Introduction
Developmental defects in the enamel (DDE) derive from disturbances in hard tissue matrices formation and/or mineralization during odontogenesis. These defects can be localized or appear more widespread, affecting single/multiple teeth or groups of teeth (COMMISSION ON ORAL HEALTH, RESEARCH AND EPIDEMIOLOGY, FDI 1992). Examples of DDE are fluorosis (FS), enamel hypoplasia (EH) and amelogenesis imperfecta (AI). Another entity of DDE is the so called “molar-incisor hypomineralisation” (MIH).
Since the early 1970’s dentists have reported a developmental defect primarily located in first molars and incisors in the permanent dentition. Early denominations referred to this clinical condition in a descriptive manner for “which is not”:
1. non-endemic stained enamel (JACKSON 1961),
2. idiopathic hypomineralisation of the enamel of the first molars (KOCH ET AL. 1987),
3. hypomineralisation of the permanent first molars not caused by fluoride (LEPPÄNIEMI ET AL. 2001)
4. cheese molars (KREULEN ET AL. 1995).
This reflected a poor understanding of its etiology that continues to this date. WEERHEIJM ET AL. baptized this pathology as MIH in 2001 and was adopted as the official denomination at the sixth annual conference of the European Academy of Paediatric Dentistry (EAPD) in 2003 (WEERHEIJM ET AL. 2001). MIH is defined as developmental (systemic) qualitative enamel defects that are present on one or more first permanent molars (FPMs), each possibly with different degrees of severity. The (central) permanent incisors might be affected additionally. If incisors are affected, at least one first molar must also show enamel hypomineralisation to confirm the diagnosis MIH.
The aim of this review is to summarize the current knowledge on the etiology, prevalence and diagnostics of MIH as well as provide guidance on treatment decision as well as discuss evidence of non- and micro-invasive interventions. A second review by our group will focus on the choice of invasive treatment options.
Prevalence and incidence
Nowadays, MIH is recognized as a global dental problem. In spite of the EAPD criteria cited above, cross-comparisons of the results from various epidemiological studies have been difficult due to the use of various indices and criteria, examination variability, methods of recording and varying age groups (JÄLEVIK 2010). Prevalence is defined by how often a condition is present in a population, and incidence by how many new cases occur each year. The reported prevalence of MIH in children and adolescents varies significantly between studies varying between 2 and 40% (JÄLEVIK 2010). A recent systematic review and meta-regression analysis (SCHWENDICKE ET AL. 2018) estimated a global mean (95% CI) prevalence for MIH of 12.9% (11.7–14.3%) with significant differences between countries. The highest numbers of prevalent cases were found in high-income and heavily populated countries. Another meta-analysis (ZHAO ET AL. 2018) estimated the prevalence of MIH around 14% globally with no statistical difference between sexes, but <10-year-olds had a higher prevalence than older individuals (15% vs 12%). It was also noted that MIH was particularly high in some regions such as South America (18%) and Spain (21%). For Switzerland no representative data have been reported so far.
A study on the distribution and severity of MIH affected molars in four areas in Germany revealed that the majority of children with MIH showed more than one affected molar (only one affected molar in 39.2%, two affected molars in 33.5%, three affected molars in 12.0% and four affected molars in 15.3%) (PETROU 2012). About half showed hypomineralisation in FPMs without additionally affected incisors. Twelve percent of the children with MIH showed hypomineralised defects in at least one of the second primary molars. Furthermore, FPMs were usually more often and more severely affected than permanent incisors. Upper permanent incisors were usually more often affected than lower permanent incisors and, if lower incisors were affected, in most cases hypomineralisation in upper permanent incisors as well as in FPMs were documented (PETROU 2012).
This was corroborated by other studies showing that the FPMs and incisors are often affected, although there can be considerable differences within a dentition. MIH has also been observed in other teeth of the permanent dentition (second molar, second premolar, canine) as well as in second primary molars and also primary canines (ELFRINK ET AL. 2012; FUCHS 2009). MIH is supposed to affect 878 million individuals, with a global number of incident cases estimated at 16.0 million people in 2016. It is, therefore, imperative to develop appropriate dental healthcare strategies to treat MIH and to identify its etiology in order to prevent.
