Failure of Tooth Eruption: A Systematic Review and Meta-Analysis Integrating Genetic Etiology, Diagnostic Accuracy, and Clinical Management Outcomes

BackgroundFailure of tooth eruption (FTE) encompasses mechanical impaction, primary failure of eruption (PFE), and syndromic disturbances. Since the seminal review by Suri et al. (2004), advances in genetics and surgical protocols warrant comprehensive synthesis. ObjectiveTo evaluate PTH1R mutation prevalence, diagnostic accuracy of clinical/radiographic criteria, comparative effectiveness of open versus closed surgical exposure for impacted canines, prognostic factors for supernumerary-associated eruptions, and management outcomes for PFE and syndromic disorders across six domains. MethodsPubMed/MEDLINE, Cochrane Library, and Google Scholar were searched (January 2004-February 2026). To enhance reproducibility, databases with broad public accessibility were prioritized. Google Scholar was used only for citation tracking and not as a primary database to minimize algorithmic bias and irreproducibility. PRISMA 2020 guidelines were followed. Protocol registered on OSF (DOI: 10.17605/OSF.IO/R5X76). Inclusion criteria: RCTs, cohort, case-control, and diagnostic accuracy studies. Genetic testing was considered the highest reference standard for diagnostic accuracy. Risk of bias assessed using ROBINS-I, QUADAS-2, and RoB 2.0. Meta-analyses used random-effects models with Hartung-Knapp adjustment. Heterogeneity was assessed using I{superscript 2} statistics, with sources explored through subgroup analyses, meta-regression, and prognostic factor analysis. GRADE evaluated evidence quality. Forest plots and funnel plots are provided in Figures 3-8 and Supplementary Figures S1-S15. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/26346646v1_fig3.gif" ALT="Figure 3"> View larger version (10K): org.highwire.dtl.DTLVardef@1d71b0forg.highwire.dtl.DTLVardef@1318309org.highwire.dtl.DTLVardef@1920208org.highwire.dtl.DTLVardef@c36c6f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 3:C_FLOATNO Forest Plot - Treatment Duration Difference (Closed vs. Open Exposure). Forest plot comparing total treatment duration (months from exposure to final alignment) between closed and open surgical exposure techniques for impacted maxillary canines (Domain 3). Data from 8 studies comprising 1,287 canines. Closed exposure was associated with significantly shorter treatment duration (mean difference -4.7 months; 95% CI: -7.3 to -2.1; p < 0.001). Heterogeneity was moderate to high (I{superscript 2} = 64.1%), partially explained by study design in meta-regression (RCTs vs. cohorts, p = 0.04). The 95% prediction interval (-9.8 to 0.4 months) indicates the range within which the true effect in a future study would fall, supporting individualized technique selection. All eight studies favored closed exposure, though confidence intervals for three cohort studies crossed zero. Study weights ranged from 4.0% to 18.2%. RCTs (Parkin 2013, Bazargani 2019, Smailiene 2020, Chaushu 2021) showed slightly larger effect sizes (range: -3.8 to -6.1 months) compared to cohort studies (Becker 2010, Fleming 2015, Kokich 2012, Zuccati 2018; range: -3.2 to -6.4 months). Diamond represents pooled estimate; squares represent individual study weights with horizontal lines indicating 95% confidence intervals. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/26346646v1_fig8.gif" ALT="Figure 8"> View larger version (40K): org.highwire.dtl.DTLVardef@42959org.highwire.dtl.DTLVardef@136c662org.highwire.dtl.DTLVardef@11a59e3org.highwire.dtl.DTLVardef@1035b2a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 8:C_FLOATNO Forest Plot - Spontaneous Eruption After Supernumerary Removal. Forest plot of spontaneous eruption rates after supernumerary removal alone from 12 studies (1,456 patients) across Domain 4. Reported rates ranged from 48% to 68% across studies (I{superscript 2} = 71.2%). High heterogeneity reflects differences in patient age (deciduous vs. mixed vs. permanent dentition), supernumerary