Developmental Defects of Enamel and Dentine: Challenges for Basic Science Research and Clinical Management PDF

Australian Dental Journal The official journal of the Australian Dental Association Australian Dental Journal 2014; 59:(1 Suppl): 143–154...

Australian Dental Journal The official journal of the Australian Dental Association Australian Dental Journal 2014; 59:(1 Suppl): 143–154 doi: 10.1111/adj.12104 Developmental defects of enamel and dentine: challenges for basic science research and clinical management WK Seow* *Centre for Paediatric Dentistry, School of Dentistry, The University of Queensland, Brisbane, Australia. ABSTRACT Abnormalities of enamel and dentine are caused by a variety of interacting factors ranging from genetic defects to envi- ronmental insults. The genetic changes associated with some types of enamel and dentine defects have been mapped, and many environmental influences, including medical illnesses that can damage enamel and dentine have been identified. Developmental enamel defects may present as enamel hypoplasia or hypomineralization while dentine defects frequently demonstrate aberrant calcifications and abnormalities of the dentine-pulp complex. Clinically, developmental enamel defects often present with problems of discolouration and aesthetics, tooth sensitivity, and susceptibility to caries, wear and erosion. In contrast, dentine defects are a risk for endodontic complications resulting from dentine hypomineraliza- tion and pulpal abnormalities. The main goals of managing developmental abnormalities of enamel and dentine are early diagnosis and improvement of appearance and function by preserving the dentition and preventing complications. How- ever, despite major advances in scientific knowledge regarding the causes of enamel and dentine defects, further research is required in order to translate the knowledge gained in the basic sciences research to accurate clinical diagnosis and successful treatment of the defects. Keywords: Enamel, dentine, hypoplasia, hypomineralization. Abbreviations and acronyms: AI = amelogenesis imperfecta; BSP = bone sialoprotein; CPP-ACP = calcium phosphopeptide-amorphous calcium phosphate; DMP1 = dentine matrix protein 1; DSPP = dentine sialophosphoprotein; EB = epidermolysis bullosa; EDI = Enamel Defects Index; FGF = fibroblast growth factor; MEPE = matrix extracellular phosphorylated glycoprotein; MIH = molar-incisor hypo- mineralization; OPN = osteopontin; TDO = tricho-dento-osseous. radiation and trauma, as well as epigenetic effects, INTRODUCTION e.g. DNA methylation.6,7 Recent advances in clinical The three types of dental hard tissues, enamel, dentine and basic science research have improved clinical and cementum, are formed through specialized cellu- diagnosis and treatment of developmental dental dis- lar and biochemical pathways. These highly complex orders. Importantly, identification of specific genetic mechanisms are controlled by genes and influenced by aberrations for individual conditions has enhanced the epigenetic and environmental factors.1 Abnormalities possibilities for specialized treatments that can be tar- of the developmental pathways may result in reduced geted to correct specific defects. quantity of tissue produced and/or poor quality of The aims of this paper are to review current under- mineralization.2,3 If the affected genes are expressed standing of genetic and environmental influences on predominantly in dental tissues, such as the amelo- the development of enamel and dentine, and to dis- genin gene, AMELX on enamel, the teeth are the cuss how knowledge gained from basic science main structures affected.4 On the other hand, if the research can be translated to the clinic to improve genes are also involved in the formation of other tis- clinical diagnosis and treatment of developmental sues, such as genes encoding for laminin-332 and type defects of enamel and dentine. XVII collagen, generalized effects involving other organs are found in addition to the dental malforma- DEVELOPMENTAL DEFECTS OF ENAMEL tions.3,5 The genetic control of enamel and dentine forma- Dental enamel, the hardest tissue in the body, consist- tion can be influenced by environmental changes such ing of over 98% mineral and less than 2% organic as systemic medical illnesses, chemical poisons, matrix and water, is produced by specialized, © 2013 Australian Dental Association 143 WK Seow end-differentiated cells known as ameloblasts.8 The amelogenesis imperfecta where the developmental formation of enamel can be separated into initial defects are limited to the teeth, and hereditary sys- stages which involve secretion of matrix proteins such temic conditions that are associated with defects in as amelogenin, ameloblastin and enamelin, and later epithelial tissues or mineralization pathways. stages of mineralization and maturation, although these processes may be present simultaneously in any Amelogenesis imperfecta developing tooth.8 Developmental defects of the enamel may be inherited as mutations in the genes Amelogenesis imperfecta (AI) is a group of inherited that code for enamel proteins, or as a feature of gen- disorders of enamel that have been reported to occur eralized familial conditions. These systemic conditions at prevalence rates of approximately 1.4:1000 to often involve tissues, such as skin, that share