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Introduction

The process of development of teeth is a very complex process resulting from interactions between the ectoderm of the oral cavity, which gives rise to cells that produce enamel, and the neural crest ectomesenchyme which gives rise to the tooth structures other than enamel. At first, i.e., during the six weeks of intrauterine life, the tooth germ starts growing, and the cells forming the mineralized portion start differentiating. Thereafter, dentin and enamel matrices are laid down by these cells, which later start mineralizing. As the completed tooth erupts into the oral cavity, components of the periodontium, which includes periodontal ligament, cementum, and alveolar bone, start surrounding the root.

Development

There are four stages in the development of the tooth germ.[1][2] These stages include:

Bud stage: This stage starts in the eighth week of intrauterine life with the emergence of enamel organs. The enamel organs are swellings formed by dental lamina under the influence of mesenchymal cells. From these enamel, organs develop each tooth.

Cap stage: This stage is marked by the growth and expansion of the enamel organ, which results in the formation of a concavity in its inner aspect. The growth continues and at about 12 weeks of intrauterine life i.e., during the late cap stage, inner enamel epithelium forms from the inner cuboidal cells of the enamel organ. The inner enamel epithelium cells are columnar in shape, unlike enamel organ cells, which are cuboidal. This layer defines the shape of the crown and later differentiates into ameloblasts responsible for the formation of enamel. The cells from the outer layer of the enamel organ form the outer enamel epithelium and remain cuboidal. They maintain the enamel organ's shape.

The condensed mesenchymal cells beneath the inner enamel epithelium form the dental papilla, which later gives forms pulp. The enamel organ has a surrounding fibrous capsule known as the dental follicle, which later forms the periodontal ligament.

At 14 weeks of intrauterine life, apart from the inner and outer enamel epithelium, two other layers, namely stratum intermedium, and stellate reticulum, is formed. The stratum intermedium lies over the inner enamel epithelium and consists of 2 or 3 layers of cells. Its functions include transportation of the nutrients to and from the enamel forming cells, the ameloblasts. The stellate reticulum layer lies between the stratum intermedium and the outer enamel epithelium. The cells in this layer are star-shaped, hence the name stellate. Their function is to protect the underlying dental tissues and maintain the shape of the tooth.

Further growth of the inner and the outer enamel epithelium cells forms a cervical loop where the two entities meet and eventually form Hertwig's root sheath, which determines the shape of the root.

Bell stage: At this stage, the dental lamina disintegrates and is ready for the formation of dental hard tissue.

Dentine formation (Dentinogenesis): Cells from the inner enamel epithelium induce the cells at the periphery of the dental papilla to form dentin forming columnar cells i.e., odontoblasts. Initially, the odontoblasts secrete an unmineralized dentin matrix. The dentine matrix that forms before the initiation of mineralization is known as predentine. When the predentin becomes approximately 5 μm thick, mineralization begins within the matrix at random points in the form of spherical zones of hydroxyapatite called calcospherites are formed within the dentine matrix and eventually these calcospherites fuse to form mineralized dentine. The first mineralized layer of dentin is termed mantle dentine, and the remaining bulk is termed as circumpulpal dentine. As the deposition continues, the odontoblast cells retreat in the direction of dental papilla, forming an S-shaped curve. This formation leaves an elongated process known as the odontoblast process, which is later surrounded by the dentinal tubules.

Enamel formation (Amelogenesis): Enamel formation starts immediately after the first layer of dentin is laid down by the odontoblasts. The cells from the inner enamel epithelium differentiate into ameloblasts. These are columnar cells attached to the stratum intermedium via ita base. A pyramidal extension is present at the secretory end of ameloblasts known as Tomes' process through which the enamel matrix is secreted at the amelodentinal junction. Once the enamel matrix is laid down, immediately, the mineralization process begins by secretion of calcium and phosphate ions into the enamel matrix, forming hydroxyapatite crystallites. As more matrixes are secreted and mineralized, the ameloblast cells move away from the amelodentinal junction forming a pattern of crystallites contained within enamel prisms. These prisms are also known as enamel rods as they run from the amelodentinal junction to the enamel surface.

As the enamel matures, the crystallites within the enamel increase in size, and the organic content reduces. Once the enamel formation completes, the ameloblast cell loses the Tomes' process, flattens, and becomes the reduced enamel epithelium. This layer protects the enamel during eruption and eventually become the junctional epithelium.

Root formation: Once the crown formation is completed, root formation starts. The Hertwig's root sheath formed by the downward growth of the inner and outer enamel epithelium grows in the apical direction, encloses the dental papilla, and outlines the shape of the root. The dental follicle forming the periodontal ligament and cementum lies external to this sheath.

Cementum formation (Cementogenesis): After completion of the root, fragmentation of the Hertwig's root sheath occurs. This process enables the cells from the adjacent dental follicle to come into contact with the root dentine. These cells further differentiate to form cementum-forming cells termed as cementoblasts. These cells are single-layered cuboidal cells on the surface of the root dentine. The cementum matrix is secreted by these cells, and later, the process of mineralization starts by deposition of hydroxyapatite crystals. The unmineralized thin layer of cementum lying on the surface is termed as cementoid.

Periodontal ligament formation: Cells of the dental follicle other than cementoblasts differentiate into fibroblasts that secrete collagen. When the formation of cementum starts, these collagen fibers secreted by fibroblasts within the dental follicle orientate themselves into bundles perpendicular to the surface of the root and form the principal fibers of the periodontal ligament. One end of these fibers become embedded in the developing cementum, and the other end in the alveolar bone and these are known as Sharpey's fibers

Molecular Level

Studies at the molecular level have demonstrated that various paracrine signaling molecules mediate the communication between the ectoderm and ectomesenchyme during tooth development. The molecules include members of the transforming growth factor (TGF-), FGF, SHH, and wingless/int1 family of secreted signaling molecules (WNT). When the epithelial budding starts, a signaling molecule in the tumor necrosis factor termed ectodysplasin appears in the dental placodes. Thereafter, during the transition phase from bud to cap stage, another molecule termed the enamel knot signaling center appears, one for each future cusp of the tooth. These molecules regulate morph differentiation of the tooth crown and also regulate the initiation of the secondary enamel knots responsible for the determination of the future epithelial cusp formations.[3][4] The exit of the enamel knot cells from the cell cycle is mediated by cyclin-dependent kinase inhibitors (p21). Nerve growth factor receptor (NGF-R) is necessary for morphologic and cytodifferentiation in the tooth.[5][6][7]

Additionally, the role of transcription factors including homeobox 9 gene (PAX9), MSX1, MSX2, DLX3, DLX5, DLX6, DLX7, BARX1, PITX2, LHX6, and LHX7 in tooth development have also been implicated. These transcription factors appear to have an inductive interaction with the growth factors resulting in tooth patterning, formation, and division of the jaws into different regions corresponding to each tooth's position.[8]

Function

Teeth play a vital role during mastication, phonetics, smiling, and giving shape to the face. The different layers of tooth i.e., enamel, dentin, pulp, and cementum, play different roles-enamel functions to protect the dentin. Dentin provides support to the overlying enamel and transmits impulses from the enamel to the dental pulp. The pulp helps in the formation of dentin and providing nutrients such as albumin, transferrin, tenascin, and other proteoglycans to the dentin. Also, it has a defensive role through the formation of new dentin, creating a barrier between irritants and slows the rate of carious decay. The cementum functions to provide attachment to the collagen fibers present in the periodontal ligament, thus maintaining the integrity of the root and its position. It is also involved in the repair and regeneration of teeth.

Pathophysiology

Any disturbance during the development of the tooth, such as disturbance in the interaction between epithelium and the mesenchyme may lead to anomaly related to number, shape, size, contour, or form. The type of anomaly depends upon the developmental stage affected. Various local and systemic factors such as local trauma, radiation damage, any nutritional deficiency, congenital disease, hormonal influences, or inflammatory process may give rise to these anomalies. The various developmental anomalies include:

Hypodontia: It is a disorder characterized by a lack of one or a few teeth and is more frequently observed in permanent teeth, particularly premolars and incisors.

Oligodontia: It refers to the development of fewer than the normal number of teeth.

Anodontia: It refers to the absence of all the teeth and may affect both primary and permanent teeth. This condition is extremely rare.

Hyperdontia: Is characterized by an increased number of teeth than the regular number of supernumerary teeth. They can occur in primary or permanent dentition. They most commonly occur in the maxillary anterior region between the incisors, in which case they are termed mesiodens. It may also occur distal to the third molar in maxilla or mandible.

Gemination: It is the condition that arises when two teeth develop from the same follicle and attempt to divide, resulting in a single tooth with two incompletely separated crowns or one incompletely separated crown but with a single root and root canal. It is sometimes also referred to as double teeth or dental twinning and is more commonly associated with the maxillary anterior region.[9][10]

Fusion: It is the condition where two teeth develop from two different dental follicles, but during the process of formation, they fuse partially or completely, resulting in a single large tooth or tooth fused completely at crown or root only. The degree of fusion depends on the stage of tooth formation at which fusion occurs. When fusion begins before the calcification stage, complete union occurs, and when it occurs at a late stage, incomplete union occurs. It is more common in the anterior region of the deciduous dentition.[11]

Concrescence: It is the fusion of two teeth at the cementum region only. It may occur either during root formation termed as true/developmental concrescence or after the completion of root formation termed as acquired/inflammatory concrescence. Unlike fusion, concrescence commonly occurs in the posterior region of the maxilla. The union of cementum may vary in degree from one small site to the involvement of the entire root surface.[12]

Dilaceration: It is a bend in the root of the tooth in any direction or deviation from the linear relationship of the crown to its root. The site of bending varies with the position of the tooth affected. In the anterior teeth, the bend presents in the apical third of the tooth, middle third in maxillary first molars, and coronal third in the third molars. Permanent teeth are commonly affected.

Dens invaginatus: It is also referred to as dens in dente or extensive compound odontoma or pregnant women anomaly and is characterized by invagination on the external surface of the tooth crown. It occurs before the calcification begins. The degree of invagination may vary from a short pit in the crown region to a deep invagination extending into the root portion or, in rare cases, even beyond the apex. A maxillary lateral incisor is the most commonly affected tooth. It can be easily identified on the radiograph by the pear-shaped invagination and narrow constriction at the opening.[13]

Dens evaginatus: It refers to an accessory cusp in the form of a tubercle or elevation or protuberance. It is also known as Leong's premolar or evaginatus odontoma or occlusal pearl. It commonly occurs on the occlusal surface of a premolar. It may also occur in the anterior region, in which case it is referred to as Talon's cusp. The syndromes commonly associated with this anomaly include Rubinstein-Taybi syndrome, Mohr syndrome, Sturge Weber syndrome, and Berardinelli Seip syndrome.[14]

Taurodontism: It is also referred to as bull's teeth and is *characterized by teeth with abnormally large pulp chambers with furcation displaced apically, resulting in larger than normal apical-occlusal height. Molars are the most commonly affected teeth. It frequently correlates with syndromes such as Klinefelter's syndrome, Mohr syndrome, orofacial digital syndrome, and Down syndrome.

Peg laterals: It is commonly seen in the maxillary anterior region affecting the maxillary lateral incisor and is characterized by a tooth that is conical in shape with a taper in the incisal region.

Amelogenesis imperfecta: It is an inherited dental defect of the enamel characterized by abnormally soft and fragile enamel resulting in thin enamel, which can easily wear off or chip off, exposing the underlying dentin and causing yellow to brown discoloration. It affects both primary and permanent dentition.

Clinical Significance

Hypodontia poses cosmetic problems. Supernumerary teeth may lead to disturbances in eruption, crowding, and deviation of the adjacent teeth. In that case, extraction merits consideration. Gemination can also cause esthetic problems as it usually appears in the anterior region of the maxilla. Also, the attempt to divide leaves behind deep grooves on the surface of the geminated tooth, which makes it more susceptible to caries, plaque accumulation, and periodontal problems. It may sometime also interfere in the eruption process of the adjacent tooth.

Fusion may lead to crowding, occlusal disturbances, and esthetic problems. Since the fused teeth have a greater surface area and root mass, resorption may become further delayed, leading to delayed or ectopic eruption of its permanent successor.

