Australian Dental Journal

The official journal of the Australian Dental Association

Australian Dental Journal 2014; 59:(1 Suppl): 1–12

doi: 10.1111/adj.12160

The dentition: the outcomes of morphogenesis leading to

variations of tooth number, size and shape
AH Brook,*† J Jernvall,‡ RN Smith,§ TE Hughes,* GC Townsend*
*School of Dentistry, The University of Adelaide, South Australia, Australia.
†Institute of Dentistry, Queen Mary University of London, United Kingdom.
‡Institute of Biotechnology, University of Helsinki, Finland.
§School of Dentistry, University of Liverpool, Liverpool, United Kingdom.

ABSTRACT
The clinical importance of variations of tooth number, size and shape is seen in many dental disciplines. Early diagnosis
allows optimal patient management and treatment planning, with intervention at an appropriate time to prevent compli-
cations in development and so reduce later treatment need. Understanding the process of dental morphogenesis and the
variations in outcomes is an important contribution to the multidisciplinary clinical team approach to treatment.
Tooth number, size and shape are determined during the initiation and morphogenetic stages of odontogenesis. The
molecular evidence of repetitive signalling throughout initiation and morphogenesis is reflected clinically in the associa-
tion of anomalies of number, size and shape. This association has been statistically modelled from epidemiological evi-
dence and confirmed by 2D and 3D measurement of human dental study casts. In individuals with hypodontia, the teeth
that are formed are smaller than the population mean and often show reduced and simplified shape. In contrast, in indi-
viduals with supernumerary teeth, the other teeth are larger than average and may show an enhanced shape.
Clinical observations in humans and studies of laboratory animals gave rise to the concept of morphogenetic fields
within the dentition. The findings, which can also be considered as reflecting gene expression territories, have been devel-
oped to incorporate field, clone and homeobox theories. The clinical distribution of developmental anomalies tends to
follow the pattern of these fields or territories.
Improved care for patients with these anomalies will come not only from utilizing a multidisciplinary clinical team but
also by expanding the approach to include other relevant scientific disciplines.
Keywords: Morphogenesis, supernumeraries, hypodontia, megadontia, microdontia.

