Dental anomalies in individuals with osteogenesis imperfecta: a systematic review and meta-analysis of prevalence and comparative studies

Abstract Background Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. OI is also known as brittle bone disease. Objective This study aims to describe the prevalence of dental anomalies (except dentinogenesis imperfecta) in individuals with OI, and compare the prevalence of dental anomalies between individuals with and without OI and between individuals with different types of OI. Search methods Searches in PubMed, Web of Science, Scopus, Ovid, and gray literature were performed in October 2022. Selection criteria Observational studies (with or without a comparison group) that evaluated the prevalence of dental anomalies in individuals with OI. Data collection and analysis: Data items were extracted by two authors. Quality assessment employing the Joanna Briggs Institute checklists and meta-analyses was conducted. Results were provided in prevalence values and odds ratio (OR) / 95% confidence interval (CI). Strength of evidence was determined. Results Eighteen studies were included. Most prevalent dental anomalies in individuals with OI included pulp obliteration (46.4%), dental impaction (33.5%), dental impaction of second molars (27%), and tooth agenesis (23.9%). Individuals with OI type III/IV had 20.16-fold greater chance of exhibiting tooth discoloration in comparison with individuals with OI type I (CI: 1.10–370.98). In comparison with the group without OI, the individuals with OI had 6.90-fold greater chance of exhibiting dental impaction (CI: 1.54–31.00). High methodological quality was found in 47% of the studies. Strength of evidence was low or very low. Conclusions Pulp obliteration, dental impaction, and tooth agenesis were the most prevalent dental anomalies in the OI group. Individuals with OI were more likely to have dental impaction than individuals without OI. Individuals with OI type III/IV (severe-moderate) are more likely to have tooth discoloration than individuals with OI type I (mild).


Introduction
Osteogenesis imperfecta (OI) is a rare genetic disorder with skeletal involvement. The estimated incidence of OI is one in every 15,000 to 20,000 live births. 1,2 The OI corresponds to a heterogeneous group of hereditary diseases, the majority of which are autosomal dominant conditions with mutations in one of the COL1A1 and COL1A2 genes. 1,3 These genes encode α1(I) and α2(I) chains of type I collagen, which is a fibril-forming collagen found in most connective tissues and abundant in bone, dentin, cornea, dermis, and tendon. 4 Mutations can form low collagen (quantitative mutations) or structurally defective collagen (qualitative mutation), responsible for a more severe skeletal phenotype. [1][2][3] Recently, rare autosomal recessive or X-linked mutations have been identified. In these cases, the genes are involved in extracellular post-modification of collagen (e.g. CRTAP, LEPRE1 and PPIB), collagen folding and intracellular trafficking (e.g. SERPINH1 and FKBP10), ossification or mineralization (e.g.

SERPINF1)
, and osteoblast development (e.g. WNT1, CREB3L1 and SP7). 1,2,5 Generally, defects in type 1 collagen secretion result in insufficient osteoid production, affecting both endochondral and intramembranous ossification. 5 Thus, the main manifestation of OI is bone frailty, which causes delayed growth and fractures throughout life. Joint laxity, bluish sclera, and hearing loss are common findings in affected individuals. [1][2][3]5 Some individuals may also be affected by valve insufficiencies and aneurysms. 3 Patients with OI have no mental deficits and they must be treated according to their age and not to their height. 3 Due to its clinical characteristics, OI was initially classified as type I (mild), type II (lethal), type III (severe), and type IV (moderate). 6 However, the International Society of Skeletal Dysplasia suggested adding type V, which is characterized by the formation of calcification in interosseous membranes. 1,2,5 Altered bone growth often leads to maxillary hypoplasia, predisposing individuals with this condition to the development of Angle class III malocclusion and anterior crossbite. 7 Changes in dental development are also frequent in individuals with OI.
Structure alteration of the dentin, acknowledged as dentinogenesis imperfecta (DI) is one of the most common features noted in individuals with OI. [1][2][3]5,6 Other dental alterations during tooth development may also result in tooth variations in number, form, and position. 8 It is important for individuals with OI to have access to prevention programs in oral health since they are more vulnerable to dental caries. [9][10] The occurrence of dental alterations can hinder some dental procedures, such as endodontic treatment. Such anomalies can also cause pain, sensitivity, altered speech, and chewing, as well as occlusal and esthetic problems.
Therefore, identifying these problems in individuals with OI can assist dentists in planning treatment while reducing the associated clinical consequences, the need for complex procedures, and the financial cost of treatment.
No systematic reviews have summarized data on the association between dental anomalies and OI yet. Considering the existing body of knowledge on this issue, compilation of data is necessary for the evaluation of the state of knowledge on a specific topic. 11 The literature already points to a strong relationship between DI and OI; 1,2,5,6 thus, DI data have not been addressed in this systematic review and meta-analysis. This study focuses on the investigation of other dental alterations that may be associated with OI. In this context, the compilation of such data will provide healthcare professionals with information on possible dental anomalies that could be identified when providing care for patients with OI. Therefore, this systematic review and metaanalysis aims to describe the prevalence of dental anomalies, except for DI, in individuals with OI.
Moreover, the objective was to compare the prevalence of dental anomalies between individuals with and without OI, and the prevalence of dental anomalies between individuals with different types of OI.

