NORMAL FORMATION AND DEVELOPMENT DEFECTS OF THE HUMAN DENTITION

PEDIATRIC ORAL HEALTH

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NORMAL FORMATION AND DEVELOPMENT DEFECTS OF THE HUMAN DENTITION J. Tim Wright, DDS, MS

The development of the human dentition involves a highly orchestrated series of events that are strictly genetically controlled. The developmental timing, location, morphology, structure, and composition of teeth are primarily determined by cascades of molecular events that are regulated by hundreds of genes.4oNormally, humans have 20 primary (i.e., deciduous, or shedding) teeth, which are lost in childhood, and 32 permanent teeth. Dentition begins to form at approximately 6 weeks in utero and continues through late adolescence, when the development of the permanent third molars is completed. Because the development of dentition is prolonged, it is susceptible to environmental influences for many years. A basic understanding of normal dentition and its development allows clinicians to accurately identdy normal and abnormal dental conditions and make recommendations for appropriate therapeutic interventions and patient counseling. Delineating normal from abnormal dental development requires careful evaluation of the patient, including a medical, dental, and family history; clinical examination; and radiographic evaluation and may require special laboratory tests. This article reviews normal dentition and fundamental concepts of tooth development and provides a conceptual framework for diagnosing developmental defects of teeth.

From the Department of Pediatric Dentistry, School of Dentistry, The University of North Carolina, Chapel Hill, North Carolina

b PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 47 * NUMBER 5 OCTOBER ZOO0

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TOOTH DEVELOPMENT

Early embryonic requisites for tooth development include the differentiation of the oral ectoderm and the migration of neural crest cells into the craniofacial region, where tooth buds form. By approximately 6 weeks of age (in utero), the oral ectoderm begins to proliferate at the future sites of primary teeth. As the oral ectoderm proliferates, it invaginates into the underlying mesenchyme, where the neural crestderived ectomesenchymal cells reside.67The continued proliferation and expansion of the oral ectoderm allow the epithelial cells to contact and interact with the underlying ectomesenchymal cells, thereby initiating the development of a tooth bud primordia. These early events in tooth development are largely regulated by the oral epithelium, requiring the expression of numerous genes, including transcription and growth factors.66, If these early, epithelial-driven developmental events do not occur, then teeth do not form. This fact has been proven experimentally in transgenic mice, in which transcription factors, such as M S X l and MSX2, were knocked out, after which no teeth developed.40 After tooth formation has been initiated by the invagination of the oral epithelium, the ectodermal cells and the underlying ectomesenchyma1 cells engage in a complex series of interactions and signaling mechanisms. Instructive biochemical messages regulating cell proliferation, differentiation, and matrix production are transmitted between the ectodermal and mesenchymal cells. These interactions result in the differentiation of highly specialized cells that produce the unique dental tissues and establish the tooth size and shape. The location and type of tooth (e.g., incisor, cuspid, premolar, or molar) are thought to be genetically determined by the differential combinatorial expression of transcription factors in the regions of the developing teeth.%The oral epithelium gives rise to the enamel organ, which differentiates into the enamel-forming cells, called ameloblasfs. The ectomesenchymal cells give rise to the odontoblasts, which form the dentin and pulp. The tooth root surface eventually is covered by cementum, which is formed by cementoblasts, which are derived from the mesenchyme. For an intact and viable tooth to develop, each of these cell types must differentiate, produce and process a unique extracellular matrix, and regulate mineralization of the extracellular matrix. All of these processes involve strict genetic control, so they represent potential pathways for hereditary defects of teeth, as is discussed later. Numerous excellent and detailed reviews on the molecular control and mechanisms of normal tooth development are available.40.60,61.68 Teeth are multifunctional appendages participating in diverse functions, such as eating and speech. The human dentition also has a crucial role in facial esthetics, so it is important in complex human socialization processes. Dentition provides an efficient masticatory system that allows incising, tearing, and grinding of food. The unique composition and structure of the teeth allows them to survive the tremendous forces and wear associated with mastication. Alteration of the composition or @

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structure of the dental tissues may cause marked alteration of durability, resistance to fracture, and retention in the oral cavity. The composition and structure of teeth give them their unique appearance. The following sections provide a brief overview of each of the dental tissues and some of their important and unique characteristics. DENTAL TISSUES Enamel

Dental enamel is the hardest tissue in the human body and provides the fracture-resistant and wear-resistant outer covering for the tooth crown. Enamel is produced by ameloblasts, which secrete a unique extracellular matrix; process this matrix; control the mineralization process; protect the formed enamel during tooth eruption; and then become a part of the epithelial attachment of the tooth to the gingiva.60Enamel has no regenerative capacity because the ameloblasts are no longer present in the fully formed and erupted tooth. Although the enamel is initially deposited as an organic matrix, it mineralizes by the tightly controlled processing of the extracellular matrix and regulation of calcium and phosphate mineral deposition.x Defects in the enamel extracellular matrix or its processing may lead to enamel formation that is deficient (hypoplastic) or hyp~mineralized.~~ Fully developed enamel consists primarily of carbonate-substituted hydroxyapatite mineral that is highly organized into a unique structure. The apatite molecules are organized into crystallites, which are then arranged and oriented into interlocking prisms (Fig. 1). This complex and highly ordered structure helps to give enamel its incredible strength and wear resistance. Healthy enamel is approximately 96% mineral by weight with about 2% water, 1% protein, and 1% other component^.^^ Alterations in the mineral composition, such as substituting fluorine for carbonate, markedly decrease the acid solubility of the Changes in the mineral, water, or protein content of enamel result in alteration of the clinical appearance, strength, dental caries, and wear resistance of the tissue. Healthy enamel is highly translucent, so much of the color of teeth is derived from the underlying dentin and pulp. Dentin

