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Genetic Factors in the Etiology of Palatally Displaced Canines
Genetic Factors in the Etiology of Palatally Displaced Canines Morgan S. Rutledge and James K. Hartsfield Jr Palatal displacement of maxillary canines (palatally displaced canines [PDCs]) can be associated with agenesis of the ipsilateral (adjacent) permanent lateral incisor, suggesting a developmental sequence secondary to a genetic influence on permanent maxillary lateral incisor development. They can also occur with small or normal ipsilateral permanent lateral incisors and or agenesis of other teeth, suggesting an overall effect on the dentition that may be primarily mediated to some degree by genetic factors. PDCs tend to cluster in some families, with segregation analysis suggesting a single gene having a dominant effect with low penetrance. The marked propensity to skip generations and variable presentation also suggests the possibility of a complex etiology with multiple genetic or environmental factors. Studies of linkage or association of specific DNA polymorphisms with the trait in multiple families and/or in large population samples are needed to not only demonstrate a genetic influence but to ultimately determine what those genetic influences are and how they interact with environmental factors. It is time for large clinical studies of patients with PDCs with the use of modern genotyping techniques to test the hypotheses of if, which, and how genetic factors influence this developmental anomaly to ultimately better understand its etiology and treatment. (Semin Orthod 2010;16:165-171.) © 2010 Elsevier Inc. All rights reserved.
axillary canine impaction occurs in approximately 2% of the general population,1-3 with palatal impaction accounting for 85%.4,5 Unlike buccal displacement of maxillary canines, palatal displacement of maxillary canines, and the frequent ensuing impaction, most often occurs in cases in which adequate perimeter arch space exists. For example, in 1983
M
Jacoby5 presented a study showing that 85% of palatally impacted canines have sufficient space to erupt. Supporting this positive correlation of palatally displaced canines (PDCs) and sufficient arch space for eruption was the finding that 21 of 25 (84%) patients with unilateral (one side) or bilateral (both sides) PDCs did not display dental crowding.6
General Practice Residency, University of Kentucky College of Dentistry, Lexington, KY. Professor and E. Preston Hicks and Chair Endowed in Orthodontics and Oral Health Research, University of Kentucky College of Dentistry, Lexington, KY. Supported in part by the E. Preston Hicks Endowed Chair in Orthodontics and Oral Health Research at the University of Kentucky. Address correspondence to James K. Hartsfield Jr, University of Kentucky College of Dentistry, 800 Rose Street, Room D416, Lexington, KY 40536-0297. Phone: (859) 323-0296; E-mail: [email protected] © 2010 Elsevier Inc. All rights reserved. 1073-8746/10/1603-0$30.00/0 doi:10.1053/j.sodo.2010.05.001
Lateral Incisor Guidance Theory of Maxillary Canine Eruption To what then can we attribute palatal displacement and impaction of maxillary canines? It has long been noted that PDCs are commonly accompanied (preceded) by agenesis of permanent maxillary lateral incisors. During normal development, the permanent canine tooth bud originates apically, distally, and palatally to its final position in the arch. The distal surface of the lateral incisor root provides guidance at a crucial stage in the canine’s nonlinear eruption
Seminars in Orthodontics, Vol 16, No 3 (September), 2010: pp 165-171
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path to redirect the tooth downward. When the lateral incisor is absent, the canine will continue on its path palatally and mesially, following the path of least resistance.7-9 The sequence of maxillary permanent lateral incisor abnormality followed by PDC is suggestive of a developmental malformation sequence, when there has been a single localized poor formation of tissue that initiates a chain of subsequent defects.10 This type of developmental abnormality is well known for the Robin and Potter sequences, involving a primary problem with mandibular growth or kidney development, respectively. The initiating event, such as hypoplastic mandibular growth or kidney agenesis, may be syndromic or nonsyndromic with a variety of genetic and environmental factors. For a developmental sequence, the etiology of the initiating abnormality can be heterogeneous, with the subsequent chain of events falling into the same general path regardless of the etiology.10,11 However, lateral incisor anomalies do not only occur ipsilateral (adjacent) to the PDC. Both sides of the arch can be affected, sometimes to varying degrees. One side may present with a missing lateral incisor and the other with a small or peg-shaped lateral incisor. Becker et al9 describe how PDCs are actually associated more frequently with anomalous lateral incisors (ie, small or peg-laterals) than with lateral incisor agenesis. Within studied populations, small permanent maxillary lateral incisors occur with 25% of PDCs, whereas peg-shaped lateral incisors occur with between 12% and 17.2%, and with lateral incisor agenesis between 5.5% and 14%, of PDCs. These percentages are in contrast to those patients presenting with maxillary lateral incisor anomalies in the general population; pegshaped laterals are found in 1.8% and missing laterals are found in 1.3%. These disparities indicate anomalous lateral incisors appear more frequently in association with PDCs than as random anomalies.6,9 When applying the “guidance theory” of maxillary canine eruption to the occurrence of anomalous incisors with PDCs, one would expect to find a greater percentage of ipsilateral maxillary permanent lateral agenesis than pegshaped or small laterals. Becker explains this apparent contradiction by describing a guidance theory that contains 5 parts (1): “normal erup-
tion,” in which the lateral incisor provides adequate guidance for eruption; (2) “first-stage impaction,” in which a lateral incisor that is either anomalous in form and/or delayed in development does not offer guidance to the erupting canine, preventing eruption in a vertical direction and contributing to mesial/palatal impaction; (3) “first-stage impaction with secondary correction,” in which the impaction is naturally corrected; (4) “second-stage impaction,” in which the location of a late-developing anomalous lateral or presence of an overretained deciduous canine during such a critical time prevents the correction of movement; and (5) “second-stage impaction with secondary correction,” in which extraction of an over-retained deciduous canine or anomalous lateral opens the space for canine eruption.9,12 Becker’s explanation could account for a study published in 1993 by Power and Short13 that demonstrated within a sample of 47 PDCs, 29 (62%) canines erupted into normal arch position after extraction of ipsilateral deciduous canines. However, 17 of the 47 canines in the sample overlapped the maxillary lateral incisor by more than one half, and only 5 from this group erupted successfully after extraction of ipsilateral deciduous canines. This finding implies that most of the severely overlapping canines were, at the time of the ipsilateral deciduous canine extraction, past the point at which the presence of an ipsilateral lateral incisor and the extraction of an ipsilateral primary canine could help guide the permanent canine into position. In addition to distance from the appropriate eruption site and the mesial movement vector of the displaced permanent canine, it is not clear whether the regional acceleratory phenomenon (an aspect of bone healing resulting in localized osteoporosis) plays a role in the correction of eruption of the displaced permanent canine following extraction of an ipsilateral primary canine. Perhaps in addition to the movement vector, the correction is less likely because the further away the displaced canine is from the location of the extracted ipsilateral primary canine, the less affect the regional acceleratory phenomenon has on bone density.14,15 Although PDC cases are generally considered “nonextraction” because adequate arch length and width usually exist, in one study in which cases in which the permanent canine failed to
