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 devel-
opmental 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 abnor-
mal dental conditions and make recommendations for appropriate thera-
peutic 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 de-
velopmental 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 differ-

entiation 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 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 ectomesenchy-
ma1 cells engage in a complex series of interactions and signaling mecha-
nisms. Instructive biochemical messages regulating cell proliferation,
differentiation, and matrix production are transmitted between the ecto-
dermal and mesenchymal cells. These interactions result in the differenti-
ation 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 odon-
toblasts, 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 extracel-
lular 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 mo-
lecular control and mechanisms of normal tooth development are avail-
able.40.60,61.68
Teeth are multifunctional appendages participating in diverse func-
tions, 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 pro-
cess; 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 extracel-
lular 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 appear-
ance, 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 inter-

act with collagen to initiate and regulate mineralization.1° Dentin con-
tains 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 extracel-
lular 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.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, 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 tremen-
dous masticatory loads placed on the dentition. All three of these tissues
can regenerate, allowing traumatized teeth (e.g., tooth avulsion) or ab-
normalities (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 com-
pared with boys, and racial influences on tooth development and erup-

35

30

25

10

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

20

18

16

14

12
h
x
v
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 evalu-
ated 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 associ-
ated with a ~yndrome.~'

TOOTH ERUPTION PROBLEMS

One of the most common questions related to tooth eruption in-

volves 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 teeth-
ing 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 syn-
dromes. For example, teeth with developmental defects, such as odonto-
dysplasia (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 radio-
graphic 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, defec-
tive 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 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.
Table 1. CONDITIONS ASSOCIATED WITH PREMATURE PRIMARY TOOTH EXFOLIATION
Condition Oral Manlfestatlons
Hypophosphatasia Tooth loss as early as 1 year of age,
(OMM 146300 & 241500) minimal soft-tissue
inflammation, large dental pulp
chambers, variable enamel
hypoplasia
Papillon LeFevere Tooth loss beginning 2nd to 3rd
syndrome (OMM year of life, marked soft-tissue
245000) inflammation, generalized
alveolar bone loss
Cyclic neutropenia Severe erythematous gingivitis, can
(OMIM 162800) have rapid periodontal
breakdown and bone loss
Chediak Higashi syndrome Ulcerations of oral mucosa, severe
(Oh4JM 214500) gingivitis, glossitis, periodontal
breakdown and bone loss
Langerhans’ cell Ulcerative gingivitis, root exposure
histiocytosis and premature tooth mobility
(Histiocytosis X) typically starting with posterior
teeth
Prepubertal periodontitis Variable gingival inflammation
(OMIM 170650) (localized minor to generalized
severe), alveolar bone loss
typically starting with posterior
teeth
Datafrom references 27, 28,44, 45, 69, and 84.
Systemic Manifestations
Decreased alkaline phosphatase, severe
cases can have bone manifestations,
bowing of legs, short stature
Hyperkeratosis of palmar and plantar
surfaces
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
Cause
Autosomal dominant and recessive
forms, mutations in tissue
nonspecific alkaline phosphatase
gene
Autosomal recessive trait,
mutation in cathepsin gene
Autosomal dominant trait, defect
in neutrophil elastase
Autosomal recessive trait,
’ deficiency of natural killer
lymphocytes
Proliferation of Langerhans’ cells
(dendritic histiocytes),
immunologic dysregulation
Autosomal dominant trait,
leukocyte defect involving
chemotaxis or phagocytosis
 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 prema-
ture primary teeth so that optimal and appropriate treatment, if neces-
sary 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 environmen-
tal 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 com-
monly missing primary teeth.
Clinical observation of a delayed or abnormal eruption pattern,
followed by confirmation of the dental complement found on radiogra-
phy, establishes the diagnosis of congenitally missing teeth. Radio-
graphic examination can be accomplished with small intraoral radio-
graphs 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 his-
tory 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 variabil-
ity 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
d e ~ e l o p m e n t .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 identi-
fied,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 re-
quired 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 im-
plants. 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 develop-
ment 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 devel-
opmental 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 exces-
sively wear.23
Hereditary enamel defects may occur as a part of a generalized
condition or syndrome or a defect involving only Many heredi-
tary 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 fragil-
ity and blistering.81The molecular defects that cause junctional epider-
molysis bulosa involve genes that produce proteins essential to main-
taining the integrity between the dermis and epidermis and are
important in normal functioning of the ameloblasts.'
Amelogenesis imperfecta (AI) represents a group of hereditary con-
ditions (Table 2) that manifest enamel defects without evidence of gener-
alized or systemic These conditions are clinically and geneti-
cally 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 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 includ-
ing 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 miner-
alized commonly is treated effectively with bonding procedures to pro-
tect the teeth and enhance esthetics.56Teeth with severely hypomineral-
ized enamel typically are treated with restorations that cover the entire
clinical crown (i.e., stainless steel or resin crowns). Infants with condi-
tions 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
Hypoplastic Crown size varies from small to
(type 1) 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,
( W e 3) soft rough enamel surface,
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)
Enamel Thickness RadiographicAppearance Inheritance
Varies from thin and smooth Enamel has normal to slightly Autosomal dominant, recessive,
to normal thickness with reduced contrast, thin or X-linked
grooves, furrows, or pits
Normal thickness with enamel Enamel has contrast similar Autosomal dominant, recessive,
that often chips and abrades to dentin, unerupted or X-linked
easily aowns have normal
morphology
Normal thickness with enamel Enamel has contrast similar Autosomal dominant, recessive
that often chips and abrades to or < dentin, unerupted
easily crowns have normal
morphology
Reduced, hypomineralized Enamel contrast normal to Autosomal dominant
areas and pits slightly > dentin, large
pulp chambers
 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 he-
reditary 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 nu-
merous 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 chromo-
some 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 ( 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 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
Dentinogenesis imperfecta
type 1 (occurs in some
forms of osteogenesis
imperfecta) (OMIM
166240)
Dentinogenesis imperfecta
type 2 (OMIM 125490)
Dentinogenesis imperfeda
type 3 (OMIM 125500)
Dentin dysplasia type 1
(OMIM 125400)
Dentin dysplasia type 2
(OMIM 125420)
DI = dentinogenesis imperfecta.
Clinical Features
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
Radiographic Features Molecular Defect
Variable pulp obliteration, bulbous Mutations of collagen type 1
crowns, altered root genes (COLIAI and
morphology, increased risk for COLIlA.2)
dentigerous cysts
Pulp chamber obliteration that can Unknown, linked to 4921
begin before tooth eruption, lOCUS
abnormal crown and root
morphology
Large pulp chambers, very thin Unknown, linked to 4921
dentin, bulbous crowns and locus
diminished root structure
Pulp obliteration and short blunt Unknown, no locus
roots in both primary and identified
permanent dentitions
Pulp obliteration in primary Unknown, linked to 4921
dentition, abnormal pulp lotus
morphology and pulp stones in
permanent dentition
 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 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 fractur-
ing, 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 charac-
terized by pulpal obliteration and short, blunted roots.30The teeth typi-
cally 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 domi-
nant 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 develop-
mental pathways. For example, conditions with molecular defects that
influence mineralization, such as hypophosphatasia (i.e., alkaline phos-
phatase 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 be-
cause 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.
 NORMAL FORMATION AND DEVELOPMENT DEFECTS OF HUMAN DENTITION 997

SUMMARY

Oral health and systemic health are intimately related, and a thor-
ough 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.

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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: tim-wright@dentistry.unc.edu