phogenetic stages of dental development. The molecu-

INTRODUCTION
The clinical importance of variations of tooth number,
size and shape is seen in many dental disciplines, par-
ticularly paediatric dentistry, orthodontics, restorative
dentistry and oral surgery. Early diagnosis allows opti-
mal patient management and treatment planning, with
intervention at an appropriate time to prevent compli-
cations in development and so reduce later treatment
need. An example is the removal of a supernumerary
tooth which would otherwise interfere with the erup-
tion of an underlying permanent tooth. Understanding
the process of morphogenesis and the variations in the
outcomes is an important contribution to the multidis-
ciplinary clinical team approach to treatment.
Variation in outcome in a developmental process,
such as the formation of the dentition, enables adapta-
tion to different environments. Tooth number, size and
shape are determined during the initiation and mor-
© 2014 Australian Dental Association
lar evidence of repetitive signalling throughout
initiation and morphogenesis is reflected clinically in
the association of anomalies of number, size and shape.
This association has been statistically modelled from
clinical and epidemiological evidence and confirmed
by 2D and 3D measurement of human dental study
casts. In individuals with hypodontia, the teeth that are
present are smaller than the population mean and often
show reduced and simplified shape. In contrast, in indi-
viduals with supernumerary teeth, the other teeth are
larger than average and may show an enhanced shape.
In the sections that follow we set out key findings
concerning the early developmental stages of teeth,
including the concepts of morphogenetic fields and
gene expression territories. These are related to the
prevalence, clinical features and associations of
human clinical findings concerning the variations of
number, size and shape. These developmental and
1
AH Brook et al.
clinical aspects are then related and a unifying model
incorporating these aspects is developed. The aetiol-
ogy of these variations is also discussed. An overview
follows of further analytical and investigative
approaches that are advancing knowledge in the area
and the conclusion relates all the new developments
considered in this paper to the exciting future of clini-
cal dentistry. This understanding is important to
enhance the diagnosis and treatment planning for
these conditions which in their more severe presenta-
tions require extensive, long-term care from multidis-
ciplinary teams.
Developmental aspects – initiation and
morphogenesis
In the previous section of this special issue the devel-
opment of the dentition as a complex adaptive system
is considered1 and the molecular and cellular interac-
tions that regulate tooth initiation, morphogenesis and
differentiation are detailed.2 Under this heading, we
consider briefly those aspects of initiation and mor-
phogenesis that are particularly relevant to exploring
variations in tooth number, size and shape.
The teeth are initiated from the dental lamina. They
form from the epithelium and underlying mesen-
chyme, regulated by inductive interactions between
these tissues. The molecular interactions involve a ser-
ies of reiterative actions between specific signalling
molecules, receptors and transcription factors,3 a
number of which are summarized in Fig. 1. Figure 2
includes the distribution of these factors in the epithe-
lium and the mesenchyme, and incorporates addi-
tional factors.
In determining tooth regions within the dental lam-
ina, Fgf and Bmp influence the location of mesenchy-
mal expression of Pax9, a paired box transcription
factor.4 Pax9 is stimulated by Fgf8 and inhibited by
Bmp2 and Bmp4 influencing the site of tooth buds.5
However, Pitx2 and Shh are also present at this stage
and tooth germs still develop in the same locations in
Pax9 knockout mice.6 The Dlx homeobox genes are
also important in early patterning of the dental
Fig. 1 Diagram of some of the signalling molecules, receptors and tran-
scription factors identified for the initiation and morphogenesis of tooth
germ development. Data derived from Galluccio et al.3
2 © 2014 Australian Dental Association
field.6–9 In addition, the Bmp antagonist Sostdc1 and
the Wnt co-receptor Lrp 4 provide extracellular com-
munication between mesenchymal and epithelial cells
based on the integration of Wnt and Bmp pathways
during regulation of tooth number.10
The action of transcription factors is necessary for
initiation and progression beyond the initiation
stage.11 Signals from the epithelium regulate expres-
sion of the transcription factors Msx1, Pax9 and
Runx2. Msx1 is induced by Bmp and Fgf, while Pax9
and Runx2 are induced by Fgf.11 Bmp4 and Msx1
regulate one another in a positive feedback loop in
the dental mesenchyme.12,13 If any one of these tran-
scription factors is absent in knockout mice, tooth
development may be arrested at the bud stage14,15 but
different members of the same family, e.g. Msx1 and
Msx2, may compensate for each other when one is
inactivated. Msx 1 and Osr2 act antagonistically in
the patterning of the tooth morphogenetic field by
controlling the expression and spatial distribution of
mesenchymal odontogenic signals along the buccolin-
gual axis.15
In early tooth morphogenesis the critical role of
timing is evidenced in the interaction of Pax9, Msx1
and Bmp4. For example, during initiation, Pax9 is not
a transcriptional regulator of Msx1 at E12.5 days
in utero in the mouse. However, at E13.5 days, Pax9
begins to induce Msx1 expression and then Pax9 and
Msx1 proteins can induce Bmp4 expression.16 This
emphasizes the importance of timing and critical peri-
ods in the developmental process.
As tooth morphogenesis advances, the primary
and secondary enamel knots control the develop-
ment of crown dimensions and cusp formation.
While the enamel knot expresses growth stimulatory
signals, its cells remain non-proliferative.17 These
non-dividing cells stimulate proliferation of both the
surrounding cells and the mesenchymal dental papil-
lae.18 The repeated activation and inhibition of sig-
nalling is related to differential growth and folding
within the tooth germ and determines dimensions
and cusp patterns. The shape of the tooth crown
results during cap and bell stages when there is
rapid proliferation of cells related to folding of the
epithelium to form cusp shapes.6
In the enamel knots, apoptosis has been suggested
as a mechanism controlling the duration of signal-
ling17,19 and the expression of Bmp4 in the enamel
knot cells is associated with their apoptosis.6 Function
of the enamel knot as a signalling centre begins to be
affected by apoptosis in the late cap to early bell
stages.20,21 Cessation of activity in the enamel knot is
linked to the expression of the cyclin-dependent
kinase inhibitor p21 induced by Bmp4.
Having undergone apoptosis at the late cap stage,
the primary enamel knot is no longer detected at the
 The dentition: outcomes of morphogenesis

Fig. 2 Diagram of the progressive development of each tooth during initiation and morphogenesis stages, relating the macroscopic variations in number,
size and shape to the molecular and cellular/tissue stages at which they arose. Epithelium – yellow; Mesenchyme – blue. Cellular and molecular aspects
derived from http://bite-it.helsinki.fi/

bell stage. Secondary enamel knots develop at the sites Table 1. Prevalence of six variations of tooth number,
of cusps in teeth with multiple cusps. They produce size and shape found in an epidemiological study of
signalling molecules stimulating proliferation of 741 three to five-year-old (primary) and 1115 eleven
nearby cells, leading to folding of the inner enamel to fourteen-year-old (permanent) schoolchildren in
epithelium and subsequent multiple cusp formation. Slough, UK23
Apoptosis in the enamel knot plays an important role
Primary (%) Permanent (%)
in regulating tooth size and shape,22 and different
dimensions are affected differently. The major role of Supernumeraries 0.8 2.1
the enamel knots in determining tooth size and shape Hypodontia 0.3 4.4
Invaginated teeth 0.1 4.1
is considered further in the section on further analyti- Double teeth 1.6 0.1
cal and investigative approaches. Megadontia 0.0 1.1
Microdontia 0.5 2.5