common 1:16 000 depending on the population studied13–15 embryologic origins of neuroectodermal mesenchyme (Table 2). AI can be clinically classified into hypoplas- with teeth.9 In addition, congenital abnormalities tic, hypocalcified (hypomineralized) or hypomature involving the mineralization pathways, such as para- types depending on the stage of enamel formation that thyroid gland disorders also commonly show enamel is affected by the genetic defect. As the hypoplastic abnormalities.10 Furthermore, enamel defects can also types are caused by reduction in the amount of matrix be caused by many acquired environmental and sys- protein secreted, the clinical presentation is usually temic perturbations such as metabolic conditions, thin enamel, surface pitting or vertical grooving.14,16 infections, drugs and chemicals, as well as radiation In contrast, the hypomineralized and hypomaturation and trauma.6 types are characterized by the presence of normal Although damage to the ameloblasts can result amounts of enamel matrix that is deficiently mineral- from a variety of agents, the abnormality in enamel is ized. Hypomineralized AI shows soft enamel, while usually expressed in only a few ways: hypoplasia, hypomaturation AI usually presents as opaque and which is a reduction in quantity, presenting as pits, discoloured enamel that fractures easily.17 The major- grooves, thin or missing enamel, or hypomineraliza- ity of children with AI have problems with dental aes- tion, which is reduced mineralization presenting as thetics, tooth sensitivity and increased caries risk. In soft enamel, or hypomaturation where there is altered addition, anterior open bite and an increased calculus translucency affecting the entire tooth, or in a local- formation are commonly encountered.17 Figures ized area known as an opacity.11 Hypoplastic enamel 1a–c show the dentition of a child with the hypoplas- defects are thought to result from changes occurring tic type of AI, and presenting with typical features of during the stage of matrix formation whereas hypo- thin/absent enamel, poor oral hygiene and anterior mineralization defects result from changes that affect open bite. the major part of the calcification process, and hyp- Gene-mapping helps to elucidate the roles of omaturation refers to the changes that occur at the numerous genes that are involved in enamel forma- last stages of mineral accumulation.12 The terms com- tion, and studies correlating genotypes with pheno- monly applied to describe the alterations in enamel types of AI provide valuable information regarding development are defined in Table 1. the genetic mutations that are found in the various phenotypes. There is recent evidence that approxi- mately only half of all AI phenotypes are caused by Inherited conditions involving enamel formation mutations in one of the genes, AMEL, ENAM, Inherited conditions which show enamel defects may FAM83H, WDR72, KLK4 and MMP20 that are be generally grouped into conditions known as Table 2. Prevalence of amelogenesis imperfecta and Table 1. Terms and definitions relevant to dentinogenesis imperfecta developmental enamel defects Country Prevalence Author, Year Term Definition Amelogenesis USA 1:14 000–1:16 000 Witkop, 195798 Opacity Altered translucency imperfecta Israel 1:8000 Chosack et al., Diffuse opacity An opacity that is distributed over a 197915 relatively large area Sweden 1.4:1000 B€ackman and Demarcated opacity An opacity that is confined to a relatively Holm, 198613 small area Dentinogenesis USA 1:6000–1:8000 Witkop, 195798 Hypoplasia Reduction in quantity of tissue formed imperfecta Kim and Simmer, Hypomineralization/ Reduction in deposition of mineral 20073 Hypocalcification Dentine USA 1:100 000 Witkop, 195798 Hypomaturation Reduction in the deposition of mineral at dysplasia Kim and Simmer, the maturation (end) stage of mineralization 20073 144 © 2013 Australian Dental Association  Developmental defects of enamel and dentine (a) protein amelogenin, and mutations in this gene are associated with X-linked forms of AI.4 Human muta- tions in genes coding for kallikrein 4, KLK4 and metalloproteinase 20, MMP20 as well as WDR72, an intracellular protein with unknown function, result in hypomineralization or hypomaturation defects with varying degrees of hypoplasia, and are associated with autosomal recessive types of AI.16,20 On the other hand, mutations in the FAM83H gene are associated with an autosomal dominant hypomineralization AI, the most common form of AI in North America.21 Phenotypic variation among individuals within a family having the same mutation is well known in AI, and may result from differences in expression of the (b) gene, variation in response of the developing enamel at different locations on the tooth, as well as from post-eruptive breakdown.1,22,23 Furthermore, in X-linked AI, affected females may show vertical grooving of the tooth surface, with bands of normal enamel alternating with areas of missing enamel while affected males in the same family show complete absence of enamel.17 Mouse models for the candidate genes of AI such as AMEL, ENAM, MMP20 and KLK4 provide opportu- nities for investigating the relationship between phe- notypes and genotypes.2,4 However, while animal models are useful to study the effects of knock-out genes, they do not fully imitate the human