Molar Incisor Hypomineralization from Inception to Intervention–Evidence Based Review

Background: Molar Incisor Hypomineralization (MIH) is considered a highly prevalent clinical problem worldwide. The etiology of MIH involves a complex interaction between systemic and environmental insults with possible genetic contribution. Early diagnosis is facilitated by collaboration between clinicians responsible for oral health management of the patient and is the key for enhancing the long-term prognosis and quality of life of affected children. MIH management is a formidable oral health challenge due to the wide spectrum of clinical presentation with the need for tailored treatment for the child affected by MIH condition. Objective: To provide dental practitioners with an updated and evidence-based overview of MIH etiology, diagnosis, and treatments modalities available for its management. Conclusion: In this review, recent clinical evidence on MIH etiology, diagnosis and treatment is presented. Given recent availability of sophisticated technologies there is an increasing number of treatment modalities now at the fingertips of all oral health clinicians alike, ranging from preventive measures, management of hypersensitivity to advanced restorative techniques. The tailored treatment plan should encompass a short and long-term approach requiring more frequent dental check-ups in order to achieve better outcomes and prognosis. Future translational clinical research to best practice that will enhance our understanding of the exact causes of MIH and allow development of standardized diagnostic criteria as well as optimal treatment strategies are warranted. Review Article Alamoudi; JPRI, 33(50A): 113-125, 2021; Article no.JPRI.75299 114


INTRODUCTION
Enamel development (amelogenesis) is a tightly regulated biological process that occurs through mineral deposition in form of hydroxyapatite crystals by the epithelially-derived cells called ameloblasts. Environmental insults, systemic exposures or inherited conditions are known to perturb amelogenesis. [1] Hypomineralization is one of the most common dental defects of developmental origin resulting from disturbances in ameloblast activity during various stages of enamel formation. [2] Molar incisor hypomineralization (MIH) in particular is among the foremost misdiagnosed dental conditions among children that have taken the spotlight in recent years and needs to be addressed in pediatric dentistry.
Originally reported nearly two decades ago, the term MIH described distinct enamel with varied severity of discolored demarcated opacities of systemic origin affecting at least one permanent molar and commonly present with affected incisors. [3] Based on this definition, in 2003 the European Academy of Pediatric Dentistry (EAPD) developed a set of guidelines for diagnostic classification of MIH according to exhibited enamel characteristics. [4] Hubbard and colleagues further coined MIH as an emerging socio-economic burden and a 'silent public health' concern. These enamel defects tend to fracture during eruption and cause not only dentin hypersensitivity but also increased susceptibility to caries.
[5] Therefore, given the burden of disease and high prevalence of MIH in some populations, [6-7] the cost of these conditions to the affected families as well as the general community can be substantial.
The EAPD definition and set of diagnostic guidelines for MIH are considered to be limited in that they do not take into account the extend of enamel defects. [8] In addition, while MIH diagnosis is reported by some studies based on the presence of at least one affected first permanent molar (FPM), other studies have based the diagnosis on affected anterior teeth when an affected FPM was not present.
[6] The presence of hypomineralization in other teeth including the second primary molars, cusp tips of second permanent molar and canines have been reported.
[5] Furthermore, evidence from several studies and systematic reviews indicate hypomineralized second primary molars are highly predictive of MIH with a 33% increase in incidence of MIH if an affected primary tooth is diagnosed. [9-11] Consequently, a number of studies have adopted other terminologies and suggest that incisor hypomineralization (IH), molar hypomineralization (MH) or deciduous molar incisor hypomineralization (DMH) terms which take into account all the other affected teeth should be included as part of the MIH spectrum. [6,12] In addition, there is inconsistency in applying diagnostic criteria that quantifies MIH enamel defects. While some studies report using EAPD system, others have applied modified criteria to include severity level of MIH or developed their own diagnostic criteria to account for extent of the defect. [6, 13] Despite these discrepancies, the prevalence of MIH remains high in the pediatric population and requires early diagnosis with the identification of 'at risk' MIH populations crucial for optimal management of the condition in these children.
The aim of this review is to provide dental practitioners with an updated and evidencebased overview of MIH etiology, diagnosis, and treatments modalities available for its management.

