Etiology, Classification, and Restorative Management of Amelogenesis Imperfecta Among Children and Young Adults: A Scoping Review

Amelogenesis imperfecta (AI) is a rare genetic disorder affecting children and adults. Knowledge about AI is limited to clinical representation and radiographical findings. Various treatments are provided to children with AI, yet no definitive treatment guideline has been suggested in the literature. This scoping review highlights the knowledge of the etiology and classification of AI and synthesizes these findings in a comprehensive review, focusing mainly on the various forms of AI in children and management with a restorative conservative approach. Five electronic databases, namely, PubMed, Google Scholar, Embase, Web of Science, and Scopus, were searched for the relevant articles. The search was performed in two phases: first for title and abstract, and second for full-text articles. The studies included in this scoping review were published from 2013 to August 2023. The data extraction was done on a customized sheet. A total of 33 studies were included in this review, of which 19 were reports and series, seven were observational, and seven were reviews. Most patients included in this review suffered from the hypoplastic type of AI (54%), followed by hypomatured (36%), and hypocalcified (10%). The treatment modalities explained were divided into the following three phases: temporary, transient, and permanent. Almost all included reports suggested the requirement for guidelines for treating AI among young children. This scoping review suggests the need for guidelines for treating AI in children. Moreover, pediatric dentists should prioritize early diagnosis and treatment and long-term follow-up for AI in children to effectively enhance the patient’s psychological well-being and overall quality of life.


Introduction And Background
Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder that affects the development of enamel [1].This condition leads to the loss of enamel structure, composition, and amount, resulting in thinning, sensitivity, and aesthetically unpleasant teeth.AI is present in both primary and permanent dentition; even if not seen macroscopically, it varies in phenotypes [2].The prevalence of AI varies from 1:700 to 1:14,000 cases, depending on the population of interest [3].Affected teeth exhibit yellow to brown discoloration, increased susceptibility to dental caries, calculus deposition, attrition, gingival hyperplasia, and often an anterior open bite.AI is caused by gene mutations (ENAM, AMEL, DLX3, and P63), which are crucial for enamel formation [4].
AI is classified into three types based on the enamel pattern and the stage at which teeth are affected.First, hypoplastic AI involves teeth with an inadequately formed enamel matrix, although the enamel is normally mineralized [5].Second, hypocalcified AI involves teeth that are normally formed but with low-density soft enamel, making them more prone to fracture.Third, hypomaturation AI initially has the proper amount of enamel, which is calcified to a certain extent, but the enamel crystals are affected, resulting in soft enamel with a tendency to fracture [6].AI is not associated with any systemic disease.Over the years, various classifications have been proposed, and in recent years, the classification has become more descriptive and involves molecular defects [7].AI's genetic etiology is caused by gene mutations, which affect the matrix protein-20, amelogenin, enamelin, and kallikrein-4 [8].These gene sequences affect the formation of the enamel matrix, leading to thin and hypoplastic enamel, or if the defect is during the maturation stage, hypomature enamel is formed [9].Along with enamel defects, AI is also associated with malocclusion, delayed eruption, attrition, anterior open bite, and deviant morphology [10].Patients with AI require multidisciplinary treatment from an early age.Various treatments (restorative, prosthetic, and orthodontic) have shown a positive outcome.However, close followup is required to maintain the treatment outcome.
The treatment of AI follows four stages, namely, emergency, prevention, stabilization, and definitive treatment [6].Treating pediatric patients with AI is challenging for the dentist as it involves handling a young child and performing extensive and demanding multiple-visit treatment [8].Moreover, preteen children also need psychological support to develop a coping strategy [7,8,11].Additionally, the investigation and treatment of AI depend on various factors, such as clinical complaints, psychological issues, and restorative challenges.AI patients have various clinical issues, such as poor oral hygiene, chronic gingivitis, caries, discoloration, and short crowns.Most pediatric patients report complaints of multiple caries and sensitivity to their dentists [12].
The treatment of primary dentition consists of restorative management and the placement of a stainlesssteel crown on posterior teeth to prevent decay.For mixed dentition, long-term temporary treatment is required for hypersensitivity, tooth substance loss, and aesthetics.The recommended long-term treatment plan for patients with AI is the placement of porcelain crowns.Although clinical use of temporary restoration is common today, recently published studies have highlighted the importance of permanent crown therapy in early adolescence without severe complications [11,13,14].
Anecdotally, AI is linked to discoloration of teeth, anterior open bite, caries, and chronic gingivitis, but this association and its impact on children and treatment planning has not been well-documented.Moreover, due to the lack of prevalence of AI cases, the knowledge regarding treatment planning of pediatric patients is limited.There is a lack of clinical burden of this disease among pediatric dentists and other specialists [13,15,16].Additionally, there are no proper treatment guidelines for this condition among children.This leads to challenges in patient service planning and treatment delivery.Therefore, this scoping review aims to highlight the knowledge of the etiology and classification and synthesize these findings in a comprehensive review, focusing mainly on various forms of AI in children and management with restorative treatment.