Dentin is the most abundant dental tissue and largely determines the size and shape of teeth. The unique structure and composition of dentin allow it to function as the substructure for the rigid enamel tissue, thereby imparting teeth with the ability to flex and absorb tremendous loads without fracturing. Dentin contains approximately 60% mineral by weight and, unlike enamel, has a substantial organic component (20%). Type 1 collagen is the predominant dentin pr0tein.3~Numerous noncol-

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Figure 1. Prismatic structure of human enamel (scanning electron micrograph, original magnification x 3000).

lagenous proteins are present in dentin, some of which apparently interact with collagen to initiate and regulate mineralization.1° Dentin contains a complex organization of tubules (Fig. 2) that are approximately 1 Frn in diameter, filled with fluid or the cellular processes of the

Figure 2. Odontoblastic processes are seen entering the dentinal tdbules in normal human dentin (scanning electron micrograph, original magnification x 2000).

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odontoblasts, and are thought to have a role in the neurosensory function of Additional dentin can be deposited along the pulpal wall in a reparative or protective mode secondary to environmental stimuli, such as trauma, tooth wear, or dental caries.

Pulp The dental pulp is a specialized tissue comprised of a layer of odontoblasts, fibroblasts, blood vessels, nerves, and a complex extracellular matrix. The pulp provides the reparative potential of teeth and neurosensory functi0n.4~The dental pulp can increase the production of dentin (reparative dentin) in an attempt to protect and wall off the vital pulp tissue from injury or noxious stimuli.71Prompt treatments of dental trauma and dental caries are critical steps toward maintaining a healthy vital pulp and allowing an injured or diseased tooth to retain a vital pulp. The pulp continues to lay down small amounts of dentin throughout the life of teeth as a part of the normal pulp physiology.64This process results in a smaller pulp chamber as people age and is part of the reason that teeth continue to yellow with age. It is critical to maintain a healthy dental pulp until the root is fully formed and its walls are of adequate thickness to maintain the tremendous forces transmitted from the crown during function. If the pulp becomes nonvital in a young tooth that lacks complete root formation, successful completion of endodontic treatment is much more difficult, and the likelihood of retaining the tooth is diminished. Cementum Cementum is a unique tissue that covers the root surface and helps to prevent teeth from becoming fused to, or resorbed by, the adjacent alveolar bone. Cementum also provides the tissues by which each tooth is anchored by a fibrous network, the periodontal ligament, to the alveolar bone of the jawss3 To perform this specialized attachment function, cementum is comprised of type 1 and other collagens, noncollagenous proteins, and a mineralized matrix. The combined organic and mineralized components of cementum allow fibers from the periodontal ligament to insert into, and be held by, the cementum. Together, the cementum, periodontal ligament, and alveolar bone produce a complex attachment system that works as a flexible sling that holds the tooth in place while allowing normal physiologic movement under the tremendous masticatory loads placed on the dentition. All three of these tissues can regenerate, allowing traumatized teeth (e.g., tooth avulsion) or abnormalities (e.g., periodontal disease) to be treated s~ccessfully.5~ A comprehensive discussion of injury and treatment is included in the article by McTigue later in this issue.

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CHRONOLOGY OF TOOTH ERUPTION

The process by which teeth emerge from their developmental crypt into the oral cavity is commonly referred to as tooth eruption, although this name conjures images of a forceful and explosive process. The migration of developing teeth into the oral cavity is a delicate process that involves not only the teeth but also the tissues through which the emerging teeth pass.39,76 Permanent teeth normally enter the oral cavity when the roots are approximately two-thirds formed. Teeth erupt rapidly after they have penetrated the oral soft tissue and, if unimpeded by a lack of space or other physical constraints, normally fully erupt into occlusion within 6 months. Usually, teeth continue to emerge until they make contact with teeth or tissue in the opposing arch. In cases of missing or malaligned teeth, teeth can overerupt because of the lack of opposition. Although tremendous variability exists in the timing and sequence of normal tooth eruption, the eruption sequence and timing shown in Figures 3 and 4 can be used as a general guide. Typically, the first primary teeth (i.e., the mandibular central incisors) emerge at between 6 and 10 months of age.37Newborn infants or neonates can have natal or neonatal teeth (i.e., teeth present at birth or shortly after birth). These teeth are most commonly the mandibular primary incisors and not extra or supernumerary teeth (Fig. 5). These teeth can be mobile and cause feeding difficulties and irritation to infants’ tongues. Extraction may be considered if the teeth are interfering with adequate feeding or they are excessively mobile. Dentition typically develops at a slightly younger age in girls compared with boys, and racial influences on tooth development and erup35

30 25

10

5 0

Central incisor

Lateral incisor

Canine

First molar

Second molar

Figure 3. Age and variability of normal primary tooth eruption. Hatched bar = mandibular; solid bar = maxillary. (Data from Lunt RC, Law DB: A review of the chronology of calcification of deciduous teeth. J Am Dent Assoc 89:872-879, 1974.)