Concrescence may give rise to complications such as a fracture of the maxillary tuberosity or floor of the maxillary sinus during the extraction of the teeth. In such cases, sectioning the tooth should precede extraction.

In dilaceration, the bend act as a nidus for bacterial invasion resulting in pulp necrosis and periapical inflammation. It poses difficulty during endodontic, orthodontic, and extraction procedures. Also, it may lead to a longer retention of the primary tooth resulting in delayed eruption or non-eruption of the permanent successor.

Dens invaginatus may act as a channel through which microorganisms enter the tooth making the tooth more susceptible to caries. Dens evaginatus, on the other hand, may fracture or abrade due to forces exerted on it when the tooth comes in occlusion; this may expose the pulp resulting in endodontic complications.

Taurodontism poses an endodontic challenge as it may be difficult to locate the canals. Peg laterals may affect the esthetic requiring prosthetic correction.

References

Disclosure: Manu Rathee declares no relevant financial relationships with ineligible companies.

Disclosure: Prachi Jain declares no relevant financial relationships with ineligible companies.

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The process of development of teeth is a very complex process resulting from interactions between the ectoderm of the oral cavity, which gives rise to cells that produce enamel, and the neural crest ectomesenchyme which gives rise to the tooth structures other than enamel.

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The Palgrave Handbook of Social Theory in Health, Illness and Medicine

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This wide-reaching handbook offers a new perspective on the sociology of health, illness and medicine by stressing the importance of social theory. Examining a range of classic and contemporary female and male theorists from across the globe, it explores various issues including chronic illness, counselling and the rising problems of obesity.

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Introduction

The term molar-incisor hypomineralisation (MIH) was first introduced in 2001 by Weerheijm et al. and it was defined as 'hypomineralisation of systemic origin, presenting as demarcated, qualitative defects of enamel of one to four first permanent molars (FPMs) frequently associated with affected incisors.' Earlier nomenclature included non-fluoride enamel opacities, internal enamel hypoplasia, non-endemic mottling of enamel, idiopathic enamel opacities and cheese molars. In 2003, MIH was further described as a developmental, qualitative enamel defect caused by reduced mineralisation and inorganic enamel components which leads to enamel discolouration and fractures of the affected teeth. Initially, the condition was described as affecting the FPMs and incisors but more recently it has been noted that these defects could affect any primary or permanent tooth. In MIH, the FPMs show rapid caries progression starting shortly after eruption in the majority of cases, which causes serious problems to patients as well as treatment challenges to dentists. Although this condition is frequently encountered in dental clinics, recent studies have shown that dentists experience significant difficulties in diagnosis and management. Therefore, the aim of this article is to highlight the most important aspects of MIH from its prevalence to treatment options in young patients.

Prevalence

Epidemiological studies from different parts of the world show a wide variation in the prevalence of MIH which can range between 2.8 to 40.2%, however, this variation may be due to a lack of standardised tools to record MIH leading to underestimation of the prevalence. In response to this finding Ghanim et al. have introduced a standardised scoring system based on the European Academy of Paediatric Dentistry (EAPD) evaluation criteria. A manual has also been recently published to facilitate and standardise its use in future epidemiological studies. Elfrink et al. suggest that at least 300 subjects should be involved in such studies. Currently, it is estimated that this condition affects one in six children worldwide.

Aetiology

The causative mechanism of MIH is still unclear, but the clinical presentation of localised and asymmetrical lesions suggests a systemic origin with the disruption in the amelogenesis process most probably occurring in the early maturation stage or even earlier at the late secretory phase. In general, the condition seems to be multifactorial and systemic factors such as acute or chronic illnesses or exposure to environmental pollutants during the last gestational trimester and first three years of life have been suggested as causative or contributing factors. The number of affected teeth was associated with the time when the potential systemic disturbance occurred; children with prenatal, perinatal and postnatal problems showing more affected teeth in increasing order. Multiple possible causes have been suggested in the literature, for instance, respiratory tract infections, perinatal complications, dioxins, oxygen starvation, low birth weight, calcium and phosphate metabolic disorders, frequent childhood diseases, use of antibiotics and prolonged breast feeding. In addition, some studies raise the possibility of a genetic role in the aetiology of MIH, indicating that a genetic variation may interact with systemic factors leading to MIH.

Diagnosis

The ideal time to diagnose MIH is as soon as it is clinically apparent either in primary or permanent dentition. The examination should be performed on clean wet teeth. The clinical presentation of MIH depends on its severity and can range from white-creamy opacities, yellow-brown opacities, post-eruptive enamel breakdown to atypical caries located on at least one FPM with or without incisor involvement. The lesions should be larger than 1 mm to be recorded as MIH. When such clinical signs exist during examination, the dentist should ask the parents about any illness that occurred in prenatal, perinatal, postnatal or the first three years of life to support the diagnosis. Figures 1 to 7 show some examples of different clinical presentations of MIH.

Patient with severe MIH affecting all FPMs and causing atypical caries and post-eruptive enamel breakdown

Mathu-Muju and Wright had classified MIH into three severity levels:

1. 1
Mild MIH: the demarcated opacities located at non-stress bearing areas, no caries associated with the affected enamel, no hypersensitivity and incisor involvement is usually mild if present

2. 2
Moderate MIH: the demarcated opacities present on molars and incisors, the post-eruptive enamel breakdown limited to one or two surfaces without cuspal involvement, atypical restorations can be needed and normal dental sensitivity

3. 3
Severe MIH: post-eruptive enamel breakdown, crown destruction, caries associated with affected enamel, history of dental sensitivity and aesthetic concerns.

Association between MIH and other hypomineralised teeth

The same demarcated defects that present on some molars and incisors in MIH have also been observed on other teeth such as second primary molars and tips of permanent canine cusps in some MIH cases. Mittal et al. have investigated the association between hypomineralised second primary molars (HSPMs) and MIH and they found that approximately half of the FPMs with MIH were associated with HSPMs. Furthermore, Negre-Barber et al. found that HSPM can be considered a predictor for MIH, indicating the need for monitoring, but the absence of HSPM does not rule out the appearance of MIH. A significant association between MIH and hypomineralised permanent canines has also been described in a paper by Schmalfuss et al. where they found approximately one quarter of MIH-affected individuals had one or more permanent canines with signs of hypomineralisation.

Differential diagnosis

Conditions which can present with hypomineralised lesions and should be distinguished from MIH include:

Fluorosis

This is associated with history of fluoride ingestion during enamel development. Clinically, fluorosis presents as diffuse, linear, patchy or confluent white opacities without a clear boundary. The severity can range from barely perceptible striations in the enamel to gross disfiguration with almost complete loss of the external part of the enamel. It affects teeth in a symmetrical, bilateral pattern unlike MIH which is asymmetrical. Moreover, teeth affected by fluorosis are caries-resistant while in MIH they are caries-prone.

Enamel hypoplasia

This is a quantitative defect with reduced enamel thickness. The borders of hypoplastic enamel lesions are mostly regular and smooth, indicating developmental and pre-eruptive lack of enamel. The margins in MIH with post-eruptive enamel breakdown are sharp and irregular due to post-eruptive shearing of weakened enamel.

Amelogenesis imperfecta

This is a genetic condition which results in enamel that is hypoplastic, hypomature, or hypomineralised. In this condition, all teeth in both dentitions are affected and a familial history is often present.

White spot lesion

This is the earliest clinical sign of caries. The lesions appear chalkier, matt or more opaque than the adjacent sound enamel. They can be distinguished from MIH because they occur in areas of plaque stagnation, such as the cervical margin of the tooth.

Traumatic hypomineralisation

This is associated with a history of dental trauma to the primary predecessor tooth. Periapical infection of the primary tooth can disturb mineralisation of the underlying tooth germ. It has a wide variety of clinical presentations differing in shape, outline, localisation and colour. It is often limited to one tooth and asymmetrical.

Anatomopathology

The histopathological data relating to MIH, reveals that, unlike other types of enamel defects, hypomineralisation in MIH begins at the amelodentinal junction (ADJ) and not at the surface of the enamel. In mild MIH the hypomineralisation remains limited to the inner enamel while the outer surface is intact. In severe MIH the whole enamel layer is hypomineralised. The affected enamel has 20% less mineral concentration according to an investigation by Fearne et al. while the protein content in MIH enamel is three-fold to 15-fold higher than that of sound enamel.

Clinical problems in MIH

The following are the most commonly reported clinical problems for patients with MIH:

Post-eruptive enamel breakdown leading to dentine exposure and this makes the tooth at risk of pulp involvement

Tooth sensitivity, which might lead to poor oral hygiene and therefore, caries susceptibility increases

Local anaesthesia problems which are possibly related to chronic pulp inflammation

Behavioural management problems due to dental fear and anxiety which is related to the pain experienced by the patients during multiple treatment appointments

Aesthetic problems in anterior teeth

Occasional eruption difficulties of molars due to enamel roughness

Negative impact on the child's school performance due to the absence from school

Financial concerns for families.

Management and treatment options

Identification of patients at risk of MIH and early diagnosis can lead to more effective and conservative management. Based on the available evidence, children at risk of MIH are those with poor general health during early childhood and/or those with HSPM(s). There are currently no guidelines available for the management of MIH, however, the EAPD published a consensus paper in 2010 as 'best clinical practice guidance for clinicians dealing with MIH.' The authors noted that there was a limited number of evidence-based research papers on this topic at that time and they suggested some areas that required further investigation. In recent years, this topic has received a lot of attention by researchers, for example in Australia in 2013 'The D3 Group' (a translational research and educational network by a group of scientists and practitioners who are interested in the developmental dental defects) has launched an official website to provide education resources and updates especially about MIH and they aim by their research to develop guidelines for MIH management. More recently, the Würzburg MIH work group (an international working group with representatives from universities in Germany, Austria and Switzerland) introduced a treatment need index for MIH (MIH TNI). The MIH TNI is unique as it is not only based on the extent of the destruction of tooth structure but also the possibility of hypersensitivity. The index can be used for epidemiological studies as well as for individual patients for assessment and treatment planning. Creation of a standardised approach for dental treatment for MIH could be possible after validation of this index. There are six measurements for index reference. These measurements are as follows: maxillary right; maxillary front; maxillary left; and the same thing for the mandible. The index values are shown in Table 1. In a recent article, Dr M Hubbard (the founder and the director of the D3 Group) stated that MIH is a common dental problem (affects one in six children on average worldwide) and affected molars may face more than a ten-fold higher risk of developing caries when severely hypomineralised. Therefore, MIH accounts for a substantial proportion of childhood caries due to its high prevalence. Further research into better clinical management and ultimately medical prevention is needed and recommended.

Table 1 MIH-TNI by Steffen et al. Reprinted by permission from Springer Nature, Eur Arch Paediatr Dent, The Würzburg MIH concept: the MIH treatment need index (MIH TNI), R. Steffen, N. Krämer, K. Bekes, 2017

The following, however, are some management and treatment options, which have been suggested in the literature so far:

Enhanced prevention, remineralisation and sensitivity management

It is very important to commence enhanced prevention as soon as MIH teeth erupt as they are prone to post-eruptive enamel breakdown and caries due to the greater porosity of enamel and its lower mechanical resistance especially in severe MIH lesions. Affected children and their parents should be provided with the appropriate dietary and preventive advice. They should be encouraged to use fluoridated toothpaste with at least 1450 ppm F to reduce caries risk and tooth sensitivity.