Evidence for Prevalence and Etiological Factors
Historically, MIH has been identified dating back to the medieval times [14] with the first epidemiology study of children reported by Koch nearly forty years ago.
[15] As a global concern, MIH has highly variable rate of prevalence up to 40% according to different studies. This is likely due to differences in methodology, diagnostic criteria, age groups of the study population and regional factors [16]  In addition to individual studies, several systematic reviews and meta-analysis have found accumulating evidence to support an association of MIH with early childhood illness and in particular fever, [39-41] as well as hypoxia, hypocalcemia and amoxicillin.
[41] However, MIH correlation with peri and prenatal factors is less clear. An earlier systematic review found only limited evidence for an association with the perinatal factors (e.g. birth complication) and prenatal factors (e.g. maternal medication use and smoking).
[40] Similarly, an independent systematic review did not find any evidence for MIH associated with maternal systemic exposure to medications.
[42] However, apart from fever and early childhood respiratory diseases, a more recent meta-analysis reported significant association of MIH with perinatal factors such as maternal illness, stress, and birth related complications.
[39] Furthermore, another systematic review and meta-analysis found evidence for a significant correlation between MIH prevalence and low birth weight and premature birth.
[43] Of note the meta-analysis only included four studies due to the significant heterogeneity among other the eligible studies. Since pooling of studies in a meta-analysis provides a higher level of evidence with statistical significance compared to systematic reviews, these findings linking MIH to maternal related as well as perinatal factors need to be explored further. Clinical implication of identifying MIH etiological origins not only contributes to our understanding of the condition but more importantly will guide us in implementing preventive measures for children at potential risk. Table 1 summarizes available evidence reported in recent systematic reviews and meta-analyses on prevalence, etiology, and diagnosis of children with MIH condition.
Given that hypomineralization is a common clinical presentation of genetic anomalies of developmental origin such as dentinogenesis imperfecta, and that amelogenesis is tightly controlled by various genes, therefore MIH as a genetic condition seems more plausible than an idiopathic condition. [41, 44-45] The support for a genetic disposition further comes from a recent genome-wide association study that identified a potential genetic locus on chromosome 22 for MIH (SCUBE1 gene).
[46] Moreover, MIH features are akin to some form of localized amelogenesis imperfecta with variations in genes expressed during amelogenesis such as ameloblastin (AMBN), amelogenin (AMELX) reported to be involved in enamel hypoplasia [47] and tuftelin (TUFT1) involved in enamel microhardness [48] may have a role in predisposing to or development of MIH experience in children.
The mineralization of the first permanent molars usually commences around birth and completed by the age of 5 years. During this period, the onset of hypomineralization can occur during disruption of enamel maturation stage. [49] Another important putative cause of MIH is presence of oral clefts which are 12 times more susceptible to tooth agenesis external to the cleft area (mandibular posterior teeth) resulting in significant disruption in enamel maturation process. [50] Nevertheless, irrespective of the specific cause of the amelogenesis disruption, during history taking it is important to note any relevant perinatal history or existing systemic conditions and closely monitor children with persistent illness during early years of childhood. [33]

