Failure Of Tooth Eruption, Primary

A number sign (#) is used with this entry because of evidence that primary failure of tooth eruption (PFE) is caused by heterozygous mutation in the PTHR1 gene (168468) on chromosome 3p21.

See also 157950 and 273050 for phenotypes with shared features of PFE.

Clinical Features

Shokeir (1974) described autosomal dominant inheritance of failure of eruption of permanent teeth. The primary dentition persisted in the adult; however, the proband showed complete or partial eruption of 11 permanent teeth.

Proffit and Vig (1981) described the characteristic features of primary failure of tooth eruption: posterior teeth are more commonly affected, and the bite distal to the first affected tooth is usually completely open; the affected teeth may or may not have initially erupted into occlusion before submerging; deciduous teeth, especially second deciduous molars are commonly submerged; involvement may be unilateral or bilateral; involved permanent teeth may become ankylosed after failure of eruption has occurred; orthodontic extrusion is unsuccessful and usually leads to ankylosis; and although other members of the family may be affected they are not usually close relatives. Proffit and Vig (1981) noted that the radiographs of the index cases with 'reinclusion of permanent molars' (157950) studied by Bosker et al. (1978) showed the same characteristics as their own patients with primary failure of eruption (PFE).

Bianchi and Roccuzzo (1991) described 3 cases and reviewed 9 published cases of primary impaction of primary second molars, in which there was no physical barrier to the eruption of the primary teeth and ankylosis appeared to be excluded. There was frequent passing of the corresponding permanent tooth and sometimes retention of the adjacent mesial bicuspid.

Rasmussen and Kotsaki (1997) described 5 cases, including 2 brothers, from a collection of 14 patients who had inherited retarded eruption in the permanent dentition as well as primary failure of eruption of one or more primary second molars. In total, 14 teeth underwent primary failure of eruption (PFE): 2 of the patients had all 4 molars unerupted; the other patients had 3, 2, and 1 unerupted tooth, respectively. There were no significant differences between sexes, jaws, or sides. The unerupted teeth were always deeply seated, most often beyond the positions where they normally develop, and in most cases their axial angulation was correct. There was no evidence of post-eruption impaction due to ankylosis. In nearly all cases the impacted teeth remained deeply buried and increased their distance from the occlusal plane with increasing age, and often there remained an open 'chimney' from the occlusal surfaces of the teeth to the margins of the alveolar processes, most visible in the mandible. The eruption of the other primary teeth was reported by parents to have been uneventful. None of the unerupted primary teeth ever erupted, and there was severely retarded eruption of all teeth in the permanent dentition. Only 1 of the cases appeared to be isolated; the others had affected sibs, parents, and/or grandparents. A conspicuous feature was the high prevalence of hypodontia, which affected 3 of the 5 cases with a total of 8 missing teeth, which were all second premolars succedaneous to unerupted primary molars. Rasmussen and Kotsaki (1997) stated that pedigree analysis of previously reported families segregating primary failure of eruption in the primary dentition combined with severely retarded eruption in the permanent dentition pointed to a single gene effect with autosomal dominant transmission.

O'Connell and Torske (1999) reported a 6-year-old girl with primary retention in the deciduous dentition and the entire permanent dentition, involving incisors, molars, and premolars in all quadrants. At 3.75 years of age, only 6 teeth had erupted (all central incisors and the lower lateral incisors); panoramic radiograph revealed the presence of all primary teeth and appropriate development of the permanent teeth. At 6 years of age, 13 of her primary teeth had erupted, and they were normal in size, shape, and quality of enamel. Radiographically all primary teeth were present, and the permanent tooth buds of all teeth except the upper second premolars were identified. Comparison with previous radiographs revealed that there had been little progress in tooth eruption; however, continued root development of the permanent teeth was noted, without progress toward the alveolar crest. In addition to the significant delay, the sequence of eruption was inappropriate, with the upper lateral incisors erupting more than 1 year apart and later than the cuspids and first molars. By age 10, no more teeth had erupted and the patient had shown minimal response to repeated surgical intervention exposing the permanent molars to facilitate eruption; the only occlusal contact was on the primary incisors, which had begun to exhibit resorption and mobility. She had normal growth and development otherwise, with no craniofacial, dermal, or skeletal dysmorphologies. There was 1 older brother with no dental problems, and no family history of dental anomalies. O'Connell and Torske (1999) stated that this was the first report of generalized primary retention or idiopathic failure of tooth eruption.

