genetic factors in the etiology of palatally displaced canines2010_16_3_165_171

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Genetic Factors in the Etiology of PalatallyDisplaced CaninesMorgan 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) perma-nent lateral incisor, suggesting a developmental sequence secondary to agenetic influence on permanent maxillary lateral incisor development. Theycan also occur with small or normal ipsilateral permanent lateral incisorsand or agenesis of other teeth, suggesting an overall effect on the dentition

that may be primarily mediated to some degree by genetic factors. PDCstend to cluster in some families, with segregation analysis suggesting asingle gene having a dominant effect with low penetrance. The markedpropensity to skip generations and variable presentation also suggests thepossibility of a complex etiology with multiple genetic or environmentalfactors. Studies of linkage or association of specific DNA polymorphisms

with the trait in multiple families and/or in large population samples areneeded to not only demonstrate a genetic influence but to ultimately deter-mine what those genetic influences are and how they interact with environ-

mental factors. It is time for large clinical studies of patients with PDCs withthe use of modern genotyping techniques to test the hypotheses of if,which, and how genetic factors influence this developmental anomaly toultimately better understand its etiology and treatment. (Semin Orthod2010;16:165-171.) 2010 Elsevier Inc. All rights reserved.

Maxillary canine impaction occurs in ap-proximately 2% of the general popula-tion,1-3 with palatal impaction accounting for85%.4,5 Unlike buccal displacement of maxillarycanines, palatal displacement of maxillary ca-nines, and the frequent ensuing impaction, mostoften occurs in cases in which adequate perim-eter arch space exists. For example, in 1983

Jacoby

5

presented a study showing that 85% ofpalatally impacted canines have sufficient spaceto erupt. Supporting this positive correlation ofpalatally displaced canines (PDCs) and sufficientarch space for eruption was the finding that 21of 25 (84%) patients with unilateral (one side)or bilateral (both sides) PDCs did not displaydental crowding.6

Lateral Incisor Guidance Theory ofMaxillary Canine Eruption

To what then can we attribute palatal displace-ment and impaction of maxillary canines? It haslong been noted that PDCs are commonly ac-companied (preceded) by agenesis of perma-nent maxillary lateral incisors. During normaldevelopment, the permanent canine tooth budoriginates apically, distally, and palatally to itsfinal position in the arch. The distal surface ofthe lateral incisor root provides guidance at acrucial stage in the canines nonlinear eruption

General Practice Residency, University of Kentucky College of Dentistry, Lexington, KY.

Professor and E. Preston Hicks and Chair Endowed in Orth-

odontics and Oral Health Research, University of Kentucky Collegeof Dentistry, Lexington, KY.Supported in part by the E. Preston Hicks Endowed Chair in

Orthodontics and Oral Health Research at the University of Ken-tucky.

Address correspondence to James K. Hartsfield Jr, University ofKentucky College of Dentistry, 800 Rose Street, Room D416, Lex-ington, KY 40536-0297. Phone: (859) 323-0296; E-mail:[email protected]

2010 Elsevier Inc. All rights reserved.1073-8746/10/1603-0$30.00/0doi:10.1053/j.sodo.2010.05.001

165Seminars in Orthodontics, Vol 16, No 3 (September), 2010: pp 165-171
mailto:[email protected]:[email protected]


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path to redirect the tooth downward. When thelateral incisor is absent, the canine will continueon its path palatally and mesially, following thepath of least resistance.7-9 The sequence of max-illary permanent lateral incisor abnormality fol-

lowed by PDC is suggestive of a developmentalmalformation sequence, when there has been asingle localized poor formation of tissue thatinitiates a chain of subsequent defects.10 Thistype of developmental abnormality is well knownfor the Robin and Potter sequences, involving aprimary problem with mandibular growth orkidney development, respectively. The initiatingevent, such as hypoplastic mandibular growth orkidney agenesis, may be syndromic or nonsyn-dromic with a variety of genetic and environ-mental factors. For a developmental sequence,the etiology of the initiating abnormality can beheterogeneous, with the subsequent chain ofevents falling into the same general path regard-less of the etiology.10,11