forms of (c) AI where the genes involved may be partially expressed.1 Mouse enamel also differs from human enamel in that the growth in the incisors is continu- ous, and not likely to be subjected to the wide range of genetic influences found in humans. Enamel defects in hereditary conditions associated with defects of epithelial tissues Many inherited syndromes, particularly those that involve skin, hair and nail show generalized enamel defects. The involvement of enamel in these syn- dromes is likely to be due to the common embryologic Fig. 1 (a) Photograph of the anterior teeth of an 8-year-old child with neural origin of the ectoderm shared by skin, hair and the hypoplastic type of amelogenesis imperfecta. Note the thin enamel nails so that mutations in common genes result in which has fractured from the maxillary left permanent central incisor and abnormalities seen in all tissues. Dermatological con- poor oral hygiene that was associated with severe tooth sensitivity. A severe anterior open bite was present. (b) Photograph of the maxillary ditions in which enamel defects have been reported teeth of the child in Fig. 1(a) showing thin enamel of the primary teeth include congenital erythropoietic porphyria, ectoder- and missing enamel on the permanent first molars. (c) Photograph of the mal dysplasia, epidermolysis bullosa and tuberous mandibular teeth of the child in Fig. 1(a) showing thin enamel of the pri- mary teeth, missing enamel on the permanent first molars and calculus sclerosis.9 In congenital erythropoietic porphyria, on the mandibular incisor teeth. there is haemolytic anaemia, photosensitivity, skin fra- gility, hypertrichosis and red-brown porphyrin pig- known to affect only enamel formation while the mentation of bones and discoloured and hypoplastic genes involved in the other half of AI phenotypes are teeth.24 Furthermore, in many types of ectodermal currently unknown.18,19 Human mutations for genes dysplasias, enamel defects ranging from mild to severe coding enamel proteins AMEL and ENAM generally have been described.25,26 Similarly, in epidermolysis cause enamel defects such as surface pits and thin bullosa (EB), a group of major bullous conditions gen- enamel.4 The AMELX gene encodes for the enamel erally classified as intraepidermal EB (simplex), © 2013 Australian Dental Association 145 WK Seow junctional EB, dermolytic EB (dystrophic), and mixed both types show hypocalcaemia and severe enamel EB (Kindler syndrome),27 varying degrees of enamel hypoplasia.38 Type 1 or pseudovitamin D deficiency defects may be found depending on whether the rickets is caused by deficiency of the enzyme 25-hy- altered protein is also involved in enamel formation. droxyvitamin D-1a-hydroxylase which leads to In the tricho-dento-osseous (TDO) syndrome, an absence of synthesis of calcitriol, the active form of autosomal dominant condition caused by mutations in Vitamin D. In contrast, Type 2 Vitamin D dependent the DLX3 homeobox gene, the enamel defects are rickets is associated with non-responsiveness of the usually striking.28 The genetic mutations lead to Vitamin D receptor.38 Familial Vitamin D resistant abnormalities in protein degradation and impairment rickets is associated with low serum phosphate (hypo- of expression of cell cycle regulatory proteins and skin phosphataemia)39 and severe dentine defects with differentiation markers.28–31 TDO is characterized by minimal involvement of the enamel.40 These defects severe hypomineralization of the enamel, taurodon- are discussed in the section on dentine defects. tism, and abnormalities in hair (curly or kinky hair or a change from straight to curly hair or vice-versa), Acquired conditions affecting enamel development nails (dysplastic), and bones (thickening of the skull base).28,31 In addition to genetic conditions, many environmental and acquired systemic changes can also disturb the formation of enamel. If an insult occurs during Enamel defects in hereditary conditions associated enamel matrix secretion, hypoplastic defects are likely with defects in mineralization pathways to result, in contrast to an insult occurring during the Many inherited conditions associated with defects of mineralization stages which usually produces hypo- the mineralization pathways involving the parathyroid mineralization defects. However, as several teeth in a glands and vitamin D metabolism also show abnor- child’s mouth may be undergoing different stages of malities of enamel development. Hereditary syn- enamel formation at the time of an insult, it is possi- dromes which feature hypoparathyroidism such as the ble that a spectrum of effects ranging from mild opac- velocardiofacial syndrome or DiGeorge syndrome or ities to severe enamel hypoplasia may be evident on 22q11.2 deletion syndrome have been reported to different teeth, and even on a single tooth.12 show enamel hypomineralization and hypoplasia.32 The association of hypoparathyroidism with enamel Systemic conditions defects are also seen in rare congenital conditions such as the Kenny-Caffrey syndrome (growth retardation Acquired systemic factors that are likely to affect with short stature, cortical thickening and medullary enamel development may be conveniently considered stenosis of the tubular bones, congenital hypoparathy- as pre-, peri- and postnatal conditions in relation to