J Oral Pathol Med (2009) 38: 1–17

doi: 10.1111/j.1600-0714.2008.00699.x ª 2008 The Authors. Journal compilation ª 2008 Blackwell Munksgaard Æ All rights reserved

www.blackwellmunksgaard.com/jopm

REVIEW ARTICLE

Dental agenesis: genetic and clinical perspectives

P. J. De Coster1, L. A. Marks1, L. C. Martens1, A. Huysseune2
1
Department of Paediatric Dentistry and Special Care, Paecamed Research, Ghent University; 2Department of Biology, Ghent
University, Ghent, Belgium

Dental agenesis is the most common developmental Keywords: Dental agenesis; growth factors; hypodontia;
anomaly in humans and is frequently associated with patterning defects; signaling molecules
several other oral abnormalities. Whereas the incidence
of missing teeth may vary considerably depending on
dentition, gender, and demographic or geographic pro-
files, distinct patterns of agenesis have been detected Introduction: patterns of dental agenesis in
in the permanent dentition. These frequently involve humans
the last teeth of a class to develop (I2, P2, M3)
Hypodontia (congenital lack of teeth or dental agenesis)
suggesting a possible link with evolutionary trends.
is the most common developmental anomaly in man,
Hypodontia can either occur as an isolated condition
often representing a significant clinical problem (1–3). It
(non-syndromic hypodontia) involving one (80% of
is frequently associated with other oral anomalies, such
cases), a few (less than 10%) or many teeth (less than
as cleft lip and ⁄ or palate (4–9), microdontia, reduction
1%), or can be associated with a systemic condition or
in tooth size and ⁄ or malformation of other teeth
syndrome (syndromic hypodontia), essentially reflecting
(10–16), short root anomaly (17, 18), impaction, delayed
the genetically and phenotypically heterogeneity of the
formation and ⁄ or delayed eruption of other teeth
condition. Based on our present knowledge of genes and
(19–24), crowding (25–27) and ⁄ or malposition of other
transcription factors that are involved in tooth devel-
teeth (28–30), maxillary canine ⁄ first premolar transposi-
opment, it is assumed that different phenotypic forms
tion (31, 32), taurodontism (20, 24, 33, 34), enamel
are caused by different genes involving different inter-
hypoplasia (12), and altered craniofacial growth (35, 36).
acting molecular pathways, providing an explanation not
Clinicians often claim that dental agenesis has
only for the wide variety in agenesis patterns but also
increased during recent decades (37, 38). There is,
for associations of dental agenesis with other oral
however, no evidence as to whether this is an evolu-
anomalies. At present, the list of genes involved in
tionary trend or an observation as a result of more
human non-syndromic hypodontia includes not only
advanced screening and diagnosis of oral anomalies.
those encoding a signaling molecule (TGFA) and tran-
The incidence of missing permanent teeth has been
scription factors (MSX1 and PAX9) that play critical roles
reported to vary from 2.6% to 11.3% depending on
during early craniofacial development, but also genes
demographic and geographic profiles, excluding third
coding for a protein involved in canonical Wnt signaling
molars, which are absent in 9–30% of the population
(AXIN2), and a transmembrane receptor of fibroblast
(39–51). In the permanent dentition, the mandibular
growth factors (FGFR1). Our objective was to review the
second premolars are most often missing, and maxillary
current literature on the molecular mechanisms that
lateral incisors are involved almost equally (39, 52, 53).
are responsible for selective dental agenesis in humans
The incidence of missing teeth in the primary dentition is
and to present a detailed overview of syndromes with
considerably lower, i.e. 0.4–0.9% in the European (54–
hypodontia and their causative genes. These new per-
57) and Brazilian population (58), and about 2.4% in
spectives and future challenges in the field of identifi-
the Japanese population (59, 60). Agenesis of one
cation of possible candidate genes involved in dental
primary tooth, most commonly a lateral incisor (43,
agenesis are discussed.
59, 61), has been found in 60% of the cases. Absence of
J Oral Pathol Med (2009) 38: 1–17
more than two primary teeth was found in 8% of
children with hypodontia in the primary dentition (61,
62). Distinct patterns of agenesis have been detected in
Correspondence: Prof. Dr. Peter J. De Coster, Dental School – Poli the permanent dentition (i.e. unilateral agenesis more
8, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
Tel: +32 9 3329461, Fax: +32 9 3323851,
common than bilateral; third molars and second pre-
E-mail: peter.decoster@ugent.be molars commonly missing in all quadrants and ⁄ or
Accepted for publication May 18, 2008 combinations of these two tooth types and the incisors)
 Dental agenesis
De Coster et al.
2
(63–67), whereas there is controversy on a possible
relationship between agenesis of a primary tooth and the
presence ⁄ absence of its permanent successor (26, 68, 69).
Prevalence rates of agenesis in both dentitions are
significantly higher in females compared than in males
(3:2 respectively) (37, 48, 53, 64, 66), but gender
apparently does not affect dental agenesis patterns (65,
66).
Although dental agenesis is occasionally caused by
environmental factors, such as infection (e.g. rubella)
(70), different kinds of trauma in the apical area of the
dentoalveolar processes (fractures, extraction of
temporary tooth) (71), chemical substances or drugs
(e.g. thalidomide, chemotherapy) (72), radiation
therapy (73, 74), or disturbances in jaw innervation
(75, 76), in a majority of cases, hypodontia has genetic
causes. When trying to elucidate the causal factors
underlying agenesis, it is necessary to analyse carefully
the pattern of hypodontia. First, the developmental
level at which defective tooth development occurred
can be very informative. Failure of initiation
(formation of an epithelial thickening) is likely to be
caused by a defect other than the one responsible for
arrest of development at cap or bell stage, where
structural genes may become more involved (see the
following section for a discussion on the molecular
networks involved in early tooth development). Unfor-
tunately, as uncalcified tooth germs cannot be
visualized in patients, such information is rare. Second,
agenesis affecting primary teeth is likely to be caused
by factors other than those affecting successor teeth.
Although the genetic networks responsible for the
formation of primary teeth have been assumed not to
be fundamentally different from those responsible for
replacement teeth (77), several lines of evidence suggest
that this is an oversimplification. This is exemplified by
studies revealing differential involvement of genes in
primary vs. permanent teeth (78), by the observation
that in some species, primary teeth form, but fail to be
replaced (79), and by recent findings indicating that
some genes act specifically in tooth cycling (80). These
studies suggest that the two members of the tooth
family (primary tooth and its permanent successor)
function rather as separate modules (81). Third, whilst
differences between upper and lower jaw quadrants can
be expected in view of the finding that, at least in mice,
the development of upper and lower teeth is under the
control of different genetic programms (82–84, and see
below), unilateral hypodontia is more likely to be
explained by extrinsic factors. Why the prevalence of
agenesis, unlike its pattern, differs between genders is
still puzzling. Part of the answer may, nevertheless, lie
in the X-linkage of causative genes, and males lacking
the protection of a second X chromosome making
them more sensitive to early lethality (as in the examples
of the disorders OFD1 and IP, see below). Finally,
perhaps the most illuminating in terms of uncovering
the etiology of agenesis is which teeth within the three
classes of teeth (incisors, canines, molars) are missing
and whether this is coincident with other develop-
mental defects.
J Oral Pathol Med
Essentially two types of hypodontia are recognized in
humans: the absence of one (circa 80%) (39, 85), a few
(less than 10%) or many teeth (less than 1%) (45, 71, 86)
can occur as an isolated condition (non-syndromic
hypodontia) and may essentially be considered a reflec-
tion of normal variation (26). Alternatively, hypodontia
can be associated with a systemic condition or with one
of the large number of clinically recognized syndromes
(syndromic hypodontia). A discussion of these two
groups will be the main focus of this review. Yet, before
embarking on these two types, we briefly recall the
evolutionary origin of the human dentition in an attempt
to explain some of the patterns encountered.
Evolution of mammalian dental patterning
The heterodont mammalian dentition (original formula
I3-C1-P4-M3 ⁄ I3-C1-P4-M3) evolved from the homodont
dentition in reptilian ancestors essentially through a
reduction in tooth numbers, the elaboration of molar
cusp patterns and a restriction of the number of tooth
replacement cycles to two. Further reductions in tooth
number, ranging from the loss of a few teeth to the loss
of entire tooth classes, characterized different mamma-
lian lineages and mirrored dietary specializations. Often,
evolutionary reductions tend to affect the last forming
elements in a series (as, e.g., in evolutionary digit loss,
87), and this appears also to be the case for the dentition
in placental mammals. Deciduous molars are initiated
from the dental determinant (88) in a mesial direction,
whilst the permanent molars develop in a distal direction
(89), thus easily accounting for the evolutionary loss of
the original P1 and P2. Incisors were originally initiated
in both directions starting from the incisor determinant
but the mesial expansion was lost, explaining the loss of
the original I1 (89). In humans, the buds of the ten
deciduous teeth develop sequentially within a short time
span (6th-8th week in utero) (90–93), and although
detailed data are lacking, the order of initiation is
probably similar to that in other placental animals, i.e.
incisor initiation progressing distally, premolar initia-
tion progressing mesially. In contrast, their successors
develop over a much larger time span, starting with the
permanent central incisor at the 20th week in utero and
ending with the second premolar at 10 months after
birth, thus apparently reversing the order of premolar
development. The three most frequent cases of agenesis
concern permanent teeth (third molars, mandibular
second premolars and maxillary lateral incisors) (64–
66). Their arrested development can perhaps simply be
explained by the fact that they are the last teeth of a
class to develop. Spatial constraints caused by the
development of the canine could explain the prevalence
of maxillary over mandibular lateral incisor agenesis
given that the maxillary canine calcifies before the
mandibular canine. Similarly, the formation of enamel
and dentin starts later in the mandibular than in the
maxillary second premolar; here, development of the
first mandibular molar could constrain development of
the last premolar. If, on the other hand, these teeth are
lacking because their deciduous precursors have failed