However, lateral incisor anomalies do notonly occur ipsilateral (adjacent) to the PDC.Both sides of the arch can be affected, some-times to varying degrees. One side may presentwith a missing lateral incisor and the other withasmall or peg-shaped lateral incisor. Becker etal9 describe how PDCs are actually associatedmore frequently with anomalous lateral incisors(ie, small or peg-laterals) than with lateral inci-

sor agenesis.Within studied populations, small permanent

maxillary lateral incisors occur with 25% ofPDCs, whereas peg-shaped lateral incisors occurwith between 12% and 17.2%, and with lateralincisor agenesis between 5.5% and 14%, ofPDCs. These percentages are in contrast to thosepatients presenting with maxillary lateral incisoranomalies in the general population; peg-shaped laterals are found in 1.8% and missinglaterals are found in 1.3%. These disparities in-dicate anomalous lateral incisors appear more

frequently in association with PDCs than as ran-dom anomalies.6,9

When applying the guidance theory of max-illary canine eruption to the occurrence ofanomalous incisors with PDCs, one would ex-pect to find a greater percentage of ipsilateralmaxillary permanent lateral agenesis than peg-shaped or small laterals. Becker explains thisapparent contradiction by describing a guidancetheory that contains 5 parts (1): normal erup-

tion, in which the lateral incisor provides ade-quate guidance for eruption; (2) first-stage im-paction, in which a lateral incisor that is eitheranomalous in form and/or delayed in develop-ment does not offer guidance to the erupting

canine, preventing eruption in a vertical direc-tion and contributing to mesial/palatal impac-tion; (3) first-stage impaction with secondarycorrection, in which the impaction is naturallycorrected; (4) second-stage impaction, in whichthe location of a late-developing anomalous lat-eral or presence of an overretained deciduouscanine during such a critical time prevents thecorrection of movement; and (5) second-stageimpaction with secondary correction, in whichextraction of an over-retained deciduous canineor anomalous lateral opens the space for canineeruption.9,12

Beckers explanation could account for astudy published in 1993 by Power and Short13

that demonstrated within a sample of 47 PDCs,29 (62%) canines erupted into normal arch po-sition after extraction of ipsilateral deciduouscanines. However, 17 of the 47 canines in thesample overlapped the maxillary lateral incisorby more than one half, and only 5 from thisgroup erupted successfully after extraction ofipsilateral deciduous canines. This finding im-plies that most of the severely overlapping ca-nines were, at the time of the ipsilateral decidu-

ous canine extraction, past the point at whichthe presence of an ipsilateral lateral incisor andthe extraction of an ipsilateral primary caninecould help guide the permanent canine intoposition. In addition to distance from the appro-priate eruption site and the mesial movementvector of the displaced permanent canine, it isnot clear whether the regional acceleratory phe-nomenon (an aspect of bone healing resultingin localized osteoporosis) plays a role in thecorrection of eruption of the displaced perma-nent canine following extraction of an ipsilateral

primary canine. Perhaps in addition to themovement vector, the correction is less likely be-cause the further away the displaced canine is fromthe location of the extracted ipsilateral primarycanine, the less affect the regional acceleratoryphenomenon has on bone density.14,15

Although PDC cases are generally considerednonextraction because adequate arch lengthand width usually exist, in one study in whichcases 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 tohave crowding and would have benefited fromadditional treatment.13 This finding indirectlysupports the empiric treatment of PDCs by ex-

traction of retained ipsilateral primary caninesto facilitate a path of eruption; and the consid-eration of palatal expansion as an adjunct in theprotocol because of the space that may begained.16 Interestingly, the use of cervical head-gear has also been reported to increase the like-lihood of the corrected eruption of PDCs inconjunction with ipsilateral primary canine ex-traction.17

Primary Genetic Influence on MaxillaryCanine Eruption

Dental Anomalies Associated With PDCs

PDCs are associated with other dental anomaliesmore often than would be expected by chance.Associated anomalies include small, peg-shaped,or agenesis of lateral incisors (as discussed pre-viously), second premolar agenesis, infraocclu-sion of primary molars, generalized maxillarycrown size reductions, enamel hypoplasia, andthird molar agenesis.18-21 Peck et al19 reported a40% concurrence of third molar agenesis withPDCs, which they compared to a 21% preva-

lence of third molar agenesis within a Europeanpopulation. Sacerdoti and Baccetti demon-strated third molar agenesis occurring in 36.6%of patients with bilateral PDCs compared with20.7% in the control group.22