DIAGNOSIS
A common feature of MIH is that the hypomineralized enamel tends to be more porous with lack of distinct crystal edges and greater interprismatic space compared to the completed mineralized enamel. [51] The porous hypomineralized enamel may also result in dentinal hypersensitivity [32] and enamel breakdown post-eruption due to masticatory forces. [52] Apart from functional impairment, patients experiencing MIH often have compromised quality of life as a direct result of poor esthetics when anterior teeth are involved and recurrent loss of restoration requiring more often dental visits. [32,53].
As mentioned before, there is currently no standardization of the diagnostic criteria for MIH which takes into account the significant differences in severity of the condition intra and inter individuals. As a result, many studies have reported use of modified criteria to include measure enamel defect or developed a specific scoring system. [5, 24, 54] The current approach to classification of MIH is either according to EAPD scoring system or the Modified Developmental Defect of Enamel (DDE) index which accounts for both type and extent of the enamel defect and divided into 3 distinct categories: demarcated opacities, diffuse opacities, or hypoplasia. [55] A more recent diagnostic approach developed by Cabral and colleagues is based on severity of the MIH (MIHseverity scoring system). [56] A recent systematic review found high heterogeneity in use of scoring system and concluded that the lack of standardized indices potentially accounts for the high variability of prevalence reports and highlights the difficulty in comparing studies to develop an evidence-based guideline for MIH optimal management. [6]

EVIDENCE-BASED TREATMENT STRATEGIES
In children affected with MIH treatment is very challenging as not only the need is amplified but also achieving a highly satisfactory restoration of affected teeth long-term is required. By the age of nine children with MIH will require ten times more dental treatment compared to children with unaffected teeth with each affected tooth reportedly requires at least two treatment. [57] Moreover, management strategies are further complicated due to limited evidence for correlation between clinical presentation of the affected enamel with severity of MIH. [58] As a result, a broad spectrum of treatment modalities has been produced to address such differences including products for preventive or restorative treatment. [4,8,35] Furthermore, differential diagnosis is mandatory to exclude other dental conditions such as amelogenesis (or dentinogenesis) imperfecta, enamel hypoplasia and fluorosis. Collaboration between pediatricians and pediatric dentists is essential to reach an early diagnosis and achieve long-term satisfactory treatment outcomes for a healthier and happier child. [21,59].
Depending on the severity of MIH a range of treatments have been found to be effective with longitudinal studies reporting their long-term success. Table 2 summarizes the evidence collected from recent systematic reviews on treatment modalities reported for children affected with MIH condition.

Preventive measures
Implementation of preventive measures following MIH diagnosis needs to be individually tailored and considered in light of collaborative efforts and patient factors including age, caries risk, hypersensitivity level as well as type and severity of the demarcated lesions. [53] Both initial risk assessment and early diagnosis are the key factors for an effective and conservative management of patients affected with MIH. The initial management phase should also include administration of remineralizing agent to affected teeth immediately after MIH diagnosis. [60]

Desensitizing agents
Several agents have been developed to address hypomineralized teeth issues. Bekes and colleagues [61] showed a significant reduction in hypersensitivity by applying an arginine paste to MIH affected teeth. The underlying mechanism involves stimulation of dentinal tubule obliteration by arginine thereby abolishing hydrodynamic pain activity. Following twice daily application of an arginine desensitizing paste on affected teeth for 8 weeks a considerable decrease in hypersensitivity was reported. [62][63] In clinic application of fluoride varnish as a desensitizing agent has also been found to alleviate dental hypersensitivity. [64][65] Further support of these clinical studies comes from a recent systematic review that showed the most effective preventive measures to reduce hypersensitivity were reported to be use of arginine pastes or fluoride varnishes. [66].

Sedative interim restorations
Interim restorations are feasible solution when it is not possible to achieve total comfort for the child during treatment. [67] Glass ionomers have been the gold standard interim restorative material for decades due to their sedative properties for hypersensitivity management. [68] A two-step procedure maybe applied during treatment to ensure the comfort of the child: The restorative procedure can be stopped and a sedative filling as an interim restoration  administered to help soothe the highly reactive tooth. After 1-2 weeks, the restorative procedure can be revisited with now a more easily anesthetized tooth and a more successful definitive restoration placed. This could particularly be a useful strategy in shorter and more comfortable appointments that allow younger patient to cooperate better. [60] Recent evidence from clinical studies has also shown glass ionomer to have a low failure rate as a restorative material over three years. [69].

