An Overview of Molecular and Genetic Alterations in Selected Benign Odontogenic Disorders Robert J. Cabay, MD, DDS
Context.—Some dental abnormalities have environmental 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 overgrowths 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
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 pathogenesis of a variety of odontogenic aberrations. These advancements may lead to better prevention and treatment paradigms and improved patient outcomes. (Arch Pathol Lab Med. 2014;138:754–758; doi: 10.5858/ arpa.2013-0057-SA)
A
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
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 documented. 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 development. Oligodontia (partial anodontia) denotes a lack of
Hyperdontia 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: [email protected]). 754 Arch Pathol Lab Med—Vol 138, June 2014
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
Table 3.
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
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 associated 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 recognizable toothlike morphologies (odontoids).22 If the dysmorphic 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
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 developing 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 preameloblasts 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 mineralization.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 mesenchymal 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 detailed.24 Keratocystic Odontogenic Tumor (Odontogenic Keratocyst)
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.
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 designation for this lesion is odontogenic keratocyst. These lesions can exhibit aggressive behavior and frequent recurrence. Keratocystic 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 tumorsuppressor 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-
Phenotypic Classification of Dentinogenesis Imperfecta
Type
Clinical Manifestations
Involved Gene(s)
I II III
Osteogenesis imperfecta with opalescent teeth Opalescent dentin Shell teeth, affects Brandywine isolate
COL1A1, COL1A2 DSPP DSPP
756 Arch Pathol Lab Med—Vol 138, June 2014
Odontogenic Molecular Pathology—Cabay
Table 5. Type
Alternate Term(s)
I
Radicular dentin dysplasia Rootless teeth
II
Coronal dentin dysplasia
Phenotypic Classification of 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, desmoplastic, 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, ARHGAP4, DCC, CDH12, CDH13, TDGF1, and TGFB1.32 The presence of monoclonality in solid/multicystic ameloblastoma 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
References 1. Eidelman E, Chosack A, Rosenzweig KA. Hypodontia: prevalence amongst Jewish populations of different origin. Am J Phys Anthropol. 1973; 39(1):129–133. 2. Jarvinen S, Lehtinen L. Supernumerary and congenitally missing primary teeth in Finnish children: an epidemiologic study. Acta Odontol Scand. 1981; 39(2):83–86. 3. Lavelle CL, Ashton EH, Flinn RM. Cusp pattern, tooth size and third molar agenesis in the human mandibular dentition. Arch Oral Biol. 1970;15(3):227– 237. 4. Muller TP, Hill IN, Peterson AC, Blayney JR. A survey of congenitally missing permanent teeth. J Am Dent Assoc. 1970;81(1):101–107. 5. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology. 3rd ed. St Louis, MO: Saunders Elsevier; 2009. 6. Stockton DW, Das P, Goldenberg M, D’Souza RN, Patel PI. Mutation of PAX9 is associated with oligodontia. Nat Genet. 2000;24(1):18–19. 7. Frazier-Bowers SA, Guo DC, Cavender A, et al. A novel mutation in human PAX9 causes molar oligodontia. J Dent Res. 2002;81(2):129–133. 8. Lidral AC, Reising BC. The role of MSX1 in human tooth agenesis. J Dent Res. 2002;81(4):274–278. 9. Lammi L, Arte S, Somer M, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet. 2004;74(5): 1043–1050. 10. Vastardis H. The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am J Orthod Dentofacial Orthop. 2000;117(6): 650–656. 11. Nasif MM, Ruffalo RC, Zullo T. Impacted supernumerary teeth: a survey of 50 cases. J Am Dent Assoc. 1983;106(2):201–204. 12. Rajab LD, Hamdan MAM. Supernumerary teeth: review of the literature and a survey of 152 cases. Int J Paediatr Dent. 2002;12(4):244–254. 13. Sedano HO, Gorlin R. Familial occurrence of mesiodens. Oral Surg Oral Med Oral Pathol. 1969;27(3):360–362. 14. Witkop CJ Jr. Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. J Oral Pathol. 1988;17(9– 10):547–553. 15. Urzua ´ B, Ortega-Pinto A, Morales-Bozo I, Rojas-Alcayaga G, Cifuentes V. Defining a new candidate gene for amelogenesis imperfecta: from molecular genetics to biochemistry. Biochem Genet. 2011;49(1–2):104–121. 16. Wright JT. The molecular etiologies and associated phenotypes of amelogenesis imperfecta. Am J Med Genet A. 2006;140(23):2547–2555. 17. Hursey RJ, Witkop CJ Jr, Miklashek D, Sackett LM. Dentinogenesis imperfecta in a racial isolate with multiple hereditary defects. Oral Surg Oral Med Oral Pathol. 1956;9(6):641–658. 18. Witkop CJ Jr, MacLean CJ, Schmidt PJ, Henry JL. Medical and dental findings in the Brandywine isolate. Ala J Med Sci. 1966;3(4):382–403. 19. MacDougall M, Dong J, Acevedo AC. Molecular basis of human dentin diseases. Am J Med Genet A. 2006;140(23):2536–2546. 20. Dean JA, Hartsfield JK Jr, Wright JT, Hart TC. Dentin dysplasia, type II linkage to chromosome 4q. J Craniofac Genet Dev Biol. 1997;17(4):172–177. 21. Rajpar MH, Koch MJ, Davies RM, Mellody KT, Kielty CM, Dixon MJ. Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization. Hum Mol Genet. 2002;11(21):2559–2565. 22. Praetorius F, Piattelli A. Odontoma, compound type. In: Barnes L, Eveson JW, Reichart P, Sidransky D, eds. Pathology and Genetics of Head and Neck Tumours. Lyon, France: IARC Press; 2005:311. World Health Organization Classification of Tumours; vol 9. 23. Praetorius F, Piattelli A. Odontoma, complex type. In: Barnes L, Eveson JW, Reichart P, Sidransky D, eds. Pathology and Genetics of Head and Neck Tumours. Lyon, France: IARC Press; 2005:310. World Health Organization Classification of Tumours; vol 9.