Review Methodology
This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guideline and modified scoping review guidelines by Arksey et al. [17] and Munn et al. [18].

Research Question
The primary research question was "What is known from the existing literature about the etiology, classification, and restorative treatment guidelines of AI among children and young adults?"The PCC designed for this research question was P = children suffering from various types of AI; C = clinical and radiological diagnosis and genotypes; and C = clinical restorative management of AI in children.The research sub-questions were "What are the different types of AI?"; "What are the etiological characteristics of AI?"; "What are the clinical and radiological findings of AI?"; "What are AI guidelines and restorative treatment options for children and young adults?"

Search Strategy
Five databases, namely, PubMed/Medline, Scopus, Google Scholar, Embase, and Web of Science, were searched to retrieve the included articles.Additionally, reference chasing was performed to check the availability of data.Observational studies, case reports, case series, and randomized control trials published in peer-reviewed journals from 2013 until August 2023 were included.The search initially focused on the title and abstract to extract data related to AI.The search strategy was appropriately formed according to the databases.The search terms, MeSH terms, and Boolean operator alone or in combination used to extract the articles included "amelogenesis imperfecta," "AI," "children," "pediatric dentistry," "restorative treatment," and "management."References were managed by Endnote 20 (Clarivate, NY, USA).

Inclusion and Exclusion Criteria
This scoping review included articles related to the objectives of this study.The included participants were children aged three to 14 with a confirmed diagnosis of AI.Letters to editors, gray literature, articles, reviews published before 2013, and articles on adult AI patients were excluded.

Study Selection
Articles selected from each database were charted on Microsoft Excel (Microsoft Corp., Redmond, WA, USA).The investigator performed the study selection and screening of the title and abstracts carefully with the help of a librarian.The following peer-reviewed article types published in the English language were screened: observational studies (case-control, cross-sectional), clinical trials, systematic reviews and narrative reviews, case reports, and case series.A manual search of articles in references was also performed.Articles were retrieved for full-text reading if they met the inclusion criteria or when there was uncertainty.The investigator did this at one-month intervals to check the intraclass reliability, and the kappa statistic was calculated at a 95% confidence interval.

Data Extraction
The investigator performed the data extraction process using a predesigned standardized form.The following customized sheets were utilized for data extraction for case reports and series: (1) author, country, and year; (2) study design; (3) number of cases; (4) type of AI; (5) treatment modalities (mainly restorative); and (6) results.The customized data sheet created for observational studies included (1) author, country, and year; (2) study design; (3) number of cases; and (4) main findings.The customized sheet for review articles included information about (1) author, country, and year; (2) review/systematic review; and (3) main findings.

Synthesis of Findings
A narrative synthesis of the findings from the included studies was performed.Results were structured according to the themes in the following manner to provide a coherent summary of the findings: (1) characteristics of included studies; (2) etiology of AI; (3) classification and types of AI; and (4) restorative and esthetic management for children, along with guidelines wherever applicable.

Results
A total of 403 articles were extracted from four different electronic databases and exported to Endnote 20 (Clarivate, NY, USA).After removing duplicates, 303 articles were retrieved for title and abstract screening, of which 238 were removed.A total of 65 articles were sought to be retrieved, of which 10 were in different languages.Finally, 55 articles were extracted for full-text reading, of which 33 articles (19 case reports/series, seven observational studies, and seven reviews) were included in this scoping review (Figure 1).The intraclass reliability was excellent for article selection (0.88) and data synthesis (0.91) after one month.Table 1 demonstrates the genotypes, phenotypes, and radiographic and clinical findings of different types of AI [4].The articles were extracted into three categories according to the study design (Tables 2-4).In the primary dentition, the use of composite to restore teeth was low.Preformed metal crowns (PMCs) and extractions were the preferred treatment options with wide standard deviations of 2.9 and 3.4, respectively.In the permanent dentition, anterior composite restorations were the most common treatment provided, with both PMCs and composites used to restore posterior teeth