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20 18 16 14 12 h

x

v

a,

10

2 8 6 4 2 0

Central Incisor

Lateral Incisor

Canine

First Second Premolar Premolar

First Molar

Second Molar

Third Molar

Figure 4. Age of normal permanent took eruption. Hatched bar = mandibular; solid bar = maxillary. (Data from McDonald RE, Avery DR: Eruption of the teeth: Local, systemic and congenital factors that influence the process. In McDonald RE, Avery DR (eds): Dentistry for the Child and Adolescent, ed 5. St. Louis, Mosby, 1987, p 190.)

Figure 5. This radiograph of a newborn with natal teeth confirms they are the normal primary central incisors and not supernumerary teeth.

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tion times exist.19Some reports show that black people have earlier tooth eruption compared with white people.21Normally, the eruption of teeth is bilaterally symmetric, with the left and right antimeres erupting at similar times. Children deviating markedly from normal tooth eruption chronology (>6 mo _t normal deviation) or symmetry should be evaluated for abnormal dental eruption or congenitally missing teeth. A generalized delay in the timing of tooth eruption can be familial or occur in patients with conditions such as Down syndrome.12Complete failure of tooth eruption is associated with various conditions that can be localized (e.g., isolated to an individual tooth), generalized, or associated with a ~yndrome.~'

TOOTH ERUPTION PROBLEMS One of the most common questions related to tooth eruption involves teething pain and how to manage cranky, teething infants. Infants commonly chew on objects and drool excessively when their teeth are actively erupting. This behavior is normal, but parents commonly report that their children are fussy, irritable, have diarrhea, are running lowgrade fevers, or have other symptoms that they attribute to teething74 The scientific literature has not definitively established an association between teething and systemic manifestations, such as low-grade fever or diarrhea.32Because teething is a normal physiologic process and no substantive data support an association of teething with significant infirmities, the management of patients with teething symptoms should be palliative. Teething infants may find comfort in chewing on chilled teething rings or other appropriate chewing devices. Nonsteroidal antiinflammatory analgesics also may be helpful for extremely irritable children who seem to be uncomfortable secondary to teething. Although some commercially available topical gels sooth gingival irritation during teething, no studies support their use for managing patients with teething discomfort. Complete failure of eruption of one or more primary teeth not congenitally missing is rare. Eruption failure of a single permanent tooth in an otherwise healthy child is relatively more common, and the cause varies. The most common cause of permanent tooth eruption failure is inadequate space. Although failure of eruption or impaction of third molars caused by inadequate space in the dental arch is common, the maxillary canines or mandibular second premolars also can be prevented from erupting because of inadequate space.n Alternatively, teeth with inadequate space may erupt ectopically or out of the normal position. Treatment of inadequate space includes selective extraction of permanent teeth or orthodontic therapy, depending on the severity and location of the inadequate space. Permanent incisors sometimes fail to erupt as a sequela of trauma to the primary teeth that damaged the underlying development of the permanent tooth. Careful monitoring of permanent

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tooth development and eruption in children having a history of trauma to the anterior teeth is indicated. Teeth can become fused to the bone or ankylosed, thereby arresting normal tooth eruption.8 If this occurs in a growing child, the tooth slowly becomes overgrown by the surrounding teeth that are continuing to erupt with the growth of the alveolar bone and jaws. Often, the first clinical clue that a tooth is ankylosed is that the tooth is no longer contacting the teeth of the opposing arch when the teeth are brought into occlusion. Ankylosis is relatively common in the primary dentition and most often involves the first primary molars (Fig. 6).8 Ankylosed primary teeth with a permanent successor usually exfoliate normally with no treatment,65but treatment may be indicated depending on the age of onset and severity of the problem. Other causes of failed tooth eruption include developmental defects of the teeth; abnormalities of bone or jaws; and cysts, tumors, or syndromes. For example, teeth with developmental defects, such as odontodysplasia (Fig. 7), can form only rudimentary tooth appendages and fail to erupt.16 Local factors, such as cysts around a developing tooth bud (e.g., dentigerous cysts), or tumors, such as hemangiomas or odontomas, may prevent tooth eruption. In all of these examples, the eruption pattern tends to lack symmetry, indicating further evaluation and radiographic assessment. Various genetic conditions can affect tooth eruption, such as the hereditary enamel defects, the amelogenesis imperfectas, that are associated with an increased prevalence of unerupted teeth.14,48 For additional information on hereditary conditions that have dental manifestations, the reader is referred to the Web site On-line Mendelian Inheritance in Man (OMIN; http: / / www.ncbi.nlm.nih.gov/ Omim / ).45 Hereditary conditions in this article are designated with the assigned Omim reference number.45

Figure 6. The result of untreated early ankylosis of the second primary molar that resulted in severe submergence of the primary teeth and displacement of the permanent premolar (arrows).

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Figure 7. Regional odontodysplasia that resulted in failure of normal tooth development and eruption in the posterior maxillary arch (arrows).