to form, the reason no doubt has to be sought in the
genetic networks that regulate primary tooth formation.
During the past decades, teeth have become a major
model in the field of evolutionary developmental biology
that connects the molecular strategies that control organ
development and morphological evolution (94–96).
Teeth are serially homologous structures, which allow
the localization and quantification of the effects of
specific gene mutations. Furthermore, it is also possible
to determine the phase of odontogenesis affected by
these conditions. These features make anomalies involv-
ing teeth an important system to provide a link between
development and evolutionary genetics (97). Experi-
mental studies have linked the spatial and temporal
patterns of the expression of regulatory genes during
development to variations in morphology between
species (98, 99). It has also been shown that mutations
in coding sequences of these master genes may have
played a role in the generation of morphological diversity
and polymorphic genetic loci have been directly associ-
ated with morphological variation (100). On the other
hand, it has become clear that the changes in dental
patterning that occurred during the evolution of pla-
cental mammals were not the result of plain gene
ablations (101, 102). Additionally, deleterious alleles do
not pass natural selection and are kept at low frequen-
cies within a population (103).
Throughout evolution a series of mechanisms have
been conserved that are responsible for patterning
different regions of the dentition along a proximal-distal
axis. It is clear from studies of gene expression that these
events occur at the molecular level within the ectome-
senchyme of the mandibular arch prior to any morpho-
logical evidence of the initiation of tooth development.
Analysis of knockout mice phenotypes indicates that
segmentation of dental fields occurs by the combinato-
rial effect of a set of genes acting on specific subregions
within the field (104, 105). These molecular segmenta-
tions result in the formation of the molar, premolar,
canine, and incisor fields (96). The genetic segmentation
of the dental field provides a molecular mechanism
to understand the loss of entire tooth families that
occurred during the evolution of some mammalian
lineages. For instance, GLI2) ⁄ )GLI3+ ⁄ ) mutant mice
have a phenotype similar to the Cervidae, Girafidae,
Antilocapridae, and Bovidae that lack all upper incisors
(104). The loss of canine and premolar teeth in rodents
has been linked to a weak expression of PAX9 gene
(106). Previous studies showed that some genes have a
strong influence on tooth development (MSX1, PAX9,
LEF1, PITX2) (101, 102, 107, 108), whereas other genes
have a less pronounced effect (DLX1, DLX2, GLI2,
GLI3) (104, 109). Evolutionary conservation of the
temporo-spatial expression pattern of a selected number
of these genes has ultimately given rise to species-specific
differences in tooth patterning. An aspect that has
received little attention in vertebrate evolution, however,
is how gene expression can be modulated by the genetic
variations that normally exist in a population to
generate morphological diversity. With respect to dental
agenesis, this question can be addressed by studying the
Dental agenesis
De Coster et al.
3
molecular strategies that determine tooth development
and tooth patterning.
Molecular mechanisms involved in
odontogenesis
Much information on the genes and transcription
factors that regulate odontogenesis has been obtained
from the murine tooth model and from transgenic
(knockout) mice, showing that tooth development is
under strict genetic control. During recent years,
an increasing number of genes have been identified that
are involved in tooth morphogenesis and it has been
shown that these regulatory genes are used sequentially
throughout the development of the tooth organ, i.e.
from tooth initiation to tooth patterning (determination
of the location, identity, size and shape of teeth) and
histogenesis of the dental tissues (110–112; see also gene
database http://bite-it.helsinki.fi). Abnormal gene func-
tion (loss-of-function, gain-of-function) may disrupt
specific signaling pathways that are involved in tooth
development, resulting not only in abnormal tooth
number but also in abnormal tooth size and ⁄ or shape.
Each signaling pathway includes numerous different
genes and their protein products that are committed to
cellular events in either the epithelial or mesenchymal
tissue layer, inducing reciprocal signaling in the adjacent
tissue in which many other genes encoding signaling
molecules are activated (Figure 2). Important signaling
pathways that are involved in organogenesis include the
bone morphogenetic protein (Bmp), fibroblast growth
factor (Fgf), tumor necrosis factor (TNF), sonic hedge-
hog (Shh), and Wnt pathways (113, 114). Most of these
cascades are essential for many aspects of embryogenesis
and their signaling molecules have been shown to have
diverse biological functions, such as cell fate determi-
nation, cell proliferation and differentiation, and histo-
differentiation. Ligand binding to the appropriate
transmembrane receptor results in activation of sequen-
tial intracellular cascades and several receptor types (e.g.
Fgfr or Fgf receptors) appear to have the ability to
activate multiple pathways simultaneously.
Embryonic development of mammalian teeth relies on
a series of reciprocal inductive signaling between two
adjacent tissues, the primitive epithelium lining the
stomodeum and mesenchymal cells arising from cranial
neural crest cells (Figure 2). Whatever be the mammalian
species or the final shape of the tooth, the oral epithelium
initiates tooth development at embryonic day 9–11 by
signaling through generic molecules such as Fgfs, Bmps,
Wnt, and Shh (115).These regulators continue to be
involved throughout further morphogenesis and cyto-
differentiation of the tooth (Fig. 1) (116–118). Signaling
molecules that determine the position and the shape of
the teeth are Msx1, Msx2, Dlx1, Dlx2, Barx1, and Pax9
(119; http://bite-it.helsinki.fi). Abnormal function of
these specific proteins causes disruption of one or more
signaling cascades, which may result in a variety of
dental anomalies that can either be generalized or local,
and either numerical, morphological and ⁄ or structural in
nature. Clinical associations of dental agenesis and tooth
J Oral Pathol Med
 Dental agenesis
De Coster et al.