morphology (conical vs. tuberculate), timing of intervention, supernumerary position (palatal vs. labial vs. between roots), tooth type affected (central incisor most common), and follow-up duration (range 1-5 years). With adjunctive orthodontic measures (space creation, traction, or both), success rates increased to 81-90% across 8 studies (892 patients). Study weights ranged from 8.4% to 8.9%. Prognostic factor analysis (Table 6) identified favorable factors including removal during deciduous dentition (OR 2.5-5.5), conical supernumerary morphology (OR 3.0-6.5), and incomplete root formation of the permanent incisor (OR 2.5-5.0). Unfavorable factors included tuberculate morphology (OR 0.2-0.4) and complete root formation (OR 0.2-0.5). Diamond represents pooled estimate; squares represent individual study estimates with horizontal lines indicating 95% confidence intervals. C_FIG ResultsFrom 3,587 records, 94 studies (9,156 patients) were included across six domains. Overall certainty of evidence ranged from low to moderate due to observational designs and heterogeneity. Domain 1 (Genetic Basis): PTH1R mutation prevalence in PFE ranged from 52-90% (16 studies, 487 patients; I{superscript 2} = 68%; Figure 6). Heterogeneity reflected differences in familial vs. sporadic cases and referral bias. Population-level prevalence remains unknown. Sixty-three variants identified. Domain 2 (Diagnostic Accuracy): "Failure to respond to orthodontic force" showed sensitivity 94% (95% CI: 91-97%) and specificity 96% (93-98%). "Progressive posterior open bite" showed sensitivity 92% (88-95%) and specificity 89% (84-92%). Reference standard heterogeneity (I{superscript 2} = 45-65%) addressed through bivariate and HSROC models. CBCT provided superior root resorption detection (97% vs. 68%; p < 0.001). Domain 3 (Canine Impaction): Open (91% [88-94%]) and closed (93% [89-95%]) exposure achieved comparable success (I{superscript 2} = 52%). Closed exposure was associated with shorter treatment duration (mean difference -4.7 months [-7.3 to -2.1]; I{superscript 2} = 64%; Figure 3) and lower postoperative pain (-1.9 VAS [-2.6 to -1.2]; I{superscript 2} = 58%; Figure 4). Prediction intervals (-9.8 to 0.4 months) support individualized technique selection. Funnel plots showed no significant publication bias (Figure 7). Domain 4 (Supernumerary): Spontaneous eruption after removal alone: 48-68% (I{superscript 2} = 71%; Figure 8); with adjunctive orthodontics: 81-90%. Heterogeneity reflected patient age, supernumerary morphology, and timing of intervention. Favorable factors: deciduous removal (OR 2.5-5.5), conical morphology (OR 3.0-6.5), incomplete root formation (OR 2.5-5.0). Domain 5 (PFE Management): Orthodontic force application failed in 88-98% and caused adjacent tooth ankylosis in 25-50%. Prosthodontic rehabilitation achieved functional occlusion in 82-94%. Implant success: 85-95%. Meta-analysis not performed due to critical heterogeneity. Domain 6 (Syndromic): Cleidocranial dysplasia alignment: 61-75%. Osteopetrosis extraction-associated osteomyelitis: 33%, favoring conservative management. Narrative synthesis only. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/26346646v1_fig6.gif" ALT="Figure 6"> View larger version (40K): org.highwire.dtl.DTLVardef@15622eborg.highwire.dtl.DTLVardef@e7403org.highwire.dtl.DTLVardef@e27724org.highwire.dtl.DTLVardef@1fbe10a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 6:C_FLOATNO Forest Plot - PTH1R Mutation Prevalence. Forest plot of PTH1R mutation prevalence in clinically diagnosed primary failure of eruption (PFE) from 16 studies (487 patients) across Domain 1. The reported prevalence varied substantially across studies, ranging from 52% to 90% (I{superscript 2} = 68%). Heterogeneity reflects differences in diagnostic criteria, patient selection (familial vs. sporadic cases), and referral bias. Subgroup analysis showed higher prevalence in familial cases (range 79-92%; 9 studies) compared to sporadic cases (range 54-71%; 12 studies). Meta-regression showed no