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erupt or only partially erupted, more than 50% of the arches were eventually determined to have crowding and would have benefited from additional treatment.13 This finding indirectly supports the empiric treatment of PDCs by extraction of retained ipsilateral primary canines to facilitate a path of eruption; and the consideration of palatal expansion as an adjunct in the protocol because of the space that may be gained.16 Interestingly, the use of cervical headgear has also been reported to increase the likelihood of the corrected eruption of PDCs in conjunction with ipsilateral primary canine extraction.17
Primary Genetic Influence on Maxillary Canine Eruption Dental Anomalies Associated With PDCs PDCs are associated with other dental anomalies more often than would be expected by chance. Associated anomalies include small, peg-shaped, or agenesis of lateral incisors (as discussed previously), second premolar agenesis, infraocclusion of primary molars, generalized maxillary crown size reductions, enamel hypoplasia, and third molar agenesis.18-21 Peck et al19 reported a 40% concurrence of third molar agenesis with PDCs, which they compared to a 21% prevalence of third molar agenesis within a European population. Sacerdoti and Baccetti demonstrated third molar agenesis occurring in 36.6% of patients with bilateral PDCs compared with 20.7% in the control group.22 Multiple studies have been carried out on tooth size in association with PDCs. Sacerdoti and Baccetti found that most (three-quarters) of PDC cases associated with small lateral incisors were those in which unilateral PDCs were associated with bilateral small lateral incisors. In contrast, 9% of unilateral PDCs were associated with contralateral (opposite-side) small lateral incisors, and 8.6% were associated with ipsilateral small incisors.22 These findings suggest that PDCs were correlated less with the small size of the ipsilateral lateral incisor than an influence on maxillary lateral incisor size in general. Extending this thought is the finding by Paschos et al23 that in patients with unilateral PDCs, both central and lateral incisors were significantly smaller buccolingually on the affected side.
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Brenchley and Oliver24 measured mesiodistal and labiopalatal widths of the 4 maxillary incisors of patients with unilateral PDCs and found a slight trend toward increased mesiodistal width of the affected side’s lateral incisor at the gingival margin accompanied by an increased taper in width toward the incisal edge. However, they found no statistically significant differences in incisor size in patients with unilateral PDCs. This appears to infer peg-shape or at least a tendency towards peg-shape. Langberg and Peck25 published a study in 2000 in which mesiodistal measurements of maxillary and mandibular central and lateral incisors demonstrated that widths were smaller for central and lateral incisors in the maxillary and mandibular arches in patients with PDCs. Patients with unilateral and bilateral PDCs were included. The article states all measurements were taken on the patients’ left side regardless of PDC location on the basis of “strong right–left metrical concordance between homologous human teeth.” This is true, although the measurement of corresponding teeth on the right and the left of the maxillary arch might have disclosed some information on PDCs and developmental fluctuating asymmetry, which is often taken as an indicator of developmental instability.26,27 In addition to most reports indicating an increased incidence of dental anomalies associated with PDCs, the etiology of PDCs can be influenced by studying who most often presents with canine displacement. Although unilateral displacement is said to occur twice as often as bilateral displacement, female-to-male occurrence is reported among unilateral PDCs as 1.65:1 and among bilateral PDCs as 4:1.22 Interestingly, anomalous laterals also present more often in female than male patients (2-3:1),9 although this does not prove cause and effect. Data indicating a greater female prevalence support the idea of a genetic influence, possibly secondary to the earlier development of the dentition in females compared with male patients,28 although other specific dental development factors may also be involved. Further evidence that canine impaction may be increased along with other dental anomalies in patients with relatively extreme genetic developmental abnormalities is provided by Shapira et al,29 who studied dental anomalies affecting
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patients with Down syndrome. They noted that Down syndrome patients consistently present with smaller, fewer teeth and delayed dental and other developmental indexes compared with control patients. Their study investigated the frequency of maxillary palatal canine impaction, tooth transposition, and third molar agenesis. Results showed 55% of subjects older than 14 years of year presented with agenesis of all four third molars, 59% with agenesis of teeth other than third molars, 15% with maxillary canine/ first premolar transposition, and PDC impaction occurring 10 times more frequently compared with the 1% to 3% occurrence within an Israeli control group not diagnosed with Down syndrome. Of the 4 patients 17 years of age or older with impacted canines, all were also missing at least one third molar, indicating a positive correlation between canine impaction and third molar tooth agenesis. Others appeared to also have impacted canines and agenesis of third molars, but because of the young ages of these patients, some could have developed third molars at a later date.29 In contrast to most other studies involving patients without Down syndrome, this study of Down syndrome subjects showed a weak connection between canine impaction and small/pegshaped laterals, with only 1 subject presenting both anomalies. The authors attributed the high incidence of canine impaction to 3 possible genetic factors seen frequently in Down syndrome patients: “an underdeveloped maxilla, delayed dental development, and the presence of small or missing lateral incisors.”29 Regardless of whether genetics causes predisposition for canine impaction or the impaction itself, the high prevalence of impacted canines as well as other concomitant dental anomalies in Down syndrome patients—a population affected by a specific genetic chromosomal abnormality—provides evidence for the importance of genetic factors. Patients with Down syndrome who have agenesis of one or more permanent maxillary lateral incisors have greater fluctuating asymmetry of the permanent maxillary central incisors than those individuals with Down syndrome who do not have permanent maxillary lateral incisor agenesis,30 suggesting a decrease in developmental stability. There is evidence that increased developmental anomalies and increased fluctu-
ating asymmetry of teeth and other structures in Down syndrome represent partially disregulated development of a general nature.31 Because there can be PDCs with maxillary permanent lateral incisors in place, a genetic factor or factors associated not just with development of the maxillary permanent lateral incisors, but with dental development in general, may be an etiologic factor.