4
A C

B D

Figure 1 Syndromal and non-syndromal hypodontia, however etiologically different, may display strikingly similar dental phenotypes. (A, B)
Agenesis of 22 permanent teeth (17, 16, 14, 12, 11, 21, 22, 23, 24, 25, 26, 27, 37, 36, 35, 34, 32, 31, 41, 42, 45 and 46) in a young adult female with
lacrimo-auriculo-dento-digital syndrome (LADD syndrome; Levy-Hollister syndrome). (C, D) Non-syndromal oligodontia in a 17-year-old male
presenting agenesis of 20 permanent teeth (12, 14, 15, 17, 18, 22, 24, 25, 31–33, 35, 37, 38, 41–43, 45, 47, 48).

patterning defects, such as e.g. abnormal tooth shape or
cusp pattern, can hence be explained on the basis of the
complex interaction of (and disruption of interaction
between) the genes and gene products in these signaling
pathways. For instance, disruption of the molecular
pathways not only of Wnt ⁄ b-catenin ⁄ Lef1 (canonical
Wnt signaling) (107, 120), Msx1 (101, 121–123)), Msx2
(124–126), Shh (127, 128), but also of p63 (129), Pitx2
(130), Gli zinc finger transcription factors (104) and
Runx2 ⁄ Cfba1 (131) causes defects affecting all teeth, in a
majority of cases presenting clinically as oligodontia or
anodontia. Depending on the molecule and its timing of
required expression in either (or both) the oral epithe-
lium and adjacent mesenchyme, tooth primordia may be
absent (Wnt, p63), or tooth development may be arrested
at the bud stage (Lef1, Msx1, Msx2, Pax9, Pitx2) or at
the cap ⁄ bell stage (Cbfa1 ⁄ Runx2) (Fig. 1). Dental
agenesis may also result from failure of Fgfs (Fgf4, -8,
-9, -20 in the epithelium (132) and Fgf3, -7, and -10 in
the mesenchyme (133) and Bmps (Bmp2, -4, -7 in the
epithelium and Bmp2 through -7 in the mesenchyme
(134), and their respective receptors required as targets or
in feedback mechanisms during early tooth development
(119, 135).
Not only patterning defects of restricted teeth or
tooth types, such as agenesis of mandibular and ⁄ or
maxillary molars, but also transformation of tooth type,
cusp defects and generation of extra teeth, may result
from dysfunction of Dlx1, Dlx2, Msx1, Msx2, Pax9,
Barx1, Lef1, and also of activinbA (136), ectodysplasin
(Eda) (137, 138) and Fgfs involved in pathways occur-
ring with advancing tooth morphogenesis and cytodif-
ferentiation. Absence of maxillary molars (Dlx1, Dlx2),
of both mandibular and maxillary molars (Fgf8), or of
all teeth except the maxillary molars (activinbA), reflects
the spatially restricted expression of either the related
homeobox genes (i.e. DLX1, DLX2) in the mesenchyme
(odontogenic homeobox code model or field model (139,
140)) or the molecules that are involved in site-specific
signaling pathways. Data from experimental studies on
developing mouse teeth support the role of the enamel
knot as an important signaling center controlling tooth
morphogenesis by concurrently stimulating cusp growth
and by direct folding of cusp slopes (96, 141–143).
Although specific genotype-phenotype correlations still
have not been established, disruption of the enamel knot
signaling loop is believed to account for a great part
of cusp defects. This has been demonstrated for
Wnt10 ⁄ Lef1, which is involved in the Fgf signaling
loop (Fgf4 ⁄ 9 and Fgf3 ⁄ 10) in the enamel knot leading to
spatial upregulation of Shh and resulting in cusp defects
(118). Disruption of the TNF signaling pathway affects
the typical cusp pattern of the molar crown in mice
(targeted disruption of Eda, and its receptor, Edar)
(138), which is a typical feature of hypohydrotic
ectodermal dysplasia (144).
So far, very few human mutations have been
described in the many genes known to cause arrested

