An Overview of Molecular and Genetic Alterations
in Selected Benign Odontogenic Disorders
Robert J. Cabay, MD, DDS
 Context.—Some dental abnormalities have environmen-
tal causes. Other odontogenic alterations are idiopathic
and may have hereditary etiologies. Investigations of these
conditions are ongoing.
Objective.—To provide a discussion of developmental
odontogenic abnormalities and benign odontogenic over-
growths and neoplasms for which genetic alterations have
been well demonstrated and well documented.
Data Sources.—Relevant peer-reviewed literature.
Conclusions.—The understanding of benign odontogenic
A n assortment of odontogenic alterations may be linked
to environmental or hereditary etiologies. The level of
understanding of the genesis of benign odontogenic lesions
at a molecular level is variable depending on the lesion in
question. The following discussion provides an overview of
developmental odontogenic abnormalities and benign
odontogenic overgrowths and neoplasms for which genetic
alterations have been well demonstrated and well docu-
mented.
DEVELOPMENTAL ALTERATIONS
IN THE NUMBER OF TEETH
Hypodontia
Hypodontia refers to the lack of development of 1 or more
teeth. This disorder can occur in the primary dentition but is
more common in the permanent dentition.1 Hypodontia in
the primary dentition most frequently involves the lateral
incisors.2 In the permanent dentition, the third molars are
most commonly affected,3 followed by the lateral incisors
and the second premolars.4 A female predominance of
approximately 3:2 has been described.5 Taking third molars
into account, the incidence of hypodontia may be as high as
20%.5 Anodontia indicates a total lack of tooth develop-
ment. Oligodontia (partial anodontia) denotes a lack of
Accepted for publication June 18, 2013.
From the Department of Pathology, College of Medicine, and the
Department of Oral Medicine and Diagnostic Sciences, College of
Dentistry, University of Illinois Hospital & Health Sciences System,
Chicago, Illinois.
The author has no relevant financial interest in the products or
companies described in this article.
Reprints: Robert J. Cabay, MD, DDS, Department of Pathology,
College of Medicine, and Department of Oral Medicine and
Diagnostic Sciences, College of Dentistry, University of Illinois
Hospital & Health Sciences System, 840 S Wood St, 130 CSN,
Chicago, IL 60612-4325 (e-mail: rcabay1@uic.edu).
754 Arch Pathol Lab Med—Vol 138, June 2014
lesions at a molecular level is rather well developed for
some lesions and at the initial stages for many others.
Further characterization of the molecular underpinnings of
these and other odontogenic lesions would result in an
enhanced comprehension of odontogenesis and the path-
ogenesis of a variety of odontogenic aberrations. These
advancements may lead to better prevention and treat-
ment paradigms and improved patient outcomes.
(Arch Pathol Lab Med. 2014;138:754–758; doi: 10.5858/
arpa.2013-0057-SA)
development of 6 or more teeth.5 Tooth development is
under tight genetic control. More than 200 genes have been
reported to be involved in odontogenesis.5 Most cases of
primary hypodontia are inherited in an autosomal dominant
fashion.5
A small percentage of nonsyndromic cases of hypodontia
have been linked to alterations in particular genes (Table 1),
including PAX9, MSX1, and AXIN2.5 Sequence analyses of
PAX9 exons 2 to 4 in affected individuals have revealed a
guanine insertion at nucleotide 219 in one family6 and a
cytosine insertion at nucleotide 793 in another family.7
Sequencing results for 2 siblings with hypodontia confirmed
a thymine to adenine mutation at MSX1 nucleotide 620,
resulting in a Met61Lys substitution.8 Direct sequencing of
AXIN2-coding regions and flanking intronic sequences in all
members of a family who had oligodontia revealed a 1966
cytosine to thymine transition in exon 7, leading to a change
of arginine 656 to a stop codon, premature termination of
translation, and predisposition to the development of
colorectal neoplasia.9 A significant number of cases of
hypodontia have been identified in patients exhibiting a
variety of syndromes (Table 2).5 This linkage suggests that
tooth development may have molecular mechanisms that
are shared by several other developmental processes.10
Hyperdontia
Hyperdontia refers to the development of an increased
number of teeth. The extra teeth are referred to as being
supernumerary teeth. They may be present anywhere in the
dental arches, but the greatest number appear in the
anterior maxilla.11 Supernumerary teeth may occur singly,
multiply, unilaterally, bilaterally, in 1 jaw, or in both jaws.