Methodology Protocol and registration
The Meta-analyses Of Observational Studies in Epidemiology (MOOSE) 12 checklist was used to report this systematic review and meta-analysis. The MOOSE is the most recommended checklist for reporting metaanalysis of observational studies in Epidemiology. 13

Eligibility criteria
Inclusion criteria were observational studies (with and without a comparison group) that evaluated the prevalence of dental alterations in individuals with OI.
No restrictions were imposed regarding language or year of publication. Studies with insufficient data to calculate the prevalence of dental anomalies and case reports; literature, integrative, and scoping reviews; conference abstracts; book chapters; and protocols were excluded. In this systematic review and metaanalysis, data on DI were not considered. The PECO question was as follows: P (Population) = individuals (any sex and age). Then, the references were imported into the Rayyan web software (Qatar Computing Research Institute, Doha, Qatar), an electronic application for systematic reviews, which assists in the selection of abstracts.

Selection of studies
Two researchers (HVP and ECBS) performed the selection of the articles independently. In Step 1, the titles and abstracts were evaluated for the preselection of articles. Those considered potentially eligible were then submitted to full-text analysis by the two researchers in Step 2. References that met the eligibility criteria in Step 2 were included. In cases of disagreement between the two researchers regarding the eligibility criteria of a given article, a third researcher (NCRC) was responsible for deciding.

Quality assessment of included studies
The assessment of the methodological quality of the included studies was conducted with critical evaluation checklists from The Joanna Briggs Institute for prevalence studies 15 and case-control studies, 16 independently. In general, the tools used consist of questions about the sample size, participants, place of recruitment, data analysis, use of valid methods to identify the assessed condition, the reliability of the method used to assess the condition, appropriate statistical analysis, and the study's response rate.
Answers to each item included "yes (high quality)," "unclear (uncertain quality)," "no (low quality)," or "not applicable." The quality in each study was classified as low if the study scored up to 49% of the items with "yes"; moderate if the study scored from 50% to 69%; and high if the study scored more than 70%.

Synthesis of results
Meta-analyses of proportion were conducted using

Strength of the evidence assessment
The strength of evidence from the selected studies for the meta-analyses was assessed using of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. 18 The summary of results was performed according to GRADEpro (www.gradepro.org).
GRADEpro is used to assess certainty of evidence and to evaluate results from meta-analyses of randomized clinical trials and observational studies.
In the assessment of observational studies, evaluation of cohort case-control, cross-sectional with a control group, and case series is feasible. Therefore, GRADEpro was used to improve the adopted method and the quality of evidence.
The components of the GRADE 18 framework were used to assess the overall quality of the available evidence of dental anomalies in individuals with OI,

Selection of studies
The searches in the electronic databases retrieved  Figure 1 shows the flowchart of the selection process of the articles.