Collating and Summarizing the Findings
This scoping review condenses a significant amount of clinically relevant information on AI, encompassing various articles addressing its etiology, classification, and management.The main findings are outlined.AI should be clinically and radiographically differentiated from similar dental disorders such as dentogenesis imperfecta, dentin dysplasia, vitamin D rickets, tetracycline staining, fluorosis, and regional odontodysplasia.While it was initially postulated that AI is an isolated trait not associated with any syndrome, recent research has identified its association with nephrocalcinosis, also known as enamel-renal syndrome, resulting from mutations in the FAM20A gene.Genetics involved in the development of AI have not been identified; however, 10 genes have been associated with AI and are found in molecular diagnosis in most cases.In the past, children with AI were only given oral hygiene instructions and fluoride applications, with treatment initiated after the complete eruption of permanent teeth [19,20].Contemporary approaches involve restorative and prosthetic treatments, along with strict dietary and oral hygiene instructions, serving as the primary line of treatment for AI in both children and adults.Additionally, all included studies suggested regular follow-up appointments to maintain good oral hygiene.

Reports From Case Reports and Series
Nineteen articles were included in this review reporting various AI cases and management in children aged between three and 14 years (Table 2).The management described in all cases reported is briefly described below.
The management of AI varies according to the age of dentition and is divided into three phases.Phase I is a temporary stage designed for primary and mixed dentition.Phase II, a transitional phase, occurs when all permanent teeth have erupted and continue into adulthood.Phase III, the permanent phase, involves treatment for fully developed permanent teeth.Studies suggest that dental treatment for children affected by AI should ensure favorable conditions for permanent teeth eruption and normal facial bone and temporomandibular growth [19,21,22,30].The treatment is divided into two stages.In the first stage, anterior teeth are minimally invasively restored for discoloration using materials such as resin-modified glass ionomer cement, polycarbonate crowns, prefabricated crowns, and direct composite restorations [25,29,34].In the second stage, fully erupted permanent molars are restored with metal-ceramic crowns to prevent caries development and the attrition of defective enamel.However, patients with severe forms of AI (hypomature and hypocalcified) face challenges as the adhesive strength of enamel and dentin is compromised.In such cases, overdentures are provided to maintain eruption and vertical dimensions of occlusions, improving the patient's tolerance for future treatment.However, this approach requires diligent oral hygiene due to plaque accumulation in the gaps [32,33].
Hypomature AI enamel is prone to fracture due to thin enamel, cervical constriction, and thin roots.
Similarly, dentine has a loose structure and lacks hardness, making intracoronal restorations contraindicated [25,26,32,34].Pulpectomy has a poor prognosis due to root structure and calcified pulp stones in the roots.As a result, extraction is often necessary for hypomatured teeth with periapical infections.In less severe cases of AI, carbamide peroxide bleaching is also recommended [25,26,32,34].
In mixed dentition, the treatment goals primarily focus on preserving tooth structure, vitality, sensitivity, esthetics, and vertical dimensions.The first line of treatment, as indicated in various included studies, is orthodontic and prosthetic rehabilitation.Restorative rehabilitation in mixed dentition is a complex procedure because the definitive treatment cannot be provided until the eruption sequence of the teeth is completed.For permanent molars, stainless-steel crowns are commonly used to maintain the vertical dimension [19,21,33].In addition, inlay and onlay restorations are preferred for preserving the occlusion of posterior teeth.Various restorative treatment modalities have been reported to enhance dental esthetics.The studies that were included suggest that indirect composite resin veneers are among the best restorative options for masking anterior teeth and improving crown morphology.Full-coverage adhesive composite resin or polycarbonate crowns are also advocated as treatment options for mixed dentition [19,21,33].
In permanent dentition, the treatment objectives are to reduce teeth sensitivity and restore vertical dimension, function, and esthetics.The final treatment commences as soon as the clinical height of the crown is established and the pulp tissue has receded.Full-mouth rehabilitation with a multidisciplinary approach is advisable at this stage, incorporating prosthodontic, endodontic, restorative, periodontic, and orthodontic management [19,20,21,26,28,33].Some studies have suggested orthognathic surgery for abnormal skeletal growth.Crown lengthening and gingival recontouring are recommended in cases with short gingival crowns and hyperplasia [16,28,40].Anterior open bite, often associated with AI, requires orthodontic treatment to correct.Root canal therapy is advised for patients with severe tooth attrition [27,33].Consultation with specialists is essential for developing a comprehensive treatment plan for individuals suffering from different types of AI.