Fissure sealants
These preventive measures are considered one of the most effective and successful treatments of MIH teeth. [67] Lygidakis and colleagues [70] reported that fissure sealant application using a two-step (etch-and-rinse) adhesive system had a higher retention rate than sealants without application of an etch. In addition, the retention of a resin-based sealant in hypomineralized molars was significantly higher than use of a glass ionomer sealant. [71]

Resin composites
Although the evidence for the use of self-etch and etch-rinse adhesives with composite resin indicates no difference in terms of effectiveness for treatment of MIH teeth, nevertheless due to diverse reports in adhesives and techniques definitive conclusions cannot be reached. 72 Studies have found that the success rate of resin self-etch or total-etch adhesives is considerably lower at 18 months [73] likely due to the enamel defect that compromises the successful adhesion of the resin to the affected dental surface. [51,74] However, Sönmez and Saat showed that following removal of the entire affected enamel, restoration of the hypomineralized teeth with a resin composite was highly successful when compared to restorations with limited removal of clinically defective enamel tissue.75 In addition, two coats of adhesive would be required for longterm success of the restoration since the porous hypomineralized surface in MIH absorbs the first adhesive coating. [76].

Resin infiltration
The application of resin infiltrate in arresting noncavitated carious lesions has been recently demonstrated. [77] However icon infiltration in MIH-affected enamel has been only evaluated in experimental studies [72] and further research is required to explore this technique on clinically hypomineralized enamels.

Amalgam restorations
Since amalgam is a non-adhesive restorative material and placement of mechanical retention further weakens the tooth structure, therefore it is best to be avoided in these atypically shaped cavities. [78]

Bleaching for esthetics
The use of hydrogen peroxide or carbamide peroxide formulations administered at different bleaching concentrations resulted in esthetic improvement in all cases with MIH. [66].

Microabrasion for esthetics
This is a minimally invasive technique which involves removal of external enamel surface defects via an abrasion and chemical erosion (18% hydrochloric acid) technique. The limitation of this technique is that treatment success depends on the depth of the discoloration. Moreover, this procedure should be limited to more superficial enamel defects with deeper defects benefiting from additional treatment measures. [79][80] For improved esthetic outcomes in mild to moderate cases of MIH, the enamel microabrasion technique maybe combined with dental bleaching. [79,81].

Deproteinization
Application of a 5% sodium hypochlorite solution following acid conditioning has been found to be ideal for deproteinization. Bond strength can be achieved after deproteinization without removal of the defected enamel surfaces. However, further research is required to evaluate the clinical effectiveness of this technique. [72,75,82].

Full coverage
Stainless steel crowns are ideal interim solution in younger patients who experience severe form of hypomineralized molars to protect the remaining tooth structure from early breakdown, relief hypersensitivity and establish plaque-free interproximal and occlusal contacts. In case of crown cementation in incomplete tooth eruption, glass-ionomer cement is the ideal material to be considered. [83][84][85]

Extraction and orthodontics
Extraction of a first permanent molars (FPM) is not ideal functionally nor it is an orthodontist's first choice for malocclusion correction. However, in case of poor long-term prognosis, best age to perform extraction of these teeth is usually before the age of 8.5-9 years. Radiographically, once the mandibular permanent second molar shows signs of calcification of bifurcation then extraction option should be considered. This will encourage forward movement of permanent second molars into a good alignment. If the mandibular FPM is extracted, then maxillary FPM should be considered as a compensation. [78,[86][87]

CONCLUSION
MIH is considered a significant dental public health concern globally. Early diagnosis by all clinicians involved in oral health management of children facilitates optimal treatment implementation as well as improved quality of life of affected children and their families. The esthetics of MIH is the most challenging aspect of its management and treatment should be tailored to address the needs of the child, to prevent loss of further tooth structure and caries development for as long as possible. This entails combining treatment as an esthetic and functional rehabilitation and to treat dental hypersensitivity where required. Therefore, importance of both short and long-term approaches to treatment planning with regular dental visits needs to be communicated to the parents for optimal clinical management and improved prognosis of MIH in affected children.

CONSENT
It is not applicable.