canines. Two canines and 1 of the other teeth demonstrated areas of yellow hypoplastic enamel. Radiographs revealed that some of the abnormal teeth had bifurcated pulp chambers and pulp stones, and premolar tooth germs were absent. Audiometry showed marked bilateral sensorineural hearing loss for frequencies above 1000 Hz. Intraoral examination of the parents, sister, maternal grandmother, and paternal grandparents revealed no dental abnormalities like those of the proband, and audiometric examination was normal in all 6 relatives.
Gregory-Evans et al. (2007) studied the Brazilian family originally reported by de Toledo et al. (1971) and found that pathologic examination of extracted affected teeth suggested fusion of a number of original teeth rather than true globodontia. Many affected individuals in this family also displayed marked palate abnormalities, causing narrowing and crowding of the incisor region and micrognathia. Detailed ophthalmologic examination in this family and the Belgian family originally described by Van Doorne et al. (1998) did not reveal any ocular coloboma. Affected patients from both pedigrees described partial hearing loss from their earliest memories, and audiometry confirmed high-frequency loss from an early age.
Otodental Dysplasia and Coloboma
Winter (1983) reported a 3-generation English family in which a mother, 2 daughters, and 2 granddaughters had high-frequency hearing loss and large 'dome-shaped' or 'bell-shaped' canines and molars with normal incisors, associated with unilateral or bilateral colobomata in 4 of the 5 affected individuals. A mesial yellowish-brown area of enamel hypoplasia was observed on the cervical aspect of a canine tooth. Radiographs showed large, irregularly forming permanent teeth, some of which appeared partially fused together. Histologic examination of a lower premolar tooth showed a supernumerary element fused to the main tooth-like mass, and the 2 coronal elements had a common pulp chamber. Pulp stones were also noted.
Vieira et al. (2002) examined 7 affected and 6 unaffected individuals from the British family with otodental syndrome originally studied by Winter (1983) and found that all affected individuals had iris and retinal coloboma associated with high-frequency progressive sensorineural deafness and globodontia. The ocular defects were markedly variable, and included microcornea, microphthalmos, lens opacity, and lens coloboma in addition to iris and retinal coloboma, and there was marked asymmetry in eye signs in 3 individuals. The hearing loss began in infancy in all individuals and progressed to a plateau by approximately 35 years of age. Although the incisors were relatively spared, the authors emphasized that those teeth were not normal, and all teeth that had not been removed showed yellowing and pitting indicative of enamel defects. In all affected individuals who had undergone radiography, enlarged pulp chambers (taurodontism), pulp stones, and abnormal roots were seen. Vieira et al. (2002) stated that this is the only genetic disease known to result in pathologically enlarged teeth.
MappingVieira et al. (2002) performed genomewide linkage analysis in the British family with otodental syndrome and coloboma originally studied by Winter (1983) and found significant linkage to chromosome 20q. However, in subsequent analysis of this family ('OD2') as well as the Brazilian ('OD1') and Belgian ('OD3') families with otodental syndrome, originally described by de Toledo et al. (1971) and Van Doorne et al. (1998), respectively, Gregory-Evans et al. (2007) demonstrated linkage to chromosome 11q, obtaining a single lod score peak of 3.9 on chromosome 11q13 in family OD1 and identifying segregating haplotypes at 11q13 in families OD2 and OD3.
Molecular GeneticsIn a Brazilian ('OD1') and a Belgian ('OD3') family with otodental syndrome, originally described by de Toledo et al. (1971) and Van Doorne et al. (1998), respectively, and in a British family with otodental syndrome and coloboma ('OD2'), originally reported by Winter (1983), Gregory-Evans et al. (2007) identified overlapping hemizygous microdeletions on chromosome 11q13 by SNP and Southern blot analysis. Family OD3 had the smallest deletion, an approximately 43-kb microdeletion extending from rs9666584 in the 5-prime untranslated region of the FGF4 gene (164980) to rs41408348 in the 5-prime untranslated region of the FGF3 gene, whereas family OD1 had an approximately 432-kb deletion, extending from rs9666584 to rs3740720 and encompassing the FGF3, C11ORF78, and TMEM16A genes (ANO1; 610108). Family OD2, in which affected individuals displayed ocular coloboma as well as otodental dysplasia, had the largest deletion, spanning up to 490 kb between rs9666584 and rs11235675 and encompassing the FGF3, C11ORF78, TMEM16A, and FADD (602457) genes. Gregory-Evans et al. (2007) suggested that FGF3 haploinsufficiency is likely the cause of otodental syndrome and that FADD haploinsufficiency accounts for the associated ocular coloboma.