J Oral Pathol Med


tooth development in mice. This may reflect basic
differences in dental agenesis mechanisms because of
species-specific characteristics, such as tooth type (only
incisors and molars in mice) and number of dentitions
(one tooth generation in mice vs. deciduous ⁄ permanent
dentition in humans). In addition, the more complex
human dentition often shows a higher dose sensitivity
for mutations compared with mice with loss-of-function
mutations in the murine orthologues. On the other
hand, as mutations causing dental agenesis may affect
conserved regulatory genes in both species, presumably
disturbing cell commitment, cell signaling and ⁄ or cell
proliferation, these experimental models may prove
helpful in unravelling the molecular mechanisms under-
lying human hypodontia.
Human tooth agenesis: a complex genetic trait
Whereas the precise developmental mechanisms respon-
sible for the various forms of hypodontia are far from
being understood, genetic defects responsible for human
dental agenesis are recently beginning to be uncovered.
So far, the best characterized mutations cause domi-
nantly inherited severe hypodontia and mutations with
recessive inheritance are known only in association with
some syndromes. Accordingly, the known mutations
explain only a restricted number of cases of agenesis.
The common hypodontia that affects only a few
premolars or incisors, as well as most cases of severe
agenesis remains so far unexplained. It is possible that
sequence variants in genes known from dominant agen-
esis and from syndromes as well as from mouse models
contribute to these forms of hypodontia and that these
variants also affect gene regulation and signaling. On the
other hand, as suggested before, the findings that second
premolars, lateral incisors and third molars (being the
last teeth within each series to develop) are the teeth
most frequently affected, could be related to spatial
constraints imposed upon the neighbouring developing
teeth, or to their susceptibility to fall below a develop-
mental threshold (145).
Non-syndromic hypodontia
Genes implicated in epithelial-mesenchymal interactions
during mouse odontogenesis serve as potential candi-
dates for tooth agenesis in humans. To date, the
mutation spectra of non-syndromic tooth agenesis in
humans have revealed defects in two such genes that
encode transcription factors, MSX1 and PAX9. Msx1
belongs to a family of transcription factors that are
expressed in overlapping patterns at multiple sites of
tissue interactions during vertebrate development (146).
Msx1 co-determines the position and shape of teeth
(so-called homeobox code model, linking patterning of
tooth types to spatially restricted expression of homeo-
box genes in the dental mesenchyme). Mice lacking
Msx1 protein function manifest cleft palate, deficient
mandibular and maxillary alveolar bones, and failure
of tooth development (101). Mutations in the homeo-
domain of human MSX1 have been associated with
Witkop tooth-and-nail syndrome (OMIM Entry 189500;
Dental agenesis
De Coster et al.
5
Online Mendelian Inheritance in Man gene database at
http://www.ncbi.nlm.nih.gov/sites/entrez). PAX9 gene
products function primarily by binding the enhancer
DNA sequences and by modifying transcriptional
activity of downstream genes (147). PAX9 homozygous
null mice lack derivatives of the third and fourth
pharyngeal arches (thymus, parathyroid gland,
ultimobranchial bodies), have craniofacial and limb
anomalies, and fail to form teeth beyond the bud stage
(102).
To date, 11 distinct disease-causing mutations in the
PAX9 gene (59 patients in 15 families) (OMIM Entry
167416) have been identified in humans and five muta-
tions in the MSX1 gene (40 patients in seven families)
(OMIM Entry 142893) all of which result in domi-
nantly inherited posterior tooth agenesis, with or
without orofacial clefting in MSX1 mutations (148–
150). Most of these mutations are located in the paired
box domain of PAX9 or the homeodomain of MSX1
(118, 125, 126, 148, 151–168), ranging from missense
mutations that change just one amino acid in the entire
protein to premature stop codons that result in
truncation of the protein products. Multiple lines of
evidence suggest that their respective protein products,
Msx1 and Pax9, play an important role in the main-
tenance of mesenchymal Bmp4 expression, which ulti-
mately drives morphogenesis of the dental organ, more
in particular, the transition from bud to cap stage
during tooth development and enamel knot induction
at the late cap stage (Fig. 1). Besides Bmp4 downregu-
lation, mutations in PAX9 could result in a selective
reduction in Pax9 binding to sites that regulate Msx1
expression levels. Mutations in either PAX9 or MSX1
can also lead to defective protein–protein interactions
that disrupt normal downstream functions important
for tooth morphogenesis. Such interactions have been
shown both at the gene and protein levels (169, 170). In
addition, MSX1 and PAX9 are dosage-sensitive genes.
In humans, haploinsufficiency of MSX1 or PAX9
results in loss-of-function in about 50% of cases
causing severe generalized hypodontia in MSX1 and
molar agenesis in PAX9. Milder phenotypes may be the
result of a defective allele generating an aberrant
protein that acts in a dominant-negative manner or
has a novel function (84). A mutation in PAX9 has also
been identified in association with severe hypodontia in
a family affected with agenesis of most permanent
molars and a variable absence of second premolars and
mandibular incisors. The insertion of a Guanine at
position 219 produced a frameshift and premature
termination of the protein. In addition, the mutation
altered the amino acid sequence within the highly
conserved paired domain (125).
More recently, two mutations in AXIN2, a negative
regulator of canonical Wnt signaling, were identified in
families with non-syndromic forms of tooth agenesis
associated with colorectal cancer (171, 172). When
compared with the pattern of agenesis of the posterior
dentition seen in MSX1- and PAX9-affected families,
individuals with a non-sense mutation in AXIN2 display
a mixed pattern of dental agenesis (171).
J Oral Pathol Med
 Dental agenesis
De Coster et al.
6