Twin and Family Studies of PDCs Pirinen et al32 published a study in 1996 in which they constructed 35 family trees (pedigrees) after examining 77 female and 29 male orthodontic patients (probands) treated for PDCs, 110 first-degree relatives (sharing on average 1 of 2 of their genes with the probands), and 93-second degree relatives (who share on average 1 of 4 genes with the probands). They found PDCs within 8 families, with 10 first- or second-degree relatives expressing the phenotype, representing a 4.9% prevalence in these relatives of patients with PDCs, 2.5 times the population prevalence.2 However, it should always be borne in mind that traits that occur more often in some families are not necessarily entirely or even partially caused by intrafamilial genetic factors, although these factors may influence how the family members tend to react to the environmental factors that they will also share.33 A report of 1 set of female monozygotic twins who were concordant for bilateral palatally displaced and unerupted permanent maxillary canines with permanent maxillary lateral incisors of normal size and position indicated that, at least in this sibling set, the guidance theory is not the only pathogenic explanation. After extraction of the maxillary deciduous canines and headgear treatment for 15 months, both girls showed normal eruption of 1 canine with continued impaction of the other.34 Although interesting, reports of a single set of monozygotic twins offer limited etiologic insight as there is no comparison of the concordance of several monozygotic and dizygotic twins from which to draw even rudimentary conclusions about the relative importance and interaction of genetic and environmental factors. The authors of another twin study published in 200835 reported monozygotic and dizygotic
Genetic Factors in the Etiology of PDCs
twins with ectopically positioned canines (buccally or lingually), as well as several patients with ectopically positioned canines and their families. Although the similar concordance between the monozygotic and dizygotic twins for ectopic canines (2 of 7 pairs of twins for each type, ie, 28.6%) indicates minimal if any genetic influence, the observation of ectopic canines in blood relatives of patients with PDCs indicated that there was a genetic component to their occurrence. The prevalence of ectopic canines was 15% among first-degree relatives compared with 4.4% to 5.5% within the geographic population (Malta). In addition, it was noted that lateral incisor agenesis was 7.88% compared with 3.21% in the general population. Thus, occurrence of ectopic canines was more common within families than would result from chance. Segregation analysis determined that ectopic canines are most likely an autosomal-dominant trait in most of the families in the study, with incomplete penetrance, because 85% of the 3-generation families showed instances in which an obligate carrier showed a normal phenotype, although the condition occurred in their children (sometimes referred to as “skipping generations”). Interestingly, although there was, as reported previously, a predilection towards females being affected, there was no evidence in the segregation analysis of sex-linked inheritance. The dominant inheritance with a relatively low penetrance of 36% indicates that although a dominant or major gene is involved, there are other factors (environmental, epigenetic, or perhaps still other genes) that influence and account for varying phenotypes.35 Unfortunately, the conclusions in this interesting paper are somewhat clouded by the lumping of buccal and palatal positioned canines that have not erupted into the classification of ectopic canines.