DiBiase and Leggat (2000) reported 2 sisters with bilateral posterior open bite due to eruption failure of the permanent dentition, most notably of the first and second molars, with greater severity in the younger sister. In both cases teeth were exposed and traction placed on them with little or no effect. An unusual feature in the sisters was the normal eruption of the upper third molars, distal to the posterior open bite. There was reported eruption failure involving permanent teeth in their father, although his records were unavailable.

Ahmad et al. (2006) analyzed 5 new and 35 published cases of PFE affecting teeth in the permanent dentition (other than the third molars). Cases were excluded from the study if there was evidence of a mechanical, pathologic, or systemic cause of obstruction, or evidence of successful orthodontic extrusion of the affected tooth or teeth. The authors suggested that the term PFE might incorporate 2 independent conditions, 1 with a localized complete failure of tooth eruption and 1 where there is some initial eruption of the affected tooth or teeth prior to the eruption failure, a condition also described as 'secondary retention' (see 157950); however, they also noted that PFE might represent a single disorder of tooth eruption with differing degrees of severity, a hypothesis supported by the fact that these 2 manifestations can occur the same subject. A family history of eruption failure or eruption problems in the primary dentition was present in 18 (40%) of the 40 cases in this study, in contrast to that of Proffit and Vig (1981). Hypodontia, a dental anomaly of known genetic origin (see 106600), was present in 5 (13%) of the PFE cases, suggesting that PFE might have a significant genetic component.

Frazier-Bowers et al. (2007) stated that PFE describes a condition in which malfunction of the eruption mechanism causes nonankylosed teeth to fail to erupt. The primary identifying characteristic is failure of an affected tooth to move along the eruption path that has been cleared for it; involved teeth can erupt partially and then cease to erupt, becoming relatively submerged although not ankylosed. Only posterior teeth are affected, resulting in a posterior open bite, and all teeth distal to the most mesial affected tooth are also affected. The condition is rarely symmetric and frequently unilateral, but can affect any or all of the posterior quadrants. A key characteristic is an abnormal or complete lack of response to orthodontic force; the authors noted that a nonankylosed tooth with PFE is likely to become ankylosed when force is applied.

Frazier-Bowers et al. (2007) studied radiographs and clinical records of 97 cases of failure of posterior eruption; 15 were familial cases from 9 families in which pedigree analysis by inspection was strongly suggestive of autosomal dominant inheritance. The authors classified 38 of the 97 cases as PFE and 19 as mechanical failure of eruption (MFE) due to ankylosis; in 32 cases, a definitive diagnosis could not be made without additional longitudinal data, and in 8 cases the affected teeth were not in occlusion but were not submerged as in PFE and MFE. The PFE group had 3 distinguishable forms: 17 of the 38 patients, designated 'type I,' had a similar lack of eruption potential of all affected teeth, with a progressive open bite from anterior to posterior; 11 patients ('type II') had variable eruption potential among the affected teeth, and displayed a tooth distal to the most mesial affected tooth with greater though inadequate eruption; and 10 patients had both types coexisting in different quadrants. There appeared to be no difference in subtypes of PFE between those with and without a family history of eruption problems. At least 1 ankylosed deciduous tooth was noted in 24 of the 97 patients, 4 patients had hypodontia, 5 had hyperdontia, and 3 had taurodontism; no other dental anomalies were noted. Other than ankylosed deciduous molars (in 5 of 15 patients), no other dental anomalies were found in the familial group.

Mapping

Decker et al. (2008) genotyped 8 affected and 4 unaffected members of a 3-generation German family segregating autosomal dominant PFE. Parametric linkage analysis with a dominant model revealed 2 regions with a maximum lod score of 2.41, a 31.8-Mb interval on chromosome 3p24.3-p14.3, flanked by markers rs1402366 and rs13074914, and an 8-Mb interval on chromosome 13q31.3-q33.1, flanked by markers rs1328369 and rs7988100. The latter region, containing 31 known protein-coding genes, was excluded by direct sequencing in 2 affected and 1 unaffected family member.

Molecular Genetics

In a 3-generation German family segregating autosomal dominant PFE mapping to a 31.8-Mb interval on chromosome 3p24.3-p14.3, Decker et al. (2008) analyzed the candidate gene PTHR1 (168468) and identified heterozygosity for a splice site mutation (168468.0001) in affected individuals. The same mutation was identified in affected individuals from another German PFE family, and a different splice splice site mutation (168468.0002) and a nonsense mutation (168468.0003) in 2 additional PFE families, respectively. The mutations, which were not found in unaffected family members or 178 German controls, were predicted to result in premature proteolytic degradation of the precursor protein or a functionless receptor, suggesting that haploinsufficiency of PTHR1 is likely to be the underlying principle of nonsyndromic PFE.