Recent sequencing analysis in families with non-
syndromic hypodontia showed that premolar agenesis
might be associated with FGFR1 (173), one of the genes
that is also involved in human craniosynostosis (pre-
mature fusion of the calvarial bones) (174). Fgfr1 is
broadly expressed in the facial primordia (175, 176), and
plays important roles in advancing skeletogenesis by
regulating osteoblast (175, 177–180) and chondroblast
(121, 175, 181) differentiation.
Furthermore, there is evidence that TGFA (TGFa)
gene may play a role in cases with isolated incisor
agenesis (152). TGFA is expressed during craniofacial
development (182) and mutation of this gene has
previously been related with cleft lip and palate (183).
Experimental evidence suggests that teeth lack a
hard-wired’ code for tooth number, cusp number or
cusp positions. Rather, a dynamic balance between
modulatory’ signaling molecules, which seems to fine
tune the overall effects of signaling networks, regulates
the final pattern. This applies, for instance, to genes such
as IKKc or NEMO (OMIM Entry 300248) (184), EDA
(OMIM Entry 300451) (117), EDAR (OMIM Entry
604095) (185), and TNF (OMIM Entry 191160) (186)
involved in the nuclear factor-kappaB (NFjB) signaling
pathway mediating tooth morphogenesis (187), p63
(target of Fgf and Bmp signaling) (OMIM Entry
603273) (188), PITX2 (Fgf target) (OMIM Entry
601542) (189), and Notch genes (involved in Bmp
signaling) (OMIM Entry 190198) (190). The fact that
dental agenesis is seen in a large number of syndromes
(syndromic hypodontia) in association with malforma-
tions of other organs (Table 1) (191–254), resulting from
mutations of one of these numerous genes, reflects the
complex and heterogeneous genetic basis of dental
agenesis.
Syndromes with dental agenesis
Ectodermal dysplasia, oral-facial-digital syndromes, and
syndromes with oral-facial clefting are conditions, which
include hypodontia as a major symptom. The latter
comprise isolated or non-syndromic cleft lip and ⁄ or
palate (CL ⁄ CLP) and a number of conditions classified
as syndromic CL ⁄ CLP, such as Pierre-Robin sequence
and Van Der Woude syndrome. In patients with non-
syndromic CL ⁄ CLP, the prevalence of hypodontia
increases with cleft severity (8). The upper lateral incisor
is the most frequently affected tooth in the cleft area both
in primary (circa 10%) and in permanent (circa 50%)
dentitions. A higher incidence of dental agenesis outside
the cleft region, more in particular involving the perma-
nent maxillary dentition, has also been reported (5, 255–
258) and suggestion has been made to distinguish clefting
associated with dental agenesis from clefting occurring
alone (150, 259). Successive linkage analysis studies have
indicated involvement in non-syndromic CL ⁄ CLP of
different loci, mapped respectively to chromosome 6p24
(OFC1, Orofacial cleft-1; OMIM Entry 119530) (260–
262), 2p13 (OFC2; OMIM Entry 602966), 19q13 (OFC3;
OMIM Entry 600757), and regions on 4q (OFC4;
OMIM Entry 608371). CL ⁄ CLP has also been linked
to mutation in a number of specific genes, such as ET1
J Oral Pathol Med
(endothelin-1) (261; OMIM Entry 131240), F13A (factor
XIII subunit A) (OMIM Entry 134570), BCL3 (proto-
oncogene B-cell leukemia 3) (OMIM Entry 109560)
(263–265), RARA (retinoic acid receptor alpha) (OMIM
Entry 180240) (266), and TGFb3 (transforming growth
factor-bèta 3) (OMIM Entry 190230) (155, 264). At
present, the role of these genes in the development of
dental agenesis for the greatest part remains unclear. On
the other hand, environmental factors such as maternal
cigarette smoking (267) and ⁄ or alcohol abuse (268), and
folic acid deficiency (269) have also been associated with
CL ⁄ CLP.
Over 200 syndromes exhibit varying levels of
CL ⁄ CLP as part of their phenotype and many of the
causative genes have now been identified. In Pierre-
Robin sequence (OMIM Entry 261800) with cleft palate,
micrognathia and glossoptosis, a 50% prevalence of
hypodontia, most frequently of mandibular teeth, has
been reported. Van Der Woude syndrome (VWS)
(OMIM Entry 119300) is one of the most common
human autosomal dominant disorders associated with
CL ⁄ CLP (about 1% of syndromic CL ⁄ CLP cases),
characteristic pitting of the lower lip mucosa and
hypodontia (in 70% of cases). Mutations in IRF6
(1q32-q41) have been identified in 50 unrelated families
with VWS. IRF6 encodes a transcription factor (Irf6
or interferon regulatory factor-6) (OMIM Entry 607199)
that is highly expressed in a variety of embryonic
craniofacial structures, including the medial edges of the
fusing palatal processes, tooth buds, hair follicles and
skin, and it has been suggested that Irf6 mediates
interactions between members of the TGFb superfamily
of signaling peptides (270–272).
Oral-facial-digital syndrome type I (OFD1) is part
of a heterogeneous group of developmental disorders
characterized by malformations of the face (facial
asymmetry, hypertelorism, and micrognathia), oral
structures (supernumerary frenulae, thickened alveolar
ridges, hypodontia of lower incisors), and digits (OMIM
Entry 311200). OFD1 is transmitted as an X-linked
dominant condition affecting females and causing mor-
tality in males. Several different mutations have been
found in CXORF5 (Xp22.3-p22.2) (273).
Ectodermal dysplasia (ED) covers a heterogeneous
group of conditions affecting ectodermal organs includ-
ing the hair, teeth, nails and glands, which are often
associated with CL ⁄ CLP. More than 150 EDs have been
described and classified into 11 clinical subgroups,
displaying a great genetic heterogeneity (144). Hypo-
hydrotic ED (HED or ED1) is the most common ED,
usually inherited as an X-linked dominant trait although
rarer autosomal dominant and recessive forms exist
(OMIM Entry 305100). X-linked dominant EDA
is caused by mutations in EDA gene (Xq12-q13.1).
The protein product, ectodysplasin A, is a novel
member of the TNF family and functions as a
signaling molecule during epithelial morphogenesis
(274). Both autosomal dominant and recessive forms
of EDA are caused by mutations in EDAR (2q11-q13)
coding for a TNF receptor, Edar (OMIM Entry
604095). The autosomal dominant ectrodactyly –
 Table 1 Syndromes with moderate to severe hypodontia