Multiple studies have been carried out ontooth size in association with PDCs. Sacerdotiand Baccetti found that most (three-quarters) ofPDC cases associated with small lateral incisorswere those in which unilateral PDCs were asso-ciated with bilateral small lateral incisors. In con-trast, 9% of unilateral PDCs were associated with

contralateral (opposite-side) small lateral inci-sors, and 8.6% were associated with ipsilateralsmall incisors.22 These findings suggest thatPDCs were correlated less with the small size ofthe ipsilateral lateral incisor than an influenceon maxillary lateral incisor size in general. Ex-tending this thought is the finding by Paschos etal23 that in patients with unilateral PDCs, bothcentral and lateral incisors were significantlysmaller buccolingually on the affected side.

Brenchley and Oliver24 measured mesiodistaland labiopalatal widths of the 4 maxillary inci-sors of patients with unilateral PDCs and founda slight trend toward increased mesiodistal widthof the affected sides lateral incisor at the gingi-

val margin accompanied by an increased taperin width toward the incisal edge. However, theyfound no statistically significant differences inincisor size in patients with unilateral PDCs. Thisappears to infer peg-shape or at least a tendencytowards peg-shape.

Langberg and Peck25 published a study in2000 in which mesiodistal measurements ofmaxillary and mandibular central and lateralincisors demonstrated that widths were smallerfor central and lateral incisors in the maxillaryand mandibular arches in patients with PDCs.Patients with unilateral and bilateral PDCs wereincluded. The article states all measurementswere taken on the patients left side regardless ofPDC location on the basis of strong rightleftmetrical concordance between homologous hu-man teeth. This is true, although the measure-ment of corresponding teeth on the right andthe left of the maxillary arch might have dis-closed some information on PDCs and develop-mental fluctuating asymmetry, which is oftentaken as an indicator of developmental instabil-ity.26,27

In addition to most reports indicating an in-

creased incidence of dental anomalies associ-ated with PDCs, the etiology of PDCs can beinfluenced by studying who most often presentswith canine displacement. Although unilateraldisplacement is said to occur twice as often asbilateral displacement, female-to-male occur-rence is reported among unilateral PDCs as1.65:1 and among bilateral PDCs as 4:1.22 Inter-estingly, anomalous laterals also present moreoften in female than male patients (2-3:1),9 al-though this does not prove cause and effect.Data indicating a greater female prevalence sup-

port the idea of a genetic influence, possiblysecondary to the earlier development of the den-tition in females compared with male patients,28

although other specific dental development fac-tors may also be involved.

Further evidence that canine impaction maybe increased along with other dental anomaliesin patients with relatively extreme genetic devel-opmental abnormalities is provided by Shapiraet al,29 who studied dental anomalies affecting

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patients with Down syndrome. They noted thatDown syndrome patients consistently presentwith smaller, fewer teeth and delayed dental andother developmental indexes compared withcontrol patients. Their study investigated the fre-

quency of maxillary palatal canine impaction,tooth transposition, and third molar agenesis.Results showed 55% of subjects older than 14years of year presented with agenesis of all fourthird molars, 59% with agenesis of teeth otherthan third molars, 15% with maxillary canine/first premolar transposition, and PDC impactionoccurring 10 times more frequently comparedwith the 1% to 3% occurrence within an Israelicontrol group not diagnosed with Down syn-drome. Of the 4 patients 17 years of age or olderwith impacted canines, all were also missing atleast one third molar, indicating a positive cor-relation between canine impaction and thirdmolar tooth agenesis. Others appeared to alsohave impacted canines and agenesis of thirdmolars, but because of the young ages of thesepatients, some couldhave developed third mo-lars at a later date.29