Reports From Observational Studies
Seven observational studies were included [37][38][39][40][41][42][43], encompassing various aspects of AI, ranging from prevalence to complex management (Table 3).Two studies from the United Kingdom examined the success of different treatment approaches for children with AI, emphasizing the necessity of a multidisciplinary approach.They concluded that preventive measures should constitute the primary line of treatment [37,40].The retrospective study by Ohrvik et al. on restorative management in children with AI reported a 44% success rate with prefabricated direct composite resin restoration but noted a 0% success rate with prefabricated veneers [38].The authors recommended further research in this area.Two case-control studies in the review indicated that dental maturity in children with AI is delayed compared to the control group.
Additionally, hypocalcified AI was seen to be associated with more dental anomalies than hypomature and hypoplastic AI [37,39].An explanatory study proposed the establishment of online groups comprising parents, children, teenagers with AI, and pediatric dentists to better understand oral health issues related to AI and identify cost-effective treatment modalities [41].A prevalence study by Yassin et al. reported that approximately 0.95% of children in the Aseer region of Saudi Arabia suffered from AI [42].Overall, these findings underscore the importance of a comprehensive and collaborative approach to managing AI and highlight areas for further research.

Reports from Review Studies
This scoping review incorporates six reviews [44][45][46][47][48][49] and one systematic review [50] among the main findings of four reviews focused on the management of children with AI (Table 4).One review reported that indirect composite restorative management yields greater success in treating AI children than indirect restoration [44].However, contrasting opinions emerged from two other reviews, suggesting that direct composite restoration is more successful than indirect methods [45,46].Another review proposed that direct and indirect composite restoration demonstrate good long-term results for children with AI [47].Furthermore, the reviews collectively emphasize the significance of primary prevention as the first line of treatment for AI children below the age of three years.The need for studies offering guidelines for managing AI in children was also highlighted.Dashash et al., in their systematic review, aimed to assess the best restorative material for AI treatment but noted the absence of a single randomized controlled trial evaluating the longevity of restorative materials [50].The authors could not complete the review and recommended planning randomized controlled trials to assess the effectiveness of restorative materials for managing AI in children.