Syndrome Dominant symptoms Genes and gene locus OMIM Entrya References
Aarskog s. Proportionate short stature translocation of 8p and Xq 100050 191
ADULT s. Ectrodactyly, nail dysplasia, breast hypoplasia TP73L (3q27) 103285 192
Alagile s. Characteristic facies, cardiac and ocular anomalies JAG1 (20p12) 118450 193
Apert s. Skull deformity, midface hypoplasia, syndactyly FGFR2 (10q26) 101200 194
Blepharo-cheilo-odontic s. Ectropion of lower eyelids, oral clefting unknown 119580 195
Branchio-oto-renal s., Type I Branchial cysts, structural ear defects, renal hypoplasia EYA1 (8q13.3) 113650 196
Charcot-Marie-Tooth disease, Type 2E Progressive late onset neuropathy NEFL (8p21) 607684 197
Cleft lip ⁄ palate - ectodermal dysplasia s. Syndactyly, ectodermal dysplasia, cleft lip ⁄ palate PVRL1 (11q23-q24) 225060 198
Coffin-Lowry s. Skeletal disorder RSK2 (Xp22.2-p22.1) 303600 199
Crouzonodermoskeletal s. Skull deformity, acanthosis nigricans, severe scoliosis FGFR3 (4q16.3) – 200
Down s. Mental retardation, characteristic facies chromosome 21 trisomy 190685 201
Dubowitz s. Short stature, microcephaly, characteristic facies unknown 223370 202
Ectodermal dysplasia, tricho-odonto-onychial type Hypotrichosis, hypodontia, hypoplastic nails unknown 129510 203
Ectodermal dysplasia, AD hypohidrotic type Hypohitrosis, hypotrichosis, hypodontia EDAR (2q11-q13) 129490 204
Ectodermal dysplasia, AR hypohidrotic type Hypohitrosis, hypotrichosis, hypodontia EDAR (2q11-q13), EDARADD 224900 205
(1q42.2-q42.3)
Ectodermal dysplasia, XD hypohydrotic type Hypohitrosis, hypotrichosis, hypodontia EDA (Xq12-q13.1) 305100 206
EEC s. Ectrodactyly, ectodermal dysplasia, orofacial clefting P68 (3q27), (7q11.2-q21.3) 129900, 604273 207
Ehlers-Danlos s., hypermobility type Joint hypermobility COL3A1 (2q31) 130020 208
Ehlers-Danlos s., dermatosparaxis type Extensive skin bruising, short stature ADAMTS2 (5q23) 225410 209
Ellis-van Creveld s. (chondroectodermal dysplasia) Short limbs, postaxial polydactyly, nail hypoplasia, EVC ⁄ EVC2 (4p16) 225500 210
cardiac defects
Fanconi renotubular s. Retarded growth, rickets, hypophosphatemia (15q15.3) 13600 211
Frontometaphyseal dysplasia Frontal hyperostosis, metaphyseal dysplasia FLNA (Xq28) 305620 212
GAPO s. Growth retardation, alopecia, pseudoanodontia, optic atrophy unknown 230740 213
Goldenhar s. (hemifacial microsomia) Unilateral deformity of external ear and half of face unknown 164210 214
Goltz-Gorlin s. (focal dermal hypoplasia) Linear skin pigmentation, fat herniation, syndactyly unknown 305600 215
Hallermann-Streiff s. Proportionate dwarfism, bird-like facies unknown 234100 216
De Coster et al.
Dental agenesis

