Normal Formation and Development Defects of the Human Dentition

Home , Ameloblast, Dentin dysplasia, Odontoblast, Periodontal fiber, Teething, Tooth loss

PEDIATRIC ORAL HEALTH 0031-3955/00 $15.00 + .OO

NORMAL FORMATION AND DEVELOPMENT DEFECTS OF THE HUMAN DENTITION

J. Tim Wright, DDS, MS

The development of the human dentition involves a highly orches- trated 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 975 976 WRIGHT

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 crest- derived 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 MSXl 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 ectomesenchy- ma1 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 eventu- ally 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 NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 977

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 cal- cium 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 de- crease 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- 978 WRIGHT

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). NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 979 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 through- out the life of teeth as a part of the normal pulp physiology.64 This 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, noncol- lagenous 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. 980 WRIGHT

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 erup-

0 Central Lateral Canine First Second incisor incisor molar 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.) NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 981

h vx a, 10 2 8

0 Central Lateral Canine First Second First Second Third Incisor Incisor Premolar Premolar Molar Molar 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. 982 WRIGHT

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 low- grade 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 anti- inflammatory 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 NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 983 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). 984 WRIGHT

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 resorp- tive 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 NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 985 the primary teeth may occur. This occurrence is relatively common in the mandibular anterior region, where the permanent teeth are posi- tioned 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 tissue- nonspecific alkaline phosphatase gene.46,84 The cementum can be extremely thin and lack sufficient structure for periodontal fiber insertion, resulting in premature tooth 10~s.~In 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. Table 1. CONDITIONS ASSOCIATED WITH PREMATURE PRIMARY TOOTH EXFOLIATION Condition Oral Manlfestatlons Systemic Manifestations Cause Hypophosphatasia Tooth loss as early as 1 year of age, Decreased alkaline phosphatase, severe Autosomal dominant and recessive (OMM 146300 & 241500) minimal soft-tissue cases can have bone manifestations, forms, mutations in tissue inflammation, large dental pulp bowing of legs, short stature nonspecific alkaline phosphatase chambers, variable enamel gene hypoplasia Papillon LeFevere Tooth loss beginning 2nd to 3rd Hyperkeratosis of palmar and plantar Autosomal recessive trait, syndrome (OMM year of life, marked soft-tissue surfaces mutation in cathepsin gene 245000) inflammation, generalized alveolar bone loss Cyclic neutropenia Severe erythematous gingivitis, can Recurrent fevers, malaise, sore throat, Autosomal dominant trait, defect (OMIM 162800) have rapid periodontal anorexia, 21-day periodicity of in neutrophil elastase breakdown and bone loss decreased neutrophils Chediak Higashi syndrome Ulcerations of oral mucosa, severe Partial albinism, neutropenia, recurrent Autosomal recessive trait, (Oh4JM 214500) gingivitis, glossitis, periodontal infections of skin and respiratory ’ deficiency of natural killer breakdown and bone loss tract, frequently lethal before age 7 y lymphocytes Langerhans’ cell Ulcerative gingivitis, root exposure Bone Iksions, multiorgan involvement, Proliferation of Langerhans’ cells histiocytosis and premature tooth mobility seborrheic scalp rash, diabetes (dendritic histiocytes), (Histiocytosis X) typically starting with posterior insipidus, growth retardation immunologic dysregulation teeth Prepubertal periodontitis Variable gingival inflammation Autosomal dominant trait, (OMIM 170650) (localized minor to generalized leukocyte defect involving severe), alveolar bone loss chemotaxis or phagocytosis typically starting with posterior teeth

Datafrom references 27, 28,44, 45, 69, and 84. NORMAL FOWATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 987 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. Radio- graphic 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 MSXl 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 988 WRIGHT

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 de~elopment.~~Hypohidrotic ED (OMIM 305100), one of the better- 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. NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 989

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 wis- dom 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 be- yond 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 Clini- cally, mild fluorosis causes a white, flecked or lacey appearance of the 990 WRIGHT 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 mesenchy- ma1 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 substan- tially, 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. NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 991