Clinical aspects: prevalence, appearance and

associations
Prevalence
The prevalence of these variations shows a range of
values between the primary and permanent denti-
tions, between the genders and between ethnic
groups. The frequency in the primary dentition is
lower for all variations except for double teeth
(geminated and fused teeth). In an epidemiological
study in the UK, the prevalences in Table 1 were
© 2014 Australian Dental Association
found.23 Similar findings have been reported by other
workers.
While supernumerary teeth are uncommon in the
primary dentition (0.2–0.8%) with no significant
gender distribution yet described, they occur more
frequently in the permanent dentition (1.5–3.8%)
with males affected approximately twice as frequently
as females.24–26
Hypodontia, the congenital absence of one or more
teeth, is unusual in the primary dentition (0.1–1.5%)
3
AH Brook et al.
with no significant gender difference, most often
occurring in the maxillary lateral incisor region.23 In
the permanent dentition, excluding the third molars, a
prevalence between 3.5% and 7.0% has been found
for most populations with a gender ratio of the order
of males to females 1:1.5.24,27,28 Findings for
hypodontia of third molars range from 9% to 37%.
The lower second premolars are congenitally absent
in 3–4% of patients, the upper lateral incisors in
1–2.5% and the upper second premolars in 1–2%.3,27,29
Megadontia is rare in the primary dentition, but
has been reported in 1.1% of children in the perma-
nent dentition from an epidemiological study of 1115
school children aged 11–14 years23 (Table 1). The
permanent upper central incisors and lower second
premolars were the teeth particularly involved.
The prevalence of microdontia in the primary denti-
tion ranges from 0.2% to 0.5%,23 affecting both
upper and lower incisors. In the permanent dentition,
many studies have concentrated on the upper lateral
incisors, with findings of 0.5% to 3.1%. Females are
affected more often than males. In patients with
severe hypodontia, microdontia can affect all tooth
types.
When considering traits related to shape, as with
those of number and size, they exhibit a quasi-
continuous mode of variation or threshold dichot-
omy.1 Such traits do not form below a phenotypic
realization threshold, but vary continuously along a
range of expression once a threshold is exceeded.30
Carabelli cusp on molars is a good example of this
and the prevalence found in a particular study will
depend on the level at which the ‘diagnosis’ is set
along the continuum. A male bias in Carabelli trait
expression is expected given that sex differences are
greater in crown size than in intercuspal distances,31
and it has been found that males are more likely to
express Carabelli trait than females.32
Similarly invaginations are a quasi-continuous trait.
They are classified according to specific degrees of
severity of the trait.33 The range of prevalences
reported is from 1% to 5% with a male to female
ratio of 2:1.23 The teeth most commonly involved are
the upper lateral incisors but cases are recorded in all
tooth types. Important for treatment planning is that
invaginations are often bilaterally symmetrical.
‘Double teeth’ have been described under a variety
of titles – fusion, gemination, dichotomy, synodontia,
schizodontia, connation. Many of these terms imply a
particular mode of origin that at present cannot be
reliably determined and, therefore, a neutral term
such as double teeth is preferred.34 The prevalence of
double teeth in the primary dentition ranges from
0.5% to 4.5% and in the permanent dentition from
0.1% to 0.3%. The overall frequency of anomalies in
the permanent dentitions that follow on from primary
4 © 2014 Australian Dental Association
dentitions with double teeth is approximately 50%.
This is another important finding for clinicians.
Clinical features and associations
Supernumerary teeth exhibit a great variety of shapes
including conical, tuberculate, supplemental and
odontome like. They are found in every region of the
permanent dentition, most frequently in the maxillary
incisor region. Approximately 75% of permanent
supernumeraries fail to erupt and are diagnosed
radiographically, sometimes when they are impeding
the eruption of another tooth. Most commonly, only
one supernumerary is present in a dentition; less
frequently there are two supernumeraries, while three
or four supernumerary teeth are rare. Supernumeraries
in the primary dentition are followed by an anomaly in
the permanent dentition in approximately 50% of
cases.
When accurate measurements are made, supernu-
merary teeth are associated with an increase in the
tooth size of other teeth, with the differences greater
in the mesiodistal than buccolingual crown dimen-
sions.35–37 Using 2D image analysis it was shown that
when a supernumerary tooth was present in the upper
anterior region, there was a gradient effect from the
site of the supernumerary, with upper and lower
incisors showing the greatest difference in size from
controls. The teeth adjacent to supernumeraries may
exhibit changes in shape37 with the upper central
incisor being more affected than the upper lateral
incisor, supporting a local field effect38 (Fig. 3;
Table 2). Supernumerary teeth are found associated
with megadontia, double teeth and invaginations
(Fig. 4).
Hypodontia of primary teeth is followed in 75% of
patients by agenesis of permanent teeth in the same
region. In the permanent dentition, the congenitally
Fig. 3 Clinical photograph of a patient with an erupted midline supernu-
merary, showing the large size of the other teeth. The size and shape of
the maxillary central and lateral incisors and the mandibular lateral inci-
sors are particularly affected. This is shown in Table 2.
 The dentition: outcomes of morphogenesis