Another interesting condition commonly associated with tooth eruption defects is cleidocranial dysplasia (CCD; OMIM 119600). This autosomal dominant condition is characterized by hypoplasia or aplasia of clavicles, defective bone formation, short stature, supernumerary teeth, defective cementum formation, and abnormal tooth eruption.29 The molecular basis of CCD is a mutation in the CBFAl gene, a member of the runt family of transcription factors, located on chromosome 6p21.42 Formation and eruption of the primary dentition is generally normal, but multiple supernumerary or extra teeth are common and the permanent dentition typically has severe eruption The cementum on teeth in patients with CCD reportedly consists almost entirely of the acellular type.63The failure of tooth eruption in patients with CCD is thought to be primarily a defect in the abnormal osteoclastic and resorptive process of the alveolar bone necessary to allow the teeth to migrate toward the oral cavity. Treatment of the oral manifestations of CCD involves extracting the supernumerary teeth and assisting the eruption of the permanent teeth by surgically exposing them and allowing passive emergence or using orthodontic therapy. PRIMARY TOOTH EXFOLIATION

All 20 primary teeth normally exfoliate as a part of the eruption process of the permanent teeth. Permanent teeth develop apical to the primary teeth and normally resorb the roots of the primary teeth as they migrate through the alveolar bone toward the oral cavity. Normally, after the permanent tooth is near the mucosal surface, virtually all of the root of the primary tooth will have resorbed. The primary tooth becomes increasingly mobile and ultimately exfoliates. If the permanent tooth fails to adequately resorb the primary tooth root, over-retention of

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the primary teeth may occur. This occurrence is relatively common in the mandibular anterior region, where the permanent teeth are positioned toward the tongue side of the primary teeth and may not resorb the roots completely (Fig. 8). In most cases, the primary teeth exfoliate normally within 1 year without treatment, but, in some cases, extraction of the over-retained primary teeth is required. Premature exfoliation of primary teeth may be caused by local factors or systemic health problems. Two primary incisors or even a mandibular primary cuspid may be exfoliated when the large permanent incisors begin to erupt. Exfoliation of multiple primary teeth in place of the one permanent tooth often indicates a tooth-arch size discrepancy, and some degree of crowding in the permanent dentition is likely. When premature exfoliation of primary teeth occurs, especially when it is not associated with the eruption of permanent teeth, clinicians must consider the possibility that a systemic condition may exist. Because some of the conditions associated with premature tooth loss are life-threatening, an accurate diagnosis is critical. Exfoliation of primary teeth that have not undergone root resorption is another clinical clue that a child may have a potentially severe systemic condition. Conditions associated with premature primary tooth exfoliation are reviewed in Table 1. The causes of these conditions and the mechanisms involved in premature tooth exfoliation are diverse. For example, defective cementum formation occurs in patients with hypophosphatasia (OMIM 146300 and 241500), a hereditary condition characterized by mineralized tissue abnormalities caused by mutations in the tissue84 The cementum can be extremely nonspecific alkaline phosphatase gene.46, thin and lack sufficient structure for periodontal fiber insertion, resulting in premature tooth 1 0 ~ sIn . ~children with hypophosphatasia, primary

Figure 8. Eruption of the permanent mandibular incisors behind the primary incisors is not infrequent because of the lingual position of the developing permanent incisor to the mandibular incisor tooth root.

Tooth loss as early as 1 year of age, minimal soft-tissue inflammation, large dental pulp chambers, variable enamel hypoplasia Tooth loss beginning 2nd to 3rd year of life, marked soft-tissue inflammation, generalized alveolar bone loss Severe erythematous gingivitis, can have rapid periodontal breakdown and bone loss Ulcerations of oral mucosa, severe gingivitis, glossitis, periodontal breakdown and bone loss Ulcerative gingivitis, root exposure and premature tooth mobility typically starting with posterior teeth Variable gingival inflammation (localized minor to generalized severe), alveolar bone loss typically starting with posterior teeth

Hypophosphatasia (OMM 146300 & 241500)

Datafrom references 27, 28,44, 45, 69, and 84.

Prepubertal periodontitis (OMIM 170650)

Langerhans’ cell histiocytosis (Histiocytosis X)

Chediak Higashi syndrome (Oh4JM 214500)

Cyclic neutropenia (OMIM 162800)

Papillon LeFevere syndrome (OMM 245000)

Oral Manlfestatlons

Condition

Recurrent fevers, malaise, sore throat, anorexia, 21-day periodicity of decreased neutrophils Partial albinism, neutropenia, recurrent infections of skin and respiratory tract, frequently lethal before age 7 y Bone Iksions, multiorgan involvement, seborrheic scalp rash, diabetes insipidus, growth retardation

Hyperkeratosis of palmar and plantar surfaces

Decreased alkaline phosphatase, severe cases can have bone manifestations, bowing of legs, short stature

Systemic Manifestations

Table 1. CONDITIONS ASSOCIATED WITH PREMATURE PRIMARY TOOTH EXFOLIATION

Autosomal dominant trait, leukocyte defect involving chemotaxis or phagocytosis

Autosomal recessive trait, ’ deficiency of natural killer lymphocytes Proliferation of Langerhans’ cells (dendritic histiocytes), immunologic dysregulation