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

tinct subtypes being recogni~ed.~~Autosomal dominant, recessive, and X-linked inheritance patterns of A1 have been rep~rted.~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 AMEL 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 Table 2. CLINICAL AND HEREDITARY CHARACTERISTICS OF AMELOGENESIS IMPERFECTA Type Clinical Appearance Enamel Thickness Radiographic Appearance Inheritance Hypoplastic Crown size varies from small to Varies from thin and smooth Enamel has normal to slightly Autosomal dominant, recessive, (type 1) normal, small teeth may lack to normal thickness with reduced contrast, thin or X-linked proximal contacts, color grooves, furrows, or pits varies from normal to opaque white-yellow brown Hypomaturation Varies from creamy opaque to Normal thickness with enamel Enamel has contrast similar Autosomal dominant, recessive, (type 2) marked yellow or brown, that often chips and abrades to dentin, unerupted or X-linked surface of teeth soft and easily aowns have normal rough, dental sensitivity and morphology open bite common Hypocalafied Opaque white to yellow-brown, Normal thickness with enamel Enamel has contrast similar Autosomal dominant, recessive (We 3) soft rough enamel surface, that often chips and abrades to or < dentin, unerupted dental sensitivity and open easily crowns have normal bite common, heavy calculus morphology formation common Hypomaturation/ White / yellow-brown mottled, Reduced, hypomineralized Enamel contrast normal to Autosomal dominant hypoplasia/ teeth can appear small and areas and pits slightly > dentin, large taurodontism lack proximal contact pulp chambers (type 4) NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 993

Figure 13. This adolescent male shows the brown tooth coloration characteristic of one X- linked 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 chromosome 4922-21, suggesting that these may be allelic m~tati0ns.l~Although the genes responsible for DI types 2 and 3 are unknown, several likely candidates have been identified, including the dentin matrix acid phospho- protein gene (DMPI) and the dentin sialophosphoprotein gene (DSPP).3,4, 3x In all three DI types, the teeth have a variable blue-gray to yellow- brown discoloration that appears opalescent because of the defective, abnormally colored dentin shining through the translucent enamel (Fig. Table 3. HERITABLE CONDITIONS OF DENTIN Condition Clinical Features Radiographic Features Molecular Defect Dentinogenesis imperfecta Variable blue-gray to yellow-brown Variable pulp obliteration, bulbous Mutations of collagen type 1 type 1 (occurs in some teeth, enamel fracturing, crowns, altered root genes (COLIAI and forms of osteogenesis excessive wear, primary teeth morphology, increased risk for COLIlA.2) imperfecta) (OMIM usually more affected than dentigerous cysts 166240) permanent Dentinogenesis imperfecta Same appearance and variability as Pulp chamber obliteration that can Unknown, linked to 4921 type 2 (OMIM 125490) in DI type 1, often similar begin before tooth eruption, lOCUS severity in primary and abnormal crown and root permanent dentitions morphology Dentinogenesis imperfeda Similar clinical phenotype as DI Large pulp chambers, very thin Unknown, linked to 4921 type 3 (OMIM 125500) types 1 and 2 although typically dentin, bulbous crowns and locus severe expression with enamel diminished root structure loss and extensive wear occurring early Dentin dysplasia type 1 Normal clinical crown morphology Pulp obliteration and short blunt Unknown, no locus (OMIM 125400) and coloration in primary and roots in both primary and identified permanent dentitions, malaligned permanent dentitions teeth, frequent dental abscess Dentin dysplasia type 2 Primary dentition has same Pulp obliteration in primary Unknown, linked to 4921 (OMIM 125420) phenotype as DI, permanent dentition, abnormal pulp lotus dentition has normal to slight morphology and pulp stones in blue gray discoloration permanent dentition

DI = dentinogenesis imperfecta. NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 995

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 1 and 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. 996 WRIGHT