Table 2. Average mesiodistal crown dimensions of Table 3. Data from an epidemiological study of the
permanent teeth (in mm) in patients with supernu- permanent dentition in 1115 schoolchildren showing
meraries compared with control group37 the highly statistically significant association between
hypodontia and microdontia in this population
Supernumerary Control
sample24
Upper central 9.05** 8.68
Upper lateral 7.10* 6.84 Hypodontia No hypodontia Total
Upper canine 8.01* 7.84
Upper 2nd molar 10.41 10.15 Microdontia 9 19 28
Lower central 5.70 5.51 No microdontia 40 1047 1087
Lower lateral 6.16* 5.97 Total 49 1066 1115
Lower canine 7.06 6.89
Chi-squared value (with Yates’ correction) = 46.1, df = 1, p <
Lower 2nd molar 10.55 10.40
0.001.
*Significant differences in the mean values at p < 0.05.
**Significant differences in the mean values at p < 0.01.

Fig. 5 A patient with hypodontia of the upper left lateral incisor and
microdontia of the upper right lateral incisor. The upper central incisors
also show a reduction in shape from the average.

Fig. 4 A patient with a supernumerary upper left lateral incisor, a mega-

dont/double tooth upper right central incisor and generalized large tooth
size.

absent teeth are most frequently those at the end of

the morphogenetic fields.39 The number of missing
teeth varies from one to the complete dentition,
referred to as anodontia. The frequency with which
these different degrees are found is compatible with a
tail of the distribution in a quasi-continuous model,
i.e. one or two teeth are missing commonly, while
very severe hypodontia only occurs rarely.39 There is
substantial evidence that hypodontia is associated
with significantly smaller than average tooth size
throughout the dentition (Table 3).24,28,35,36,40 The
more severe the hypodontia, the greater the reduction
in tooth size.40 Associated with hypodontia and the
small tooth size are changes in shape. Again, the
greater the number of missing teeth and the smaller
the formed teeth, the more evident is the different
shape with tapering crowns from the incisal/occlusal
surfaces towards the cemento-enamel junction, more
rounded contours and reduction in cusp number in
posterior teeth (Figs. 5 and 6). These clinical findings
have been confirmed by 2D and 3D analysis of dental
study models.35,40,41
© 2014 Australian Dental Association
Fig. 6 A patient with severe hypodontia and marked tapering of the
lower incisors and canines into a conical shape.
Relating developmental and clinical aspects
The outcome of the developmental process is a denti-
tion, seen as a phenotype. Valuable findings have
emerged from animal as well as human studies in
relating phenotype to genotype. Therefore, where
relevant, the findings from animal models are consid-
ered alongside those from human studies, while
acknowledging the limitations of extrapolating from
experiments on animals.
The human clinical phenotype reflects the progres-
sive nature of the developmental process, with differ-
ent teeth of a given tooth type forming and maturing
at different times. The time gradient tends to follow
5
AH Brook et al.
the spatial gradient from mesial to distal in each tooth
region. Therefore, within a given tooth type, there
will be teeth at different developmental stages. Simi-
larly, between different tooth types, there will be
some overlap in development, but also different devel-
opmental stages at a given point of time. The com-
plexity of these time and space parameters of dental
development is reflected in the complexity of the
clinical phenotypes of dental anomalies of number,
size, form and structure.
These phenotypes need to be considered in the
order of the stage of the developmental process at
which they have occurred. In keeping with the multi-
layered nature of the process, the clinical outcome
relates to evidence of the tissue changes and to the
molecular genetic/epigenetic/environmental interac-
tions.1 In addition, the multidimensional outcomes for
each tooth reflect more than the influences of the
molecular factors that would be considered if each
tooth developed in isolation. The interactions of the
developing tooth germs for nutrition and space
reflected in their position in morphogenetic fields also
affect the clinical phenotype.1,24,32
A unifying model for the developmental and clinical
findings
The molecular evidence of repetitive signalling
throughout initiation and morphogenesis is reflected
in the association of anomalies of number, size and
shape seen together clinically in the same dentition
(Figs. 3–6). These associations have been validated by
laboratory measurement of human dental study mod-
els.36–38,42
A model has been previously published which incor-
porated the clinical and epidemiological findings for
variation in tooth number and size.24 Here the model
is developed further to include tooth shape in the light
of molecular evidence and further laboratory studies
of clinical material (Fig. 7). This model is based on
the underlying continuous distribution of tooth size
and shape, and the quasi-continuous nature of the
variations in tooth number. The prevalence of the dif-
ferent degrees of severity of supernumeraries and hyp-
odontia is compatible with a quasi-continuous
distribution, as are the variations in tooth size and
shape associated with these variations in number. It
incorporates the gender differences in tooth size,
reviewed in the clinical aspects section above, by
having separate curves for males and females. With
the thresholds added on the curves it also accounts
for the higher prevalences of hypodontia and micr-
odontia in females and the higher prevalences of
megadontia and supernumeraries in males. The model
also includes the associations between anomalies. At
one end of the distribution are hypodontia and small
6 © 2014 Australian Dental Association
Fig. 7 A unifying aetiological model which incorporates the clinical and
epidemiological findings for variations in tooth size, shape and number.
and tapering teeth and at the other are supernumerar-
ies and large teeth, with some variations in shape.
The shading between thresholds indicates that as teeth
are nearer to the extremes of size, their shape tends
also to change to a greater degree. This accords with
the findings from animal models of cusp development
and human studies of Carabelli trait and molar
cusps.30,31,43,44
The reiterative nature of the molecular interactions
between factors in the epithelium and mesenchyme
throughout initiation and morphogenesis is also in
agreement with the model. Many of the same genes
are active at different stages throughout initiation and
morphogenesis (Fig. 7). Thus, for tooth number, size
and shape, as well as in patients with a PAX9 muta-
tion, there is hypodontia, microdontia and tapering,
rounded tooth shape.35
The aetiology of variations in number, size and shape
The aetiology of these variations within the popula-
tion is multifactorial with evidence of chromosomal,
polygenic, single gene and major environmental influ-
ences in this complex aetiology; different factors may
exert a major influence in different individuals.24
Mutations in MSX1, PAX9, AXIN2, EDA, EDAR
and WNT10A have been identified in families with
non-syndromic hypodontia.2,45–48 Msx1 and Pax9 are
co-expressed in dental mesenchyme at the bud and
cap stages. Many human mutations of PAX9 have
been reported in hypodontia families, of which a
number are missense mutations.3 The DNA binding
and transcriptional ability of Pax9 proteins are
affected differently in each different mutation.49 Mis-
sense mutations of Pax9 affecting the paired domain
do not disrupt the physical interaction with Msx1
while, in the G51S mutation, synergistic cooperation
with Msx1 is decreased or abolished in Bmp4/Lucifer-
ase assays. Functional regulation of Pax9 by homeo-
box proteins is necessary for early tooth development.
In the G51S mutation, the phenotype presents as
moderate to severe hypodontia, yet there is intact
 The dentition: outcomes of morphogenesis