Etiology and pathogenesis
MIH has been reported to have a negative impact on children’s quality of life and socio-psychological status (DANTAS-NETA ET AL. 2016). Affected teeth are in higher need for dental treatment, especially those with post-eruptive enamel breakdown (PEB). As a consequence, caries lesions develop more easily, leading finally to pulpal inflammation along with hypersensitivity or pain. Thus, it is of great importance to identify the etiology of MIH and to understand its pathogenesis. Despite an augmented interest in MIH and much published research on the subject, its etiology remains, to this day, not completely understood (CROMBIE ET AL. 2009; ALALUUSUA 2010; SILVA ET AL. 2016).
Environmental causes
MIH is considered to establish due to an impaired calcium and phosphate incorporation during enamel matrix formation and enamel maturation. Ameloblasts are sensitive to insults, both indirect and direct. Even the smallest changes in the environment of the ameloblasts may irreversibly disrupt the formation of the enamel matrix and the maturation of the enamel. Another key factor in understanding the etiology of MIH is the chronology of tooth mineralization. The mineralization of enamel in a first permanent molar starts just before birth and is completed in the first year of life (REID & DEAN 2006). Therefore, it seems logical that any possible cause must have occurred during the period from just before birth until the first year of life (Fig. 1, SCHROEDER 2000, DULLA ET AL. 2018). Research on the etiology of MIH have compiled a long list of candidates but failed to prove causality due to low numbers of prospective birth-cohort studies. Nonetheless, ongoing studies have elucidated some risk factors (e.g. “LISA” and “GINIplus”; FLEXEDER et al. 2020). “LISA” (Influence of life-style factors on the development of the immune system and allergies in East and West Germany) and “GINIplus" (German Infant Study on the influence of Nutrition Intervention PLUS environmental and genetic influences on allergy development) are two populated-based German birth cohorts. They aim to describe the natural course of chronic diseases and intermediate phenotypes in childhood and its determinants and to identify potential genetic effect modifications.
Potential environmental causes can be grouped into either being of prenatal, perinatal or postnatal origin (Table I). As indicated in Table I there was little evidence of an association between the most frequently investigated prenatal factors (maternal smoking, illness, medication) and MIH as well as perinatal factors (prematurity, low birth weight, cesarean delivery, birth complications) and MIH. A consistent finding is that early childhood illness, in particular pyrexia, appears to be associated with MIH.
Genetic influence
The amelogenesis phase has been shown to be modulated by genes (FINCHAM ET AL. 1999) and the size, shape, structure and composition of the enamel seem to be influenced by genetic variations. The potential role of genetics or epigenetics in association with MIH has been discussed (VIEIRA & MANTON 2019; HO?EVAR ET AL. 2020). Several genes related to MIH, such as Enam, Ameloblastin, Amelogenin, Bone morphogenetic protein 2 have been investigated (BUSSANELI ET AL. 2019; JEREMIAS ET AL. 2013). In addition to these single gene effects, gene-to-gene interactions may also play a role in MIH (PANG ET AL. 2020). However, data based on twin studies (TEIXEIRA ET AL. 2018) only showed tendencies of an influence of genetics on MIH prevalence, while higher family income and gestational bleeding were strongly positively associated with MIH. Genetic variability may influence the etiology, but seems not to act as the primary cause of MIH. ?
Some intriguing observations
MIH can affect one sibling and not the other(s) and teeth forming at the same period can be affected to varying degrees or not at all. Histological studies reported that MIH lesions extend through the full thickness of enamel, affecting mainly the coronal and not the cervical enamel, and often the buccal surface of the tooth (CROMBIE ET AL. 2013; FAGRELL ET AL. 2013; GAMBETTA-TESSINI ET AL. 2017). VIEIRA & MANTON attempted to address these variables in the clinical presentation of MIH (VIEIRA & MANTON 2019). According to these authors, the reason why only one side of a bilateral structure is affected likely involves differential gene expression between the left and right despite the dentition being mirrored between one side and the other. As for the disturbances of specific areas, and the multiple degrees of the severity, they postulated that this resulting anatomical appearance is a combination of random microenvironment influences (i.e., pressure from surrounding liquid within the connective tissues surrounding the enamel organ) and/or genetic variants (i.e., differential levels of expression at the cellular level and the directionality of molecular signaling).
Diagnosis
General diagnostic criteria and a simple classification system were set by the EAPD to facilitate the diagnosis of MIH (WEERHEIJM ET AL. 2003). It can be summarized by the following:
• The visual aspect of the lesion is opaque, clearly demarcated from the healthy enamel, varies in colour (white, yellow, brownish) and size. The darker opacity indicates more hypomineralised (softer) enamel.