Improving the mineralisation of MIH teeth after eruption is possible according to some in-vivo and in-vitro studies; though, a complete resolution seems to be difficult due to the depth and/or the thicknesses of these lesions. In an effort to remineralise the MIH teeth, the long-term use of products containing casein phosphopepetide amorphous calcium phosphate (CPP-ACP) is recommended especially at early stages where the surface enamel of newly erupted teeth is not completely matured. The CPP-ACP ingredient helps to increase the bio-availability of calcium and phosphate within saliva and therefore encourages remineralisation and desensitisation of MIH teeth. The CPP-ACP has the ability to bond strongly with the biofilm on teeth and also can stabilise calcium, phosphate and fluoride ions within saliva by the presence of CPP which prevents spontaneous precipitation and allows penetration of these ions deep into the subsurface lesion; these factors are effective in improving the remineralisation process throughout the body of lesion whereas the fluoride-alone products tend to mainly remineralise the surface layer. Tooth Mousse (GC Corporation, Tokyo, Japan) and MI Paste Plus (GC Corporation, Tokyo, Japan) are the most commonly used dental products containing CPP-ACP. Tooth Mousse has a 10% CPP-ACP while MI Paste Plus has 10% CPP-ACP plus 0.2% NaF (900 ppm F). The combined use of fluoride and CPP-ACP has been shown to give enhanced benefits than using either agent alone. It should be noted that CPP-ACP products are contraindicated in children who are allergic to milk protein due to the presence of casein. Sugar-free chewing gum and lozenges containing CPP-ACP are also available and can be recommended. Pasini et al. found significant improvement in tooth sensitivity of MIH teeth after four months use of Tooth Mousse and, therefore, these products can also be recommended to patients with mild pain to external stimuli.

Another effective product that can be used is Enamelon Treatment Gel (Premier Dental, USA), it contains both fluoride (970 ppm F) and amorphous calcium phosphate (ACP). Studies have shown that this product provides substantive amounts of fluoride and ACP ions to enhance remineralisation with similar benefits when compared to 5,000 ppm fluoride products. Another product that has been found to enhance remineralisation and reduce sensitivity is NovaMin containing toothpaste. NovaMin, a very fine Bioglass particulate (NovaMin Technology, GlaxoSmithKline, Florida, UK), with a particle size of ∼18 μm is used as an active repair agent in toothpaste. This material mineralises tiny holes in the dentine leading to decreased sensitivity. Multiple studies suggest that, NovaMin containing toothpastes have better remineralisation capability than CPP-ACP Tooth Mousse as the former attaches to the enamel surface more compactly. These can be applied in Essix-style retainers overnight.

As a part of prevention at the dental clinic, it is recommended to fissure seal MIH molars. If the enamel surface of MIH molars is intact, resin-based fissure sealants can be used with adhesive application before placement as this will increase fissure sealant retention. Some researchers indicate that enamel pre-treatment with deproteinising agents such as 5% sodium hypochlorite or papain-based papacarie gel for 60 seconds after etching increases bond strengths significantly. If the MIH molars are partially erupted, hypersensitive or have post-eruptive enamel breakdown, it is recommended to fissure seal them with glass ionomer cement, these will serve as a temporary management option as retention of such material is poor. It has to be noted that the intention here is different from conventional fissure sealants. Entire occlusal surface coverage, with glass ionomer cement, flowable or filled composite is often desired up to cusp level. Generally, all applied fissure sealants should be regularly monitored and replaced when lost. Moreover, patients should receive regular professional applications of fluoride varnishes/gels as a part of the enhanced prevention protocol and to reduce tooth sensitivity.

Local anaesthesia

Difficulty to anaesthetise the MIH molars is well reported in the literature. The hypomineralised enamel is a poor insulator and therefore, the pulp is not well protected from external thermal stimuli. As a result, the tooth becomes hypersensitive to hot and cold temperatures. This chronic stress on the pulp leads to an inflammatory response within the pulp and pH changes at periapical tissue level leading to hypersensitive pulp nerve tissue which excite with less stimulation than normally necessary. The clinical implication of this is a hypersensitive tooth that is difficult to anaesthetise even with increasing the local anaesthetic dose. For restorative treatment of MIH teeth, it is important for the dentist to achieve adequate local anaesthesia in order to perform good quality restorative treatment as well as to reduce behaviour management problems.

To overcome this difficulty, multiple options have been suggested in the literature. Some researchers suggest the use of inhalation sedation to increase the pain threshold during dental treatment. The use of anaesthetic adjuncts such as intraligamental, intraosseous and palatal anaesthesia is also an effective option. Different types of local anaesthetics (LA) are available and the 2% lidocaine HCL and 4% articaine HCL are possibly the most frequently used LA agents. Studies that compare the effectiveness of these LA agents in inferior alveolar nerve block, found that none has been shown to have a superior effect over the other, while studies that compare their effectiveness in infiltration anaesthesia showed that articaine was significantly more effective. Moreover, buccal infiltration with articaine as a LA adjunct to inferior alveolar nerve block was found to be effective in achieving more profound anaesthesia. Providing the dental treatment under rubber dam isolation can prevent sensitivity from other teeth during procedures which are not anaesthetised and the use of saliva ejector instead of high-volume suction could be a more gentle option for hypersensitive tooth.

Some preoperative management techniques have also been described, such as the use of desensitising toothpaste before the restorative appointment. Fayle recommended the application of fluoride varnish at a pre-restorative appointment. Sedative interim restorations such as glass ionomer cements can be used in case the pain is uncontrollable and it is difficult to complete the restorative treatment. Glass ionomer cements have sedative properties in cases of hypersensitivity and they help by soothing the highly sensitive tooth. After one to two weeks, the restorative treatment could be completed. This two-step technique can offer shorter and more comfortable appointments for young patients.

Finally, in cases where there is extreme difficulty to perform the proposed treatment and all the options have failed, general anaesthesia could be the last option, however, in these situations a more radical treatment should be planned.

Treatment options for molars

It has been reported that these teeth have five to ten times more dental treatment need than molars without MIH. When managing these teeth, the first clinical consideration is whether to restore or extract. This depends on factors such as: child's age; severity of MIH; pulp involvement; presence of third molar germ(s); restorability of the tooth/teeth; expected long-term prognosis; and long-term treatment cost.

Resin infiltration

Also known as erosion-infiltration, this technique uses a very low viscosity resin which is capable of penetrating demineralised enamel. Icon by DMG (Hamburg, Germany) is the only material available for this procedure. Its manufacturer recommends this material to treat incipient caries and/or carious white spot lesions reaching up to the outer third of dentine. The Icon system consists of: Icon-Etch (15% hydrochloric acid), Icon-Dry (99% ethanol) and Icon-Infiltrant (Methacrylate-based resin). The hydrochloric acid is used to eliminate the relatively intact surface layer and open access to the body of the lesion, then the fluid resin is infiltrated into the broad channels of communication. Although this product has no bioactive properties, so it does not allow for future mineral augmentation of the lesion, researchers suggest that it could protect against acid attack, improve enamel micromechanical properties and decrease post-eruptive enamel breakdown and/or possible improvement in bonding and restorative outcomes. Crombie et al. suggest that in MIH molars, the resin infiltrant has the potential to penetrate surfaces like hypomineralised cuspal inclines which are susceptible to post-eruptive enamel breakdown without interfering with occlusion or being broken by occlusal forces so this material can be effective if used as 'fissure sealant', but the material here will be infiltrated into the hypomineralised enamel therefore this procedure, if done, is irreversible and it requires excellent isolation. Crombie et al. also suggest a possible benefit of this material, if it is applied before composite restoration, in improving bonding by increasing surface hydrophobicity and the area of the resin-enamel interface.

Regarding micromechanical properties, studies have reported improvement in enamel hardness of MIH lesions which were infiltrated with Icon resin infiltrant, however, there was only a 15% increase in hardness which does not reach the normal values. Although, laboratory studies found that resin infiltrant is capable of penetrating developmentally hypomineralised enamel, this occurs in an inconsistent manner, not as extensively as reported in carious lesions and does not reach ADJ. It seems that teeth with severe MIH can be infiltrated more than mild cases due to its greater porosity and reduced mineral density. Increasing etching time could be needed in MIH cases as suggested by Kumar et al.. Denis et al. indicate that this technique seems inappropriate especially in mild MIH cases where the defect is located beneath the superficial two thirds of relatively healthy enamel. Therefore, this technique is not yet strongly recommended and requires further investigation.

Restorations

When restoring hypomineralised teeth, dentists frequently face difficulty in defining the cavity margins. Cavity design plays a critical role, as defective enamel remnants compromise the end result. It is recommended that the cavity design should involve removal of all the porous but not necessarily discoloured enamel, until resistance to the bur or to the probe is achieved.

Glass ionomer cement (GIC) or resin modified GIC restorations can be considered only as an intermediate approach until definitive restoration is placed. Resin composite is the material of choice and recommended for one to three surface restorations and the pre-treatment with 5.25% sodium hypochlorite can improve the bond strength. Amalgam should be avoided due to atypically shaped cavities in MIH molars so further breakdown often occurs at the margins, it is a non-adhesive so does not restore the strength of the tooth, and is a poor insulator.

Full or partial coverage

Preformed metal crowns (PMCs) can be used successfully in severely damaged MIH molars with high long-term survival rates. PMCs can prevent further post-eruptive enamel breakdown, manage sensitivity, are not expensive, can establish correct interproximal and occlusal contacts, require no/little tooth preparation, and can be done in single visit. Non-precious metal, gold or tooth-coloured indirect onlays can be used in older children but the procedure is time-consuming, technique-sensitive and expensive, however, studies found that this kind of treatment is clinically successful over five-year follow-ups. Preformed malleable composite temporary crowns that come in different sizes (Protemp Crown Temporisation Material by 3M ESPE) can offer an aesthetic option. With this material some tooth preparation is required and the crown will require some adjustments but the process is considered easy and requires a single visit. There are as yet no studies that assess the performance of these crowns in MIH molars.

Extraction of severely affected molars

For severely affected FPMs with poor prognosis, extraction might be considered at the dental age of eight to ten years. This will give the second permanent molars (SPM) an opportunity to drift into the FPM position. Before a decision to extract the molars is made, full dental assessment should be carried out to check for the presence, position and normal formation of the developing permanent dentition to ensure favourable orthodontic conditions. Therefore, it is advisable to seek an orthodontic opinion before extraction and consideration should be given to further FPM extractions for balancing and compensation reasons.

The spontaneous mesial eruption of SPMs is more likely to occur when the SPM follicle is still entirely within bone. It has been suggested that the ideal timing of FPM extraction is indicated radiographically by the calcification of the bifurcation of the roots of the lower SPMs. However, studies show that the stage of SPM development may not be as critical as current guidance suggests. The chance of ideal positioning of the SPMs after the extraction of FPMs at the ideal time is 94% for upper SPMs and 66% for lower SPMs. In the upper arch, complete space closure is mostly to be expected regardless of extraction timing while in the lower arch even when FPMs are extracted at what is generally accepted to be the ideal timing, a significant proportion of patients will still exhibit incomplete space closure or tooth malalignment. Therefore, fixed appliance orthodontic treatment might be needed to close the residual space but this will take less time than if the extraction of FPMs were performed after eruption of SPMs.

Treatment options for incisors

Aesthetic concerns are common in patients with MIH with incisor involvement. In young patients, these teeth should be treated in a conservative approach as they have immature anterior teeth with large and sensitive pulps. Therefore, it is preferred to postpone the aesthetic treatment as the enamel opacities often become less profound in the long term. In general, the yellow-whitish defects are less severe than the yellow-brownish defects and the defects on the incisors are milder than those on molars, however, the defects on the incisal edge tend to undergo post-eruptive breakdown more than those within the labial surface, and are thus clinically more difficult to manage. The following are some possible treatment options for anterior teeth with MIH, which could be used alone or in a combination of methods to achieve better aesthetic results.

Microabrasion

This involves the removal of a small amount of surface enamel (no more than 100 μm (0.1 mm)) through abrasion and erosion using 18% hydrochloric or 37.5% phosphoric acid with pumice. The process abrades the surface enamel while also polishing it which leads to changes in optical properties and this may improve the aesthetics. Microabrasion is indicated when the discolouration is limited to the outer surface of enamel and it is more effective at eliminating brown mottling. This technique was suggested in the literature for aesthetic management of MIH incisors with limited benefit if used alone due to the anatomopathology of MIH lesions. Some researchers suggest this technique to remove a hypermineralised superficial layer of enamel followed by home application of CPP-ACP products as this was found to improve remineralisation outcomes.