DNA binding and increased transcriptional activation

but lack of responsiveness to modulation by Msx1. In
general, the more severe phenotypes, with more con-
genitally absent teeth, relate to haploinsufficiency of
Pax9 while those with mild or moderate hypodontia
are associated with hypomorphic alleles.49 Differences
in the patterns of hypodontia have been seen, with
those having mutations of MSX1 particularly showing
congenitally absent anterior teeth and those with
PAX9 mutations predominantly affecting posterior
teeth. Mutations in MSX1 are also associated with
orofacial clefting, with and without hypodontia, and
with Witkop syndrome.50–52
Mutations in WNT10A were found in 56% of
patients in a study of isolated hypodontia.53 This is in
accordance with the major role of Wnt in the initia-
tion of tooth formation shown in transgenic mice.54,55
Inhibition of Wnt signalling can cause hypodontia and
over-expression can give rise to supernumerary teeth.
Similarly, inhibition of the EDA pathway leads to
hypodontia while stimulation of EOA expression in
mice can induce the formation of extra teeth.56,57
The frequency of congenital absence of individual
teeth also relates to their position in the different mor-
phogenetic fields (Fig. 8).32 In the permanent denti-
tion, the third molars, second premolars, upper lateral
incisors and lower central incisors are the most fre-
quently absent teeth.39 These findings come from popu-
lation and multiple clinical case studies. They probably
reflect a general influence in hypodontia patients to
reduced tooth tissue formation that results in lesser size
and morphological changes in the earlier forming teeth
in a field, i.e. affecting morphogenesis, while the later Fig. 8 A diagram of the frequency of congenitally missing teeth at each
site in a group of patients.39 The arrows external to the dental arches
forming teeth at the end of the field have earlier effects indicate the direction of the morphogenetic fields. The later forming teeth
on development, i.e. affecting initiation, and so fail to in each field are more frequently missing than the first formed teeth.
progress beyond the bud stage. While this is the general
pattern in a population, in some individuals and fami- aetiology in an individual or family, a number of
lies with hypodontia the pattern is different. In some, factors may also be involved. The effect on tooth size
the congenitally absent teeth may be concentrated in in individuals having hypodontia is seen throughout
the anterior region, while in others it is principally the the dentition. All teeth that develop in hypodontia
molar region which is affected. subjects tend to be smaller than those in control
Regional influences within the dentition are shown groups when measured by classical manual techniques
in a study of the distribution of congenitally absent and by image analysis.36,40 This is also in accordance
teeth in 200 individuals with hypodontia. If one third with the aetiological model proposed (Fig. 7).24,42
molar is congenitally absent, the frequency of other An additional finding is that different dimensions of
third molars also being congenitally absent is much individual teeth, e.g. mesiodistal and buccolingual
greater than expected by chance.39 Regional effects on crown diameters, are influenced to different degrees in
tooth size were also seen in four ethnic groups; while hypodontia subjects compared to controls. Thus, in
Chinese had the largest teeth overall, this effect was the family with a mutation of PAX9, the mesiodistal
seen predominantly in the anterior regions, while dimensions of the formed teeth were smaller to a
European and North American white Caucasians had different degree than the buccolingual dimensions.35
larger molars than Chinese.58 A further finding in this PAX9 family was that
Sometimes a mutation in a major single gene, e.g. different teeth were affected to different extents. The
PAX9, shows different degrees of hypodontia, micr- reduction in size was greatest in permanent canines in
odontia and shape change in different members of the the hypodontia family members with PAX9 muta-
same family (Table 5).35 Thus, when considering the tion.35
© 2014 Australian Dental Association 7
AH Brook et al.

Table 4. The distribution of congenitally missing teeth in a family with a mutation of PAX9.35 The dark stars show
the teeth missing. This illustrates the variation of the number of missing teeth in family members having the same
mutation of PAX9. Affected family member II:3 is the third sibling in the second generation (II) while III:6 is the
sixth sibling in the third generation

right quadrants left quadrants

molars premolars can incisors incisors can premolars molars
Affected family 3 2 1 2 1 1 2 1 1 2 1 1 2 1 2 3
members 3 2 1 2 1 1 2 1 1 2 1 1 2 1 2 3