Need for Genetic Linkage/Association Studies of PDCs With the Use of Polymorphic DNA Markers Multiple genes, including those that code for proteins called transcription factors that modify gene expression, such as MSX1, PAX9, and AXIN2 among others, play a role in odontogenesis and agenesis.36-38 Mossey39 pointed out that because PDCs occur with other anomalies, such
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as reduced tooth size and tooth agenesis, and that these types of genes influence dental patterning and development, then perhaps genes, such as these may also affect canine development/displacement/impaction. He also discussed how this theory of tooth development being affected by these genes appears to coincide with Butler’s field theory. In Butler’s theory, mammalian dentition develops in 3 domains: incisors, canines, and molars/premolars. One tooth within each domain is considered functionally more important and evolutionarily more stable, and it tends to be the more central tooth. For example, the central incisor development is more stable (stability meaning least common to varying in size, morphology, or position or least likely to not develop) than the lateral incisor, and within the premolar/molar group, the first molar is most stable.39,40 Anomalies associated with displaced canines are congruent with a general perturbation in dental development, as lateral incisors and third molars (the molar furthest from the first molar) are the most common teeth affected concurrent with PDCs. Although in a segregation analysis study Camilleri et al35 concluded that a single gene model is the most likely mode of inheritance for PDCs, the large incidence of skipping generations suggests the possibility that at least some of the families studied have a complex etiology. Also, as the authors noted, there could be heterogeneity across the families. The genetics of PDCs are therefore not simple. Even if most cases or affected families are due to a single autosomal dominant or major gene, the low penetrance and variable expressivity suggest the possibility of a complex etiology. In complex traits, multiple genes interact together with environmental factors, possibly including nutrition, trauma, oral habits, and muscle development to produce a given phenotype or trait. These traits are sometimes termed “discontinuous” because the presence of the trait (penetrance) or the severity (expressivity) of the phenotype may depend on an individual’s particular genetic make-up and environmental influence.21,41 Although much is yet to be learned about the etiology of palatal canine displacement, evidence gathered to date points to the etiology of PDCs fitting more than 1 pathogenic model. Both genetic and environmental factors contribute to a possible complex etiology, in
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which each case could be influenced by both factors to varying degrees.21 This complexity may present as a mechanism possible in overall dental development in females, as a developmental sequence involving the ipsilateral permanent maxillary lateral incisor, or a perturbation tending to affect the more developmentally variable part of the dentition interacting with the pattern of tooth development. After all, impaction of permanent mandibular canines does occur, often with a crown to the mesial in an orientation parallel to the lower mandibular border; this is less common than their later developing and erupting permanent maxillary counterparts. How then to move forward? The complexity and interaction of genetic factors and their proteins in the odontogenic homeobox code model of dental development patterning includes a nested expression pattern of homeobox genes. They produce a combination code of proteins that contain sections, such as homeoboxes that can interact with DNA, affecting gene expression and helping to define tooth type in different areas of the jaw. Thus, a particular combination of the genetic factors must be expressed to have teeth form, and for particular teeth to be formed.38 This indicates that protein, and therefore genetic variation, may affect not only specific teeth, but dependent on the structure and amounts of the protein(s), may have a tendency to affect other teeth as well. This is indicated by the tendency for crown size of present teeth to be reduced with hypodontia, the variation in hypodontia that can occur in some patients with mutations in genes usually associated with particular patterns, with still other teeth occasionally involved,42 and the strong association between second premolar agenesis and agenesis of other permanent teeth, as well as a significantly increased occurrence of small permanent maxillary lateral incisors and PDCs.43,44 Studies of linkage or association of specific DNA polymorphisms with the trait in multiple families and/or in large population samples are needed to not only demonstrate a genetic influence, but to ultimately determine what those genetic influences are and how they interact with environmental factors.45,46 It is time for large clinical studies of individuals with PDCs in which modern genotyping techniques are used
to test the hypotheses of if, which, and how genetic factors influence this developmental anomaly to ultimately better understand its etiology and treatment.
Acknowledgments The authors thank Dr. Lorri Ann Morford for her review of the manuscript.
References 1. Brin I, Becker A, Shalhav M: Position of the maxillary permanent canine in relation to anomalous or missing lateral incisors: A population study. Eur J Orthod 8:1216, 1986 2. Thilander B, Jakobsson SO: Local factors in impaction of maxillary canines. Acta Odontol Scand 26:145-168, 1968 3. Dachi SF, Howell FV: A survey of 3,874 routine fullmonth radiographs. II. A study of impacted teeth. Oral Surg Oral Med Oral Pathol 14:1165-1169, 1961 4. Nordenram A, Stromberg C: Positional variations of the impacted upper canine. A clinical and radiologic study. Oral Surg Oral Med Oral Pathol 22:711-714, 1966 5. Jacoby H: The etiology of maxillary canine impactions. Am J Orthod 84:125-132, 1983 6. Zilberman Y, Cohen B, Becker A: Familial trends in palatal canines, anomalous lateral incisors, and related phenomena. Eur J Orthod 12:135-139, 1990 7. Al-Nimri K, Gharaibeh T: Space conditions and dental and occlusal features in patients with palatally impacted maxillary canines: An aetiological study. Eur J Orthod 27:461-465, 2005 8. McConnell TL, Hoffman DL, Forbes DP, et al: Maxillary canine impaction in patients with transverse maxillary deficiency. ASDC J Dent Child 63:190-195, 1996 9. Becker A: The Orthodontic Treatment of Impacted Teeth. Abingdon, London, Informa Healthcare, 2007 10. Jones KL: Smith’s Recognizable Patterns of Human Malformation. Philadelphia, W B Saunders Company, 1997 11. Cohen MM Jr: Robin sequences and complexes: Causal heterogeneity and pathogenetic/phenotypic variability. Am J Med Genet 84:311-315, 1999 12. Becker A, Smith P, Behar R: The incidence of anomalous maxillary lateral incisors in relation to palatallydisplaced cuspids. Angle Orthod 51:24-29, 1981 13. Power SM, Short MB: An investigation into the response of palatally displaced canines to the removal of deciduous canines and an assessment of factors contributing to favourable eruption. Br J Orthod 20:215-223, 1993 14. Frost HM: The biology of fracture healing. An overview for clinicians. Part I. Clin Orthop Relat Res 283293, 1989 15. Deguchi T, Takano-Yamamoto T, Yabuuchi T, et al: Histomorphometric evaluation of alveolar bone turnover between the maxilla and the mandible during experimental tooth movement in dogs. Am J Orthod Dentofac Orthop 133:889-897, 2008 16. O’Higgins EA, Lee RT: How much space is created from expansion or premolar extraction? J Orthod 27:11-13, 2000