Autosomal dominant trait, defect in neutrophil elastase

Autosomal recessive trait, mutation in cathepsin gene

Autosomal dominant and recessive forms, mutations in tissue nonspecific alkaline phosphatase gene

Cause

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teeth that show no evidence of root resorption may begin exfoliating as early as 1 year of age.36Premature exfoliation of primary teeth also can indicate that a child has a malignant condition, such as histiocytosis X, or an immunologic problem, such as cyclic neutropenia. Referral to a pediatric dentist for thorough evaluation is indicated in cases of premature primary teeth so that optimal and appropriate treatment, if necessary or available, can be initiated promptly. CONGENITALLY MISSING TEETH

Developmentally absent teeth may result from a local environmental insult (e.g., trauma to a primary tooth), a more generalized environmental disturbance (e.g., head and neck radiation), or as a genetic defect involving only the teeth (single or multiple) or may be the manifestation of a syndrome. The presence of congenitally missing teeth is common and varies among races and tooth types. Approximately 5% of white people have congenitally missing permanent maxillary lateral incisors or premolars (the most commonly missing teeth excluding third molars), whereas only 1% of black people have congenitally missing teeth.2l Congenitally missing primary teeth are less prevalent than are missing permanent teeth, with mandibular central incisors being the most commonly missing primary teeth. Clinical observation of a delayed or abnormal eruption pattern, followed by confirmation of the dental complement found on radiography, establishes the diagnosis of congenitally missing teeth. Radiographic examination can be accomplished with small intraoral radiographs or panoramic radiography. A thorough medical, dental, and family history and clinical and radiographic evaluations are necessary to accurately diagnose the presence and cause of congenitally missing teeth. The management of patients with missing teeth varies and may be complex, requiring long-term treatment with multiple therapeutic phases. Young children suspected of having missing teeth or abnormal eruption patterns should be referred for dental evaluation. Many individuals presenting with missing teeth have a family history of missing teeth (Fig. 9). Although the molecular defects causing congenitally missing teeth are heterogeneous, several specific genetic mutations have been identified. For example, a missense mutation in the M S X l gene (i.e., the gene coding for a transcription factor) causes an autosomal dominant trait of missing lateral incisors and third molars.” A mutation in the transcription factor gene PAX9 is associated with an unusual pattern of missing teeth. Individuals with missing teeth can be offered genetic testing to determine whether the molecular basis of their conditions is known and to help to establish recurrence risk and variability of expression. Numerous hereditary syndromes include congenitally missing teeth as a characteristic. In some instances, only a few or no teeth may be missing (e.g., Down syndrome), or, as in the case of a group of conditions

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Figure 9. A young woman missing all her posterior teeth. Her father was similarly affected.

known as the ectoderrnal dysplasias (ED), multiple teeth (hypodontia) or all teeth (anodontia) may be missing. More than 100 conditions can be classified as EDs, many of which are associated with abnormal tooth ED (OMIM 305100), one of the betterd e ~ e l o p m e n t .Hypohidrotic ~~ recognized forms of these conditions, is characterized by a decreased ability to sweat (hypohidrosis), sparse hair (hypotrichosis), and missing or malformed teeth (hypodontia; Fig. lo), any or all teeth missing, and conical-shaped incisor^.'^ Genes for the classic X-linked recessive form and for an autosomal dominant and recessive ED have been identified,3I,41 allowing individuals with these types of EDs to confirm their diagnosis, which can be problematic because of phenotypic overlap

Figure 10. This child with X-linked ED has a conical shaped incisor and multiple missing teeth characteristic of this condition.

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between and variable expression of these conditions. Having a correct molecular-based diagnosis allows families to obtain accurate genetic counseling. Conical or misshapen teeth usually can be treated using bonding techniques to achieve a greatly improved esthetic appearance. Dental management of hypodontia or anodontia often involves the use of fixed and removable prostheses to replace the missing teeth to enhance oral function and facial esthetics.22Clinicians should provide children who are missing multiple anterior teeth with prostheses before they begin The optimal age for treatment is dictated by the extent of treatment needed and by a child’s ability to cooperate during the required procedures and maintain the appliances after placement. The management of patients with severe hypodontia or anodontia typically involves numerous treatment phases over a patient’s lifetime. Many children with severe hypodontia or anodontia benefit from dental implants. Although each case must be evaluated individually, current wisdom suggests that dental implant procedures typically are best delayed until adolescence or early adulthood.26

ENAMEL DEFECTS Because enamel formation is. a highly regulated process requiring many genes and occurs over a long period, it is not surprising that more than 100 causes of abnormal enamel formation exist.62Environmental influences or genetic mutations can affect various developmental phases or specific processes, causing aberrant enamel formation, which explains the high prevalence of enamel defects reported in the general population (range, 25-80%).43,57 Abnormal enamel matrix secretion or extracellular matrix processing are associated with many of these developmental disturbances. Although premature cessation of ameloblast function may result in thin or pitted enamel, the processes involved in the development of hypomineralized enamel are apparently complex and not clearly understood. Numerous environmental insults, from trauma to infection, may cause developmental defects in enamel. Exposure to excessive amounts of elements such as lead, mercury, and fluorine also may cause abnormal enamel development. Because of the therapeutic use of fluoride in dental caries prevention and the continued controversy surrounding its use, clinicians should be familiar with the enamel defect associated with excess fluoride consumption, fluorosis. Optimal fluoride consumption (= 0.05 mg/kg/d) results in a substantial caries reduction and a positive effect on enamel formation, but as fluoride consumption increases beyond the optimal level, the risk for fluorosis, a hypomineralization of the enamel, increases.52The mechanism by which excessive fluoride consumption causes fluorosis is not fully understood, but several developmental pathways likely are affected by excess fluoride levels.6,2o Clinically, mild fluorosis causes a white, flecked or lacey appearance of the