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 Treat- ment 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 metabo- lism 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.25 Other systemic conditions with dentin involvement include Ehlers-Danlos syndrome, mucopolysaccharidoses, and tumoral calcinosis. NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 997

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 Com- mun 2115-129, 1994 2. Aldred MJ, Crawford PJM, Roberts E, et a1 Identification of a nonsense mutation in the amelogenin gene (AMELX) 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 phospho- protein gene (DMPU to the dentinogenesis imperfecta 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 DH 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, Wier RA: Dental and facial characteristics in Down’s syndrome (mongol- ism). 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 X- linked hypohidrotic ectodermal dysplasia. J Med Genet 28:181-185,1991 998 WRIGHT

16. Crawford PJM, Aldred MJ: Regional odontodysplasia: A bibliography. J Oral Pathol Med 18:251-263, 1989 17. Crosby AH, Scherpbier-Heddema T, Wijmenga C, et ak Genetic mapping of the dentinogenesis imperfecta type LI locus. Am J Hum Genet 57832-839, 1995 18. Dean JA, Hartsfield JKJ, Casada JC, et al: Genetic linkage of dentin dysplasia type I1 to chromosome 4ql3. J Craniofac Genet Dev Biol 17172-177, 1997 19. Demirjian A, Levesque GY: Sexual differences in dental development and prediction of emergence. J Dent Res 59:lllO-1122, 1980 20. DenBesten PK, Giambro NJ: Dental fluorosis. In Robinson C, Kirkham J, Shore R (eds): Dental Enamel Formation to Destruction. Boca Raton, CRC Press, 1995, pp 245-264 21. Dixon GH, Stewart RE: Genetic aspects of anomalous tooth development. In Stewart RE, Prescott GH (eds): Oral Facial Genetics. St. Louis, CV Mosby, 1976, pp 124-150 22. Farrington FH The team approach to the management of ectodermal dysplasias. In Salinas CF, Opitz JM,Paul NW (eds): Recent Advances in Ectodermal Dysplasias. New York, Alan R. Liss, 1988, pp 237-242 23. Fejerskov 0, Manji F, Baelum V The nature and mechanisms of dental fluorosis in man. J Dent Res 69692-700, 1990 24. Freire-Maia N, Pinheiro M. Ectodermal Dysplasias: A Clinical and Genetic Study. New York, Alan R. Liss, 1984, p 251 25. Gardner DG: Genetic disorders affecting the dental pulp. In Stewart RE, Prescott GH (eds): Oral Facial Genetics. St. Louis, CV Mosby, 1976, pp 288-312 26. Guckes AD, Brahim JS, McCarthy GR, et al: Using endosseous dental implants for patients with ectodermal dysplasia. J Am Dent Assoc 122:59-62, 1991 27. Henthom PS, Whyte MP: Missense mutations of the tissue-nonspecific alkaline pho- phatase gene in hypophosphatasia. Clin Chem 382501-2505,1992 28. Horwitz M, Benson KF, Person RE, et al: Mutations in EM,encoding neutrophil elastase, defiie a 21 day biological clock in cyclic haematopoiesis. Nat Genet 23433- 436, 1999 29. Jensen BL, Kreiborg S Development of the dentition in cleidocranial dysplasia. J Oral Pathol Med 1989-93, 1990 30. Kalk WWI, Batenburg RHK, Vissink A Dentin dysplasia type I five cases within one family. Oral Surg Oral Med Oral Pathol Oral Radio1 Endod 86:175-178, 1998 31. Kere J, Srivastava AK, Montonen 0, Zonana J, et al: X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 13:409416, 1996 32. King DL: Teethiig revisited. Pediatr Dent 16179-182, 1994 33. Lagerstrom M, Dahl N, Nakahori Y, et al: A deletion in the amelogenin gene (AMG) causes X-linked amelogenesis imperfecta (AIHI). Genomics 10971-975, 1991 34. Lagerstrom-Fermer M, Landegren U: Understanding enamel formation from mutations causing X-linked amelogenesis imperfecta. Connect Tissue Res 32:241-246, 1995 35. Linde A, Goldberg M: Dentinogenesis. Crit Rev Oral Biol Med 4679-728, 1993 36. Lundgren T, Westphal 0, Bolme P, et al: Retrospective study of children with hypophosphatasia with reference to dental changes. Scand J Dent Res 99357-364, 1991 37. Lunt RC, Law DB: A review of the chronology of calcification of deciduous teeth. J Am Dent Assoc 89S72-879, 1974 38. MacDougall M, Jeffords LG, Gu IT, et al: Genetic linkage of the dentinogenesis imperfecta type I11 locus to chromsome 4q. J Dent Res 781277-1282, 1999 39. Marks SC The basic and applied biology of tooth eruption. Connect Tissue Res 32149-157, 1995 40. Mass R, Bei M: The genetic control of early tooth development. Crit Rev Oral Biol Med 8:4-39, 1997 41. Monreal AW, Ferguson BM, Headon DJ, et al: Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22:366-369, 1999 42. Mundlos S, Otto F, Mundlos JB, et al: Mutations involving the transcription factor CBFAl cause cleidocranial dysplasia. Cell 89773-779, 1997 43. Murray J, Shaw L: Classification and prevalence of enamel opacities in the human deciduous and permanent dentitions. Arch Oral Biol24:7-13, 1979 NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 999