II:3

II:4

III:2

III:5

III:6

IV:1

Table 5. The mean mesiodistal dental crown dimen- In patients with supernumerary teeth, different
sions (in mm) of patients with varying degrees of hyp- effects on the whole dentition are observed compared
odontia, severe (6+ teeth missing), moderate (3–5), with those seen in patients with hypodontia. A series
mild (1–2), and their unaffected relatives. These are of population studies show males more frequently
compared to a control group. The table shows have supernumerary teeth than females, as well as lar-
decreasing tooth size as there is increasing hypodon- ger teeth than females.24 In patients with supernumer-
tia. A finding of major importance is that the relatives ary teeth, the other teeth in the dentition tend to be
with a full complement of teeth had highly statisti- larger than those of controls.34,37 This difference is
cally significant smaller teeth than controls40 seen in the whole dentition, but there is a gradient
effect on the degree of difference. Thus, when the
Severe Moderate Mild Unaffected Control
relative supernumerary tooth is in the upper central incisor
region, the incisor teeth in the maxilla and mandible
Upper 7.80*** 8.24*** 8.43*** 8.30*** 9.26
central
are the teeth that show the greatest difference in size.
Upper 1st 6.43*** 6.44*** 6.72*** 6.81*** 7.37 Image analysis measurements of the maxillary central
premolar incisors adjacent to the supernumerary show an effect
Lower 1st 6.63** 6.72** 6.82** 7.11** 7.56
premolar
on shape, as well as size, with the teeth having a more
barrel-shaped outline from the labial view than con-
*** p < 0.001 ** p < 0.01. trols.
From studies of the mouse dentition it is suggested
that mutations affecting Fgf, Eda, Bmp, Runx2, Apc,
Supporting evidence for the influence of multiple Shh and b-catenin are related to the occurrence of
factors in hypodontia comes from studies of families supernumerary teeth.10,57,59–62 Activation of b-catenin
with severe hypodontia. In families with a member or ablation of Apc, an inhibitor of Wnt signalling, in
who had six or more missing permanent teeth, exclud- embryonic mouse oral epithelium results in supernu-
ing the third molars, those family members with com- merary teeth. The oral epithelium in adult mice
plete dentitions had teeth that were statistically remains responsive to b-catenin gain-of-function or
significantly smaller than controls (Table 4).36,40 APC loss-of-function and is still able to form new
8 © 2014 Australian Dental Association