• The enamel thickness is normal, but its breakdown appears after the eruption of the affected tooth (PEB).
• When restorations are present, these extend in most cases to the buccal and palatal/lingual surfaces with an opacity at the margin of the restoration.
• For incisors, these restorations are not related to a history of trauma.
• A missing FPM, in an otherwise sound dentition, can be an indication of a history of MIH.
• In some cases, eruption difficulties of FPMs due to enamel roughness have been proposed (ALMUALLEM & BUSUTTIL-NAUDI 2018).
Several descriptive classifications have been proposed; e.g. LEPPÄNIEMI ET AL. 2001 rated the severity of MIH within three categories:
1. Mild: opacities without PEB;
2. Moderate: opacities with PEB limited to enamel;
3. Severe: PEB with dentin involvement, atypical restorations and tooth extraction due to MIH.
Another simple classification system, also based on the severity of MIH, proposed distinction between mild and severe cases (LYGIDAKIS ET AL. 2010):
1. In mild cases, the demarcated opacities do not exhibit a PEB, but can present occasional sensitivity to external stimulus with less aesthetic concerns.
2. In severe cases, the demarcated enamel is associated with PEB, hypersensitivity (HS) and high aesthetic demands.
In an attempt to standardize MIH diagnostic criteria and treatment needs, conceived a classification system that links the severity of the lesion to a treatment need index (TNI) (STEFFEN ET AL. 2017). This index is based on four values (Fig. 2) regarding two key symptoms that are considered the most important ones with respect to MIH: HS and PEB. The highest value is recorded for each sextant by the use of good light and drying with an air syringe.
Teeth affected by MIH show various characteristics (Figs. 3-8). HS is a common symptom in MIH teeth that might impair oral hygiene, limit dietary habits, cause chronic pain and trigger dental anxiety. Its intensity depends on the severity of the lesion. A recent study (RAPOSO ET AL. 2019) concluded that mild cases of MIH are associated with HS of a low intensity, while severe cases showed more frequently higher degrees of HS. Severely hypomineralised teeth are at higher risk of developing caries, which could increase HS considerably. The cause of this HS appears to be chronic pulp inflammation due to repeated triggers, whether thermal, mechanical, or bacterial (FAGRELL ET AL. 2008). PEBs occur due to the severe porosity of the hypomineralised opaque areas that fracture when subjected to masticatory forces, resulting in unprotected dentin being more prone to external triggers (GARG ET AL. 2012). Interestingly, whitish discolored MIH teeth seem to be at ca. 33% lower risk for PEB than yellowish/brownish ones (CABRAL ET AL. 2016). ?
Clinical examination
With the complete eruption of all first molars and incisors at ca. eight years of age hypomineralised enamel of relevant teeth can be preferably detected and MIH be diagnosed (LYGIDAKIS ET AL. 2010). Nonetheless, MIH might be diagnosed during the eruption of the FPM. An early diagnosis may limit the degree and size of PEB and the high risk of subsequent HS and dental caries (GARG ET AL. 2012).
FPMs are first screened for MIH and then for caries. Teeth should be cleaned with a toothbrush and fluoride toothpaste and examined in wet condition using a mirror and probe. The tooth surface can also be gently cleaned with a cotton roll but should preferably not be dried. Intraoral photography is a great tool to better examine and assess the damaged tooth on a computer monitor (CHEN ET AL. 2013). Subsequently, the tooth is dried using air jet or, if not possible with cotton rolls, to examine for caries and to evaluate possible HS.
Differential diagnosis
MIH might be mixed up with three different other types of DDE: FS, EH, and AI. It can be helpful that MIH is the most prevalent type. It is a well-demarcated qualitative “chalky” defect (contrary to EH), non-symmetrical (contrary to FS, AI), limited to one or more FPM (contrary to AI, FS), with or without central permanent incisors implication (contrary to FS, AI), caries prone (contrary to FS), generally but not always hypersensitive (contrary to FS), with no history of trauma on the affected tooth (WEERHEIJM 2004; COMMISSION ON ORAL HEALTH, RESEARCH AND EPIDEMIOLOGY, FDI 1992; ELCOCK ET AL. 2006; CRAWFORD ET AL. 2007) (Table II). Furthermore, traumatic injury as well as prolonged periapical inflammation process of a primary tooth may affect the development or maturation of the permanent successor and lead to a so-called Turner’s tooth / Turner’s hypoplastic tooth, which is one example for EH.