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17. Baccetti T, Leonardi M, Armi P: A randomized clinical study of two interceptive approaches to palatally displaced canines. Eur J Orthod 30:381-385, 2008 18. Baccetti T: A controlled study of associated dental anomalies. Angle Orthod 68:267-274, 1998 19. Peck S, Peck L, Kataja M: Site-specificity of tooth agenesis in subjects with maxillary canine malpositions. Angle Orthod 66:473-476, 1996 20. Peck S, Peck L, Kataja M: The palatally displaced canine as a dental anomaly of genetic origin. Angle Orthod 64:249-256, 1994 21. Hartsfield JK Jr: Genetics and orthodontics, in Graber TM, Vanarsdall RL, Vig KWL (eds): Orthodontics: Current Principles and Techniques. St. Louis, Elsevier Mosby, 2005, 1213 22. Sacerdoti R, Baccetti T: Dentoskeletal features associated with unilateral or bilateral palatal displacement of maxillary canines. Angle Orthod 74:725-732, 2004 23. Paschos E, Huth KC, Fassler H, et al: Investigation of maxillary tooth sizes in patients with palatal canine displacement. J Orofac Orthop 66:288-298, 2005 24. Brenchley Z, Oliver RG: Morphology of anterior teeth associated with displaced canines. Br J Orthod 24:41-45, 1997 25. Langberg BJ, Peck S: Tooth-size reduction associated with occurrence of palatal displacement of canines. Angle Orthod 70:126-128, 2000 26. Sprowls MW, Ward RE, Jamison PL, et al: Dental Arch asymmetry, fluctuating dental asymmetry, and dental crowding: A comparison of tooth position and tooth size between antimeres. Semin Orthod 14:157-165, 2008 27. Cassidy KM, Harris EF, Tolley EA, et al: Genetic influence on dental arch form in orthodontic patients. Angle Orthod 68:445-454, 1998 28. Demirjian A, Goldstein H, Tanner JM: A new system of dental age assessment. Hum Biol 45:211-227, 1973 29. Shapira J, Chaushu S, Becker A: Prevalence of tooth transposition, third molar agenesis, and maxillary canine impaction in individuals with Down syndrome. Angle Orthod 70:290-296, 2000 30. Townsend GC: Fluctuating dental asymmetry in Down’s syndrome. Aust Dent J 28:39-44, 1983 31. Thornhill R, Moller AP: Developmental stability, disease and medicine. Biol Rev Camb Philos Soc 72:497-548, 1997
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32. Pirinen S, Arte S, Apajalahti S: Palatal displacement of canine is genetic and related to congenital absence of teeth. J Dent Res 75:1742-1746, 1996 33. King L, Harris EF, Tolley EA: Heritability of cephalometric and occlusal variables as assessed from siblings with overt malocclusions. Am J Orthod Dentofac Orthop 104: 121-131, 1993 34. Leonardi R, Peck S, Caltabiano M, et al: Palatally displaced canine anomaly in monozygotic twins. Angle Orthod 73:466-470, 2003 35. Camilleri S, Lewis CM, McDonald F: Ectopic maxillary canines: Segregation analysis and a twin study. J Dent Res 87:580-583, 2008 36. Matalova E, Fleischmannova J, Sharpe PT, et al: Tooth agenesis: From molecular genetics to molecular dentistry. J Dent Res 87:617-623, 2008 37. Callahan N, Modesto A, Meira R, et al: Axis inhibition protein 2 (AXIN2) polymorphisms and tooth agenesis. Arch Oral Biol 54:45-49, 2009 38. Tucker A, Sharpe P: The cutting-edge of mammalian development; how the embryo makes teeth. Nat Rev Genet 5:499-508, 2004 39. Mossey PA: The heritability of malocclusion. Part 2. The influence of genetics in malocclusion. Br J Orthod 26: 195-203, 1999 40. Vastardis H: The genetics of human tooth agenesis: New discoveries for understanding dental anomalies. Am J Orthod Dentofac Orthop 117:650-656, 2000 41. Mossey PA: The heritability of malocclusion. part 1 Genetics, principles and terminology. Br J Orthod 26:103113, 1999 42. Cobourne MT: Familial human hypodontia—Is it all in the genes? Br Dent J 203:203-208, 2007 43. Garib DG, Peck S, Gomes SC: Increased occurrence of dental anomalies associated with second-premolar agenesis. Angle Orthod 79:436-441, 2009 44. Peck S, Peck L, Kataja M: Concomitant occurrence of canine malposition and tooth agenesis: Evidence of orofacial genetic fields. Am J Orthod Dentofac Orthop 122: 657-660, 2002 45. Abass SK, Hartsfield JK Jr: Investigation of genetic factors affecting complex traits using external apical root resorption as a model. Semin Orthod 14:115-124, 2008 46. Hartsfield JK Jr: Personalized orthodontics, The future of genetics in practice. Semin Orthod 14:166-171, 2008
axillary canine impaction occurs in approximately 2% of the general population,1-3 with palatal impaction accounting for 85%.4,5 Unlike buccal displacement of maxillary canines, palatal displacement of maxillary canines, and the frequent ensuing impaction, most often occurs in cases in which adequate perimeter arch space exists. For example, in 1983
M
Jacoby5 presented a study showing that 85% of palatally impacted canines have sufficient space to erupt. Supporting this positive correlation of palatally displaced canines (PDCs) and sufficient arch space for eruption was the finding that 21 of 25 (84%) patients with unilateral (one side) or bilateral (both sides) PDCs did not display dental crowding.6
General Practice Residency, University of Kentucky College of Dentistry, Lexington, KY. Professor and E. Preston Hicks and Chair Endowed in Orthodontics and Oral Health Research, University of Kentucky College of Dentistry, Lexington, KY. Supported in part by the E. Preston Hicks Endowed Chair in Orthodontics and Oral Health Research at the University of Kentucky. Address correspondence to James K. Hartsfield Jr, University of Kentucky College of Dentistry, 800 Rose Street, Room D416, Lexington, KY 40536-0297. Phone: (859) 323-0296; E-mail: [email protected] © 2010 Elsevier Inc. All rights reserved. 1073-8746/10/1603-0$30.00/0 doi:10.1053/j.sodo.2010.05.001
Lateral Incisor Guidance Theory of Maxillary Canine Eruption To what then can we attribute palatal displacement and impaction of maxillary canines? It has long been noted that PDCs are commonly accompanied (preceded) by agenesis of permanent maxillary lateral incisors. During normal development, the permanent canine tooth bud originates apically, distally, and palatally to its final position in the arch. The distal surface of the lateral incisor root provides guidance at a crucial stage in the canine’s nonlinear eruption