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enamel (Fig. 11). Severe fluorosis results in the enamel being markedly hypomineralized, with a brown color and propensity to break and excessively wear.23 Hereditary enamel defects may occur as a part of a generalized condition or syndrome or a defect involving only Many hereditary disorders of the ectodermal and combined ectodermal and mesenchyma1 types, such as the trichodento-osseous syndrome (OMIM 1903320), incontinentia pigmenti, tuberous sclerosis, and junctional epidermolysis bullosa (OMIM 226700), may have marked enamel involvement.n Enamel defects associated with syndromic conditions vary substantially, depending on the molecular defect and the role of the genes in tooth formation. For example, in the trichodento-osseous syndrome, an autosomal dominant disorder caused by a mutation in the Distal-less 3, homeobox gene (DLX3), the teeth have enamel hypoplasia that may be smooth or pitted (Fig. 12) and have taurodontism or elongation of the pulp chamber.4y,82 Individuals with this condition also have kinky, curly hair at birth and develop dense or thickened bone.82The DLX3 gene functions as a transcription factor regulating the expression of other genes and is important in hair, tooth, and bone formation. Individuals with junctional forms of eyidermolysis bullosa have varying severities of generalized enamel hypoplasia and variable expression of skin fragility and blistering.81The molecular defects that cause junctional epidermolysis bulosa involve genes that produce proteins essential to maintaining the integrity between the dermis and epidermis and are important in normal functioning of the ameloblasts.' Amelogenesis imperfecta (AI) represents a group of hereditary conditions (Table 2) that manifest enamel defects without evidence of generalized or systemic These conditions are clinically and genetically diverse. The most widely accepted classification system for A1 considers mode of inheritance and clinical manifestations, with 14 dis-

Figure 11. These incisors with moderate fluorosis have an opaque white appearance and a round lesion (arrow) in which hypomineralized enamel has been abraded from the surface during normal function.

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Figure 12. The permanent incisors of this adolescent male with the tricho-dento-osseous syndrome are small and have thin enamel.

tinct subtypes being r e c o g n i ~ e dAutosomal .~~ dominant, recessive, and X-linked inheritance patterns of A1 have been r e p ~ r t e d .The ~ clinical phenotype ranges from thin enamel that is normal in color to enamel that is severely hypomineralized and readily abrades from the teeth as they erupt into the oral cavity.*O Depending on the A1 type, the teeth can be extremely sensitive to thermal and chemical stimuli. Although the molecular defects remain unknown for all the autosomal forms of AI, they will likely be identified in the near future. Various point mutations and a large deletion have been identified in the A M E L X gene that codes for amelogenin, the most abundant enamel matrix protein.2,13, 33, 34 The phenotypic result of these mutations varies, with enamel defects including hypoplasia with or without hypomineralization (Fig. 13). Treatment of enamel defects is predicated on the diagnosis and specific phenotype. For example, hypoplastic enamel that is well mineralized commonly is treated effectively with bonding procedures to protect the teeth and enhance esthetics.56Teeth with severely hypomineralized enamel typically are treated with restorations that cover the entire clinical crown (i.e., stainless steel or resin crowns). Infants with conditions that are associated with enamel defects should be referred for dental evaluation and early intervention assessment before age 1 year.

DENTIN DEFECTS

Although dentin formation can be influenced by environmental factors, developmental defects from environmentally induced causes

Clinical Appearance

Crown size varies from small to normal, small teeth may lack proximal contacts, color varies from normal to opaque white-yellow brown Hypomaturation Varies from creamy opaque to (type 2) marked yellow or brown, surface of teeth soft and rough, dental sensitivity and open bite common Hypocalafied Opaque white to yellow-brown, soft rough enamel surface, ( W e 3) dental sensitivity and open bite common, heavy calculus formation common Hypomaturation/ White / yellow-brown mottled, hypoplasia/ teeth can appear small and taurodontism lack proximal contact (type 4)

Hypoplastic (type 1)

Type

RadiographicAppearance

Inheritance

Autosomal dominant, recessive

Autosomal dominant

Normal thickness with enamel Enamel has contrast similar that often chips and abrades to or < dentin, unerupted easily crowns have normal morphology Reduced, hypomineralized areas and pits

Enamel contrast normal to slightly > dentin, large pulp chambers

Autosomal dominant, recessive, or X-linked

Enamel has normal to slightly Autosomal dominant, recessive, reduced contrast, thin or X-linked

Normal thickness with enamel Enamel has contrast similar that often chips and abrades to dentin, unerupted easily aowns have normal morphology

Varies from thin and smooth to normal thickness with grooves, furrows, or pits

Enamel Thickness

Table 2. CLINICAL AND HEREDITARY CHARACTERISTICS OF AMELOGENESIS IMPERFECTA

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Figure 13. This adolescent male shows the brown tooth coloration characteristic of one Xlinked form of amelogenesis imperfecta (pro41thre amelogenin mutation).