Pain control & therapy
For the affected and suffering quite young child, visiting a dentist is often accompanied with a great portion of anxiety and reluctance. In order to rebuild the bridge of trust between the child and the dentist, a painless first examination is absolutely essential. Thermal stimuli such as air syringe, cold water, or cold instruments should be avoided. Any subsequent dental treatment should be performed under a very effective pain control protocol (JÄLEVIK & KLINGBERG 2002).
Pain is a subjective experience especially when it overlaps with anxiety and fear. The fear of having pain can be overwhelming for a child especially in case of previous traumatic dental experiences. A prerequisite for any pain control protocol to be effective is to ensure a proper emotional management of the suffering child otherwise, the protocol is doomed to failure. This behavioral and emotional management is the standard in pediatric dentistry (MCNEIL ET AL. 2006). A combination of three techniques i.e. analgesic, anesthetic and sedation is often necessary in pain management of MIH teeth.
Systemic analgesic premedication
The use of an analgesic premedication can be helpful in the treatment of hypersensitive MIH molars. The choice of the drug can be paracetamol or non-steroidal anti-inflammatory drugs NSAID (Ibuprofen or Metamizole). STEFFEN & VAN WAES described a treatment protocol based on patients suffering from chronic back pain. The protocol recommends the ingestion of a very high but short-term dosage (24-48h). The anti-inflammatory effect of NSAIDs is desirable especially in chronically inflamed MIH teeth. In order to influence chronic pain, medication should be taken > 24 hours before the dental treatment. The four doses are distributed as follows: > 24h, 12h, 6-8h before dental treatment and the last dose shortly before the procedure (STEFFEN & VAN WAES 2011).
Anesthesia
Treatment of MIH affected teeth in young patients is challenging due to chronic pulpal inflammation caused by porous enamel and exposed dentin. Failure in achieving profound and sufficient anesthesia may lead to behavior problems and affect the quality of restorations. The clinician might reach the maximum anesthetic dose (limited by weight and age) and the tooth remains hypersensitive. Type and dose of the anesthetic are not as important as the accessory techniques employed to achieve anesthesia (DISCEPOLO & BAKER 2011). For lower FPM, inferior alveolar nerve block adjunct to buccal infiltration is commonly used. Periodontal ligament injections can help in the establishment of anesthesia although its safety is constantly debated. Intraosseous injection technique used in endodontics, is also proven to be effective and provides profound anesthesia of long duration (60 minutes or greater) (NUSSTEIN ET AL. 2005). Crestal intraosseous local anesthesia by the use of a computer-assisted injection system is an effective and safe technique to achieve profound anesthesia in MIH-affected hypersensitive teeth. This technique could be beneficial when treating an MIH tooth with a pulpitis (DIXIT & JOSHI 2018; DISCEPOLO & BAKER 2011; FOUAD & LEVIN 2006). ?
Sedation
While anesthesia helps to reduce pain, sedation helps tremendously in removing the emotional context of fear and anxiety accompanying the dental treatment. Drug sedation can be used especially in very young children. However, whenever the child maintains nasal breathing, inhalation sedation (nitrous oxide / oxygen mixture) is the medication of choice especially in treating MIH cases (ESCH 2009; STEFFEN & LANGERWEGER 2018; STEFFEN 2018). If the child shows no cooperation at all, general anesthesia remains the only option.
Treatment decision
Fortunately, not all MIH affected teeth need immediate treatment. In any case, an intensive prophylactic protocol should be administered as early as MIH is diagnosed. The purpose is to delay enamel breakdown and prevent the development of dental caries. Based on the MIH-TNI, BEKES ET AL. have developed two therapy schemes for patients with either low or high caries risk. Prophylaxis is based on a self-applied “home” and a professional “in office” part. The former comprises mainly the home-use of fluoride toothpaste, but also other preventive measures (e.g. CPP-ACP mousse) haven been proposed, but no conclusive evidence of increased beneficial effects exists. It should be combined with regular professional application of fluoride varnishes (BEKES ET AL. 2016; FÜTTERER ET AL. 2020). Nonetheless all of these recommendations are mainly based on clinical studies regarding caries prevention, since no distinct non-invasive intervention has yet been proven to be more efficacious than another with respect to PEB prevention and/or HS reduction in teeth affected by MIH.