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path to redirect the tooth downward. When the lateral incisor is absent, the canine will continue on its path palatally and mesially, following the path of least resistance.7-9 The sequence of maxillary permanent lateral incisor abnormality followed by PDC is suggestive of a developmental malformation sequence, when there has been a single localized poor formation of tissue that initiates a chain of subsequent defects.10 This type of developmental abnormality is well known for the Robin and Potter sequences, involving a primary problem with mandibular growth or kidney development, respectively. The initiating event, such as hypoplastic mandibular growth or kidney agenesis, may be syndromic or nonsyndromic with a variety of genetic and environmental factors. For a developmental sequence, the etiology of the initiating abnormality can be heterogeneous, with the subsequent chain of events falling into the same general path regardless of the etiology.10,11 However, lateral incisor anomalies do not only occur ipsilateral (adjacent) to the PDC. Both sides of the arch can be affected, sometimes to varying degrees. One side may present with a missing lateral incisor and the other with a small or peg-shaped lateral incisor. Becker et al9 describe how PDCs are actually associated more frequently with anomalous lateral incisors (ie, small or peg-laterals) than with lateral incisor agenesis. Within studied populations, small permanent maxillary lateral incisors occur with 25% of PDCs, whereas peg-shaped lateral incisors occur with between 12% and 17.2%, and with lateral incisor agenesis between 5.5% and 14%, of PDCs. These percentages are in contrast to those patients presenting with maxillary lateral incisor anomalies in the general population; pegshaped laterals are found in 1.8% and missing laterals are found in 1.3%. These disparities indicate anomalous lateral incisors appear more frequently in association with PDCs than as random anomalies.6,9 When applying the “guidance theory” of maxillary canine eruption to the occurrence of anomalous incisors with PDCs, one would expect to find a greater percentage of ipsilateral maxillary permanent lateral agenesis than pegshaped or small laterals. Becker explains this apparent contradiction by describing a guidance theory that contains 5 parts (1): “normal erup-
tion,” in which the lateral incisor provides adequate guidance for eruption; (2) “first-stage impaction,” in which a lateral incisor that is either anomalous in form and/or delayed in development does not offer guidance to the erupting canine, preventing eruption in a vertical direction and contributing to mesial/palatal impaction; (3) “first-stage impaction with secondary correction,” in which the impaction is naturally corrected; (4) “second-stage impaction,” in which the location of a late-developing anomalous lateral or presence of an overretained deciduous canine during such a critical time prevents the correction of movement; and (5) “second-stage impaction with secondary correction,” in which extraction of an over-retained deciduous canine or anomalous lateral opens the space for canine eruption.9,12 Becker’s explanation could account for a study published in 1993 by Power and Short13 that demonstrated within a sample of 47 PDCs, 29 (62%) canines erupted into normal arch position after extraction of ipsilateral deciduous canines. However, 17 of the 47 canines in the sample overlapped the maxillary lateral incisor by more than one half, and only 5 from this group erupted successfully after extraction of ipsilateral deciduous canines. This finding implies that most of the severely overlapping canines were, at the time of the ipsilateral deciduous canine extraction, past the point at which the presence of an ipsilateral lateral incisor and the extraction of an ipsilateral primary canine could help guide the permanent canine into position. In addition to distance from the appropriate eruption site and the mesial movement vector of the displaced permanent canine, it is not clear whether the regional acceleratory phenomenon (an aspect of bone healing resulting in localized osteoporosis) plays a role in the correction of eruption of the displaced permanent canine following extraction of an ipsilateral primary canine. Perhaps in addition to the movement vector, the correction is less likely because the further away the displaced canine is from the location of the extracted ipsilateral primary canine, the less affect the regional acceleratory phenomenon has on bone density.14,15 Although PDC cases are generally considered “nonextraction” because adequate arch length and width usually exist, in one study in which cases in which the permanent canine failed to
Genetic Factors in the Etiology of PDCs
erupt or only partially erupted, more than 50% of the arches were eventually determined to have crowding and would have benefited from additional treatment.13 This finding indirectly supports the empiric treatment of PDCs by extraction of retained ipsilateral primary canines to facilitate a path of eruption; and the consideration of palatal expansion as an adjunct in the protocol because of the space that may be gained.16 Interestingly, the use of cervical headgear has also been reported to increase the likelihood of the corrected eruption of PDCs in conjunction with ipsilateral primary canine extraction.17
Primary Genetic Influence on Maxillary Canine Eruption Dental Anomalies Associated With PDCs PDCs are associated with other dental anomalies more often than would be expected by chance. Associated anomalies include small, peg-shaped, or agenesis of lateral incisors (as discussed previously), second premolar agenesis, infraocclusion of primary molars, generalized maxillary crown size reductions, enamel hypoplasia, and third molar agenesis.18-21 Peck et al19 reported a 40% concurrence of third molar agenesis with PDCs, which they compared to a 21% prevalence of third molar agenesis within a European population. Sacerdoti and Baccetti demonstrated third molar agenesis occurring in 36.6% of patients with bilateral PDCs compared with 20.7% in the control group.22 Multiple studies have been carried out on tooth size in association with PDCs. Sacerdoti and Baccetti found that most (three-quarters) of PDC cases associated with small lateral incisors were those in which unilateral PDCs were associated with bilateral small lateral incisors. In contrast, 9% of unilateral PDCs were associated with contralateral (opposite-side) small lateral incisors, and 8.6% were associated with ipsilateral small incisors.22 These findings suggest that PDCs were correlated less with the small size of the ipsilateral lateral incisor than an influence on maxillary lateral incisor size in general. Extending this thought is the finding by Paschos et al23 that in patients with unilateral PDCs, both central and lateral incisors were significantly smaller buccolingually on the affected side.