tend not to have the severe clinical sequelae that occur with enamel defects, but dentin malformations that severely affect the form and function of teeth occur in numerous syndromic and nonsyndromic hereditary conditions. The most common Mendelian traits affecting dentin historically have been classified based on phenotype and histologic features.59,7x The dentinogenesis imperfectas (DIs) and dentin dysplasias (DD; Table 3 ) were classified using clinical, radiographic, and histopathologic features in 1973, and this nosology remains in use today.59DI has been classified based on its association with osteogenesis imperfecta (type 1; OMIM 166240) or not (type 2; OMIM 125490) or with the Brandywine triracial isolate and large pulp chambers (type 3; OMIM 125500). The molecular defects in patients with osteogenesis imperfecta include numerous mutations in the pro-alpha chains of collagen type 1 that result in a phenotype characterized by increased bone fragility.” Although the dental phenotypes of DI types 1 and 2 seem similar, type 2 is not associated with any of the nondental phenotypic features of osteogenesis imperfecta and is not caused by a collagen 1 defect. DI types 2 and 3 are autosomal dominant conditions that have been linked to chromoAlthough some 4922-21, suggesting that these may be allelic m~tati0ns.l~ the genes responsible for DI types 2 and 3 are unknown, several likely candidates have been identified, including the dentin matrix acid phosphoprotein gene ( D M P I ) and the dentin sialophosphoprotein gene (DSPP).3,4, 3x In all three DI types, the teeth have a variable blue-gray to yellowbrown discoloration that appears opalescent because of the defective, abnormally colored dentin shining through the translucent enamel (Fig.

Variable blue-gray to yellow-brown teeth, enamel fracturing, excessive wear, primary teeth usually more affected than permanent Same appearance and variability as in DI type 1, often similar severity in primary and permanent dentitions Similar clinical phenotype as DI types 1 and 2 although typically severe expression with enamel loss and extensive wear occurring early Normal clinical crown morphology and coloration in primary and permanent dentitions, malaligned teeth, frequent dental abscess Primary dentition has same phenotype as DI, permanent dentition has normal to slight blue gray discoloration

Dentinogenesis imperfecta type 1 (occurs in some forms of osteogenesis imperfecta) (OMIM

DI = dentinogenesis imperfecta.

Dentin dysplasia type 2 (OMIM 125420)

Dentin dysplasia type 1 (OMIM 125400)

Dentinogenesis imperfeda type 3 (OMIM 125500)

Dentinogenesis imperfecta type 2 (OMIM 125490)

166240)

Clinical Features

Condition

Table 3. HERITABLE CONDITIONS OF DENTIN

Pulp obliteration in primary dentition, abnormal pulp morphology and pulp stones in permanent dentition

Pulp obliteration and short blunt roots in both primary and permanent dentitions

Pulp chamber obliteration that can begin before tooth eruption, abnormal crown and root morphology Large pulp chambers, very thin dentin, bulbous crowns and diminished root structure

Variable pulp obliteration, bulbous crowns, altered root morphology, increased risk for dentigerous cysts

Radiographic Features

Unknown, linked to 4921 lotus

Unknown, no locus identified

locus

Unknown, linked to 4921

lOCUS

Unknown, linked to 4921

Mutations of collagen type 1 genes (COLIAI and COLIlA.2)

Molecular Defect

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14). Because of the lack of support of the poorly mineralized underlying dentin, the enamel commonly fractures from the teeth, leading to rapid wear and attrition of the teeth. The severity of discoloration and enamel fracturing in patients with all DI types is highly variable, even within the same family. If left untreated, the entire DI-affected dentition may be worn off to the gingiva. In patients with DI types 1and 2, radiographs show pulpal obliteration caused by rapid and excessive deposition of dentin (Fig. 15). The pulp chambers are large in patients with DI type 3. Treatment of patients with DI depends on the severity of discoloration and propensity for enamel loss. In severe cases, full coverage crowns typically are the treatment of choice, but in cases without enamel fracturing, bonding may be used to improve the esthetics of the discolored teeth. Two types of DD are recognized. DD type 1 (OMIM 125400) is a rare dentin defect that seems to be inherited as an autosomal dominant condition, with a prevalence of 1 in 100,000 persons.30 Clinically, the dental crowns appear normal, but radiographically, the teeth are characterized by pulpal obliteration and short, blunted roots.30The teeth typically are mobile, commonly abscess, and can be lost prematurely. The affected dentin has a unique cascading waterfall appearance apparently caused by a cyclical developmental process of premature odontoblast death, new odontoblast recruitment, dentin deposition, and odontoblast death. The molecular defect in patients with DD type 1 is unknown. No known specific treatment approach exists for DD type 1, although an effort to keep occlussal forces to a minimum and avoiding orthodontic

Figure 14. Marked discoloration and severe attrition of the primary dentition are seen in this child with dentinogenesis imperfecta type II.