44. Nagle DL, Karim MA, Woolf EA, et al: Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 14:307-311, 1996 45. Online Mendelian Inheritance in Man [Online]. Baltimore, MD Center for Medical Genetics, Johns Hopkins University and National Center for Biotechnology Informa- tion, National Library of Medicine, 2000. Available: http: / / www.ncbi.nlm.nih.gov/ Omim [2000, May 41 46. Ozono K, Yamagata M, Michigami T, et al: Identification of novel missense mutation (Phe3IOLeu and Bly 439 Arg) in a neonatal case of hypophosphatasia. J Clin Endocrinol Metab 81:4458-4461, 1996 47. Pashley DH Dynamics of the pulpo-dentin complex. Crit Rev Oral Biol Med 7104 133, 1996 48. Peters E, Cohen M, Altini M: Rough hypoplastic amelogenesis imperfecta with follicu- lar hyperplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 7487-92, 1992 49. Price JA, Bowden D, Wright JT, et al: Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum Mol Genet 7563-569, 1998 50. Ranta H, Lukinmaa PL, Waltimo J: Heritable dentin defects: Nosology, pathology, and treatment. Am J Med Genet 45:193-200, 1993 51. Rasmussen P: Inherited primary failure of eruption in the primary dentition: Report of five cases. J Dent Child 65:43-47, 1997 52. Richards A, Likimani S, Baelum V, et al: Fluoride concentrations in unerupted fluorotic human enamel. Caries Res 26:328-332, 1992 53. Ripamonti U, Reddi AH Tissue engineering, morphogenesis, and regeneration of the periodontal tissues bv bone moruhogenetic proteins. Crit Rev Oral Biol Med I" 8:35&163, 1997 54. Robinson C, Fuchs P, Deutsch D, et al: Four chemically distinct stages in developing enamel from bovine incisor teeth. Caries Res 123-11, 1978 55. Robinson C, Weatherell JA, Hallsworth AS: Variations in the composition of dental enamel within thin ground sections. Caries Res 5:44-57, 1971 56. %ow WK Clinical diagnosis and management strategies of amelogenesis imperfecta variants. Pediatr Dent 15:384-393, 1993 57. Seow WK Enamel hypoplasia in the primary dentition: A review. Journal Dentistry Children 58:441-452, 1991 58. Sharpe PT: Homeobox genes and orofacial development. Connect Tissue Res 3217- 25, 1995 59. Shields ED, Bixler D, El-Kafrawy AM: A proposed classification for heritable human dentine defects with a description of a new entity. Arch Oral Biol 18:543-553, 1973 60. Simmer JP, Fincham AG: Molecular mechanisms of dental enamel formation. Crit Rev Oral Biol Med 6:84-108, 1995 61. Slavkin HC Molecular determinants of tooth development: A review. Crit Rev Oral Biol Med 1:l-16, 1990 62. Small 8, Murray J: Enamel opacities: Prevalence, classification and aetiological considerations. J Dent 6:33-42, 1978 63. Smith NH, Sydney NSW: A histologic study of cementum in a case of cleidocranial dysostosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 25:47@478, 1968 64. Solheim T Amount of secondary dentin as an indicator of age. Scand J Dent Res 100:193-1 99, 1992 65. Steigman