Discussion
This scoping review is the first to map and characterize the etiology, classification, and restorative treatment modalities of AI among children from a dental perspective.AI is a dental developmental disorder characterized by enamel defects and usually occurs without any underlying systemic disease [7].AI comprises diverse phenotypes such as discoloration of teeth, taurodontism, and tooth malformation.The most common differential AI diagnoses include fluorosis, dentinogenesis imperfecta, enamel hyperplasia, and tetracycline stains [46].AI can be diagnosed using clinical examination, radiological evaluation, and histopathological examination.Existing literature suggests that diagnosing rare genetic diseases should involve assessing genetic mutations and biochemical abnormalities and should consider family history [23,24,47].
In this scoping review, 75% of articles consisted of case reports and case series, indicating that AI is a rare disorder, and accumulating large samples for a clinical study is not feasible.Moreover, the prevalence of AI was recorded as 1:700 to 1:14,000, depending on the population of interest [7], with patients included in this review falling within the age group of three to 14 years.Treating patients within this age group is crucial, particularly for esthetic reconstruction and functional rehabilitation.This treatment is mandatory to prevent further damage to the teeth and disruptions in the vertical growth pattern.Most patients included in this review suffered from the hypoplastic type of AI (54%), followed by hypomatured (36%), and hypocalcified (10%).Similar findings were observed in other systematic reviews [48].In this review, it was impossible to evaluate the prevalence of AI among the genders as, in most cases, gender was not mentioned.However, a study by Adorno-Farias et al. reported an equal prevalence of AI among the genders [49].
Pediatric dentists must comprehend the pathogenesis and clinical findings associated with various types of AI at an early stage.This will help them design proper treatment and protect teeth at an early age.The time required for managing AI in children varies based on the type and condition of the patient.Moreover, the patient's cooperation with dental treatment is crucial, as it significantly influences the duration of the treatment.Timely prevention and corrective treatment can be achieved by following a few therapeutic measures, including (1) establishing rapport with family members and the patient; (2) re-establishing oral and masticatory functions while maintaining the vertical growth of facial muscles and alveolar bones; (3) preventing teeth from developing dental caries and periapical lesions leading to pain and sensitivity; (4) preserving the vitality, form, and size of the tooth; (5) maintaining proper eruption of permanent teeth; (6) decreasing the risk factors leading to tooth fractures; (7) maintaining the normal profile of an individual; and (8) preventing problems with temporomandibular disorders.Therefore, for AI patients' early diagnosis, multidisciplinary approaches are required.The primary purpose of conducting this review is to obtain a prognosis and plan treatment because late intervention makes treatment complicated and time-consuming.Overall, the selection of restorative treatment and techniques for treating AI patients depends on the age and cooperation of the patient at the beginning of treatment, the parents' consultation, and the severity of the disease.Due to long dental visits and the requirement of extensive dental procedures, pediatric dentists should consider using pharmacological sedation as a rationale for performing the treatment.
Literature suggests that the varying etiology of AI and a wide array of clinical problems make the restorative management of AI challenging for dentists [50,51].As both the esthetic and function are compromised in AI patients, their management usually requires full mouth rehabilitation, depending on the condition and severity of the disease.AI patients often experience emotional trauma, leading to difficulties in eating, pain during brushing, social avoidance, and low self-esteem.The dental management of children with AI is challenging and requires a proper approach and comprehensive treatment strategy that outlines future treatment needs [31,37,42].Pediatric dentists assisting children with AI should understand the clinical and psychological demands of the condition.This understanding is crucial to ensure that the extended procedures associated with AI treatment are manageable for children and that the disease does not burden them [31].
This scoping review has several limitations.First, the age limit considered by the author is from three to 14 years, a period during which the maturation of teeth does not occur.Hence, a proper management approach cannot be decided.This decision can be justified because the early treatment approach in patients with AI helps plan future treatment.Second, the articles were presented only in the English language.This can be justified because studies demonstrating the treatment of diseases are mostly published in English and cited by studies in other languages or converted into various languages [52,53].Therefore, studies published in English are mostly cited and included in narrative, systematic, and scoping reviews; this is likely to introduce a bias (reductionism) [52,53].While there is a chance that some articles and case reports in other languages may have been missed, the author is confident that the inclusion of substantial articles published in high-quality journals makes this scoping review comprehensive.
In conclusion, pediatric dentists should prioritize early diagnosis and treatment and long-term follow-up for AI in children to effectively enhance the patient's psychological well-being and overall quality of life.The selection of a treatment approach should be based on an individual's specific functional, cosmetic, restorative, and occlusal needs.However, the severity of tooth structure damage remains the primary factor in determining the treatment choice, and successful management results in improved oral hygiene and patient nutritional needs.High motivation from children and their parents is required to maintain a preventive approach, as they need to adhere to and follow all instructions.

Conclusions
AI is a group of inherited genetic disorders that pose significant challenges in diagnostic and restorative dental treatment.Currently, no gold standard or guidelines are available for managing patients with AI.However, multidisciplinary approaches have shown favorable outcomes, particularly in children.There is a critical need for cumulated evidence on outcomes supporting restorative and conservative treatment across different types of AI.With proper guidelines, clinicians can plan comprehensive treatment for children with AI, optimizing their oral health and long-term prognosis.Therefore, it is highly recommended to plan and develop research aiming to compare the treatment planning, restorative materials utilized, and techniques for restoring the teeth of AI patients, which will eventually help develop a guideline for treatment planning.

FIGURE 1 : 1 :
FIGURE 1: PRISMA-ScR flowchart.PRISMA-ScR: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews

TABLE 3 : Case-control and cross-sectional studies on children with amelogenesis imperfecta.
2023 Bin Saleh et al.Cureus 15(12): e49968.DOI 10.7759/cureus.499687 of 13 Dental treatment of amelogenesis imperfecta (AI) patients with direct composite restoration and periodontal scaling has provided outstanding results.Other treatments, including the adhesive bonding technique, have shown limited results with longevity of treatment outcomes.Hence, scientific evidence suggests indirect composite restoration over direct composite restoration Review Direct composite restorations are strongly recommended for children and adolescents with AI, as they can be easily adjusted according to dentoalveolar development and are minimally invasive.Diagnosis and treatment of AI patients with anterior open bite require comprehensive treatment with multiple approaches.This will provide patients with a better quality of life and satisfaction