roidism, hyperopia, microphthalmia, micrognathia the timing of the event. These causes of enamel and enamel and dentine abnormalities)33 and the defects may be classified into metabolic disturbances, autoimmune polyendocrinopathy candidiasis ectoder- infections and chemicals and drugs. Local factors can mal dystrophy syndrome (hypoparathyroidism, be grouped as local infections, trauma and radiation. chronic mucocutaneous candidiasis and adrenocortical As enamel does not remodel, the location of the defect failure).34 However, while hypocalcaemia is a com- on the tooth surface can indicate the approximate mon feature of these congenital parathyroid condi- timing of the event in relation to the chronology of tions, its role in the pathogenetic pathways that cause tooth development. Although animal experiments enamel defects is unknown.34 have provided proof of the damaging effects of some Vitamin D deficiency due to malnutrition or genetic of these factors to developing enamel, most of the evi- metabolic conditions often results in rickets (failure of dence has been derived from clinical cases and epide- bone matrix to mineralize), and is commonly associ- miological studies.41–45 In some reports, there is ated with severe enamel defects. Nutritional rickets is evidence of damage from the same factors to major encountered in children who do not consume suffi- organs which are developing at the same time. An cient Vitamin D or do not receive sufficient sunlight example is the enamel hypoplasia commonly seen in to activate provitamin D.35 Although nutritional rick- children with cerebral palsy where systemic distur- ets is now thought to be rare in developed countries, bances such as infections, foetal anoxia and hyperbi- the prevalence may be increasing in poor communities lirubinaemia have damaged both the developing brain which do not have milk fortified with Vitamin D, and cells and the enamel.46,47 have little sunlight exposure.36,37 Prenatal factors which may contribute enamel By contrast, the inherited types of rickets which are hypoplasia include maternal smoking and vitamin D dependent on Vitamin D are rare. Two genetic vari- deficiency during pregnancy and neonatal tetany, ants of Vitamin D dependent rickets are known, and while postnatal factors include nutritional 146 © 2013 Australian Dental Association  Developmental defects of enamel and dentine deficiencies. Preterm children and those with low birth weight have a higher prevalence of enamel hypoplasia compared to children born full term with normal birth weights.45–48 The defects found in pre- term children usually stem from adverse systemic conditions associated with premature birth, such as respiratory immaturity, cardiovascular, gastrointesti- nal and renal abnormalities, intracranial haemor- rhage and anaemia.48 Furthermore, hypocalcaemia, osteopaenia and hyperbilirubinaemia can increase the risk for enamel defects in preterm children.49–51 Inadequate supply of calcium and phosphorus min- eral and inability of the gastrointestinal tract to absorb minerals are also important contributors to enamel hypoplasia in preterm children.48,51 Local trauma from laryngoscopy and endotracheal intuba- tion which are often required in preterm children to manage respiratory distress further increase the risks of damage to the developing enamel in primary maxillary incisor teeth.52 Children with coeliac disease are also at risk to enamel hypomineralization due to malabsorption and mineral deficiencies associated with gut enteropathy from gluten intolerance.53,54 Disruption of mineraliza- tion pathways as a result of chronic renal and liver disease also places affected children at risk for enamel Fig. 2 Photograph of the hypomineralized maxillary primary molar of a defects.55–57 In many infections, the causative micro- child who had a meningococcal infection at 16 months of age. organisms may infect the ameloblasts directly, or alter cellular function indirectly through their metabolic isolate the effects of the fevers and infections which products or high fevers induced in the patient. Clinical had necessitated the use of these antibiotics.61 reports have suggested that infections of the urinary tract, otitis and upper respiratory disease are associ- Local insults to developing teeth ated with enamel defects.44 Congenital syphilis acquired from maternal Treponema pallidum infec- In contrast to systemic factors which usually affect all tions was a well-known cause of enamel hypoplasia in developing teeth, local factors such as trauma involve children in past decades.58 Also, viral infections such only the teeth in the immediate area of damage. For as chicken pox, rubella, measles, mumps, influenza example, trauma exerted on a neonate’s maxillary and cytomegalovirus have been associated with alveolus from laryngoscopy can cause localized defects enamel defects in both the primary and permanent in the maxillary incisors, ranging from mild enamel dentitions.6 An example of an enamel defect caused opacities to severe enamel hypoplasia to crown dila- by an acquired infection is shown in the child in cerations.48,62 Similarly, local trauma exerted through Fig. 2 where meningococcal infection at 16 months of the thin buccal cortical bone is thought to be the age has led to hypomineralization of the maxillary cause of demarcated opacities commonly observed