Tooth bleaching

The aim is to camouflage white opacities by increasing the overall brightness of the teeth. This option is indicated for adolescents. The possible side-effects of bleaching are: sensitivity, mucosal irritation, and enamel surface alterations. Home bleaching through daily placement of 10% carbamide peroxide gel into custom fitted trays is the gentlest bleaching option prescribed by the dentist, but for more protection, the combined use of CPP-ACP Tooth Mousse and bleaching gel is recommended. The CPP-ACP Tooth Mousse will protect the tooth structure and remineralise the MIH opacities during the bleaching process without interfering with bleaching effect. The combined use of hydrogen peroxide and CPP-ACP, could be done with a ratio range from 1:6 to 3:4, depending on the opacity response to the bleaching agent.

Etch-bleach-seal technique

This technique was suggested by Wright to remove yellow-brown stains. The affected tooth should be etched first with 37% phosphoric acid for 60 seconds, followed by continuous application of 5% sodium hypochlorite as the bleaching agent for five to ten minutes. Then the tooth should be re-etched and covered with a protective layer such as clear fissure sealant or composite bonding agent. With this technique the yellow-brown stains can be eliminated leaving a white mottled appearance which is more aesthetically acceptable.

Resin infiltration

This technique was discussed earlier in 'treatment options of molars.' Additionally, it can have some benefits in aesthetic management of MIH incisors as well. Since the refractive index of the resin infiltrant (1.52) is close to that of healthy enamel (1.62), this can improve the optical properties by improving the translucency and therefore improving the aesthetics. As mentioned earlier, this technique seems inappropriate especially for mild MIH cases where the defect is located beneath the superficial two thirds of relatively healthy enamel, Attal et al. suggested a modification in this technique for aesthetic management of MIH incisors and this was introduced as 'deep resin infiltration technique.' The technique involves preparing the affected tooth by an intraoral sandblasting device to ensure that the infiltration can indeed reach the full extent of the lesion in case of MIH. This should remove no more than 500 μm from surface enamel and after resin infiltration, some composite could be added to tooth surface. The bonding between resin infiltrant and composite is of very good quality. Studies assessing the longevity of the aesthetic result found stable results for at least six months with the main drawback being material discolouration. Paris et al. suggest that well-polished infiltrated enamel is resistant to discolouration. However, these findings are related to the regular resin infiltration technique, as in the situation of deep infiltration the resin infiltrant is not in contact with the external environment. In general, the use of resin infiltration technique in MIH teeth requires further investigation, improvement in material properties and/or technique modifications to be strongly recommended in MIH cases.

Composite restorations or veneers

Composite restorations involve removal of defective enamel and composite resin build-up using opaque resins to avoid excessive enamel reduction, while composite veneers could be a more conservative approach as it can be achieved with no tooth preparation that is, no removal of even defective enamel. These options could be indicated for large enamel defects that require treatment due to exposed dentine or chipped enamel. The bond strength to hypomineralised enamel can be improved significantly by pre-treatment with 5.25% sodium hypochlorite for one minute after etching. The composite resins are susceptible to discolouration, wear and marginal fractures, therefore, long-term maintenance is required.

Porcelain veneers

These are indicated for patients aged 18 years and above when the gingival margin has matured. It can be an option when the other techniques failed to produce satisfactory results.

Conclusion

Children with poor general health in early childhood or with hypomineralised second primary molars should be considered at risk of MIH. Therefore, they should be monitored more frequently during eruption of the FPMs. Management of these teeth should consider their long-term prognosis, as well as management of the presenting features such as pain. Aesthetic management of MIH incisors should be as conservative as possible and the extent of treatment depends on the patient's age, aesthetic concern and lesion severity. The remineralisation and resin infiltration techniques are possible effective conservative approaches in managing MIH teeth but these treatment modalities require further investigation to introduce the best technique/protocol in using them for MIH cases.

Since MIH is considered common, it should be diagnosed and managed in primary care wherever possible. Automatic referral to a dental teaching hospital or salaried service is a frequent approach. If MIH is as common as we think it is, it is illogical to expect the problem to be routinely managed in a specialist setting.

Author information

Affiliations

1. Paediatric dental department, East Riyadh Specialized Dental Center, Riyadh, 13226, Riyadh, Saudi Arabia

Z. Almuallem

2. Edinburgh Dental Institute, Edinburgh, EH3 9HA

A. Busuttil-Naudi

Corresponding author

Correspondence to Z. Almuallem.

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Molar incisor hypomineralisation (MIH) - an overview - British Dental Journal

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Recent data indicates that molar-incisor hypomineralisation (MIH) is a frequently - encountered dental condition worldwide. The condition could be associated with dental complications that might affect patients' quality of life as well as create treatment challenges to dentists.

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Modified child dental anxiety scale v2 2019 (1)

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The use of silver diamine fluoride (SDF) in dental practice

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The use of silver diamine fluoride (SDF) in dental practice

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A large multidisciplinary team were instrumental in drafting and editing the content for these pages. We would like to take this opportunity to thank everyone involved, from content authors to peer reviewers, your time and dedication is greatly appreciated.

Dr Kathy Wilkinson (Chair and Lead for Child Safeguarding), Consultant Paediatric Anaesthetist, Norwich

Ms Janice Barber, Senior Partner, Hempsons

Ms Natalie Bell (SafeguardingPlus Project Manager), Business Co-ordinator, Clinical Quality and Research Directorate, RCoA

Dr Liam Brennan, Consultant Paediatric Anaesthetist, Cambridge

Dr Alistair Cranston, Consultant Paediatric Anaesthetist, Birmingham

Dr Chris Danbury, Consultant in Anaesthetics and Intensive Care Medicine, Reading

Ms Sharon Drake, Director of Clinical Quality and Research, RCoA

Dr Lisa Gemmell, Consultant in Anaesthesia and Intensive Care, Paisley

Dr Hilary Glaisyer, Consultant Paediatric Anaesthetist, London

Dr Deborah Hodes, Consultant Paediatrician, London

Mrs Mandie Kelly, Website & Publications Officer, RCoA

Dr Jacqueline McCarthy, West of Scotland Training Scheme, Paisley

Dr Paul McConnell (Lead for Adult Safeguarding and Adult Consent and Ethics), Consultant in Anaesthesia and Intensive Care Medicine, Paisley

Dr Jillian McFadzean, Consultant Paediatric Intensivist, Edinburgh

Dr Andrew McLeod, Consultant Anaesthetist, London

Dr Alison Mott, Consultant Paediatrician, Cardiff

Ms Sara Payne, Association of Paediatric Anaesthetists, Lay Reviewer

Dr Kerry Robinson, Consultant Paediatrician, London

Dr Jane Simpson, Consultant Paediatrician, London

Dr Sarah Steele, Consultant Paediatrician, Norwich

Dr Hugo Wellesley (Lead for Child Consent and Ethics), Consultant Paediatric Anaesthetist, London

Mr Robert Wheeler, Consultant Neonatal & Paediatric Surgeon, Southampton

We would also wish to acknowledge that most of the references and links used in these pages originate elsewhere. We have endeavoured to include all relevant attributions and sought appropriate permissions wherever possible.

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A large multidisciplinary team were instrumental in drafting and editing the content for these pages. We would like to take this opportunity to thank everyone involved, from content authors to peer reviewers, your time and dedication is greatly appreciated.

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British Society of Paediatric Dentistry (BSPD) > Resources > Position Statements

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The (BSPD) is the national society specifically concerned with the oral health of children in the UK it provides meetings, publications and news.

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Downloads

Guidance in Brief summarises the main recommendations and clinical practice advice within the full guidance

Full Guidance provides more detail about the recommendations and how to follow them, including illustrated step-by-step advice on individual clinical techniques and flowcharts for decision making about prevention and management options

Also available via the SDCEP Dental Companion app.

Versions in accessible formats (Word) are also available

These publications are only available as downloadable online resources. They are not available in print.

About this guidance

Prevention and Management of Dental Caries in Children aims to support dental teams to improve and maintain the oral health of their younger patients through the delivery of preventive care and, where necessary, effective management of dental caries. The second edition includes advice on

assessment of the child and family

helping the family manage dental care

delivery of preventive care based on caries risk

choosing from the range of caries management options available

delivery of restorative care, including how to carry out specific treatments

referral and recall

management of suspected dental neglect

working with other agencies to support and safeguard the wellbeing of children and young people

NICE has accredited the process used by the Scottish Dental Clinical Effectiveness Programme to produce its Prevention and Management of Dental Caries in Children guidance. Accreditation is valid for 5 years from 15 March 2016. More information on accreditation can be viewed at www.nice.org.uk/accreditation. Further information about NICE accreditation of SDCEP guidance can be viewed at NICE Accreditation.

The British Society of Paediatric Dentistry has endorsed this guidance as a source of reliable, high quality professional advice that promotes the provision of safe and effective oral health care for patients.

Guidance development

The second edition of this guidance is based on consideration of available evidence and the opinion of dental experts and experienced practitioners and has been subject to open consultation and peer review prior to finalising for publication.

Recommendations for caries prevention in children are primarily based on the evidence on which the Scottish Intercollegiate Guideline Network (SIGN) guideline 138 Dental Interventions to Prevent Caries in Children is based. Recommendations on the management of dental caries have been expanded, with a more comprehensive approach to management of children's primary and permanent teeth and management techniques presented in a separate section.

The methodology used for the development of this guidance, including details of the evidence search strategy, evidence appraisals and information about conflict of interests can be found in the Prevention and Management of Dental Caries in Children Methodology document, available on request. For further information on the SDCEP guidance development process, please click here or contact the SDCEP office ( scottishdental.cep@nes.scot.nhs.uk).

Guidance Development Group

A Guidance Development Group comprising individuals from relevant branches of the dental profession and two patient representatives was convened to update this guidance.

Barbara Chadwick (Co-Chair)

Professor of Paediatric Dentistry, Vice-Dean, School of Dentistry, Cardiff University

Nicola Innes (Co-Chair)

Professor of Paediatric Dentistry, School of Dentistry, University of Dundee

Paul Ashley

Consultant in Paediatric Dentistry, UCL Eastman Dental Institute, London

Sarah-Louise Blackwood

Patient Representative

David Conway

Professor of Dental Public Health, University of Glasgow

Timothy Cooke

Senior Dental Officer, Public Dental Service, Nairn, NHS Highland

Brett Duane

Associate Professor in Dental Public Health, Trinity College, Dublin

Dafydd Evans

Honorary Senior Lecturer in Paediatric Dentistry, University of Dundee

Martin Foster

Specialist in Paediatric Dentistry, Children's Dental Service, NHS Lothian

Alex Keightley

Consultant and Honorary Senior Clinical Lecturer in Paediatric Dentistry, Edinburgh Dental Institute

Nicole Kettles

General Dental Practitioner

Peter King

Childsmile Programme Manager (West Region)

Maxine Lee

BSc Programme Lead, Oral Health Sciences, Dundee Dental Hospital

Gillian Nevin

General Dental Practitioner; Assistant Director of Postgraduate GDP Education, NHS Education for Scotland

Derek Richards

Consultant in Dental Public Health, South East Scotland

Marguerite Robertson

Patient Representative

Margaret Ross

Senior Lecturer for Dental Care Professionals, Edinburgh Dental Institute

SDCEP acknowledges the important contribution of all those who commented during the consultation and peer review stages.

Review and updating

For this guidance, a review of the topic will take place five years after publication and, if this has changed significantly, the guidance will be updated accordingly.

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Guidance in Brief summarises the main recommendations and clinical practice advice within the full guidance Full Guidance provides more detail about the recommendations and how to follow them, including illustrated step-by-step advice on individual clinical techniques and flowcharts for decision making about prevention and management options Also available via the SDCEP Dental Companion app .

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Multifactorial intervention in diabetes care using real-time monitoring and tailored feedback in type 2 diabetes

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In 2011, we demonstrated that an individualized health management system employing advanced medical information technology, designated ubiquitous (u)-healthcare, was helpful in achieving glycemic control without hypoglycemia in patients with diabetes. Following this, we generated a new multidisciplinary u-healthcare system by upgrading our clinical decision support system (CDSS) rule engine and integrating a physical activity-monitoring device and dietary feedback into a comprehensive package.