Classification of supernumerary teeth is based on location
and morphology. A male predominance of approximately
2:1 has been described.12 The incidence of hyperdontia is
much less than that of hypodontia5 (likely less than 3%).
Odontogenic Molecular Pathology—Cabay
 Table 1. Genes Associated With Hypodontia
PAX9
MSX1
AXIN2
Many cases of hyperdontia described in the literature are
familial. Some cases seem to exhibit autosomal dominant
inheritance with lack of penetrance in some generations.13
Studies linking hyperdontia to specific genetic alterations
are lacking. But, much like hypodontia, a significant number
of cases of hyperdontia have been identified in patients
exhibiting a variety of syndromes (Table 3).5
DEVELOPMENTAL ALTERATIONS
IN THE STRUCTURE OF TEETH
Amelogenesis Imperfecta
Ameloblasts within the developing tooth germ are very
sensitive to external stimuli, and many factors can result in
enamel abnormalities. Primary hereditary abnormalities of
enamel that are unrelated to other disorders are included in
the family of conditions termed amelogenesis imperfecta.5 A
number of subtypes of amelogenesis imperfecta exist,
encompassing numerous patterns of inheritance and a
variety of clinical manifestations (Figure 1). These conditions
are clinically and genetically complex, and several different
classification systems have been used. Witkop14 estimated
the frequency of amelogenesis imperfecta to be 1:14 000 and
formulated a widely accepted classification system based on
phenotype and apparent pattern of inheritance. An ideal
classification system has not yet been established,5 but
classification based on the molecular genetics of the various
subtypes of amelogenesis imperfecta is moving forward.15
Amelogenesis imperfecta can be inherited in an autosomal
dominant, autosomal recessive, or X-linked fashion.16
Several genes have been implicated in the development of
amelogenesis imperfecta, including AMELX, ENAM, DLX3,
FAM83H, MMP20, KLK4, and WDR72.15
Dentinogenesis Imperfecta
Dentinogenesis imperfecta is a hereditary abnormality of
dentin in the absence of systemic disease. Its prevalence is
estimated to be approximately 1:8000.5 Some or all of the
teeth in the primary and permanent dentitions of an affected
individual may be involved. The primary teeth are usually
the most severely altered, followed by the permanent
incisors and first molars. The second and third molars are
Table 2. Some Syndromes Associated
With Hypodontiaa
Crouzon
Down
Ectodermal dysplasia
Ehlers-Danlos
Focal dermal hypoplasia
Gorlin
Hurler
Progeria
Rieger
Sturge-Weber
Tooth-and-nail
Turner
a
This modified table was published in Neville et al.5 Copyright Elsevier
2009, reprinted with permission.
Arch Pathol Lab Med—Vol 138, June 2014
Table 3. Some Syndromes Associated
With Hyperdontiaa
Apert
Cleidocranial dysplasia
Crouzon
Down
Ehlers-Danlos
Gardner
Sturge-Weber
a
This modified table was published in Neville et al.5 Copyright Elsevier
2009, reprinted with permission.
the least affected.5 The teeth often have a blue, brown, or
yellow hue and increased translucency. Enamel may
separate from the underlying dentin. Dentinogenesis
imperfecta displays almost 100% penetrance but variable
expressivity.5 A group of affected individuals located initially
in southern Maryland (the ‘‘Brandywine isolate’’) were
noted to have shell-like teeth with enlarged pulp chambers.