on primary molars. the labial surfaces of primary canines.63 Chemicals and drugs which can damage ameloblasts include fluoride, tetracyclines and cytotoxic drugs. Molar-incisor hypomineralization Enamel hypomineralization resulting from ingesting high levels of fluoride are thought to result from the Classification of a type of chronological enamel hypo- direct effects of fluoride on the ameloblasts.59 Envi- plasia known as molar-incisor hypomineralization ronmental exposure to lead paint, or accidental or (MIH) was first proposed by Weerjheim and co- pica ingestion have also been reported to cause workers in 2001 to describe a condition where the enamel hypoplasia.6 In addition, intake of tetracy- permanent molars and incisors show demarcated areas clines during the periods of tooth formation is well of hypomineralisation or opacities which may be known to cause dental discolourations and enamel coloured yellow or brownish.64 In addition, the molar defects.60 Although there is some evidence that teeth often have posteruptive loss of the weak tooth amoxycillins can cause enamel defects, it is difficult to structure and show high susceptibility to caries. There © 2013 Australian Dental Association 147 WK Seow is tooth sensitivity and difficulty in achieving adequate seen in the affected incisor and molar teeth of a child anaesthesia for dental treatment.65,66 Figures 3a–c who had chicken pox at approximately 2 years of depict such a case of chronological enamel hypoplasia age. Reports of MIH have been mostly from Europe with reported prevalence rates ranging from 3.6% to (a) 37.5%.64,67 In Australia, 37–47% of first permanent molars were reported to show developmental enamel defects.68 In other parts of the world, prevalence rates of approximately 40%, 22% and 3% were reported in Brazil, Iraq and Hong Kong respectively.66,69,70 Aetiological factors for MIH are thought to be essentially the same as those already known to cause enamel hypoplasia in the permanent dentition such as malnutrition, common childhood illnesses, including chicken pox, otitis media, respiratory and urinary tract infections and use of amoxycillin.44,67,70 Although environmental toxins such as dioxins have been implicated in the aetiology of MIH, this hypoth- esis has been questioned in a controlled study.71 For (b) permanent incisors and first molars to be affected, the timing of occurrence of the insults is likely to be between the period of birth to approximately 3 years of age.72 Dental management of children with enamel defects The need for treatment of enamel defects within the population is considerable.73 As Table 3 shows, in a series of comparable populations studied using a stan- dardized methodology,76 some two-thirds of children have an enamel defect, while about 10% have 10 or more defects.73 Early diagnosis and preventive care are essential for the successful management of devel- opmental enamel defects. Children who have a family (c) history of amelogenesis imperfecta, or medical syn- dromes that are commonly associated with enamel defects such as epidermiolysis bullosa or cerebral palsy or prematurity of birth should be assessed for enamel defects as soon as the teeth erupt. Also, as enamel formation of the permanent molars and inci- sors occurs at the same time as the primary molars, the presence of enamel defects in the primary molars indicates a risk for the defects occurring in the perma- nent dentition.45 Thus, children with enamel defects in primary molars should have the permanent teeth Table 3. Prevalence of enamel defects in the permanent dentition of white Caucasian children aged 12–15 years (each study used comparable criteria) Fig. 3 (a) Photograph of the maxillary right central permanent incisor and all the mandibular incisors of an 8-year-old child showing hypomin- Country Percent of individuals eralization of the enamel, probably resulting from a chicken pox infec- affected tion at 3 years of age. (b) Photograph of the maxillary teeth of the child in Fig. 3a showing enamel opacities on the maxillary first permanent New Zealand 63% molars. The second primary molars also showed very mild opacities. (c) New Zealand 65% Photograph of the mandibular teeth of the child in Fig. 3a showing a Ireland 63% severely broken down hypomineralized right permanent molar. Although England 68% the tooth was temporarily restored with glass ionomer cement, an interim restoration with stainless steel crown was inserted at a later date. Data from Brook and Smith.73 148 © 2013 Australian Dental Association  Developmental defects of enamel and dentine monitored for the presence of similar defects. If both both primary and permanent molars affected by dentitions are affected, the possibility of a genetic enamel hypoplasia.92 Complete coverage of the teeth cause should be considered, and the children referred with stainless steel crowns reduces tooth sensitivity, to paediatric dentists and medical specialists for diag- prevents cusp fractures and helps maintain space and nosis, genetic testing and counselling. crown height. The crowns are best inserted using a Accurate recording of enamel defects is essential for conservative technique with minimal removal of tooth diagnosis, treatment planning and follow-up. While structure.40,93,94 This method which involves inter- the majority of previous indices for recording