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Technique Tips Managing young patients with MIH

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Technique Tips Managing young patients with MIH

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(ISON)

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Referring patients to Royal Liverpool Dental Hosptial

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Referring patients to Royal Liverpool Dental Hosptial

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Royal Liverpool and Broadgreen University Hospitals Trust

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The hospital caters for a variety of dental health needs including surgeries for dental extractions, minor oral surgery and designated clinics for the treatment of medically compromised patients and patients with latex allergy. In addition there is a general anaesthetic extractions surgery and recovery area and operating facilities for day case patients requiring treatment under general anaesthesia or intravenous sedation.

The Liverpool University Dental Hospital is a teaching hospital and as such we are able to accept a limited number of patients suitable for treatment by undergraduate and postgraduate students, junior hospital staff and specialist trainees.

Specialists or consultants also treat patients who fall within certain priority groups. Restorative waiting times for student treatment are variable and often show seasonal fluctuations relating to undergraduate timetables, student intake and examinations.
There are a limited number of staff hygienists, who only see priority cases.

In order to be referred for treatment you must be referred by your dentist or by the attending dentist who has dealt with your emergency treatment.

See below for referral guideline documents, which lay out the criteria for being accepted for treatment. These include some documents for use by professionals:

Liverpool University Dental Hospital Referral Guidelines

Dental Referral Proforma

Periodontal Protocol

Form for referring a patient for treatment by a dental student

See below for information for TMJ patients including:

TMJ Patient Information Leaflet

TMJ Exercises

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The hospital caters for a variety of dental health needs including surgeries for dental extractions, minor oral surgery and designated clinics for the treatment of medically compromised patients and patients with latex allergy. In addition there is a general anaesthetic extractions surgery and recovery area and operating facilities for day case patients requiring treatment under general anaesthesia or intravenous sedation.

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Fluoride is a naturally occurring mineral found in water in varying amounts, depending on where in the UK you live.
It can help prevent tooth decay, which is why it's added to many brands of toothpaste and, in some areas, to the water supply through a process called fluoridation.

Tooth decay

Tooth decay, also known as dental decay or dental caries, is a major health concern worldwide and is still a big problem in the UK. Despite being preventable, it's one of the most common reasons for hospital admission in children.

Tooth decay is the destruction of tooth tissue caused by acids made by bacteria in dental plaque. Dental plaque is a sticky film that constantly forms on the teeth. Each time you have sugary food and drink, the bacteria in plaque produce acid that attacks teeth.

If you eat or drink sugary foods frequently throughout the day, you have more "acid attacks", which can lead to tooth decay. This can eventually lead to cavities (holes) in the teeth and infection, which is why teeth sometimes need to be removed.

Read more about the causes of tooth decay.

Fluoride toothpaste

Brushing your teeth thoroughly with fluoride toothpaste is one of the most effective ways of preventing tooth decay.

A range of toothpastes are available containing different levels of fluoride. The amount of fluoride in the toothpaste can be found on the side of the tube and is measured in parts per million (ppm).

Toothpastes containing 1,350 to 1,500ppm fluoride are the most effective. Your dentist may advise you to use higher-strength toothpaste if you or your child is at particular risk of tooth decay.

Children under 3 years old should brush twice daily, with a smear of toothpaste containing at least 1,000ppm fluoride.

Children between 3 and 6 years old should brush at least twice daily with a pea-sized amount of toothpaste containing more than 1,000ppm fluoride.

Adults should brush at least twice daily with a toothpaste containing 1,350-1,500ppm fluoride.

Don't use mouthwash at the same time as brushing. Use it at an alternative time, because it washes away the fluoride in the toothpaste

Read more about:

Fluoride dental treatments

Fluoride mouth rinses

Fluoride mouth rinses can be prescribed for adults and children aged 8 and above who have tooth decay. They should be used every day, in addition to brushing twice daily with toothpaste containing at least 1,350ppm fluoride.

Rinses should be used at different times to brushing to avoid washing the toothpaste off your teeth, as this reduces the beneficial effects of the fluoride in the toothpaste.

Fluoride varnish

Fluoride varnish can be applied to both baby teeth and adult teeth by a dentist. The process involves painting a varnish containing high levels of fluoride onto the surface of the tooth every 6 months to prevent decay. It works by strengthening tooth enamel, making it more resistant to decay.

From the age of 3, children should be offered fluoride varnish treatment at least twice a year. Fluoride varnish should be offered 2 or more times a year for children of all ages with tooth decay or those at high risk of developing it.

Ask your dentist about fluoride varnish. Find a dentist near you.

Community water fluoridation

Most water supplies contain some fluoride and in the early 20th century, levels of tooth decay were found to be associated with fluoride levels in drinking water.

This led to the introduction of schemes to add fluoride to water supplies to improve dental health.

Community water fluoridation schemes have operated for more than 70 years; the first scheme was introduced in the US in 1945. The first substantive UK scheme was established in Birmingham in 1964.

Community water fluoridation in England

Around 5.8 million people in England receive fluoridated water. This means fluoride has been added to bring it up to around 1mg of fluoride per litre of water, which is a level found to reduce tooth decay levels.

The decision about whether to add fluoride to the water supply is made by individual local authorities. Areas where water fluoridation schemes are currently in place include parts of:

the West Midlands

the North East

the East Midlands

Eastern England

the North West

Yorkshire and Humber

In some parts of the country, such as parts of the North East and Midlands, the public water supply naturally contains a level of fluoride that's similar to that seen in schemes. Some private water supplies contain more than this amount.

Your local water supplier should be able to tell you how much fluoride is in your water supply and whether any is added. Most companies have an online facility where you can use your postcode to check the water in your area.

What research has been carried out?

Over the past 50 years, there have been several reviews of the safety and effectiveness of water fluoridation schemes.

Recent large reviews that have been carried out include:

Overall, these reviews found that water fluoridation appears to contribute to reduced tooth decay levels and doesn't seem to be associated with any significant health risks.

Is fluoride safe?

There have been some concerns that fluoride may be linked to a variety of health conditions. Reviews of the risks have so far found no convincing evidence to support these concerns.

However, a condition called dental fluorosis can sometimes occur if a child's teeth are exposed to too much fluoride when they're developing. Read more about looking after children's teeth and looking after your baby's teeth.

Mild dental fluorosis can be seen as very fine pearly white lines or flecking on the surface of the teeth. Severe fluorosis can cause the tooth's enamel to become pitted or discoloured.

It's uncommon in the UK for fluorosis to be severe enough to seriously affect the appearance of teeth. This is because fluoride levels in water are carefully monitored by the Drinking Water Inspectorate (DWI) and adjusted if necessary.

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Fluoride is a naturally occurring mineral found in water in varying amounts, depending on where in the UK you live. It can help prevent tooth decay, which is why it's added to many brands of toothpaste and, in some areas, to the water supply through a process called fluoridation.

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The Eatwell Guide shows how much of what we eat overall should come from each food group to achieve a healthy, balanced diet.
You do not need to achieve this balance with every meal, but try to get the balance right over a day or even a week.

Most of us still are not eating enough fruit and vegetables. They should make up just over a third of the food we eat each day.

Aim to eat at least 5 portions of a variety of fruit and veg each day. Choose from fresh, frozen, tinned, dried or juiced.

Remember that fruit juice and smoothies should be limited to no more than a combined total of 150ml a day.

Fruit and vegetables are a good source of vitamins, minerals and fibre.
Find out more about how to get your 5 A Day

Starchy food should make up just over a third of the food we eat. Choose higher fibre or wholegrain varieties, such as wholewheat pasta and brown rice, or simply leave the skins on potatoes.

There are also higher fibre versions of white bread and pasta.

Starchy foods are a good source of energy and the main source of a range of nutrients in our diet.
Find out more about starchy foods

These foods are good sources of protein, vitamins and minerals. Pulses, such as beans, peas and lentils, are good alternatives to meat because they're low in fat and they're a good source of fibre and protein, too.

Choose lean cuts of meat and mince, and eat less red and processed meat like bacon, ham and sausages.

Aim for at least 2 portions (2 x 140g) of fish every week, 1 of which should be oily, such as salmon, sardines or mackerel.

Find out about fish and meat.

Milk, cheese, yoghurt and fromage frais are good sources of protein and some vitamins, and they're also an important source of calcium, which helps keep our bones healthy.

Try to go for lower-fat and lower-sugar products where possible, like semi-skimmed, skimmed or 1% fat milk, reduced-fat cheese or plain low-fat yoghurt.
Find out more about milk and dairy foods

Unsaturated fats are healthier fats and include vegetable, rapeseed, olive and sunflower oils.

Remember all types of fat are high in energy and should be eaten in small amounts.
Find out more about the different types of fat in our diet

These foods include chocolate, cakes, biscuits, sugary soft drinks, butter, ghee and ice cream.

They're not needed in our diet, so should be eaten less often and in smaller amounts.
Get tips on cutting down on sugar

Water, lower-fat milks, lower-sugar or sugar-free drinks and tea and coffee all count.

Fruit juice and smoothies also count towards your fluid consumption, but they contain free sugars that can damage teeth, so limit these drinks to a combined total of 150ml a day.
Find out more about water, drinks and your health

How does the Eatwell Guide work?

The Eatwell Guide divides the foods and drinks we consume into 5 main food groups.

Try to choose a variety of different foods from each of the groups to help you get the wide range of nutrients your body needs to stay healthy.

It's important to get some fat in your diet, but foods that are high in fat, salt and sugar have been placed outside of the main Eatwell Guide as they're not necessary as part of a healthy, balanced diet and most of us need to cut down on these.

Unsaturated fats from plant sources (for example, vegetable oil or olive oil) are healthier types of fat.

But all types of fat are high in energy (calories), so they should only be eaten in small amounts.

On average, women should have around 2,000 calories a day (8,400 kilojoules) and men should have around 2,500 calories a day (10,500 kilojoules). We all need different amounts of energy (or calories) from food to be a healthy weight. How much you need depends on lots of things, including how active you are.

Find out how food labels can help you choose between foods and pick those lower in fat, saturated fat, sugar and salt.

Combination foods

Many foods, such as pizzas, casseroles, pasta dishes and sandwiches, are combinations of the food groups in the Eatwell Guide.

With these meals, check the ingredients and think about how these fit with the sections on the guide to help you achieve a balanced diet.

Does the Eatwell Guide apply to everyone?

The Eatwell Guide applies to most of us, whether we're a healthy weight or overweight, whether we eat meat or are vegetarian, and no matter what our ethnic origin.

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Background

Amelogenesis imperfecta (AI) is a term used to describe a group of hereditary conditions that affect the structure and appearance of dental enamel, often in conjunction with changes in other intra-oral and/or extra-oral tissues. The structure and clinical appearance of dental enamel of nearly all teeth are affected in both primary and secondary dentition and is characterised by hypomineralisation and/or hypoplasia with discolouration, sensitivity and fragility. The term amelogenesis imperfecta is also used to describe enamel phenotypes in other syndromes.

Dental enamel is an epithelial-derived tissue comprised of highly organised hydroxyapatite crystals that form in a defined extracellular space. It is acellular and has no intrinsic repair potential. It is formed by ameloblasts during tooth developmental stages after dentinogenesis. The entire process of amelogenesis is under genetic control. Mutations in genes responsible for amelogenesis result in diverse phenotypes showing a wide spectrum of characteristics. The aim of this series of review papers is to understand the epidemiology, genetics, classification, clinical presentation, diagnosis and management options. The condition is associated with high morbidity for the patients, and therefore early detection and careful planning and management in a multidisciplinary environment is a key ingredient to a successful outcome.

Amelogenesis

Enamel is derived from epithelial (ectodermal) origin while dentine, cementum, pulp and periodontal ligament are derived from mesenchymal (mesodermal) origin. Enamel formation begins from cells that are derived from the internal enamel epithelium of the dental organ after initiation of dentinogenesis. Amelogenesis has been described in mainly three functional stages: presecretory, secretory and maturation stages. In the presecretory stage ameloblasts acquire their characteristics and develop an extensive protein synthetic apparatus to secrete the organic matrix of enamel. In the secretory phase the ameloblasts secrete the entire thickness of the enamel. At this stage the hydroxyapatite crystals are separated by organic and water contents. In the maturation stage the ameloblasts allows inorganic ions to be secreted and exchanged for the water and organic contents, resulting in an increase in the inorganic content and the length and width of the enamel prisms. Dental enamel is made of highly organised hydroxyapatie crystals occupying 95% of the maxtrix volume. Ameloblasts control the secretion, formation and maturation of the enamel matrix using matrix molecules such as enamelin, amelogenin, ameloblastin, tuftelin, amelotin, dentine sialophophoprotein and matrix enzymes such as kallikrein-4 and matrix metalloproteinaise-20.

