Genetic Factors in the Etiology of PalatallyDisplaced 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 165-171 165 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 . the correction is less likely because the further away the displaced canine is from the location of the extracted ipsilateral primary canine. small permanent maxillary lateral incisors occur with 25% of PDCs.10 This type of developmental abnormality is well known for the Robin and Potter sequences. and with lateral incisor agenesis between 5. sometimes to varying degrees. Within studied populations. When the lateral incisor is absent. the canine will continue on its path palatally and mesially. at the time of the ipsilateral deciduous canine extraction.14. the less affect the regional acceleratory phenomenon has on bone density.” in which a lateral incisor that is either anomalous in form and/or delayed in development does not offer guidance to the erupting canine. and only 5 from this group erupted successfully after extraction of ipsilateral deciduous canines. These percentages are in contrast to those patients presenting with maxillary lateral incisor anomalies in the general population.2%.5% and 14%.” 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. whereas peg-shaped lateral incisors occur with between 12% and 17. preventing eruption in a vertical direction and contributing to mesial/palatal impaction. small or peg-laterals) than with lateral incisor agenesis.6. However. Becker et al9 describe how PDCs are actually associated more frequently with anomalous lateral incisors (ie.9. may be syndromic or nonsyndromic with a variety of genetic and environmental factors. following the path of least resistance.11 However. and (5) “second-stage impaction with secondary correction. Becker explains this apparent contradiction by describing a guidance theory that contains 5 parts (1): “normal erup- tion.” in which the impaction is naturally corrected.166 Rutledge and Hartsfield path to redirect the tooth downward. 29 (62%) canines erupted into normal arch position after extraction of ipsilateral deciduous canines. (4) “second-stage impaction. These disparities indicate anomalous lateral incisors appear more frequently in association with PDCs than as random anomalies. of PDCs. with the subsequent chain of events falling into the same general path regardless of the etiology. (3) “first-stage impaction with secondary correction. 17 of the 47 canines in the sample overlapped the maxillary lateral incisor by more than one half. involving a primary problem with mandibular growth or kidney development. pegshaped laterals are found in 1.3%. Perhaps in addition to the movement vector.” in which extraction of an over-retained deciduous canine or anomalous lateral opens the space for canine eruption.9 When applying the “guidance theory” of maxillary canine eruption to the occurrence of anomalous incisors with PDCs. The initiating event. In addition to distance from the appropriate eruption site and the mesial movement vector of the displaced permanent canine.” in which the lateral incisor provides adequate guidance for eruption. One side may present with a missing lateral incisor and the other with a small or peg-shaped lateral incisor. (2) “first-stage impaction. 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. For a developmental sequence. Both sides of the arch can be affected.10.12 Becker’s explanation could account for a study published in 1993 by Power and Short13 that demonstrated within a sample of 47 PDCs.7-9 The sequence of maxillary permanent lateral incisor abnormality followed by PDC is suggestive of a developmental malformation sequence. such as hypoplastic mandibular growth or kidney agenesis. This finding implies that most of the severely overlapping canines were.8% and missing laterals are found in 1. when there has been a single localized poor formation of tissue that initiates a chain of subsequent defects. 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. respectively. lateral incisor anomalies do not only occur ipsilateral (adjacent) to the PDC. one would expect to find a greater percentage of ipsilateral maxillary permanent lateral agenesis than pegshaped or small laterals. the etiology of the initiating abnormality can be heterogeneous. ” This is true. Patients with unilateral and bilateral PDCs were included. 167 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. which is often taken as an indicator of developmental instability.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. 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.28 although other specific dental development factors may also be involved.26. Although unilateral displacement is said to occur twice as often as bilateral displacement.6% of patients with bilateral PDCs compared with 20.9 although this does not prove cause and effect.7% in the control group.6% were associated with ipsilateral small incisors. Data indicating a greater female prevalence support the idea of a genetic influence. more than 50% of the arches were eventually determined to have crowding and would have benefited from additional treatment. second premolar agenesis. 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. possibly secondary to the earlier development of the dentition in females compared with male patients. 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. 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.16 Interestingly.