This subpopulation was recorded to have the highest
incidence of any dental genetic disease (about 1:15).17,18
Similar tooth structure alterations can sometimes be seen
in conjunction with osteogenesis imperfecta (osteogenesis
imperfecta with opalescent teeth), but this disorder is
associated with mutation of the COL1A1 or COL1A2 gene,19
making it a disease that is genotypically distinct. However,
many clinicians use a commonly accepted phenotypic
classification (Table 4) that includes this dentin-affecting
disorder as a type of dentinogenesis imperfecta.5,19 In a
genotypic sense, dentinogenesis imperfecta is most associ-
ated with various mutations of the DSPP gene.19
Dentin Dysplasia
Dentin dysplasia is a hereditary abnormality of dentin
with no correlation to systemic disease that is distinct from
dentinogenesis imperfecta. Two phenotypes have been
described (Table 5).5,19 Dentin dysplasia type I has a
prevalence of approximately 1:100 000.8 Dentin dysplasia
type II has a prevalence of approximately 1:10 000.20
Dentin dysplasia is inherited in an autosomal dominant
fashion. Sequencing of a portion of exon 2 of the DSPP gene
revealed a thymine to guanine transversion at nucleotide 16
associated with the development of dentin dysplasia type
II.21 Because the phenotypic and genotypic characteristics of
dentinogenesis imperfecta and dentin dysplasia type II are
so similar, it may be more prudent to consider dentin
dysplasia type II as a variant of dentinogenesis imperfecta
rather than grouping it with dentin dysplasia type I.5
BENIGN ODONTOGENIC
OVERGROWTHS/NEOPLASMS
Odontoma
An odontoma is a tumorlike malformation that contains
elemental tooth matrix materials. This kind of overgrowth of
odontogenic material is considered to be a hamartoma.22,23
An odontoma can be classified as a compound odontoma
(odontoma, compound type) if its elements have recogniz-
able toothlike morphologies (odontoids).22 If the dysmor-
phic nature of the enamel, dentin, and cementum collection
precludes the recognition of toothlike structures, the
malformation can be classified as a complex odontoma
(odontoma, complex type).23 Some odontomas may display
compound and complex features. Most odontomas are
detected in the first 2 decades of life.5 They are found slightly
Odontogenic Molecular Pathology—Cabay 755

Figure 1. Diffuse rough hypoplastic (type IF) amelogenesis imperfecta
(courtesy of Sara C. Gordon, DDS, MSc, FRCD(C), FDSRCS(Ed)).
Figure 2. Keratocystic odontogenic tumor (odontogenic keratocyst)
with detachment of cyst-lining epithelium (hematoxylin-eosin, original
magnification 3200) (courtesy of Sara C. Gordon, DDS, MSc,
FRCD(C), FDSRCS(Ed)).
Figure 3. Ameloblastoma, solid/multicystic type (hematoxylin-eosin,
original magnification 3400) (courtesy of Sara C. Gordon, DDS, MSc,
FRCD(C), FDSRCS(Ed)).
Table 4. Phenotypic Classification of Dentinogenesis Imperfecta
Type Clinical Manifestations
I Osteogenesis imperfecta with opalescent teeth
II Opalescent dentin
III Shell teeth, affects Brandywine isolate
756 Arch Pathol Lab Med—Vol 138, June 2014
more often in the maxilla than in the mandible. The
compound type occurs more often in the anterior maxilla;
the complex type appears more often in the molar regions of
either jaw.5 There is no sex predilection.22,23
Some cytokeratins that are expressed in normal develop-
ing and developed dental tissues are also expressed in
odontomas. Odontomas express cytokeratin 14, which is
absent in advanced amelogenesis, and cytokeratin 7, which
is present in Hertwig root sheath and stellate reticulum.
Cytokeratin 19, which is strongly expressed in preamelo-
blasts and secretory ameloblasts, is not expressed in
odontomas.24 This cytokeratin expression profile suggests
that odontomas are analogs of the developing tooth germ
that lack complete differentiation of preameloblasts or
ameloblasts and display abnormal enamel organ mineral-
ization.24
A gene that plays an important role in early tooth
morphogenesis, LHX8, has been shown to have a higher
level of expression in human odontoma-derived mesen-
chymal cells than in adult dental mesenchymal stem cells.24
This overexpression of LHX8 may have a role in odontoma
formation, but the specific mechanism by which the LHX8
gene promotes such an overgrowth has not been de-
tailed.24
Keratocystic Odontogenic Tumor
(Odontogenic Keratocyst)
Keratocystic odontogenic tumor is a cystic lesion arising
from dental laminal epithelium and is usually found in the
mandible or maxilla.25 The older, more traditional designa-
tion for this lesion is odontogenic keratocyst. These lesions can
exhibit aggressive behavior and frequent recurrence. Kera-
tocystic odontogenic tumors can arise sporadically or in
association with the nevoid basal cell carcinoma (Gorlin)
syndrome.