The diversity of enamel malformations observed in AI is believed to reflect the differences in the timing during amelogenesis, when the disruptions occur. Flaws incorporated during formation of the dentino-enamel junction can result in an enamel layer that shears easily from the underlying dentine. Secretory stage defects result in insufficient crystal elongation and leave the enamel layer pathologically thin, or hypoplastic. Maturation stage defects, such as those that might occur if the enamel matrix is not properly degraded and reabsorbed, produce an enamel layer that is of normal thickness, but is pathologically soft.

Epidemiology

The reported prevalence of AI varies widely in the literature. Studies have shown values ranging between 43:10,000 in Turkey,1 14:10,000 in Sweden,2 10:10,000 in Argentina3 and 1.25:10,000 in Israel.4 These values suggests that the average global prevalence is <0.5% (<1 in 200).

Classification

Various classification systems have been described in the literature, dating back to as early as the 1940s. AI presents with various phenotypes and makes appearance invalid as a criterion for sorting. With advances over time and a better understanding of the genetics of AI, genotypic information can be used to distinguish between different forms. Molecular genetic tools will allow more precise diagnosis and classification in the future. A recent paper by Aldred et al. discusses previous systems used and proposes a new model for classifying AI based on four broad areas.5 These are described below:

Mode of inheritance: autosomal dominant, autosomal recessive, X-linked, isolated case

Molecular basis: chromosomal localisation/locus/mutation

Biochemical outcome: putative result of mutation when known

Phenotype: hypoplastic, hypocalcified, hypomaturation, hypomaturation-hypoplastic with taurodontism.

Aetiology

AI is caused by mutations or altered expression in five genes: AMEL (amelogenin), ENAM (enamelin), MMP20 (matrix metalloproteinaise-20), KLK4 (kallikrein-4) and FAM83H.6,7,8,9,10,11,12,13,14,15,16 Table 1 describes the phenotypes associated with the mutations or variable expression associated with these genes. Unlike other genes that cause AI, FAM83H does not encode an extracellular matrix protein. Its location inside the cell is completely unknown, as is its function.

Table 1 Aetiology of amelogenesis imperfecta. The genes are listed on the left side of the column. Mutations or alterations in the expression of these genes result in the various phenotypes associated with amelogenesis imperfecta as described in the columns on the right side

Sporadic cases of AI may represent new mutations, illustrative of variable expressions of the genes. In such cases, careful assessment of other family members is important to exclude non-genetic causes.17

Clinical description

The phenotype (clinical appearance) of AI shows a spectrum of clinical variability ( Fig. 1) and this depends on the pattern of inheritance, the mutation involved, expression of matrix proteins and biochemical changes associated with the mutations.

Some of these show composites/crowns placed by the patients' practitioners to mask sensitivity or for aesthetic reasons

Characterisitcs of hypoplastic AI

Enamel of reduced thickness due to a defect in the formation of normal matrix

Pitting and grooves

Hard and translucent enamel

Radiographically, the enamel contrasts normally from dentine.

Characteristics of hypocalcified AI

Defect in enamel calcification

Enamel of normal thickness

Weak in structure

Appears opaque or chalky

Teeth become stained and rapidly wear down

Radiographically, enamel is less radio-opaque than dentine.

Characterisitcs of hypomaturation AI

Enamel of normal thickness but mottled in appearance

Slightly softer than normal and vulnerable to tooth wear, but not as severe as the hypocalcified type

Radiographically, similar radiodensity as dentine.

Characteristics of hypomaturation-hypoplasia with taurodontism

Mixed hypomaturation and hypoplasia appearance

Taurodontism: body and pulp chamber enlarged, and the floor of pulp chamber and furcation is moved apically down the root.

A review paper in the literature reported other clinical features of AI such as delay in dental eruption, microdontia, deviant crown and morphology, root resorption, short roots, enlarged pulp chamber, pulp stones, dens in dente, tooth agenesis, crowding of teeth, gingival enlargement, gingivitis and periodontitis.18 Additionally there are other reported skeletal abnormalities such as overbite, overjet and cross bites in this review paper.18

Diagnosis

It is important to understand the different phenotypes and associated inheritance patterns related to AI to help narrow down the search for a candidate gene in order to establish a definitive molecular aetiology.

Factors to consider during diagnosis include family history, pedigree plotting (a diagram of a family health history tree), clinical observations and radiographic assessment. Further laboratory-based genetic diagnosis can be done, but this is more useful as a research tool.

It is important to identify other causes of defects in enamel, both extrinsic and intrinsic, to exclude these during diagnosis of AI. These include past medical history (tertracycline staining), dental fluorosis, enamel hypoplasia, trauma, or molar-incisor hypomineralisation (MIH).

Discussion

The appearance of teeth and problems associated with the enamel (such as sensitivity, staining and roughness) can be of major psychological and functional concern to the patient. The aim of any treatment plan is early diagnosis, pain management, prevention, stabilisation, restoration of any defects and regular maintenance.

The management of teeth begins in the primary dentition, followed by the secondary dentition as the teeth erupt. Children with AI may also present with malocclusion and it is therefore essential that a multidisciplinary management involving paediatric dentists, orthodontists, oral surgeons, oral and maxillofacial surgeons and restorative dentists is sought to maintain pro-active care for the patient. At all stages, however, it is important to reinforce and maintain good oral hygiene.

In the next three papers of this series, we aim to describe the role of each of the specialties: paediatric dentistry, orthodontic dentistry and restorative dentistry and their role in management of AI.

Box 1: Amelogenesis imperfecta

1. 1
Amelogenesis imperfecta: an introduction

2. 2
Managing the paediatric patient with amelogenesis imperfecta

3. 3
Amelogenesis imperfecta: the orthodontic perspective

4. 4
The interdisciplinary management of patients with amelogenesis imperfecta - restorative dentistry

Author information

Affiliations

1. Specialist Registrar in Restorative Dentistry, Eastman Dental Hospital

K. Gadhia

2. Specialist Registrar in Paediatric Dentistry, Birmingham Dental Hospital

S. McDonald

3. Consultant Orthodontist, University Hospital of North Staffordshire

N. Arkutu

4. Consultant in Restorative Dentistry, Birmingham Dental Hospital

K. Malik

Corresponding author

Correspondence to K. Gadhia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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Cite this article

Gadhia, K., McDonald, S., Arkutu, N. et al. Amelogenesis imperfecta: an introduction. Br Dent J 212, 377-379 (2012). https://doi.org/10.1038/sj.bdj.2012.314
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Further reading

Kanwal Sohail

, Amber Kiyani

& Rabeea Zeb

Journal of Oral Medicine and Oral Surgery (2020)

Jing Zhang

, Jian Wang

, Chengwei Ma

& Junxia Lu

International Journal of Molecular Sciences (2020)

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, Ana Ortega-Pinto

, Paulina Gajardo

, Ana Salazar

, Irene Morales-Bozo

, Fabiola Werlinger

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, Alfredo Molina-Berríos

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Journal of Applied Oral Science (2019)

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Journal of Prosthodontics (2019)

BDJ In Practice (2019)

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Amelogenesis imperfecta (AI) is an inherited disorder that is associated with mutations in five genes (AMEL; ENAM; MMP20; KLK4 and FAM83H) with a wide range of clinical presentations (phenotypes). It affects the structure and appearance of enamel of all teeth, both in the primary and secondary dentition.

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Genetics, environment  and dental anomalies

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Genetics, environment  and dental anomalies

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Abstract

Dental anomalies are caused by complex interactions between genetic, epigenetic and environmental factors during the long process of dental development. This process is multifactorial, multilevel, multidimensional and progressive over time. In this paper the evidence from animal models and from human studies is integrated to outline the current position and to construct and evaluate models, as a basis for future work.

Dental development is multilevel entailing molecular and cellular interactions which have macroscopic outcomes. It is multidimensional, requiring developments in the three spatial dimensions and the fourth dimension of time. It is progressive, occurring over a long period, yet with critical stages. The series of interactions involving multiple genetic signalling pathways are also influenced by extracellular factors. Interactions, gradients and spatial field effects of multiple genes, epigenetic and environmental factors all influence the development of individual teeth, groups of teeth and the dentition as a whole. The macroscopic, clinically visible result in humans is a complex unit of four different tooth types formed in morphogenetic fields, in which teeth within each field form directionally and erupt at different times, reflecting the spatio-temporal control of development.

Even when a specific mutation of a single gene or one major environmental insult has been identified in a patient with a dental anomaly, detailed investigation of the phenotype often reveals variation between affected individuals in the same family, between dentitions in the same individual and even between different teeth in the same dentition. The same, or closely similar phenotypes, whether anomalies of tooth number or structure, may arise from different aetiologies: not only mutations in different genes but also environmental factors may result in similar phenotypes. Related to the action of a number of the developmental regulatory genes active in odontogenesis, in different tissues, mutations can result in syndromes of which dental anomalies are part. Disruption of the antagonistic balance between developmental regulatory genes, acting as activators or inhibitors can result in dental anomalies. There are critical stages in the development of the individual tooth germs and, if progression fails, the germ will not develop further or undergoes apoptosis. The reiterative signalling patterns over time during the sequential process of initiation and morphogenesis are reflected in the clinical association of anomalies of number, size and form and the proposed models.

An initial step in future studies is to combine the genetic investigations with accurate recording and measurement of the phenotype. They also need to collate findings at each level and exploit the accurate definition of both human and murine phenotypes now possible.

Keywords: Dental anomalies, Genetic, Epigenetic, Environmental, Aetiology

1. Introduction

1.1. Aims

The aims of this paper are to review and evaluate current knowledge concerning the aetiology of anomalies of dental development and to propose models to interpret this information as a stimulus for future investigations.

1.2. Overview

Dental anomalies are caused by complex multifactorial interactions between genetic, epigenetic and environmental factors during the long process of dental development. This process is multilevel, multidimensional and progressive. It involves multiple interactions and critical stages. In this paper the evidence from animal models, most frequently murine, and from human studies is integrated to outline the current position and to construct and evaluate models, as a basis for future work.

Dental development is multilevel in that it entails molecular and cellular interactions which have macroscopic, clinical phenotypic outcomes. It is multidimensional, requiring developments in the three spacial dimensions, the x, y, z axes and the fourth dimension of time. It is progressive, occurring over a long period, yet with critical stages of development. The series of interactions involve multiple genetic signalling pathways between the ectodermal and the neural crest derived mesenchymal cell layers. The cell signalling is also influenced by extracellular factors. While the term epigenetic can refer to the addition or removal of methyl groups to DNA or the attachment of acetyl groups of histones, here the broader definition of epigenetic is adopted, that is an alteration in gene expression without changes in nucleotide sequencing. This broader view includes interaction between cells at a tissue level as epigenetic events in addition to those directly affecting DNA. At the histological level there are interactions between developing tooth germs.

Interactions, gradients and spacial field effects of multiple genes, epigenetic and environmental factors all influence the development of individual teeth, groups of teeth and the dentition as a whole. The macroscopic, clinically visible result in humans is a complex unit of four different tooth types formed in morphogenetic fields, in which teeth within each field form directionally and erupt at different times. A current, clinically relevant update of the morphogenetic fields concept, applied by Butler to the mammalian dentition and refined by Dahlberg for the human dentition, incorporates a synthesis with the clone theory and the odontogenic homeobox code.

Therefore, to evaluate current knowledge of the aetiology of developmental anomalies of the dentition further and to propose aetiological models, the developmental process will be reviewed and then the anomalies will be considered as they occur sequentially in this process: number, size, shape and structure. The conclusions from the evaluation will be based on the structure of the above initial overview and emerging issues for future studies will be outlined.