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. peg-shaped. and the consideration of palatal expansion as an adjunct in the protocol because of the space that may be gained.65:1 and among bilateral PDCs as 4:1.18-21 Peck et al19 reported a 40% concurrence of third molar agenesis with PDCs.27 In addition to most reports indicating an increased incidence of dental anomalies associated with PDCs. and third molar agenesis. both central and lateral incisors were significantly smaller buccolingually on the affected side. Sacerdoti and Baccetti demonstrated third molar agenesis occurring in 36. Associated anomalies include small. generalized maxillary crown size reductions. Extending this thought is the finding by Paschos et al23 that in patients with unilateral PDCs.29 who studied dental anomalies affecting . or agenesis of lateral incisors (as discussed previously). the etiology of PDCs can be influenced by studying who most often presents with canine displacement.22 Interestingly. female-to-male occurrence is reported among unilateral PDCs as 1.22 Multiple studies have been carried out on tooth size in association with PDCs. However. which they compared to a 21% prevalence of third molar agenesis within a European population. This appears to infer peg-shape or at least a tendency towards peg-shape. infraocclusion of primary molars. and 8. enamel hypoplasia.13 This finding indirectly supports the empiric treatment of PDCs by extraction of retained ipsilateral primary canines to facilitate a path of eruption. 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. 9% of unilateral PDCs were associated with contralateral (opposite-side) small lateral incisors. 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. they found no statistically significant differences in incisor size in patients with unilateral PDCs. In contrast.Genetic Factors in the Etiology of PDCs erupt or only partially erupted. anomalous laterals also present more often in female than male patients (2-3:1). 34 Although interesting. and 93-second degree relatives (who share on average 1 of 4 genes with the probands). all were also missing at least one third molar. and the presence of small or missing lateral incisors. 2. 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.31 Because there can be PDCs with maxillary permanent lateral incisors in place. but with dental development in general. 15% with maxillary canine/ first premolar transposition. The authors of another twin study published in 200835 reported monozygotic and dizygotic . at least in this sibling set.29 In contrast to most other studies involving patients without Down syndrome. Results showed 55% of subjects older than 14 years of year presented with agenesis of all four third molars. 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. The authors attributed the high incidence of canine impaction to 3 possible genetic factors seen frequently in Down syndrome patients: “an underdeveloped maxilla. with 10 first. fewer teeth and delayed dental and other developmental indexes compared with control patients. but because of the young ages of these patients. may be an etiologic factor. some could have developed third molars at a later date. They found PDCs within 8 families.168 Rutledge and Hartsfield patients with Down syndrome.”29 Regardless of whether genetics causes predisposition for canine impaction or the impaction itself. 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.or second-degree relatives expressing the phenotype. 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. with only 1 subject presenting both anomalies. Others appeared to also have impacted canines and agenesis of third molars. although these factors may influence how the family members tend to react to the environmental factors that they will also share. this study of Down syndrome subjects showed a weak connection between canine impaction and small/pegshaped laterals. 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. 59% with agenesis of teeth other than third molars. They noted that Down syndrome patients consistently present with smaller. Of the 4 patients 17 years of age or older with impacted canines. 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. delayed dental development.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. a genetic factor or factors associated not just with development of the maxillary permanent lateral incisors.30 suggesting a decrease in developmental stability.2 However. the guidance theory is not the only pathogenic explanation. 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. indicating a positive correlation between canine impaction and third molar tooth agenesis. Their study investigated the frequency of maxillary palatal canine impaction. representing a 4. both girls showed normal eruption of 1 canine with continued impaction of the other. 110 first-degree relatives (sharing on average 1 of 2 of their genes with the probands). After extraction of the maxillary deciduous canines and headgear treatment for 15 months. and third molar agenesis.5 times the population prevalence. tooth transposition.9% prevalence in these relatives of patients with PDCs. 6%) indicates minimal if any genetic influence. He also discussed how this theory of tooth development being affected by these genes appears to coincide with Butler’s field theory. and muscle development to produce a given phenotype or trait. there could be heterogeneity across the families. mammalian dentition develops in 3 domains: incisors. The genetics of PDCs are therefore not simple. and within the premolar/molar group. Thus. there are other factors (environmental. and molars/premolars. such 169 as reduced tooth size and tooth agenesis. 