Hanhart s. Hypoglossia, hypodactyly unknown 103300 217

Hay-Wells s. Ectodermal dysplasia, ankyloblepharon, cleft lip ⁄ palate TP73L (3q27) 106260 218
Incontinentia pigmenti (Bloch-Sulzberger s.) Anomalies of the skin, hair, nails, eyes and teeth IKKc (NEMO) (Xq28) 308300 219
Johanson-Blizzard s. Aplastic nasal alae, hypotonia, growth retardation UBR1 (1515-q21.1) 243800 220
Kabuki s. Mental retardation, characteristic facies, postnatal dwarfism unknown 147920 221
Kartagener s. Bronciectasis, dextrcardia, infertility DNAI1 (9p21-p13), DNAH5 244400 222
(5p15-p14), DNAHC11 (7p21)
KBG s. Short stature, mental retardation, macrodontia unknown 148050 223
LADD s. (Levy-Hollister s.) Lacrimal duct atresia, ear and tooth deformity FGFR2 (10q26), FGFR3 (4p16.3), 149730 224
FGF10 (5p13-p12)
Larsen s. Bilateral knee dislocation, pes cavus, characteristic facies FLNB (3p14.3) 150250 225
Laurence-Moon s. Spastic paraplegia, mental retardation, pigmentary retinopathy MKKS (20p12) 245800 226
McCune-Albright s. Polyostotic fibrous dysplasia, skin hyperpigmentation GNAS1 (20q13.2) 174800 227
Moebius s. Facial palsy, orofacial dysmorfism, limb malformations (13q12.2-q13) 157900 228
Mulvihill-Smith s. Dwarfism, multiple pigmented nevi, progeria unknown 176690 229
Neu-Laxova s. Growth retardation, microcephaly, limb malformations unknown 256520 230
Oral-facial-digital s., Type I Malformations of face, oral cavity and fingers CXORF5 (Xp22.3-p22.) 311200 231
Pseudoxanthoma elasticum Cutis laxa, retinal agioid streaks ABCC6 (16p13.1) 26400 232
Rapp-Hodgkin s. Anhidrotic ectodermal dysplasia, cleft lip ⁄ palate TP73L (3q27) 129400 233
Rieger s., Type I Hypoplastic iris, umbilical hernia, anal stenosis PITX2 (4q25-q26) 180500 234
Rieger s., Type II (Type I with:) Multisystem anomalies, craniofacial dysmorfism RIEG2 (13q14) 601499 235
Rothmund-Thomson s. Dermatosis, bone defects, scalp defects, hypogonadism RECQL4 (8q24.3) 268400 236

J Oral Pathol Med

7
 Dental agenesis
De Coster et al.

8
ectodermal dysplasia – orofacial cleft (EEC) syndrome
References
(OMIM Entry 129900) is characterized by central
reduction defects in the hands and feet (ectrodactyly)

253
237
238
239
240
241
242
243
244

245
246
247
248
249
250

251
252

254
often associated with syndactyly, ectodermal dysplasia
manifesting as dry skin, sparse hair, dystrophic nails,
OMIM Entrya

missing primary (first molars) and permanent teeth,

602361
180849
255800
210600
603903
270200
182290
117550
183600

211370
119300
193500
277600
193530
194050

189500
194190
conical teeth, and CL ⁄ CLP. Several different mutations

–
of P68 gene (3q27) have been revealed in EEC families,
but linkage to chromosome 7 (7q11.2-q21.3) (275) and
SHFM3 (10q24), SHFM4 (3q27), SHFM5 (2q31)
the chromosome 19 pericentromeric region has also
been reported (276). A homozygous loss-of-function
mutation in the PVRL1 gene (11q23-q24) (poliovirus
receptor related-1) has been linked to CLPED-1, an

CYLN2 ⁄ GTF2IRD1 ⁄ GGTF2I (7q11.23)

autosomal recessive CLP-ectodermal dysplasia syn-

deletion of long arm of chromosome 22

deletion of short arm of chromosome 4
drome (277) (OMIM Entry 225060). Patients with
ATR (3q22.1-q24), (18p11q11), (14q)
Genes and gene locus
CREBBP (16p13.3), EP300 (22q13)

CLPED-1 have scanty eyebrows, sparse and dry hair,

SHFM1 (7q21), SHFM2 (Xq26),

syndactyly of the fingers and toes, CL ⁄ CLP, nail

ELN (7q11.2), LIMK1 ⁄ RFC2 ⁄
ADAMTS10 (19p13.3-p13.2)

dysplasia, hypodontia of the upper central incisors,

and abnormal size and shape of tooth crowns. Incon-
HBB ⁄ HbSC (11p15.5)

tinentia pigmenti (IP) or Bloch-Sulzberger syndrome is a

ALDH3A2 (17p11.2)

rare multisystem disorder classified as an ED condition

IRF6 (1q32-q41)
HSPG2 (1p36.1)

RAI1 (17p11.2)

MSX1 (4p16.1)

with additional ocular and central nervous anomalies.

PAX3 2q35)

EVC (4p16)

IP is an X-linked dominant disorder due to mutations in

unknown
unknown

the IKKc or NEMO gene (Xq28) (278) (OMIM Entry

(5q35)

308300). Mostly females are affected as males with the

mutation usually do not survive through gestation. Over
90% of patients with IP have associations of severe
Clavicular hypoplasia, craniofacial disproportion, digital anomalies

hypodontia (about 43%), microdontia and supernumer-

ary cusps in the posterior permanent teeth (about 30%),
Wide nasal bridge, pigmentary disturbance, cochlear deafness
Mental retardation, broad thumbs ⁄ toes, facial dysmorphism

Online Mendelian Inheriance in Man; http://www.ncbi.nlm.nih.gov/Omim (last accessed May 2008).

delayed tooth eruption, and ⁄ or taurodontia (279). A

Short stature, brachydactyly, joint stiffness, lens anomalies
Postaxial polydactyly, short limbs, small and conical teeth
Aortic stenosis, elfin face, mental and statural deficiency

distinct form of EDA with immunodeficiency (HED-ID)

(OMIM Entry 300291) segregates as an X-linked reces-
Characteristic facies, mental retardation, hypotonia
Growth retardation, microcephaly, beak-like facies
Functional asplenia, high morbidity by septicemia

sive trait (280, 281), which is allelic to IP. IKKc, the

Ichthyosiform erythroderma, spastic quadriplegia

protein in focus, is required for activation of NFjB, a

Dominant symptoms

Short staturen myotonia, joint contractures

transcription factor transducing TNF signaling. Witkop

Brachymetapody, anodontia, hypotrichosis
Pits ⁄ sinuses of lower lip, cleft lip ⁄ palate

tooth-and-nail syndrome (TNS) (OMIM Entry 189500)

is an autosomal dominant disorder characterized by nail
Growth retardation, closure defects

dysplasia, severe hypodontia, and conical teeth. Muta-

Cerebral gigantism, rapid growth
Growth retardation, hypotonia

tions in MSX1 gene (on 4p16.1) have been identified in

several unrelated families with TNS.
Tooth and nail hypoplasia
Severe limb malformation

Hypodontia features not only in a number of other

unrelated and relatively frequent syndromes, such as
Down syndrome, Klinefelter syndrome, Wolf-Hirsch-
horn syndrome, Rieger syndrome, and Ellis-van Creveld
syndrome, but also in a number of syndromes with
rather low prevalence (Table 1).