2. The development of the dentition - molecular and cellular interactions

2.1. Molecular and cellular interactions - overview

During this multilayered developmental process the temporal relationships between the layers as indicated in are important, as are the critical periods determining whether the process will continue or cease at a particular point for individual teeth or groups of teeth.

Mutations in developmental regulatory genes are related to dental development defects. At a number of stages of the long developmental process repeat signalling sequences are observed (). Clinically identified associations between some anomalies in humans may well be related to the reiterate nature of parts of the process, as considered further below in the section on anomalies of number, size and form.

In other tissues in the foetus similar interactions, involving many of the same genes, occur in developmental processes. Signalling molecules and growth factors such as Tgf8, Fgf, Shh and Wnt, as well as transcription factors mediating the signals to the nucleus and regulating gene expression, are involved. BMP7 is a central mediator of epithelial-mesenchymal interactions that are necessary for the correct development of structures belonging to the oro-facial complex. These common developmental factors between dental and other tissues may be reflected in the presence of dental anomalies in clinical syndromes, e.g. ectodermal dysplasia, when mutations occur in genes acting in multiple developmental processes.

Epigenetic factors also play a critical role in tooth development with, for example, histone demethylase regulating dental stem cell differentiation. Spatial epigenetic information present at each stage of the developmental process, influences later development. Cells can generate patters during development by autonomous mechanisms, by inductive mechanisms involving interaction between cells and by morphogenetic mechanisms.

2.2. Initiation

Thickening of the oral epithelium takes place at specific sites to form dental placodes. In determining tooth region within the dental lamina, Fgf and Bmp influence the location of mesenchymal expression of Pax9, a paired box transcription factor. Pax9 is stimulated by Fgf8 and inhibited by Bmp2 and Bmp4. This antagonistic signalling may determine the site of tooth buds but Pitx2 and Shh are also present at this stage and tooth germs still develop in the same locations in Pax9 knockout mice. The Dlx homeobox genes are also important in early patterning of the dental field. In addition, the Bmp antagonist Wise and the Wnt co-receptor Lrp 4 provide 5 extracellular communication between mesenchymal and epithelial cells based on the integration of Wnt and Bmp pathways during regulation of tooth number. At the initiation stage Wise expression is observed in tooth mesenchyme and Lrp 4 in tooth epithelium. At the bud stage Lrp 4 becomes restricted to the epithelial cells at the tips of the bud, while Wise is absent from this area but expressed elsewhere in the tooth epithelium and mesenchyme.

Transcription factors in the Msx, Dlx and Lhx families are necessary to initiation and progression beyond the initiation stage. Epithelial signals regulate expression of the transcription factors Msx1, Pax9 and Runx2. Msx1 is induced by Bmp and Fgf; Pax9 and Runx2 by Fgf. Bmp 4 and Msx 1 regulate one another in a positive feedback loop in dental mesenchyme. If any one of these transcription factors is absent in knockout mice, tooth development may arrest at the bud stage but different members of the same family, e.g. Msx1 and Msx2, may compensate for each other when one is inactivated. Msx 1 and Osr 2 act antagonistically in the patterning of the tooth morphogenetic field by controlling the expression and spatial distribution of mesenchymal odontogenic signals along the bucco-lingual axis. The mouse mandibular first molar tooth germ can inhibit second molar development and an inhibitory cascade model in which initiation of posterior molars depends upon a balance between intermolar inhibition and mesenchymal activation to determine sequential molar initiation has been proposed.

2.3. Morphogenesis

As tooth morphogenesis advances, the primary and secondary enamel knots, control the development of crown dimensions and cusp formation. The repeated activation and inhibition of signalling is related to differential growth and folding within the tooth germ and determines dimensions and cusp pattern. Enamel knot cells express Fgfs in the dental epithelium regulating growth and folding. The shape of the tooth crown results from this morphogenesis during cap and bell stages when there is rapid proliferation of cells related to folding of the epithelium to form cusp shapes. While the enamel knot expresses growth stimulatory signals, its cells remain non-proliferative. These non-dividing cells stimulate proliferation of both the surrounding cells and the mesenchymal dental papillae. Lpr 3 has restricted expression in the primary enamel knot while Wise is expressed in the mesenchyme at this stage.

Having undergone apoptosis at the late cap stage, the primary enamel knot is no longer detected at the bell stage. Secondary enamel knots develop at the sites of cusps in teeth with multiple cusps. They produce signalling molecules stimulating proliferation of nearby cells leading to folding of the inner enamel epithelium and subsequent cusp formation.

By this stage the presence or absence, the size and shape of the individual tooth has been determined. The signalling factors which determine tooth region and tooth type are much the same. The reiterative signalling at the different stages of initiation and morphogenesis may explain the association of differences in tooth size and shape seen in individuals with abnormal tooth number. The occurrence of anomalies, e.g. hypodontia, at different sites around the dentition also relates to alterations in these same signalling processes in all teeth.

2.4. Differentiation

At the bell stage when the underlying cusp pattern has been established, the enamel and dentine forming cells differentiate. Initially the odontoblasts secrete the dentine matrix and subsequently the adjacent epithelial cells differentiate into ameloblasts and secrete enamel matrix. The odontoblasts and ameloblasts then control the phases of mineralisation of enamel and dentine. Pleiotrophin (PTN) is expressed in both odontoblasts and ameloblasts and has a critical role in dentinogenesis.

The dentine matrix is predominantly collagen, but also contains other proteins which are mainly products of the Dspp gene present in odontoblasts. Tgf-B signalling controls Dspp expression during odontoblast maturation, with overexpression of TgfB1 causing decreased expression of Dspp. The Dspp gene is cleaved to produce Dpp, Dsp and Dgp. Dpp is cleaved off by Bmp1, while Dgp is cleaved by Mmp2 and Mmp20, multiple Mmps being found in dentine. Dpp may act as a nucleator of hydroxapatite formation. Dlx3 influences morphogenesis and patterning and in dentinogenesis Dlx3 is expressed during dentine morphogenesis and histodifferentiation and is also present in ameloblasts. In pre-odontoblast cells Bmp2 regulation of Dspp transcription is mediated by the Dlx3/Osx signalling pathway.

The histone demethylase Jmjd3 regulates the odontogenic differentiation of dental stem cells through an epigenetic mechanism. Jmjd3 knock-down in dental stem cells by small interference RNA results in decreased expression of extracellular dentine matrices. Jmjd3 is essential for the gene expression of homeobox and bone morphogenetic proteins by modifying methylation.

Histodifferentiation for root development follows. The odontogenic epithelium extends apically and odontoblasts and cementoblasts develop on its inner and outer surfaces, respectively. Formation of the root dentine and the cementum follows. Fibroblasts and osteoblasts arising from the dental follicle and the supporting and eruption mechanism of the periodontium are formed.

3. Clinical outcomes

3.1. Dental anomalies - overview

The outcome of the developmental process is the dentition seen as the phenotype. Valuable findings have emerged from animal as well as human studies in relating phenotype to genotype. Therefore where relevant the findings from animal models will be considered in this section alongside the human studies, while acknowledging the limitations of extrapolating from the animal models.

The human clinical phenotype reflects the progressive nature of the developmental process with different teeth of a given tooth type forming and maturing at different times, with the time gradient following the spatial gradient from mesial to distal of each tooth region. Therefore within a given tooth type there will be teeth at different developmental stages. Similarly, between different tooth types there will be some overlap in development, but also different developmental stages at a given point of time. The complexity of these time and space parameters of dental development is reflected in the complexity of the clinical phenotypes of dental anomalies of number, size, form and structure.

These phenotypes will be considered in the order of the stages of the developmental process at which they have occurred. In keeping with the multilayered nature of the process, the clinical outcome needs to be related to evidence of the tissue changes and to the molecular genetic-epigenetic-environmental interactions.

In addition, the multidimensional outcomes for each tooth reflect more than the influences of the molecular factors that would determine it if each tooth developed in isolation. The interactions of the developing tooth germs for nutrition and space, reflected in their position in morphogenetic fields affect the clinical phenotype.

3.2. Anomalies of number, size and shape occurring during initiation and morphogenesis

The molecular evidence of repetitive signalling throughout initiation and morphogenesis is reflected in the association of the anomalies of number, size and shape seen together clinically in the same dentition. This association has been validated by laboratory measurement of human dental study models.

Hypodontia is associated with smaller tooth size that the average for the given population. The smaller teeth in the individual with hypodontia often also show morphological changes with reduced form seen, for example, as tapering of the crown of microdont lateral incisors and reduced cusp number and more rounded occlusal perimeter in molars ().

Hypodontia is a common condition in the population, present in some 25% of individuals. The aetiology within the population is multifactorial. Brook reviewed evidence of chromosomal, polygenic, single gene and environmental influences in this complex aetiology; different factors are a major influence in different individuals. Based on the gender differences in tooth size, frequency of anomalies of number and size and associations between them an aetiological model incorporating all the multifactorial influences was proposed ().

A number of recent studies have concentrated upon identifying mutations in some of the major single genes. Mutations in MSX1, PAX9, AXIN2 and EDA have been identified in families with non-syndromic hypodontia. Msx1 and Pax9 are co-expressed in dental mesenchyme at the bud and cap stages. Eighteen human mutations of PAX9 have been reported in hypodontia families, of which nine are missense. The DNA binding and transcriptional ability of Pax9 proteins are affected differently in each mutation. Missense mutations of Pax9 affecting the paired domain do not disrupt the physical interaction with Msx1 while in the G51S mutation synergistic co-operation with Msx1 is decreased or abolished in Bmp4/Luciferase assays. Functional regulation of Pax9 by homeobox proteins is necessary for early tooth development. The more severe clinical phenotypes correlate with mutations which result in the abrogation of DNA. In the G51S mutation the phenotype is moderate to severe hypodontia, yet there is intact DNA binding and increased transcriptional activation but lack of responsiveness to modulation by Msx1. In general the more severe phenotypes, with more congenitally absent teeth occur, relate to haploinsufficiency of Pax9 while those with mild or moderate hypodontia are associated with hypomorphic alleles. Differences in the patterns of hypodontia have been seen, with those having mutations of MSX1 showing particularly congenitally absent anterior teeth and those with PAX9 mutations hypodontia predominantly of posterior teeth. Mutations in MSX1 are also associated with oro-facial clefting, with and without hypodontia and with Witkop syndrome.

The aetiological model reflects the well documented gender differences with females more often affected by hypodontia than males in a ratio of 1.5:1. Hypodontia, with small tooth size and reduced tooth form, usually occurs without systemic conditions. Occasionally it is seen as part of a syndrome such as ectodermal dysplasia.

The frequency of congenital absence of individual teeth also relates to their position in the different morphogenetic fields. In the permanent dentition the third molars, the second premolars, the upper lateral incisors and the lower central incisors are the most frequently absent teeth. These findings come from population and clinical multiple case studies. They probably reflect a general influence in hypodontia patients to reduced tooth tissue formation that results in smaller size and morphological changes in the earlier forming teeth in a field, i.e. affecting morphogenesis, while the later forming teeth at the end of the field have earlier effects on development, i.e. at initiation, and so fail to progress beyond the bud stage. While this is the general pattern in a population, in some individuals and families with hypodontia the pattern is different. In some the congenitally absent teeth may be concentrated in the anterior region while in others it is principally the molar region which is affected, reflecting mutations in such genes as PAX9 and MSX1.

The effect on tooth size in individuals having hypodontia is seen throughout the dentition. All teeth that develop in hypodontia subjects are smaller than those in control groups when measured by classical manual techniques and by image analysis. This is also in accord with the aetiological model proposed.

Supporting evidence for the multifactorial nature of hypodontia comes from studies of families with severe hypodontia. In families with a member who had six or more missing permanent teeth, excluding the third molars, those family members with complete dentitions had teeth that were statistically significantly smaller than controls.