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24. Kim JY, Jeon SH, Park JY, Suh JD, Choung PH. Comparative study of LHX8 expression between odontoma and dental tissue-derived stem cells. J Oral Pathol Med. 2011;40(3):250–256. 25. Agaram NP, Collins BM, Barnes L, et al. Molecular analysis to demonstrate that odontogenic keratocysts are neoplastic. Arch Pathol Lab Med. 2004;128(3): 313–317. 26. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268): 1668–1671. 27. Gomes CC, Diniz MG, Gomez RS. Review of the molecular pathogenesis of the odontogenic keratocyst. Oral Oncol. 2009;45(12):1011–1014. 28. Henley J, Summerlin DJ, Tomich C, Zhang S, Cheng L. Molecular evidence supporting the neoplastic nature of odontogenic keratocyst: a laser capture microdissection study of 15 cases. Histopathology. 2005;47(6):582–586. 29. Malˇci´c A, Juki´c S, Ani´c I, et al. Alterations of FHIT and P53 genes in keratocystic odontogenic tumor, dentigerous and radicular cyst. J Oral Pathol Med. 2008;37(5):294–301.
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30. Heikinheimo K, Jee KJ, Morgan PR, Nagy B, Knuutila S, Leivo I. Genetic changes in sporadic keratocystic odontogenic tumors (odontogenic keratocysts). J Dent Res. 2007;86(6):544–549. 31. Gardner DG, Heikinheimo K, Shear M, Philipsen HP, Coleman H. Ameloblastomas. In: Barnes L, Eveson JW, Reichart P, Sidransky D, eds. Pathology and Genetics of Head and Neck Tumours. Lyon, France: IARC Press; 2005:296– 300. World Health Organization Classification of Tumours; vol 9. 32. Heikinheimo K, Jee KJ, Niini T, et al. Gene expression profiling of ameloblastoma and human tooth germ by means of a cDNA microarray. J Dent Res. 2002;81(8):525–530. 33. Gomes CC, Oliveira Cda S, Castro WH, de Lacerda JC, Gomez RS. Clonal nature of odontogenic tumours. J Oral Pathol Med. 2009;38(4):397–400. 34. Gomes CC, Duarte AP, Diniz MG, Gomez RS. Current concepts of ameloblastoma pathogenesis. J Oral Pathol Med. 2010;39(8):585–591. 35. Oikawa M, Miki Y, Shimizu Y, Kumamoto H. Assessment of protein expression and gene status of human epidermal growth factor receptor (HER) family molecules in ameloblastomas. J Oral Pathol Med. 2013;42(5):424–434.
Odontogenic Molecular Pathology—Cabay
Context.—Some dental abnormalities have environmental 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 overgrowths 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
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 pathogenesis of a variety of odontogenic aberrations. These advancements may lead to better prevention and treatment paradigms and improved patient outcomes. (Arch Pathol Lab Med. 2014;138:754–758; doi: 10.5858/ arpa.2013-0057-SA)
A
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
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 documented. 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 development. Oligodontia (partial anodontia) denotes a lack of
Hyperdontia 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: [email protected]). 754 Arch Pathol Lab Med—Vol 138, June 2014
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
Table 3.
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
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 associated 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 recognizable toothlike morphologies (odontoids).22 If the dysmorphic 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
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 developing 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 preameloblasts 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 mineralization.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 mesenchymal 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 detailed.24 Keratocystic Odontogenic Tumor (Odontogenic Keratocyst)
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.
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 designation for this lesion is odontogenic keratocyst. These lesions can exhibit aggressive behavior and frequent recurrence. Keratocystic 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 tumorsuppressor 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-
Phenotypic Classification of Dentinogenesis Imperfecta
Type
Clinical Manifestations
Involved Gene(s)
I II III
Osteogenesis imperfecta with opalescent teeth Opalescent dentin Shell teeth, affects Brandywine isolate
COL1A1, COL1A2 DSPP DSPP
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Table 5. Type
Alternate Term(s)
I
Radicular dentin dysplasia Rootless teeth
II
Coronal dentin dysplasia
Phenotypic Classification of 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, desmoplastic, 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, ARHGAP4, DCC, CDH12, CDH13, TDGF1, and TGFB1.32 The presence of monoclonality in solid/multicystic ameloblastoma 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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