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.5% within the geographic population (Malta).35 Unfortunately. although there was. because 85% of the 3-generation families showed instances in which an obligate carrier showed a normal phenotype. PAX9. and it tends to be the more central tooth.21. The prevalence of ectopic canines was 15% among first-degree relatives compared with 4. trauma. or position or least likely to not develop) than the lateral incisor. the observation of ectopic canines in blood relatives of patients with PDCs indicated that there was a genetic component to their occurrence. Even if most cases or affected families are due to a single autosomal dominant or major gene. The dominant inheritance with a relatively low penetrance of 36% indicates that although a dominant or major gene is involved. One tooth within each domain is considered functionally more important and evolutionarily more stable.41 Although much is yet to be learned about the etiology of palatal canine displacement. and that these types of genes influence dental patterning and development. Need for Genetic Linkage/Association Studies of PDCs With the Use of Polymorphic DNA Markers Multiple genes. as well as several patients with ectopically positioned canines and their families. Also. occurrence of ectopic canines was more common within families than would result from chance. possibly including nutrition. canines. a predilection towards females being affected.88% compared with 3. Segregation analysis determined that ectopic canines are most likely an autosomal-dominant trait in most of the families in the study. the first molar is most stable.4% to 5. ie. or perhaps still other genes) that influence and account for varying phenotypes. Interestingly. in . play a role in odontogenesis and agenesis. 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. such as these may also affect canine development/displacement/impaction.39. with incomplete penetrance. In complex traits. Although in a segregation analysis study Camilleri et al35 concluded that a single gene model is the most likely mode of inheritance for PDCs. multiple genes interact together with environmental factors. there was no evidence in the segregation analysis of sex-linked inheritance. such as MSX1. it was noted that lateral incisor agenesis was 7. including those that code for proteins called transcription factors that modify gene expression. 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.36-38 Mossey39 pointed out that because PDCs occur with other anomalies. the large incidence of skipping generations suggests the possibility that at least some of the families studied have a complex etiology.21% in the general population. 28. then perhaps genes. In addition. as lateral incisors and third molars (the molar furthest from the first molar) are the most common teeth affected concurrent with PDCs. the low penetrance and variable expressivity suggest the possibility of a complex etiology. although the condition occurred in their children (sometimes referred to as “skipping generations”). the central incisor development is more stable (stability meaning least common to varying in size.40 Anomalies associated with displaced canines are congruent with a general perturbation in dental development. and AXIN2 among others. epigenetic. as the authors noted. For example. as reported previously. In Butler’s theory. oral habits. morphology.Genetic Factors in the Etiology of PDCs twins with ectopically positioned canines (buccally or lingually). Although the similar concordance between the monozygotic and dizygotic twins for ectopic canines (2 of 7 pairs of twins for each type. Deguchi T. 1989 15. 1986 2. which. Part I. Cohen MM Jr: Robin sequences and complexes: Causal heterogeneity and pathogenetic/phenotypic variability. 2007 10. References 1. Angle Orthod 51:24-29. this is less common than their later developing and erupting permanent maxillary counterparts. Shalhav M: Position of the maxillary permanent canine in relation to anomalous or missing lateral incisors: A population study. Smith P.874 routine fullmonth radiographs. a particular combination of the genetic factors must be expressed to have teeth form. Oral Surg Oral Med Oral Pathol 14:1165-1169. Nordenram A.21 This complexity may present as a mechanism possible in overall dental development in females. A clinical and radiologic study. They produce a combination code of proteins that contain sections. Zilberman Y. et al: Maxillary canine impaction in patients with transverse maxillary deficiency. Stromberg C: Positional variations of the impacted upper canine. anomalous lateral incisors. Behar R: The incidence of anomalous maxillary lateral incisors in relation to palatallydisplaced cuspids. Am J Orthod 84:125-132. Frost HM: The biology of fracture healing. and for particular teeth to be formed. such as homeoboxes that can interact with DNA.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. Thus. II. et al: Histomorphometric evaluation of alveolar bone turnover between the maxilla and the mandible during experimental tooth movement in dogs. 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. Howell FV: A survey of 3. Becker A: Familial trends in palatal canines. This is indicated by the tendency for crown size of present teeth to be reduced with hypodontia. as a developmental sequence involving the ipsilateral permanent maxillary lateral incisor. Jones KL: Smith’s Recognizable Patterns of Human Malformation. may affect not only specific teeth. Acknowledgments The authors thank Dr. Becker A. Lee RT: How much space is created from expansion or premolar extraction? J Orthod 27:11-13. but dependent on the structure and amounts of the protein(s). 1966 5. 1990 7. and related phenomena. Dachi SF. 1999 12. or a perturbation tending to affect the more developmentally variable part of the dentition interacting with the pattern of tooth development. affecting gene expression and helping to define tooth type in different areas of the jaw. 1968 3. Informa Healthcare. 2000 .42 and the strong association between second premolar agenesis and agenesis of other permanent teeth. Acta Odontol Scand 26:145-168. Al-Nimri K. 2005 8. London. Philadelphia. 1997 11. 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