The gene associated with nevoid basal cell carcinoma
syndrome is known to have a tumor suppressor function
and to be related to the PTCH gene.25,26 This relationship
has prompted investigations into a possible connection
between the PTCH gene and the formation of the
odontogenic cysts often seen in individuals with the
syndrome. These cystic lesions have been shown to carry
frequent allelic losses in the PTCH gene and some others,
including CDKN2A, TP53, MCC, TSLC1, LTAS2, and FHIT
(Table 6).25,27–29 Interestingly, all of these genes have tumor-
suppressor functions.27 The presence of these allelic losses
supports the supposition that these lesions are neoplastic
rather than developmental25 and gives credence for the use
of keratocystic odontogenic tumor as a designation for these
lesions. This evidence extends to the development of
sporadic keratocystic odontogenic tumors in addition to
the syndromic occurrences. Other genetic studies of
keratocystic odontogenic tumors have detected deletions
within cadherin-related genes (CDH5 and CDH18), possibly
providing an explanation for the frequently observed
detachment of the cyst-lining epithelium from the under-
Involved Gene(s)
COL1A1, COL1A2
DSPP
DSPP
Odontogenic Molecular Pathology—Cabay
 Table 5. Phenotypic Classification of Dentin Dysplasia
Type Alternate Term(s)
I Radicular dentin dysplasia
Rootless teeth
II Coronal dentin dysplasia
lying stroma, a histopathologic hallmark of these lesions
(Figure 2).30
Ameloblastoma
Ameloblastoma is an epithelial odontogenic tumor that
arises without participation of odontogenic mesenchyme.5
There are 4 major histopathologic types of ameloblastoma:
solid/multicystic (Figure 3), extraosseous/peripheral, des-
moplastic, and unicystic.31 The solid/multicystic type is the
most common, and most ameloblastomas occur in the
posterior mandible. Ameloblastomas tend to expand bone
as they grow. The extraosseous/peripheral type has a male
to female predominance of approximately 1.9:1, whereas the
other types show no sex predilection.31 The unicystic type is
most often diagnosed during the second or third decade of
life,5 while the other types occur over a very wide age
range.31 Ameloblastomas are slow growing, invade locally,
and exhibit a high rate of recurrence if not removed
adequately.5,31
The differentiation level of ameloblastomas corresponds
to the cap/bell stage of developing teeth. Gene expression
profiling of ameloblastomas by cDNA (complementary
DNA) microarray has revealed that more than 30 genes
display significant changes in expression levels when
compared to corresponding gene expression levels of
deciduous tooth germs in the cap and bell stages of tooth
development.32 The FOS oncogene was overexpressed to the
greatest degree, followed by the TNFRSF1A gene (encoding
tumor necrosis factor receptor 1). All tumors that were
evaluated showed underexpression of SHH, TRAF3, ARH-
GAP4, DCC, CDH12, CDH13, TDGF1, and TGFB1.32 The
presence of monoclonality in solid/multicystic ameloblasto-
ma has been demonstrated,33 but the sequence of molecular
events leading to tumor development has not been
detailed.34 A more recent study35 found distinct expression
of HER family molecules, especially EGFR and HER4, which
may provide predictive outcome information in patients
with ameloblastomas.
Table 6. Tumor-Suppressor Genes Showing Frequent
Allelic Loss in Keratocystic Odontogenic Tumor
(Odontogenic Keratocyst)
PTCH
CDKN2A
TP53
MCC
TSLC1
LTAS2
FHIT
Arch Pathol Lab Med—Vol 138, June 2014
Clinical and Histologic Features
Short, conical, or absent tooth roots
Partial or full coronal pulp chamber obliteration
Disorganized radicular dentin
Well-formed enamel and coronal dentin
Opalescent, bulbous primary teeth with cervical constriction and
pulpal obliteration
Disorganized dentin in primary teeth
Normally colored permanent teeth with enlarged, thistle tube–shaped
pulp chambers
Pulp stones in permanent teeth
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