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Brenchley and Oliver24 measured mesiodistal and labiopalatal widths of the 4 maxillary incisors of patients with unilateral PDCs and found a slight trend toward increased mesiodistal width of the affected side’s lateral incisor at the gingival margin accompanied by an increased taper in width toward the incisal edge. However, they found no statistically significant differences in incisor size in patients with unilateral PDCs. This appears to infer peg-shape or at least a tendency towards peg-shape. Langberg and Peck25 published a study in 2000 in which mesiodistal measurements of maxillary and mandibular central and lateral incisors demonstrated that widths were smaller for central and lateral incisors in the maxillary and mandibular arches in patients with PDCs. Patients with unilateral and bilateral PDCs were included. The article states all measurements were taken on the patients’ left side regardless of PDC location on the basis of “strong right–left metrical concordance between homologous human teeth.” This is true, although the measurement of corresponding teeth on the right and the left of the maxillary arch might have disclosed some information on PDCs and developmental fluctuating asymmetry, which is often taken as an indicator of developmental instability.26,27 In addition to most reports indicating an increased incidence of dental anomalies associated with PDCs, the etiology of PDCs can be influenced by studying who most often presents with canine displacement. Although unilateral displacement is said to occur twice as often as bilateral displacement, female-to-male occurrence is reported among unilateral PDCs as 1.65:1 and among bilateral PDCs as 4:1.22 Interestingly, anomalous laterals also present more often in female than male patients (2-3:1),9 although this does not prove cause and effect. Data indicating a greater female prevalence support the idea of a genetic influence, possibly secondary to the earlier development of the dentition in females compared with male patients,28 although other specific dental development factors may also be involved. Further evidence that canine impaction may be increased along with other dental anomalies in patients with relatively extreme genetic developmental abnormalities is provided by Shapira et al,29 who studied dental anomalies affecting
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patients with Down syndrome. They noted that Down syndrome patients consistently present with smaller, fewer teeth and delayed dental and other developmental indexes compared with control patients. Their study investigated the frequency of maxillary palatal canine impaction, tooth transposition, and third molar agenesis. Results showed 55% of subjects older than 14 years of year presented with agenesis of all four third molars, 59% with agenesis of teeth other than third molars, 15% with maxillary canine/ first premolar transposition, and PDC impaction occurring 10 times more frequently compared with the 1% to 3% occurrence within an Israeli control group not diagnosed with Down syndrome. Of the 4 patients 17 years of age or older with impacted canines, all were also missing at least one third molar, indicating a positive correlation between canine impaction and third molar tooth agenesis. Others appeared to also have impacted canines and agenesis of third molars, but because of the young ages of these patients, some could have developed third molars at a later date.29 In contrast to most other studies involving patients without Down syndrome, this study of Down syndrome subjects showed a weak connection between canine impaction and small/pegshaped laterals, with only 1 subject presenting both anomalies. The authors attributed the high incidence of canine impaction to 3 possible genetic factors seen frequently in Down syndrome patients: “an underdeveloped maxilla, delayed dental development, and the presence of small or missing lateral incisors.”29 Regardless of whether genetics causes predisposition for canine impaction or the impaction itself, the high prevalence of impacted canines as well as other concomitant dental anomalies in Down syndrome patients—a population affected by a specific genetic chromosomal abnormality—provides evidence for the importance of genetic factors. Patients with Down syndrome who have agenesis of one or more permanent maxillary lateral incisors have greater fluctuating asymmetry of the permanent maxillary central incisors than those individuals with Down syndrome who do not have permanent maxillary lateral incisor agenesis,30 suggesting a decrease in developmental stability. There is evidence that increased developmental anomalies and increased fluctu-
ating asymmetry of teeth and other structures in Down syndrome represent partially disregulated development of a general nature.31 Because there can be PDCs with maxillary permanent lateral incisors in place, a genetic factor or factors associated not just with development of the maxillary permanent lateral incisors, but with dental development in general, may be an etiologic factor.