In contrast to most other studies involvingpatients without Down syndrome, this study ofDown syndrome subjects showed a weak connec-tion between canine impaction and small/peg-shaped laterals, with only 1 subject presentingboth anomalies. The authors attributed the high

incidence of canine impaction to 3 possible ge-netic factors seen frequently in Down syndromepatients: an underdeveloped maxilla, delayeddental development, and the presence of smallor missing lateral incisors.29 Regardless ofwhether genetics causes predisposition for ca-nine impaction or the impaction itself, the highprevalence of impacted canines as well as otherconcomitant dental anomalies in Down syn-drome patientsa population affected by a spe-cific genetic chromosomal abnormalitypro-vides evidence for the importance of genetic

factors.Patients with Down syndrome who have agen-esis of one or more permanent maxillary lateralincisors have greater fluctuating asymmetry ofthe permanent maxillary central incisors thanthose individuals with Down syndrome who donot have permanent maxillary lateral incisoragenesis,30 suggesting a decrease in develop-mental stability. There is evidence that increaseddevelopmental anomalies and increased fluctu-

ating asymmetry of teeth and other structures inDown syndrome represent partially disregulateddevelopment of a general nature.31 Becausethere can be PDCs with maxillary permanentlateral incisors in place, a genetic factor or fac-

tors associated not just with development of themaxillary permanent lateral incisors, but withdental development in general, may be an etio-logic factor.

Twin and Family Studies of PDCs

Pirinen et al32 published a study in 1996 inwhich they constructed 35 family trees (pedi-grees) after examining 77 female and 29 maleorthodontic patients (probands) treated forPDCs, 110 first-degree relatives (sharing on av-erage 1 of 2 of their genes with the probands),and 93-second degree relatives (who share onaverage 1 of 4 genes with the probands). Theyfound PDCs within 8 families, with 10 first- orsecond-degree relatives expressing the pheno-type, representing a 4.9% prevalence in theserelatives of patients with PDCs, 2.5 times thepopulation prevalence.2 However, it should al-ways be borne in mind that traits that occurmore often in some families are not necessarilyentirely or even partially caused by intrafamilialgenetic factors, although these factors may influ-ence how the family members tend to react to

the environmental factors that they will alsoshare.33

A report of 1 set of female monozygotic twinswho were concordant for bilateral palatally dis-placed and unerupted permanent maxillary ca-nines with permanent maxillary lateral incisorsof normal size and position indicated that, atleast in this sibling set, the guidance theory isnot the only pathogenic explanation. After ex-traction of the maxillary deciduous canines andheadgear treatment for 15 months, both girlsshowed normal eruption of 1 canine with con-

tinued impaction of the other.34

Although inter-esting, reports of a single set of monozygotictwins offer limited etiologic insight as there is nocomparison of the concordance of severalmonozygotic and dizygotic twins from which todraw even rudimentary conclusions about therelative importance and interaction of geneticand environmental factors.

Theauthors of another twin study publishedin 200835 reported monozygotic and dizygotic



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twins with ectopically positioned canines (buc-cally or lingually), as well as several patients withectopically positioned canines and their families.Although the similar concordance between themonozygotic and dizygotic twins for ectopic ca-

nines (2 of 7 pairs of twins for each type, ie,28.6%) indicates minimal if any genetic influ-ence, the observation of ectopic canines inblood relatives of patients with PDCs indicatedthat there was a genetic component to theiroccurrence. The prevalence of ectopic canineswas 15% among first-degree relatives comparedwith 4.4% to 5.5% within the geographic popu-lation (Malta). In addition, it was noted thatlateral incisor agenesis was 7.88% comparedwith 3.21% in the general population. Thus,occurrence of ectopic canines was more com-mon within families than would result fromchance.

Segregation analysis determined that ectopiccanines are most likely an autosomal-dominanttrait in most of the families in the study, withincomplete penetrance, because 85% of the3-generation families showed instances in whichan obligate carrier showed a normal phenotype,although the condition occurred in their chil-dren (sometimes referred to as skipping gener-ations). Interestingly, although there was, asreported previously, a predilection towards fe-males being affected, there was no evidence in

the segregation analysis of sex-linked inheri-tance. The dominant inheritance with a relativelylow penetrance of 36% indicates that although adominant or major gene is involved, there areother factors (environmental, epigenetic, or per-haps still other genes) that influence and ac-count for varying phenotypes.35 Unfortunately,the conclusions in this interesting paper aresomewhat clouded by the lumping of buccal andpalatal positioned canines that have not eruptedinto the classification of ectopic canines.