S, Koyoumdjisky-Kaye E, Matrai Y: Relationship of submerged deciduous molars to root resportion and development of permanent successors. J Dent Res 53238-93, 1974 66. Thesleff I: Homeobox genes and growth factors in regulation of craniofacial and tooth morphogenesis. Acta Odontol Scand 53129-134, 1995 67. Thesleff I, Aberg T Tooth morphogenesis and differentiation of ameloblasts. In Chad- wick DJ, Cardew G (eds): Dental Enamel. Chichester, John Wiley & Sons, 1997, pp 3-17 68. Thesleff I, Nieminen P: Tooth morphogenesis and cell differentiation. Curr Opin Cell Biol 8:844-850, 1996 69. Toomes C, James J, Wood AJ, et a1 Loss-of-function mutations in the cathepsin C gene results in periodontal disease and palmoplantar keratosis. Nat Genet 23:421-424, 1999 70. Trimble LD, West RA, McNeill RW: Cleidocranial dysplasia: Comprehensive treatment of the dentofacial abnormalities. J Am Dent Assoc 105661-666, 1982 71. Tziafas D: Basic mechanisms of cytodifferentiation and dentinogenesis during dental pulp repair. J Dev Biol39:281-290, 1995 72. van der Linden FPGM. Theoretical and practical aspects of crowding in the human dentition. J Am Dent Assoc 89139-153, 1974 73. Vastardis H, Karimbux N, Guthua SW, et ak A human MSXZ homeodomain missense mutation causes selective tooth agenesis. Nat Genet 13:417421, 1996 74. Wake M, Hesketh K, Allen M. Parent beliefs about infant teething: A survey of Australian parents. J Paediatr Child Health 35:446449,1999 75. Weatherell J, Deutsch D, Robinson C, et al: Fluoride concentrations in developing enamel. Nature 256230-232, 1975 76. Wise GE The molecular biology of initiation of tooth eruption. J Dent Res 74303- 306, 1995 77. Witkop C, Sauk J: Heritable defects of enamel. In Stewart R, Prescott G (eds): Oral Facial Genetics. St. Louis, CV Mosby, 1976, pp 151-226 78. Witkop CJJ:Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited, problems in classification. J Oral Pathol 17547-553, 1989 79. Wright JT:Hereditary defects of enamel. In Robinson C, Kirkham J, Shore R (eds): Dental Enamel Formation to Destruction. Boca Raton, FL, CRC Press, 1995, pp 193-222 80. Wright JT, Deaton TC, Hall KI, et al: The mineral and protein content of enamel in amelogenesis imperfecta. Connect Tissue Res 31:247-252, 1995 81. Wright JT, Hall KI, Deaton TG, et al: Structural and compositional alteration of tooth enamel in hereditary epidermolysis bullosa. Connect Tissue Res 34:271-279, 1996 82. Wright JT, Kula K, Hall KI, et ak Analysis of the tricho-dento-osseous syndrome genotype and phenotype. Am J Med Genet 72197-204,1997 83. Yamamoto T, Hinridwn Kv: The development of cellular cementum in rat molars, with special reference to the fiber arrangement. Anat Embryo1 (Berl) 188537-549, 1993 84. Zurutuza L, Muller F, Gibrat JF, et al: Correlations of genotype and phenotype in hypophsphatasia. Hum Mol Genet 81039-1046, 1999

. 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]