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Figure 15. The abnormal tooth morphology and complete obliteration of the dental pulp chambers characteristic of dentinogenesis imperfecta type II.

treatment for the malaligned teeth may increase the longevity of the dentition.30 DD type 2 (OMIM 125420) is also inherited as an autosomal dominant trait. The primary dentition of DD type 2 seems virtually identical to that of DI type 2, with yellow-brown to blue-gray discoloration of the teeth and pulpal obliteration, but in patients with DD type 2, the color of permanent dentition is normal or only minimally discolored but the permanent dentition displays abnormal pulpal morphology that may be shaped like a thistle tube in the anterior teeth.5oPulp stones also are common in the permanent teeth. Because of the similar phenotype of the primary teeth, DD type 2 may be an allelic mutation of the gene responsible for DI type 2. Although the molecular defect for DD type 2 is unknown, it has been linked to the same region as DI type 2 on chromosome 4921, consistent with it being an allelic mutation.I8 Treatment of DD type 2 in the primary dentition follows the same course as that used for children with DI. Many systemic conditions include abnormal dentin formation as a result of the molecular defect interfering with different dentin developmental pathways. For example, conditions with molecular defects that influence mineralization, such as hypophosphatasia (i.e., alkaline phosphatase defect) and vitamin D-resistant rickets (i.e., vitamin D metabolism defect), can have significant dentin involvement. Many children with vitamin D-resistant rickets develop dentoalveolar abscesses because of large pulps with extensive pulp projections (pulp horns) that become exposed to the oral environment and allow for bacterial invasion into the tooth.25Other systemic conditions with dentin involvement include Ehlers-Danlos syndrome, mucopolysaccharidoses, and tumoral calcinosis.

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SUMMARY Oral health and systemic health are intimately related, and a thorough evaluation of the oral health of children is critical in providing appropriate health care. By understanding the normal sequence and patterns of tooth development, clinicians can readily identify children who deviate from normal dental development and provide appropriate interventions or make appropriate referrals. Developmental defects of the human dentition are not uncommon and can severely adversely affect the physical and psychological health of children. Despite the severity of some developmental defects of the dentition, the ability to diagnose and manage these conditions, in most cases, allows children the benefit of optimal oral health. References 1. Aberdam D, Aguzzi A, Baudoin C, et al: Developmental expression of nicein adhesion protein (laminin-5) subunits suggests multiple morphogenic roles. Cell Adhes Commun 2115-129, 1994 2. Aldred MJ, Crawford PJM, Roberts E, et a1 Identification of a nonsense mutation in the amelogenin gene ( A M E L X ) in a family with X-linked amelogenesis imperfecta (AIH1). Hum Genet 90:413-416,1992 3. Alpin Hh4, Hirst KL, Crosby AH, et a1 Mapping of the human dentin matrix phosphoprotein gene (DMPU to the dentinogenesisimperfecta type I1 critical region at chromosome 4921. Genomics 30347-349,1995 4. Alpin Hh4, Hirst KL, Dixon MJ: Refinement of the dentinogenesis imperfecta type I1 locus to an interval of less than 2 centimorgans at chromosome 4921 and the creation of a yeast artificial chromosome contig of the critical region. J Dent Res 78:1270-1276,1999 5. Backman B, Holmgren G: Amelogenesis imperfecta: A genetic study. Hum Hered 38189-206, 1988 6. Bawden J, Crenshaw M, LeGeros R, et al: Consideration of possible biologic mechanisms of fluorosis. J Dent Res 741349-1352, 1995 7. Belanger G. Early treatment considerations for oligodontia in ectodermal dysplasia: A case report. Quiitessence International 25:705-711, 1994 8. Brearley LJ, McKibben D H Ankylosis of primary molar teeth: I. Prevalence and characteristics. Journal Dentistry Children 40:54-63, 1973 9. Bruckner RJ, Rickles NH, Porter DR: Hypophosphatasia with premature shedding of teeth and aplasia of cementum. Oral Surgery 153351-1369, 1962 10. Butler WT, Ritchie HH, Bronckers ALJJ: Extracellular matrix proteins of dentine. In Chadwick DJ, Cardew G (eds): Dental Enamel. Chichester, John Wiley & Sons, pp 107-117, 1997 11. Byers PH, Chessler SD, Starman BJ, et a1 Molecular basis of osteogenesis imperfecta. In Slavkin H, Price P (eds): The Chemistry and Biology of Mineralized Tissues. Amsterdam, Elsevier Science, 1992, pp 427-432 12. Cohen MM, W i e r RA: Dental and facial characteristics in Down’s syndrome (mongolism). J Dent Res 44397-208, 1965 13. Collier PM, Sauk JJ, Rosenbloom J, et al: An amelogenin gene defect associated with human X-linked amelogenesis imperfecta. Arch Oral Biol42:235-242, 1997 14. Collins MA, Mauriello SM, Tpdall DA, et al: Dental anomalies in amelogenesis imperfecta: A radiographic assessment. Oral Surg Oral Med Oral Pathol Oral Radio1 Endod 88:358-364, 1999 15. Crawford PJM,Aldred JM, Clarke A Clinical and radiographic dental findings in Xlinked hypohidrotic ectodermal dysplasia. J Med Genet 28:181-185,1991

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Address reprint requests to J. Tim Wright, DDS, MS Department of Pediatric Dentistry School of Dentistry CB # 7450 The University of North Carolina Chapel Hill, NC 27599-7450 e-mail: [email protected]