Need for Genetic Linkage/Association Studiesof PDCs With the Use of Polymorphic DNAMarkers

Multiple genes, including those that code forproteins called transcription factors that modifygene expression, such as MSX1, PAX9, andAXIN2among others,play arole in odontogen-esis and agenesis.36-38 Mossey39 pointed out thatbecause PDCs occur with other anomalies, such

as reduced tooth size and tooth agenesis, andthat these types of genes influence dental pat-terning and development, then perhaps genes,such as these may also affect canine develop-ment/displacement/impaction. He also dis-

cussed how this theory of tooth developmentbeing affected by these genes appears to coin-cide with Butlers field theory. In Butlers theory,mammalian dentition develops in 3 domains:incisors, canines, and molars/premolars. Onetooth within each domain is considered func-tionally more important and evolutionarily morestable, and it tends to be the more central tooth.For example, the central incisor development ismore stable (stability meaning least common tovarying in size, morphology, or position or leastlikely to not develop) than the lateral incisor,and within the premolar/molar group, the firstmolar is most stable.39,40 Anomalies associatedwith displaced canines are congruent with a gen-eral perturbation in dental development, as lat-eral incisors and third molars (the molar fur-thest from the first molar) are the most commonteeth affected concurrent with PDCs.

Although ina segregation analysis study Ca-milleri et al35 concluded that a single genemodel is the most likely mode of inheritance forPDCs, the large incidence of skipping genera-tions suggests the possibility that at least some ofthe families studied have a complex etiology.

Also, as the authors noted, there could be het-erogeneity across the families. The genetics ofPDCs are therefore not simple. Even if mostcases or affected families are due to a singleautosomal dominant or major gene, the lowpenetrance and variable expressivity suggest thepossibility of a complex etiology.

In complex traits, multiple genes interact to-gether with environmental factors, possibly in-cluding nutrition, trauma, oral habits, and mus-cle development to produce a given phenotypeor trait. These traits are sometimes termed dis-

continuous because the presence of the trait(penetrance) or the severity (expressivity) of thephenotype may depend on an individuals par-ticular genetic make-up and environmental in-fluence.21,41 Although much is yet to be learnedabout the etiology of palatal canine displace-ment, evidence gathered to date points to theetiology of PDCs fitting more than 1 pathogenicmodel. Both genetic and environmental factorscontribute to a possible complex etiology, in



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which each case could be influenced by bothfactors to varying degrees.21

This complexity may present as a mechanismpossible in overall dental development in fe-males, as a developmental sequence involving

the ipsilateral permanent maxillary lateral inci-sor, or a perturbation tending to affect the moredevelopmentally variable part of the dentitioninteracting with the pattern of tooth develop-ment. After all, impaction of permanent man-dibular canines does occur, often with a crownto the mesial in an orientation parallel to thelower mandibular border; this is less commonthan their later developing and erupting perma-nent maxillary counterparts. How then to moveforward?

The complexity and interaction of geneticfactors and their proteins in the odontogenichomeobox code model of dental developmentpatterning includes a nested expression patternof homeobox genes. They produce a combina-tion code of proteins that contain sections, suchas homeoboxes that can interact with DNA, af-fecting gene expression and helping to definetooth type in different areas of the jaw. Thus, aparticular combination of the genetic factorsmust be expressed to have teethform, and forparticular teeth to be formed.38 This indicatesthat 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 sizeof present teeth to be reduced with hypodontia,the variation in hypodontia that can occur insome patients with mutations in genes usuallyassociated with particular patterns, with stillother teeth occasionally involved,42 and thestrong association between second premolaragenesis and agenesis of other permanent teeth,as well as a significantly increased occurrence ofsmall permanent maxillary lateral incisors and

PDCs.43,44

Studies of linkage or association of specificDNA polymorphisms with the trait in multiplefamilies and/or in large population samples areneeded to not only demonstrate a genetic influ-ence, but to ultimately determine what thosegenetic influences are and how they interactwith environmental factors.45,46 It is time forlarge clinical studies of individuals with PDCs inwhich modern genotyping techniques are used

to test the hypotheses of if, which, and howgenetic factors influence this developmentalanomaly to ultimately better understand its eti-ology and treatment.

AcknowledgmentsThe authors thank Dr. Lorri Ann Morford for her review ofthe manuscript.

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