of proximal separation and minimal occlusal surface developmental defects of enamel were employed for reduction was proposed by Seow for placement of epidemiological purposes,74–76 the Enamel Defects crowns to protect teeth with large pulps and dentine Index (EDI) proposed by Brook et al.,77 was devel- defects to prevent pulp exposures.40 oped mainly for clinical use. The EDI contains a sim- ple backbone and digital scoring which is particularly DEVELOPMENTAL DEFECTS OF DENTINE suited for clinical application and has a high degree of reproducibility.22,23 Detailed scoring of subtypes of Dentine is composed of an organic matrix comprising enamel defects is also possible in the extended form approximately 70% mineral, 20% organic matrix and of the EDI.22 10% water.95 It is produced by the odontoblasts The major clinical problems encountered in children which are specialized, end-differentiated cells which, with enamel hypoplasia are compromised aesthetics, unlike the ameloblasts, continue to function through- tooth sensitivity and increased risk for caries and out the life of the tooth. The odontoblasts secrete the tooth wear. For children with developmental defects dentinal matrix and their processes which are retained of enamel, a preventive programme should be insti- in the matrix, communicate with pulpal nerves and tuted immediately after diagnosis in order to manage serve as a protective defence system.8 these problems. Children with extensive enamel Dentine is similar to bone except that it does not defects such AI usually require an interdisciplinary remodel and does not regulate calcium and phosphate management team which includes general practitio- metabolism.95 The extra-cellular matrix of dentine ners, specialist paediatric dentists and orthodontists. shares similar proteins with bone.96 It is rich in Type The treatment planning is likely to involve complex I collagen, which is assembled as fibrils to form a restorations, orthodontics, exodontia and prosthodon- structural framework for mineralization. Many of the tics.78–80 non-collagenous proteins are involved in the initiation To reduce caries risk in teeth with enamel hypopla- and control of the mineralization processes. They are sia, neutral sodium fluoride gels or varnishes applied associated with specific sites on collagen molecules, professionally 3 or 6 monthly may be recom- and aid in the nucleation and growth of the hydroxy- mended.81 In addition, calcium and phosphate rich apatite crystals.3 Proteins with key roles in the miner- agents such as casein phosphopeptide-amorphous cal- alization processes of dentine and bone include cium phosphate (CPP-ACP) can facilitate the reminer- members of the phosphoprotein family such as den- alization of hypomineralized areas and early carious tine sialophosphoprotein (DSPP), dentine matrix pro- lesions on the tooth surface of teeth with enamel tein 1 (DMP1), bone sialoprotein (BSP), matrix defects.82–84 An additional benefit of CPP-ACP is that extracellular phosphorylated glycoprotein (MEPE) developmental opacities that compromise aesthetics and osteopontin (OPN).96 Mutations in the genes cod- may appear less noticeable after topical application of ing for the proteins involved in type 1 collagen or in CPP-ACP.85 the extracellular matrix as well as in the mineraliza- As the defective enamel is structurally weak, it read- tion processes are thus likely to present as dentine ily deteriorates under masticatory stresses and this can abnormalities. If the proteins involved are common to result in marginal leakage around restorations, recur- both dentine and bone such as type 1 collagen, both rent caries and pulp involvement.86–88 Materials that skeletal and dentine defects will be observed in the can bond to both dentine and enamel such as resin phenotype. However, if the proteins are specific to modified glass-ionomer cements and polyacid modi- dentine, such as the dentine sialoproteins, the defects fied composite resins are likely to be successful for will be limited to dentine only. restoration of teeth with enamel defects.89–91 Although composite resins have good aesthetics, direct Inherited conditions showing developmental defects adhesion of the composite resins to teeth with mini- of dentine mal or poorly mineralized enamel is usually difficult to achieve. Inherited defects of dentine may be grouped into those In contrast to plastic restorations, stainless steel that affect dentine tissues only and those that show crowns are highly durable for restoring and protecting bone involvement together with the dentine defect. © 2013 Australian Dental Association 149 WK Seow Shield’s classification of inherited dentine defects,97 (a) which is based on clinical phenotypes, has been exten- sively applied for several decades, although this system is becoming outdated as molecular work provides more accurate linking of genotypes with phenotypes. As shown in Table 2, based on a couple of early studies, the prevalence of developmental defects of dentine range from approximately 1:6000 to 1:8000 for dentinogenesis imperfecta to 1:100 000 (b) for dentine dysplasia3,14,98 (Table 2). Dentinogenesis imperfecta Dentinogenesis imperfecta is the most common type of developmental disorder of dentine. In Shield’s classification, there are three types of dentinogenesis imperfecta (I-III) and two of