Conclusions and future perspectives

Yunis-Varon s. (gracile bone dysplasia)

Dental agenesis is genetically and phenotypically a

heterogeneous condition. It is assumed that different
phenotypic forms are caused by different genes involving
Split-hand ⁄ foot malformation

Weill-Marchesani s., AR type

Weyers acrofacial dysostosis

different interacting molecular pathways, providing an

Witkop tooth-and-nail s.

explanation not only for the wide variety in agenesis

Waardenburg s., Type I
Tuomaala-Haapanen s.

patterns but also for associations of dental agenesis

Table 1 (Continued)

Rubinstein-Taybi s.

Wolf-Hirschhorn s.
Schwartz-Jampel s.

Sjögren-Larsson s.

Van der Woude s.

with other oral anomalies. More than 200 genes have so

Sickle cell anemia

Smith-Magenis s.

far been identified, which are expressed during tooth

development, and mutations in several of these genes are
Williams s.

del(22q) s.
Syndrome

Seckel s.

known to cause arrested tooth development in mice.

Sotos s.

Only few genotype-phenotype correlations have yet been

established in humans with non-syndromic hypodontia,
a

J Oral Pathol Med

 Dental agenesis
De Coster et al.

Figure 2 Reciprocal signaling during early tooth development. Failure of one of the involved signaling proteins, transcription factors and ⁄ or their
receptors may result in patterning defects. Dental agenesis may result from arrested tooth development at the initiation, bud or cap stage (adapted
after Peters & Balling 1999(116), Thesleff 2003(113) and Mustonen 2004(117). (A) One of the earliest markers for the dental epithelium (yellow) is
Pitx2 mRNA expression in the dental lamina.The epithelial thickening (dental placode) functions as a signaling center secreting several growth
factors and signaling molecules, such as Fgfs, Bmps, Shh and Wnts. Also, p21 and Notch genes encoding Notch1, Notch2 and Notch3 are
upregulated in the placode. In the mesenchyme (blue) the epithelial signals induce expression of Pax9, Ptc, Msx1, Msx2, Bmp4 and Lef1. Fgfr1c and
Fgfr2b are expressed throughout the dental and oral epithelium. (B) At bud stage, the dental epithelium continues to express several growth factors
and signaling molecules. Shh and Bmp2 proteins are expressed at the tip of the bud, the future enamel knot. Notch1, -2 and -3 are expressed in the
stellate reticulum of the epithelium. Dental mesenchyme expresses Pax9, Msx1 and Bmp4, which are involved in a reciprocal signaling loop. (C) At
cap stage, the enamel knot (red) contains cells that have stopped proliferating and differentiate into a signaling center secreting factors like Shh,
Fgf4, Fgf9 and Bmps that control the growth of the surrounding tissue (epithelium and mesenchyme). Dental mesenchyme responds by secreting
Bmp4 and Msx2. Fgf signaling loop involves both mesenchymal expression of Msx1, Runx2, Fgf3 and Fgf10, mediated by Fgfr1c, Fgfr2c, Fgfrb
and Fgfr2b (Klein et al. 2006 (118)).

such as mutation in MSX1 causing severe oligodontia and
mutation in PAX9 causing loss of permanent molars, in
some instances together with upper lateral incisors and
premolars. In addition, a number of genes, such as MSX1,
MXS2 (282), EGF, EGFR and FGF3 (283), have been
excluded as candidate genes for the most common forms
of non-syndromic (incisor-premolar) hypodontia,
whereas mutations in MSX1, PAX9 and AXIN2 have
been ruled out in a number of instances with severe
oligodontia (284).
From previous studies, it is clear that PAX9 and
MSX1 are essential for the establishment of the odon-
togenic potential of the mesenchyme through the main-
tenance of mesenchymal Bmp4 expression. However,
the relationship between MSX1, PAX9 and BMP4 genes
at the molecular level remains unknown. As a logical
next step, this molecular relationship must be examined
more closely. In addition, based on previous studies that
have shown that the paired domain of Pax proteins and
the homeodomain of Msx1 participate in protein–
protein interactions, the first step is to address potential
interactions of Pax9 with other homeodomain-contain-
ing transcription factors that are co-expressed in devel-
oping dental mesenchyme. Of all the candidate genes
that are expressed in developing tooth organs, LEF1,
DLX1, DLX2, BARX1, LHX6 and LHX7 represent
suitable candidates based upon knowledge of their
function and specific expression patterns and because
tooth agenesis phenotypes were observed in transgenic
null mice. Also, a number of additional genes encoding
molecules that are expressed in early (initiation stage)
dental epithelium, such as BMP2, BMP4, BMP7,
DLX5, FGF1, FGF2, FGF4, FGF8, FGF9, GLI2 and
GLI3, amongst others, are potential candidates for tooth
agenesis in humans.
During the past decades, considerable efforts have
been expended on detecting gene loci that contribute
to susceptibility for dental agenesis. However, the
success in such genetic identification attempts has been
limited, and most of the fundamental questions relat-
ing to the genetic epidemiology of dental agenesis
remain unanswered. In contrast to what has been
found for monogenic traits, the results related to
complex traits often have been rather inconsistent
(285). Further research should take into account the
unique characteristics of the phenotype in both syndro-
mic and non-syndromic forms, such as a careful
description of the missing teeth (pattern of occurrence,
i.e. uni- vs. bilateral, upper vs. lower, tooth types
involved, arch location etc.) and of the malformations
found on the teeth present. It may presumably show
that human dental agenesis is caused by several
independent defective genes, acting alone or in com-
bination with other genes and leading to a specific

J Oral Pathol Med

 Dental agenesis
De Coster et al.
10
phenotypic pattern. These insights will significantly
add to our knowledge of the complex cellular events
that give rise to the tooth and of the molecular
developmental strategies that control the patterning of
the human dentition.
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