Twin and Family Studies of PDCs Pirinen et al32 published a study in 1996 in which they constructed 35 family trees (pedigrees) after examining 77 female and 29 male orthodontic patients (probands) treated for PDCs, 110 first-degree relatives (sharing on average 1 of 2 of their genes with the probands), and 93-second degree relatives (who share on average 1 of 4 genes with the probands). They found PDCs within 8 families, with 10 first- or second-degree relatives expressing the phenotype, representing a 4.9% prevalence in these relatives of patients with PDCs, 2.5 times the population prevalence.2 However, it should always be borne in mind that traits that occur more often in some families are not necessarily entirely or even partially caused by intrafamilial genetic factors, although these factors may influence how the family members tend to react to the environmental factors that they will also share.33 A report of 1 set of female monozygotic twins who were concordant for bilateral palatally displaced and unerupted permanent maxillary canines with permanent maxillary lateral incisors of normal size and position indicated that, at least in this sibling set, the guidance theory is not the only pathogenic explanation. After extraction of the maxillary deciduous canines and headgear treatment for 15 months, both girls showed normal eruption of 1 canine with continued impaction of the other.34 Although interesting, reports of a single set of monozygotic twins offer limited etiologic insight as there is no comparison of the concordance of several monozygotic and dizygotic twins from which to draw even rudimentary conclusions about the relative importance and interaction of genetic and environmental factors. The authors of another twin study published in 200835 reported monozygotic and dizygotic
Genetic Factors in the Etiology of PDCs
twins with ectopically positioned canines (buccally or lingually), as well as several patients with ectopically positioned canines and their families. Although the similar concordance between the monozygotic and dizygotic twins for ectopic canines (2 of 7 pairs of twins for each type, ie, 28.6%) indicates minimal if any genetic influence, the observation of ectopic canines in blood relatives of patients with PDCs indicated that there was a genetic component to their occurrence. The prevalence of ectopic canines was 15% among first-degree relatives compared with 4.4% to 5.5% within the geographic population (Malta). In addition, it was noted that lateral incisor agenesis was 7.88% compared with 3.21% in the general population. Thus, occurrence of ectopic canines was more common within families than would result from chance. Segregation analysis determined that ectopic canines are most likely an autosomal-dominant trait in most of the families in the study, with incomplete penetrance, because 85% of the 3-generation families showed instances in which an obligate carrier showed a normal phenotype, although the condition occurred in their children (sometimes referred to as “skipping generations”). Interestingly, although there was, as reported previously, a predilection towards females being affected, there was no evidence in the segregation analysis of sex-linked inheritance. The dominant inheritance with a relatively low penetrance of 36% indicates that although a dominant or major gene is involved, there are other factors (environmental, epigenetic, or perhaps still other genes) that influence and account for varying phenotypes.35 Unfortunately, the conclusions in this interesting paper are somewhat clouded by the lumping of buccal and palatal positioned canines that have not erupted into the classification of ectopic canines.
Need for Genetic Linkage/Association Studies of PDCs With the Use of Polymorphic DNA Markers Multiple genes, including those that code for proteins called transcription factors that modify gene expression, such as MSX1, PAX9, and AXIN2 among others, play a role in odontogenesis and agenesis.36-38 Mossey39 pointed out that because PDCs occur with other anomalies, such
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as reduced tooth size and tooth agenesis, and that these types of genes influence dental patterning and development, then perhaps genes, such as these may also affect canine development/displacement/impaction. He also discussed how this theory of tooth development being affected by these genes appears to coincide with Butler’s field theory. In Butler’s theory, mammalian dentition develops in 3 domains: incisors, canines, and molars/premolars. One tooth within each domain is considered functionally more important and evolutionarily more stable, and it tends to be the more central tooth. For example, the central incisor development is more stable (stability meaning least common to varying in size, morphology, or position or least likely to not develop) than the lateral incisor, and within the premolar/molar group, the first molar is most stable.39,40 Anomalies associated with displaced canines are congruent with a general perturbation in dental development, as lateral incisors and third molars (the molar furthest from the first molar) are the most common teeth affected concurrent with PDCs. Although in a segregation analysis study Camilleri et al35 concluded that a single gene model is the most likely mode of inheritance for PDCs, the large incidence of skipping generations suggests the possibility that at least some of the families studied have a complex etiology. Also, as the authors noted, there could be heterogeneity across the families. The genetics of PDCs are therefore not simple. Even if most cases or affected families are due to a single autosomal dominant or major gene, the low penetrance and variable expressivity suggest the possibility of a complex etiology. In complex traits, multiple genes interact together with environmental factors, possibly including nutrition, trauma, oral habits, and muscle development to produce a given phenotype or trait. These traits are sometimes termed “discontinuous” because the presence of the trait (penetrance) or the severity (expressivity) of the phenotype may depend on an individual’s particular genetic make-up and environmental influence.21,41 Although much is yet to be learned about the etiology of palatal canine displacement, evidence gathered to date points to the etiology of PDCs fitting more than 1 pathogenic model. Both genetic and environmental factors contribute to a possible complex etiology, in
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which each case could be influenced by both factors to varying degrees.21 This complexity may present as a mechanism possible in overall dental development in females, as a developmental sequence involving the ipsilateral permanent maxillary lateral incisor, or a perturbation tending to affect the more developmentally variable part of the dentition interacting with the pattern of tooth development. After all, impaction of permanent mandibular canines does occur, often with a crown to the mesial in an orientation parallel to the lower mandibular border; this is less common than their later developing and erupting permanent maxillary counterparts. How then to move forward? The complexity and interaction of genetic factors and their proteins in the odontogenic homeobox code model of dental development patterning includes a nested expression pattern of homeobox genes. They produce a combination code of proteins that contain sections, such as homeoboxes that can interact with DNA, affecting gene expression and helping to define tooth type in different areas of the jaw. Thus, a particular combination of the genetic factors must be expressed to have teeth form, and for particular teeth to be formed.38 This indicates that protein, and therefore genetic variation, may affect not only specific teeth, but dependent on the structure and amounts of the protein(s), may have a tendency to affect other teeth as well. This is indicated by the tendency for crown size of present teeth to be reduced with hypodontia, the variation in hypodontia that can occur in some patients with mutations in genes usually associated with particular patterns, with still other teeth occasionally involved,42 and the strong association between second premolar agenesis and agenesis of other permanent teeth, as well as a significantly increased occurrence of small permanent maxillary lateral incisors and PDCs.43,44 Studies of linkage or association of specific DNA polymorphisms with the trait in multiple families and/or in large population samples are needed to not only demonstrate a genetic influence, but to ultimately determine what those genetic influences are and how they interact with environmental factors.45,46 It is time for large clinical studies of individuals with PDCs in which modern genotyping techniques are used
to test the hypotheses of if, which, and how genetic factors influence this developmental anomaly to ultimately better understand its etiology and treatment.
Acknowledgments The authors thank Dr. Lorri Ann Morford for her review of the manuscript.
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