significant association with geographic region, mutation detection method, or year of publication (p > 0.05 for all). Trim-and-fill analysis suggested one potentially missing study with negligible impact on pooled prevalence. Study weights ranged from 5.7% to 6.8%. The most frequently reported studies include Frazier-Bowers 2010 (0.75, 95% CI: 0.58-0.87), Risom 2013 (0.82, 95% CI: 0.66-0.92), and Park 2025 (0.89, 95% CI: 0.74-0.96). Reported estimates should not be extrapolated to unselected clinical populations; population-level prevalence remains unknown. Diamond represents pooled estimate; squares represent individual study estimates with horizontal lines indicating 95% confidence intervals. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/26346646v1_fig4.gif" ALT="Figure 4"> View larger version (17K): org.highwire.dtl.DTLVardef@1737e7forg.highwire.dtl.DTLVardef@175c6a4org.highwire.dtl.DTLVardef@1446af8org.highwire.dtl.DTLVardef@caff01_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 4:C_FLOATNO Forest Plot - Postoperative Pain Difference (Closed vs. Open Exposure). Forest plot comparing postoperative pain scores (visual analog scale, VAS 0-10 at 24-48 hours) between closed and open surgical exposure techniques for impacted maxillary canines (Domain 3). Data from 5 studies comprising 842 patients. Closed exposure was associated with significantly lower pain scores (mean difference -1.9; 95% CI: -2.6 to -1.2; p < 0.001). Heterogeneity was moderate (I{superscript 2} = 58.2%), reflecting differences in pain measurement timing (24h vs. 48h), analgesic protocols, and study design (RCT vs. cohort). The consistent direction of effect across all studies supports robustness of findings. All five studies favored closed exposure for reduced postoperative pain. Study weights ranged from 17.5% to 22.4%. RCTs (Parkin 2013, Bazargani 2019, Chaushu 2021) showed slightly larger effect sizes (range: -1.8 to -2.4) compared to cohort studies (Becker 2010, Fleming 2015; range: -1.2 to -1.6). Diamond represents pooled estimate; squares represent individual study weights with horizontal lines indicating 95% confidence intervals. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/26346646v1_fig7.gif" ALT="Figure 7"> View larger version (29K): org.highwire.dtl.DTLVardef@12bbffdorg.highwire.dtl.DTLVardef@1497eb8org.highwire.dtl.DTLVardef@1e879eorg.highwire.dtl.DTLVardef@59d3ae_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 7:C_FLOATNO Funnel Plot - Publication Bias for Canine Studies. Funnel plot assessing publication bias for 7 studies comparing treatment duration between open and closed surgical exposure for impacted maxillary canines (Domain 3). The plot appears reasonably symmetrical, with studies distributed evenly around the pooled estimate. Eggers test was non-significant (p = 0.38), suggesting no strong evidence of publication bias for this outcome. Each circle represents an individual study. The funnel shape represents the pseudo 95% confidence interval limits. The symmetrical distribution indicates that small and large studies are similarly distributed around the pooled effect estimate, supporting the robustness of the finding that closed exposure is associated with shorter treatment duration (mean difference -4.7 months; 95% CI: -7.3 to -2.1). The absence of publication bias strengthens confidence in the meta-analytic findings for this outcome. C_FIG ConclusionsThese findings support a paradigm shift toward genetically informed orthodontic decision-making across six integrated domains. PTH1R mutations are frequently reported in PFE, though population prevalence remains unknown. Open and closed canine exposure techniques have comparable success; closed exposure offers advantages in comfort and treatment duration. Early supernumerary intervention improves outcomes. Heterogeneity across domains reflects clinical diversity and was addressed through appropriate statistical methods. Orthodontic forces should be avoided in confirmed PFE. RegistrationOpen Science Framework (DOI: 10.17605/OSF.IO/R5X76)