From studies of the mouse dentition it is suggested that mutations affecting Fgf, Eda, Bmp, Runx2, Apc, Shh and b-catenin are related to the occurrence of supernumerary teeth. Activation of b-catenin or ablation of Apc, an inhibitor of Wnt signalling, in embryonic mouse oral epithelium result in supernumerary teeth. The oral epithelium in adult mice remains responsive to b-catenin gain-of-function or APC loss-of-function and is still able to form new teeth. In the mouse supernumerary teeth may develop from vestigial tooth buds that are present in the incisor region and in diastema between the incisors and molars. These vestigial buds usually undergo apoptosis, but if degeneration by apoptosis does not occur a supernumerary tooth or element is formed. Supernumerary incisor and molar teeth as well as fused and large molar teeth develop in Lrp 4 and Wise deficient mice. Mice lacking the transcription factor Osr 2, odd-skipped related-2 develop supernumerary teeth lingual to their molar teeth of the normal series. Histological analysis traced initiation of these supernumerary teeth to aberrant thickening of the oral epithelium lingual to the first molar tooth buds. Expression of Pitx 2 and Shh was detected in the supernumerary dental placodes and expression of the dental mesenchyme markers Msx 1 and Lef 1 were upregulated and expanded lingually. Bmp 4 induces expression of ectodin whose inactivation was associated with fused first and second molars as well as supernumerary teeth in mice.

Disruption of the antagonistic balance between Msx 1 and Osr 2 may underlie the hypodontia in Msx 1 null mice, the supernumerary teeth in Osr 2 deficient mice and the hypodontia in humans with Msx 1 mutations.

Other important factors from mouse studies of the multilevel developmental process include the effects of upregulation and downregulation of specific genes and the results at a histological and clinical level on tooth number, size and shape. Changes in the regulation of Shh are related to holoprosencephaly, hypodontia and supernumerary teeth. Hypodontia and small size of teeth occur in mice that lack specific Eda-signalling pathway molecules.

The relationship between development and anomalies of number, size and shape of teeth in modern human studies reflects the reiterative patterns seen in mouse models of signalling of the ectodermal-mesenchymal interactions during tooth germ initiation and morphogenesis. Epigenetic events relating to the spatial arrangement of cells and the timing of the interactive signalling may explain differences in tooth number, size and shape and dental asymmetry in monozygotic twins.

3.3. Anomalies of tooth structure occurring during differentiation and biomineralisation

As the developmental process continues a marked change occurs from the determining of the tooth germ as one of a series of structures, its position in the jaws in relation to other tooth germs and its size and shape, to its definition as a unit consisting of different hard and soft tissues each contributing to its function as an organ.

3.3.1. Developmental defects of dentine

In the multilayered process the first hard tissue to differentiate and commence mineralisaiton is dentine. Clinically, inherited anomalies in man have been classified as three types of dentinogenesis imperfecta and two types of dentine dysplasia. The inheritance patterns of these families are autosomal dominant. The clinical and radiographic appearance varies not only between the different anomalies of dentine, but also between affected family members with the same mutation, between the primary and permanent dentitions in an affected individual and even between teeth in the same dentition.

At a tissue level, as differentiation commences the odontoblasts secrete the dentine matrix which, while mainly collagen, also includes proteins from the Dspp gene. At the molecular level dentinogenesis imperfecta and dentine dysplasia have been related to non-functional variants of Dspp in a mouse model. Transgenic mice overexpressing TgfB1 under the upstream regulatory sequence of Dspp have teeth with decreased mineralisation and abnormal formation of dentine, resembling those of patients with dentinogenesis imperfecta and dentine dysplasia. Pleiotrophin has a critical role in dentinogenesis: Ptn knock out mice have a dentine phenotype with enlargement of pulp chambers and decreased mineralisation of dentine. Anomalous collagen in Ehlers-Danlos syndrome has been related to the dentine abnormalities found in these patients.

3.3.2. Developmental defects of enamel

This group of dental anomalies is common in the population. The large majority of enamel defects are isolated to the dentition but they are also described in patients with syndromes. The aetiology of developmental defects of enamel is complex and in the population is multifactorial. The major single gene defects are uncommon while a number of important environmental factors have been substantiated.

3.3.3. Defects of uncertain aetiology

Some developmental defects do not present with patterns that can be related to those patterns seen in conditions of known aetiology. Regional odontodysplasia is a rare developmental anomaly affecting all the dental hard tissues in a segment of the dentition. There is some evidence to suggest that the pathogenesis involves vascular deficiencies during development, while another possibility is a somatic mutation.

Molar-incisor hypomineralisation is the term given to enamel opacities of presumed systemic origin affecting one or more first permanent molars and some or all permanent incisors. It has a high frequency, affecting between 4% and 17% in different studies in a range of populations. The lesions vary in extent from small demarcated white, yellow or brown opacities to those covering much or the entire crown. The aetiology remains unclear. The defects appear to be related to altered ameloblast function during the transitional and maturation phases. A family history of enamel defects is more frequently reported in children with MIH than controls, but this association has not been found to be statistically significant. Systemic environmental insults have been explored in a number of studies. Among possible toxins various polyhalogenated aromatic hydrocarbons, dioxins and dibenzofurans may disturb tooth development. MIH was significantly more common among children of mothers who had health problems during pregnancy. A medical problem related to birth, e.g. premature birth, prolonged delivery, cyanosis, was found frequently in one group of affected children. The developmental stage of the ameloblasts at the time of the insult may be important, with the transitional stages of enamel maturation being particularly susceptible to such insults as infection with varicella zoster virus.

MIH often occurs asymmetrically and so differs from 'chronological hypoplasia', which usually has symmetrical defects and an identifiable systemic environmental insult. MIH may have a multifactorial aetiology with a genetic predisposition associated with one or more of a range of systemic insults occurring at a susceptible stage in the development of specific teeth. Problems remain when in a seeming random manner several teeth are severely affected while their antimeres are unaffected. Interestingly there is also an irregular pattern of enamel defects sometimes in patients with epidermolysis bullosa.

3.3.4. A unifying model for the aetiology of enamel defects

As reviewed above many specific causes of enamel defects, genetic and environmental, have been identified. Genetically these include mutations and deletions of single genes, both those affecting the oral tissues alone and those related to more widespread syndromes. Some enamel defects may also be due to multifactorial inheritance. Environmental factors may be local or systemic and their effect depends on the stage of development of each tooth, the severity and duration of the insult and the host's susceptibility.

The complexity of the aetiology is emphasised by the gene-gene and gene-environment interactions already considered. In both human and mouse studies, for example, there is considerable individual and strain variation in enamel defects in response to a standardised fluoride intake. The complexity of the clinical situation extends to considering why, for example, some permanent incisors, presumably developing simultaneously, have enamel defects and others do not in such conditions as molar-incisor hypomineralisation and epidermolysis bullosa.

To interpret these findings a model is proposed based on a multifactorially determined continuous distribution with thresholds delineating those affected (). The location of an individual in this distribution is determined by the interaction of the factors outlined above.

4. Conclusions and forward

The findings reviewed above illustrate that the aetiology of dental defects is multifactorial and requires the dental developmental process to be considered on multiple levels, in multiple dimensions and as a progression over time.

4.1. Multifactorial

It is multifactorial with various genetic, epigenetic and environmental factors. The interactions and outcomes of these factors during development are complex. Even when a specific mutation of a single gene or one major environmental insult has been identified, detailed investigation of the phenotype often reveals variation between affected individuals in the same family, between dentitions in the same individual and even between different teeth in the same dentition.

Mutations and deletions at different points in the same gene result in different phenotypes, as seen with AMELX and DSPP genes. The phenotype seems to depend not only on the severity of the genetic defect but more on the site of the change and its effect on the protein product. The same, or closely similar phenotypes, whether anomalies of tooth number or structure, may arise from different aetiologies: not only mutations in different genes but also environmental factors may result in similar phenotypes. Related to the action of a number of the developmental regulatory genes active in odontogenesis, in different tissues, mutations can result in syndromes of which dental anomalies are part. A different causation is at work when the developmental dental defect is secondary to the systemic effects of the syndrome as seen in the enamel defects in patients with Coeliac disease or vitamin D-resistant rickets.

Further factors to be considered in this multifactorial aetiology are chromosomal anomalies; epigenetic effects, both 'narrow' effects on DNA and broader alterations in gene expression; and environmental effects, both general, long term (as nutritional deficiencies) as major, short term insults.

In view of this multifactorial nature of dental anomalies, in future, in addition to seeking specific mutations of single genes, the complex background within which they are acting should be explored. The antagonistic balance between developmental regulatory genes, acting as activators or inhibitors of odontogenic potential, results in the normal phenotype of tooth number, size and form. If the positive feedback loop between genes in the dental mesenchyme is disrupted hypodontia or supernumeries can result. If the normal balanced control of Shh activity is upregulated or down regulated, dental anomalies occur. The signalling pathways of which the single gene is part are important as well as their interactions and the possibility of compensation by substitutions or recovery. Further investigations are needed to identify new genetic loci associated with specific anomalies, e.g. amelogenesis imperfecta. In addition further genotype-phenotype investigations are required in which the phenotype is accurately recorded and measured exploiting the new 2D and 3S techniques available.

4.2. Multilevel

The events and outcomes of dental development occur and present at three different levels, which need to be collated to increase understanding. Molecular and cellular interactions, both intracellular and extracellular determine the macroscopic phenotype. Future studies need to collate findings at each of these levels, fully defining the phenotype, both human and murine.

4.3. Multidimensional

The molecular and cellular interactions and their outcomes are multidimensional. The x, y and z axes are affected to different extents by specific genes, resulting in the morphology of the individual tooth. In addition there is a precise spatio-temporal pattern in the sequential initiation, morphogenesis and differentiation of tooth germs. Antagonistic signalling controls expression and influences the spacial distribution of odontogenic signals in morphogenetic fields. To form the dentition, apoptosis within enamel knots plays an important role in regulating tooth size and shape. Different tooth germs are at different stages of development at any one time point and therefore a substantial disruption, e.g. a major environmental insult, over a defined chronological period may cause different defects in different teeth depending on the developmental stage of the individual tooth germ.

The clinical phenotype reflects these spatio-temporal effects. The tooth size of the whole dentition is influenced when variations in tooth number occur, but within the dentition there is a gradient with the greatest effect on size being close to the site of the anomaly. The variations of number, size and shape most frequently occur at the boundaries of morphogenetic fields. Considering particular tooth types the congenital absence of one third molar is associated with an increased risk of absence of its antimere as well as the third molars in the opposing arch. Related to these findings is the work in animal models on the spatial distribution of specific genes around the arch.

4.4. Progression over time

Time is another important dimension in the normal and abnormal development of the dentition. Different genes control different stages of the developmental process. The activity of genes is switched on and switched off. Transient signalling centres in the enamel knots have been identified, with apoptosis following cessation of signalling. There are critical stages in the development of individual tooth germs and, if progression fails, the germ will not develop further and may undergo apoptosis. Some of the transcription factors necessary for progression have been identified and different members of the same family of factors may compensate when one is inactivated.

The reiterative signalling patterns over time during the sequential process of initiation and morphogenesis are reflected not only in the variation of molar cusps but also in the clinical presentation of the association of anomalies of number, size and form. This association, proposed from a series of studies has been modelled () and further tested, confirming its validity.48,58,59,61,62 In the future human and murine studies of anomalies of tooth number, full clinical phenotyping including the accurate determination of tooth size and shape is needed to relate the phenotype outcome to the multifactorial developmental process and allow further modelling. To link phenotype to the genotype in mammalian teeth a mathematical model has been developed integrating experimental data on gene interactions and growth.

Time also is a factor within each morphogenetic field with the later developing tooth being smaller, less complex in shape and showing greater variability. Moreover in patients with hypodontia, not only is there reduced tooth size and form compared to controls, but the teeth erupt later, showing that the whole developmental process is affected. A diagram to summarise visually the various inputs to the aetiology of dental anomalies is given in .

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Multilevel complex interactions between genetic, epigenetic and environmental factors in the aetiology of anomalies of dental development

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Dental anomalies are caused by complex interactions between genetic, epigenetic and environmental factors during the long process of dental development. This process is multifactorial, multilevel, multidimensional and progressive over time. In this paper the evidence from animal models and from human studies is integrated to outline the current position and to construct and evaluate models, as a basis for future work.

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Inhalation sedation Patient information leaflet

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Inhalation sedation Patient information leaflet

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