Dental anomalies of number
Nine studies evaluated the presence of tooth agenesis in individuals with OI. 21,22,27,28,30- The shape of the roots (short thin and curved) was evaluated in five studies. 20,24,29-31 Individuals with OI had a higher prevalence of narrow roots when compared to individuals without OI of the same sex and age (p<0.001). 31 The presence of short roots was more common in individuals with OI type III/IV (severe-moderate) than in individuals with OI type I (mild) (p<0.001). 29 The prevalence of cervical constriction and bulbous crown was evaluated in six studies. 19,24,29-31 It was more prevalent in individuals with OI (p<0.001), 31 especially in individuals with OI type III/IV (moderate-severe) (p<0.001). 29 Other types of dental anomalies of form were also evaluated in the studies included in this systematic review and meta-analysis, such as root dilaceration, 31 dens invaginatus, 22

Dental anomalies of location
Ectopic eruption was investigated in three studies. 21,22,31 Individuals with OI had a higher prevalence of ectopic tooth when compared to individuals without OI of the same sex and age (p<0.049). 31 The presence of dental transposition was found. 22 Dental impaction was investigated in eight studies. 19, 21,22,27,[30][31][32]35 Supplementary File 3 presents the characteristics and results of the included studies.

Strength of the evidence assessment
In the meta-analyses of prevalence, based on the GRADE evaluation, the strength of evidence was classified as "Low" for evaluation of four dental anomalies (agenesis, impaction of second molars, tooth impaction, and taurodontism) and "Very low" for another five anomalies (bulbous crown, discoloration, ectopic eruption, microdontia, and pulp obliteration).
The meta-analysis that compared the prevalence of tooth impaction between individuals with and without OI was classified as "Very Low," as well as the meta-analyses that compared discoloration and pulp obliteration between individuals with OI type III/IV versus OI type I (Supplementary File 6). This probably occurs, in part, due to the lack of space caused by growth problems of the maxilla, which is very common in OI, 7 leading to a greater occurrence of impacted maxillary second molars. 26 Another factor that may contribute to tooth impaction is the excessive bulbosity or volume of the crowns, which impairs the eruption process. 21 Genetic analysis studies indicate that impacted teeth in individuals with OI are also associated with qualitative mutations in the COL1A1/  23,31,34,42 Dentin is produced by odontoblasts as predentin, a mesenchymal product composed of collagen fibers and phosphoprotein. 43 Due to mutations in the genes that encode type I collagen, defects in the dentin can occur in individuals with OI, such as the nonformation of the tooth. 22,27 The composition of bone and dentin is similar, but some fundamental physiological differences exist. 26 Dentin presents no osteoclasts or continual remodeling. Therefore, the effects of bisphosphonates on bone tissue are not applicable to dentin.

Discussion
Individuals with severe and moderate OI (types III and IV) are more likely to develop discoloration compared with mild OI (type I), indicating an association between this dental abnormality and the severity of the OI phenotype. Studies have shown that this condition occurs due to the qualitative mutation in type I collagen. Independently of the severity of OI, discoloration mainly affects teeth with a thinner enamel (anterior and mandibular teeth). 20,33 According to Taqi, et al. 33 (2021), tooth discoloration is associated with pulp canal obliteration in individuals with OI, and the risk of developing both conditions increases when teeth are out of contact. Also, evidence suggests that tooth discoloration is more related to enamel thickness and a thinner enamel may increase the translucency of the discolored dentin. 33 The lack of occlusal forces may stimulate odontoblasts to secrete more dentin in a progressive, immature way, resulting in pulp canal obliteration and tooth discoloration. Thus, the hypothesis is raised that the oral environment plays a role in structural dental anomalies, which may indicate that odontoblasts present mechanical receptors that respond to mechanical stress.
No correlation has been found between taurodontism and any type of mutation in the COL1A1/COL1A2 genes in this population. 26,33 Thus, the cause of this condition may not be related to a specific type of collagen abnormality. 26 Children with OI generally exhibit a more severe form of taurodontism compared with children diagnosed with some type of syndrome. 26 One study suggests that taurodontism in individuals with OI is likely associated with delayed pulp maturation. 33 Dental anomalies in individuals with osteogenesis imperfecta: a systematic review and meta-analysis of prevalence and comparative studies 2023;31:e20230040 9/10 Conclusion Pulp obliteration, dental impaction, and tooth agenesis were the most prevalent dental anomalies in the OI group. Individuals with OI were more likely to have dental impaction than individuals without OI.
Individuals with OI type III (severe) and IV (moderate) are more likely to have tooth discoloration than individuals with OI type I (mild).

Funding
This study was funded in part by the Brazilian

Conflict of interest
The authors declare no conflict of interest.

Data availability statement
The datasets generated and analyzed during the current study are available in the SciELO Data