Table 6. The prevalence of hypodontia, microdontia
and supernumerary teeth in samples of Romano-
Britons and modern Britons of European ancestry.69
The differences are reflected in the separate curves
for each population in Fig. 9
Romano-British Modern British
(%)
Hypodontia (3rd molars) 39.0
Hypodontia (except 3rd 13.0
molars)
Microdontia (except 3rd 6.4
molars)
Supernumeraries 1.2
teeth.59 In the mouse, supernumerary teeth may
develop from vestigial tooth buds that are present in
the incisor region and in the diastema between the inci-
sors and molars. These vestigial buds usually undergo
apoptosis, but if degeneration by apoptosis does not
occur a supernumerary tooth or element is formed.63
Supernumerary incisor and molar teeth, as well as
fused and large molar teeth, develop in Lrp4 and
Sostdc1 deficient mice. Mice lacking the transcription
factor Osr2, develop supernumerary teeth lingual to
their normal molar teeth.15 Initiation of these supernu-
merary teeth is related to aberrant thickening of the
oral epithelium lingual to the first molar tooth buds.15
Bmp4 induces expression of Sostdc1 whose inactiva-
tion was associated with fused first and second molars
as well as supernumerary teeth in mice.60,64
Disruption of the antagonistic balance between
Msx1 and Osr2 may underlie the hypodontia noted in
Msx1 null mice, the supernumerary teeth in Osr2 defi-
cient mice, and the hypodontia observed in humans
with Msx1 mutations.15
Other important factors from mouse studies include
the effects of up-regulation and down-regulation of
specific genes and the results at a histological and clin-
ical level on tooth number, size and shape. Changes
in the regulation of Shh are related to holoprosen-
cephaly, hypodontia and supernumerary teeth.63
In the absence of Pax9, the mesenchymal expression
of Msx1, Lef1 and Bmp4 is down-regulated and tooth
Fig. 10 A diagram of the major influences during the long development process from genotype to phenotype of the tooth. Changes in one or more of
these major factors leads to increased variation.
© 2014 Australian Dental Association
The dentition: outcomes of morphogenesis
(%)
12.7
4.4
2.5
Fig. 9 The unifying aetiological model of Fig. 7 developed further to
2.1 incorporate data for Romano-Britons.69 The solid lines represent modern
Britons of European ancestry and the dotted lines Romano-Britons. It is
suggested that the curves are shifted to the left in the Romano-Britons
because of major environmental insults throughout the period of dental
development.
development is arrested at the bud stage, resulting in
hypodontia.4 Loss of Eda leads to a smaller primary
enamel knot and decreased expression of signalling
molecules, with the phenotypic outcome of smaller
teeth with reduced cusp morphology and altered out-
line shape.65 Mouse studies also suggest Sostdc1 plays
a major role in determining tooth size and shape.
Sostdc1, a Bmp and Wnt antagonist, integrates pro-
apoptotic and pro-survival signals from the enamel
knot and determines the area of the Bmp signal.64
Mice deficient in Sostdc1 show an increased area of
Shh expression and large primary enamel knots, lead-
ing to large molars with a mesiodistal crest connecting
cusps and supernumerary teeth.60 Supernumerary
teeth and increased molar size and complexity are also
seen with expression of an Edar receptor promoted by
K14.66 In EVC mutant mice the morphology of
molars was markedly affected with changes in the
relative size and shape of first and second molars.67
The relationship between development and anoma-
lies of number, size and shape of teeth in human stud-
ies reflects the reiterative patterns seen in mouse
models of signalling of the ectodermal–mesenchymal
interactions during tooth germ initiation and morpho-
genesis. Epigenetic events relating to the spatial
arrangement of cells and the timing of the interactive
signalling may explain differences in tooth number,
9
AH Brook et al.
size and shape, as well as dental asymmetry in mono-
zygotic twins.68
Similar findings for tooth number, size and shape in
modern human populations were gained in studies of
Romano-Britons. Females had smaller teeth than males
and had a higher frequency of hypodontia and micr-
odontia; males had larger teeth and a higher frequency
of supernumerary teeth and megadontia (Table 6).69,70
The teeth of the Romano-Britons were smaller than
modern Britons, possibly reflecting major environmen-