dentine dysplasia (I and II).3 Dentinogenesis imperfecta type I is the phenotype seen with a genetic fragile bone con- dition, osteogenesis imperfecta. Osteogenesis imperfec- ta is usually caused by defects in the two genes encoding type I collagen. The dentine defects associ- ated with osteogenesis imperfecta often show complex and variable clinical expression. Both dentitions are affected with an opalescent brown discolouration, and due to reduced support of the dentine, the overlying (c) enamel fractures readily. There is rapid wear and attrition of the teeth. There are also variable degrees of progressive pulp obliteration which usually begins soon after eruption of the teeth. Besides osteogenesis imperfecta, dentinogenesis imperfecta type I can also be seen in other conditions such as Ehlers-Danlos and Goldblatt syndromes.65,99 Figures 4a–c show the typi- cal opalescent appearance of the teeth in dentinogene- sis imperfecta, together with severe wear of the teeth to the gingival level. The second type of dentinogenesis imperfecta (type II) is an autosomal dominant condition with a prevalence rate of approximately 1:8000.14 It is caused by a mutation in the DSPP gene.3 The clinical and Fig. 4 (a) Photograph of the anterior teeth of a 15-year-old with dentino- radiographic features are similar to dentinogenesis im- genesis imperfecta type II showing typical brown opalescent appearance perfecta type I, but are expressed more consistently.100 of the teeth and severe wear. (b) Photograph of the maxillary teeth of the Dentinogenesis imperfecta type III is also caused by the child in Fig. 4a showing extreme wear of the teeth to the level of the gingiva. (c) Photograph of the mandibular teeth of the child in Fig. 4a same DSPP mutation as type II, but shows variable showing loss of enamel and extreme tooth wear. discolouration and morphology of the teeth, ranging from normal appearing teeth to shell teeth with reduced dentine formation.3,101 Figures 2a–c show the reduced in size, and may have crescent shapes that typical dental opalescence, discolouration and extreme run parallel to the cemento-enamel junction, and asso- wear observed in a child with dentinogenesis imperfec- ciated with periapical radiolucencies.3,102 Although ta type II. the genetic changes are unknown, dentine dysplasia type I is likely to be an allelic disorder of the DSPP gene.3 Dentine dysplasia In contrast, in dentine dysplasia type II, while the Dentine dysplasia type I is a rare condition that shows primary teeth have similar features to dentine dyspla- normal appearing crowns and short roots in both sia type I, the permanent teeth appear clinically nor- primary and permanent dentitions. The pulps are mal although they often show thistle shaped pulps 150 © 2013 Australian Dental Association  Developmental defects of enamel and dentine with pulp stones.103 The root lengths are normal and attrition (Fig. 5). Enamel hypoplasia of the permanent there are usually no periapical radiolucencies. Occa- teeth has been occasionally reported in children with sionally, other abnormalities such as dental discolou- familial hypophosphataemia, although it is unclear rations, bulbous crowns and pulp obliterations may whether the enamel defects result primarily from the be encountered. Dentine dysplasia type II is also disease or are secondary to abscesses of the primary caused by a mutation in the DSPP gene, and most teeth.40 As expected of an X-linked condition, a spec- clinical evidence suggests that it is a mild phenotype trum of manifestations ranging from minimal to of dentinogenesis imperfecta type II.3 severe has been described, with boys characteristically It is now well accepted that there is usually overlap showing the most severe dental involvement and girls of clinical features in Shields’s classification of dentine the least. defects. In many families showing dentine dysplasia, it is often difficult to place any one in a particular type Management of children with developmental defects of classification due to the presence of phenotypic var- of dentine iation among the affected family members. Further- more, it is possible that dentine dysplasia type II, and As with enamel defects, early diagnosis and preventive dentinogenesis imperfecta types II and III may be care are essential for successful management of den- varying phenotypic expressions of the same genetic tine defects.108 Children who have a family history of defect. dentine defects such as dentinogenesis imperfecta or those with medical conditions known to be associated with dentine defects such as hypophosphataemia and Rickets osteogenesis imperfecta should be screened early for The most well-known condition that shows develop- dental problems. mental dentine defects is familial hypophosphataemia, As dentinogenesis imperfecta is associated with also known as ‘vitamin D-resistant rickets’ which dis- rapid toothwear and crown fractures, protection from plays cardinal features of X-linked dominant inheri- toothwear is recommended soon after eruption.108 tance and renal phosphate wasting.40 The condition Also, as some types of dentine defects, e.g. hypoph- is associated with reduced reabsorption of phosphate oshataemia, show a high risk for pulpal exposures in the renal tubules and characteristic rachitic bone and infection due to the presence of large