Indication and choice of treatment is driven by local factors (HS with or without PEB) and general factors (mainly patient age). For a FPM affected by MIH without PEB with or without HS, sealing therapy with a resin-based fissure sealant is the method of choice in addition to intensive home-based preventive measures. In a high caries risk patient with partially erupted FPM, the application of a flowable glass ionomer cement (GIC) is recommended as an intermediate protection. In order to stabilize the porous structure of hypomineralised molars, resin infiltration seem to prevent from enamel breakdown to a greater extent when compared with fluoride varnish (NOGUEIRA ET AL. 2020). If HS persists after the application of a sealant, a direct or indirect restoration should be chosen.
The presence of PEB (with or without HS) will result in an invasive, mostly restorative treatment. The extent of it will determine whether the tooth is restorable or not. The treatment of a FPM with PEB but without HS is determined by the localization and the size of the defect. If the loss of substance is not in the fissure and includes less than 1/3 of the tooth surface, the application of a sealant is recommended. However, if there is substance loss located in the fissure or defect size is more than 1/3 of the tooth or the defect is close to the pulp, then short-term temporary restoration using GIC with or without an orthodontic band should be the therapy of choice. After the tooth has matured, the temporary filling can be replaced by a definitive restauration. Alternatively, a temporary long-term restoration in form of a steel crown can also be an option.
If a FPM shows substance loss and HS, the treatment follows the same stages as in MIH-TNI 2 (BEKES ET AL. 2016). It should be noted that restorative recommendations are only based on a low scientific evidence level (see second paper regarding MIH of our group; WEBER ET AL. 2021). If future extraction is indicated, orthodontic treatment should follow. The aim is to allow the second permanent molar to erupt naturally as a substitute of the lost FPM. Thus, the timing of the extraction (ca. 8-11 years of age depending on the status of tooth development) is of great importance.
Therapy of MIH affected incisors
For improvement of aesthetically compromised MIH-incisors, the resin infiltration technique originally developed to arrest and mask caries lesions, has been proposed. However, in contrast to caries lesions and fluorotic teeth, MIH is not always completely masked by resin infiltration only. A higher degree of surface removal (etching) prior to the application of the infiltrating resin has been proposed for better aesthetic results. Still, in non-satisfying cases, as well as when hypoplastic areas are apparent from the beginning, composite on top of deeply infiltrated areas are necessary to achieve optimal results (MEYER-LÜCKEL ET AL. 2017; MEYER-LÜCKEL ET AL. 2020).
Conclusion
• The reported prevalence of MIH in children and adolescents varies significantly between studies varying between 2.4 to 40.2% (JÄLEVIK 2010). Globally a mean (95% CI) prevalence for MIH of 12.9% (11.7–14.3%), with significant differences between countries, has been estimated (SCHWENDICKE ET AL. 2018).
• FPMs are usually more often and more severely affected than permanent incisors. Upper permanent incisors are more often affected than lower permanent incisors (PETROU 2012).
• Despite an augmented interest in MIH and much published research on the subject, its etiology is still not completely understood (CROMBIE ET AL. 2009; ALALUUSUA 2010; SILVA ET AL. 2016). The current evidence suggests that multiple, most presumably environmental and medical risk factors trigger MIH during enamel formation and maturation.
• MIH might be mixed up with three different other types of DDE: FS, EH, and AI. Careful diagnostic differentiation should be made before starting any dental treatment.
• In an attempt to standardize MIH diagnostics and treatment a new classification system that links the severity of the lesion to a TNI has been proposed (STEFFEN ET AL. 2017). The index is based on two most important key symptoms with respect to MIH: HS and PEB.
• Without PEB sealing is strongly recommended in order to prevent caries. For hypersensitive teeth as well as those with PEB use of GIC as an intermediate cover, but mainly composite resins are materials of choice. Resin infiltration might be a suitable additional option in particular for aesthetic improvement in visible teeth. It should be noted that restorative recommendations are only based on a low scientific evidence level (WEBER ET AL. 2021).
Conflicts of interest
JAD declares no conflicts of interest, real or perceived, financial or nonfinancial. HML is appointed as inventor for patents of an infiltration technique for dental caries lesions, held by Charité-Universitätsmedizin Berlin, and receives royalties from DMG, the manufacturer of Icon.