tal effects such as poor nutrition, ingestion of high
levels of toxin (lead) and recurrent infections.69 These
findings are compatible with the multifactorial model
and provide an example of the interaction of genetic
and environmental factors. The curves of the Romano-
Britons are incorporated in Fig. 9 as dotted lines. They
are similar curves to modern Britons of European
ancestry, but the distributions are moved to the left,
probably by these major environmental insults present
throughout development.
Figure 10 is a diagram incorporating the different
factors, genetic/epigenetic/environmental, that influence
the special and temporal development of the tooth and
result in the erupted tooth, the final phenotype.
Further analytical and investigative approaches
A gene network model has been formulated to reflect
the development of mammalian teeth from the cap stage
to the early bell stage.43 The resultant crown shapes
approximate to the morphology found in the mammals
studied and the intermediate stages correspond to the
correct temporal spacing in the stages and known
expressions of the genes incorporated in the model.
This model predicts co-variation among such vari-
ables as tooth size, intercuspal distance and cusp size.
A key factor in the model is the signalling activity of
the enamel knots. In a study of Carabelli cusp expres-
sion it was found that this model’s predictions were
supported both across and within individuals. By com-
paring right-left pairs of upper first molars on dental
study casts of orthodontic patients, it was shown that
small variations in developmental timing or in the
spacing of enamel knots could affect cusp pattern.30
A computational model of tooth development sum-
marizes mathematically the basic genetic and cellular
interactions that regulate tooth shape development.71
This developmental model produces a phenotype with
3D morphology from the parameters of each individ-
ual. The model has reproduced the morphological
variation seen in natural populations and creates a
genotype-phenotype map of how development leads
to adult morphology and its variation.71
Another approach to the study of shape variation is
geometric morphometric analysis.72 It is geometric in
that it provides a set of rules for analysing data of
10
positions, distances and angles in 3D representation of
objects. The morphometric component is the mathe-
matical quantification of the object.73–75 Shape is the
key concept of geometric morphometric analysis; it is
defined as all the geometric information that remains
when location, scale and rotational effects are filtered
out from an object.76 Geometric morphometric analy-
sis attempts to measure subtle differences in shape,
e.g. in premolars and molars, and so examine differ-
ent contributions from aetiological factors.41,77–81 In
examining objects, an important issue is landmark
reliability.82 Geometric morphometric analysis has
been applied to early Pleistocene hominin teeth from
China compared with samples from Africa, Asia, Eur-
ope and with modern humans to investigate possible
evolutionary relationships.83
An additional approach to identifying further
genetic mutations involved in variations of number,
size and shape is whole exome sequencing.84 The
approach has been used in other craniofacial develop-
mental conditions such as craniosynotosis.85
CONCLUSIONS
The variations considered in this paper are seen on a
daily basis in clinical practice. Early diagnosis allows
optimal patient management and treatment planning.
In many instances, this will be by a multidisciplinary
team. Intervention at appropriate times can sometimes
reduce complications and the amount and complexity
of future treatment. Understanding the process of
development and the aetiological factors is also
important clinically when discussing the condition,
including aetiology, and the possible treatment with
patients and their family. Advancing care for patients
with these anomalies will come from both multidisci-
plinary team care and from research in a range of sci-
entific disciplines. Future clinical practice will involve
personalized, precision care, based on an individual’s
genetic profile.
DISCLOSURE
The authors have no conflicts of interest to declare.
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Address for correspondence:
Professor Alan Brook
School of Dentistry
The University of Adelaide
Adelaide SA 5005
Email: alan.brook@adelaide.edu.au
© 2014 Australian Dental Association