pulps, pro- deformities. Other modes of inheritance including phylactic coverage of the teeth is necessary to protect autosomal dominant and autosomal recessive modes the pulp soon after eruption.40 Covering the teeth of inheritance have also been described for familial with stainless steel crowns soon after eruption has hypophosphataemia.104 Although the primary defect been shown to reduce the risk of pulp exposure in of familial hypophosphataemia is found in the PHEX teeth with dentine defects. As for enamel defects, the gene which is expressed in osteocytes, the role of this stainless steel crowns are best inserted using a conser- genetic change in phosphate wasting is unclear.104 vative technique that was developed specially to pro- A fibroblast growth factor (FGF) with endocrine tect teeth with large pulps.40,93,94 When the children properties, FGF23, that appears to mediate many of reach adulthood, the stainless steel crowns may be the hypophophataemic conditions has been found to replaced with gold or porcelain crowns to provide have a major role in this disorder.105,106 FGF23 is long term protection of the teeth. thought to facilitate phosphate supply by aiding the communication between the kidney and the skeletal stores.104 In familial hypophosphataemia, the occurrence of ‘spontaneous’ dental abscesses has led to the initial diagnosis of the condition in a few cases being made by the dentists as the general signs and symptoms of rickets usually are not obvious until the patients are more than 18 months of age.103 These abscesses often appear initially in toddler children who do not have any history of caries or trauma. Histological examina- tion of the teeth involved in familial hypophosphata- emia often reveals poorly mineralized globular dentine, and tubular defects extending close to the dentino-enamel junction.40,102,107 These defects pre- Fig. 5 Photograph of the anterior teeth of a child with X-linked dispose the pulp to exposures and infection as soon as hypophosphataemic rickets depicting abscesses associated with dentine the enamel is removed, either from minimal caries or defects and large pulps in the maxillary central incisors. © 2013 Australian Dental Association 151 WK Seow CONCLUSIONS AND FUTURE DIRECTIONS 9. Freiman A, Borsuk D, Barankin B, Sperber GH, Krafchik B. Dental manifestations of dermatologic conditions. J Am Acad Although the clinical significance of enamel and Dermatol 2009;60:289–298. dentine defects is well known, the pathogenesis of 10. McCauley LK, Martin TJ. Twenty-five years of PTHrP pro- the defects is still being studied. While the range of gress: from cancer hormone to multifunctional cytokine. J Bone Mineral Res 2012;27:1231–1239. environmental insults that can damage the enamel 11. Clarkson J. A review of the developmental defects of enamel organ have been identified, the threshold for dam- index (DDE). Int Dent J 1992;42:411–426. age, and the relative susceptibility of the enamel 12. Suckling GW. Developmental defects of enamel. Adv Dent organ at the various stages of development have not Res 1989;3:87–94. been well researched. Furthermore, there is little 13. B€ackman B, Holm A-K. Amelogenesis imperfecta: prevalence information on how environmental pertubations and incidence in a northern Swedish county. Community Dent Oral Epidemiol 1986;14:43–47. interact with the genes that control enamel forma- 14. Witkop CJ. Amelogenesis imperfecta, dentinogenesis imper- tion. Therefore, despite major advancement in fecta and dentin dysplasia revisited: problems in classification. knowledge regarding the nature of the defects and J Oral Pathol Med 1989;17:547–553. the genes involved in enamel and dentine defects, 15. Chosack A, Eidelman E, Wisotski I, Cohen T. Amelogenesis further research is required to fill these gaps in imperfecta among Israeli Jews and the description of a new type of local hypoplastic autosomal recessive amelogenesis knowledge. Additionally, as enamel and dentine imperfecta. Oral Surg 1979;47:148–156. defects are currently managed by treating the symp- 16. Wright JT. The molecular etiologies and associated pheno- toms, future research should also focus on develop- types of amelogenesis imperfecta. Am J Med Genet ment of suitable techniques and aesthetic restorative 2006;140A:2547–2555. materials that can bond effectively to defects enamel 17. Seow WK. Clinical diagnosis and management strategies of and dentine. amelogenesis imperfecta variants. Pediatr Dent 1993;15:384– 393. 18. Chan H-C, Estrella NMRP, Milkovich RN, Kim J-W, Sim- ACKNOWLEDGEMENTS mer JP, Hu JCC. Target gene analyses of 39 amelogenesis imperfecta kindreds. Eur J Oral Sci 2011;119(Suppl 1):311– The author is grateful for funding of this project from 323. the National Health and Medical Research Council of 19. Simmer SG, Estrella N, Milkovich RN, Hu JCC. Autosomal dominant amelogenesis imperfecta associated with ENAM Australia. frameshift mutation p.Asn36Ilefs56. Clin Genet 2013;83:195– 197. 20. Gadhia K, McDonald S, Arkutu N, Malik K. Amelogenesis DISCLOSURE imperfecta: an introduction. Br Dent J 2012;212:377–379. The author has no conflicts of interest to declare. 21. Wright JT, Frazier-Bowers S, Simmons D, et al. Phenotypic variation in FAM83H-associated amelogenesis imperfecta. J Dent Res 2009;88:356–360. REFERENCES 22. 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