Developmental Disorders of the Dentition: An Update tooth review.pdfin humans and mice, indicating...

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 163C:318–332 (2013)

A R T I C L E

Developmental Disorders of the Dentition:An UpdateOPHIR D. KLEIN, SNEHLATA OBEROI, ANN HUYSSEUNE, MARIA HOVORAKOVA,MIROSLAV PETERKA, AND RENATA PETERKOVA

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Dental anomalies are common congenital malformations that can occur either as isolated findings or as part of asyndrome. This review focuses on genetic causes of abnormal tooth development and the implications of theseabnormalities for clinical care. As an introduction, we describe general insights into the genetics of toothdevelopment obtained from mouse and zebrafish models. This is followed by a discussion of isolated as well assyndromic tooth agenesis, including Van der Woude syndrome (VWS), ectodermal dysplasias (EDs), oral‐facial‐digital (OFD) syndrome type I, Rieger syndrome, holoprosencephaly, and tooth anomalies associated with cleft lipand palate. Next, we review delayed formation and eruption of teeth, aswell as abnormalities in tooth size, shape,and form. Finally, isolated and syndromic causes of supernumerary teeth are considered, including cleidocranialdysplasia and Gardner syndrome. © 2013 Wiley Periodicals, Inc.

KEYWORDS: mouse; zebrafish; teeth; hypodontia; supernumerary teeth; craniofacial; syndrome

How to cite this article: Klein OD, Oberoi S, Huysseune A, Hovorakova M, Peterka M, Peterkova R.2013. Developmental disorders of the dentition: An update. Am J Med Genet Part C

Semin Med Genet 163C:318–332.

INTRODUCTIONGenetic causes have been identified forboth isolated tooth malformations andfor the dental anomalies seen in patients

or: NIH; Grant numbers: DP2‐OD00or: California Institute of Regenerator: Grant Agency of the Czech Repin, M.D., Ph.D. is Associate ProfessDirector of the Program in Craniofanderlying craniofacial and dental dedevelopment of teeth, facial skeletoeroi, D.D.S., M.D.S. is Associate Pd treatment for children with cranleft lip, cleft palate, and other cranioc mutations and how they affect deune, Ph.D. is Professor and Head oftructure, and evolution of the skeletevo aspects of skeletal tissues and skal column.akova, Ph.D. is a researcher in the Laf Sciences CR, Prague, Czech Repubnts in tooth development.erka, M.D., Ph.D. is Head of the DeRepublic. He is an Associate Profesborn defects at the Clinic of Plastic Sogenesis and epidemiology of deverkova,M.D., Ph.D. is Head of the LabiencesCR, Prague, Czech Republic. Hthological development of teeth anopment. She is interested in their rognificance.dence to: Ophir D. Klein, M.D., [email protected]/ajmg.c.31382ublished online in Wiley Online Lib

ey Periodicals, Inc.

with craniofacial developmental abnor-malities. Congenitally missing teethare seen in a host of syndromes, andsupernumerary teeth are also central

719, R01‐DE021420.ive Medicine; Grant number: RN2‐00933.ublic; Grant number: CZ:GA 9CR:GAP305/12/1766.or in the Departments of Orofacial Sciences and Pcial and Mesenchymal Biology at UCSF. Dr. Klein's rvelopment. His laboratory uses mouse models to stun, and other organs, as well as the regeneration ofrofessor of Orthodontics with the UCSF Center foriofacial disorders. Her research focuses on developfacial anomalies. She also collaborates with the Cenntal and facial defects in various craniofacial anomathe Biology Department at Ghent University, Belgi

on, with particular attention to teeth. She uses varioueletal elements. Current studies in her group focus o

boratory of Odontogenesis, Department of Teratololic. She is currently working on tooth development in

partment of Teratology at the Institute of Experimesor at the 1st Medical Faculty, Charles University inurgery, 3rdMedical Faculty in Prague. His research inlopmental anomalies.oratory of Odontogenesis, Department of Teratologyer focus ismorphology, including embryology, histolod adjacent structures. During her research career, sle during normal ontogeny, their involvement in the

., Director, Program in Craniofacial and Mesenchym

rary (wileyonlinelibrary.com): 4 October 2013

diagnostic findings in a number ofsyndromes. Additionally, mutations inseveral genes have been associated withboth hypodontia and orofacial clefting

ediatrics, Chair of the Division of Craniofacialesearch focuses in large part on understandingdy the mechanisms responsible for the normalthese organs.Craniofacial Anomalies, where she providesing new methods to assess the outcomes ofter's medical geneticists on research seeking tolies.um. Her research interests are focused on thes teleost fish and other non‐mammalian speciesn the dermal skeleton (including the teeth) and

gy at the Institute of Experimental Medicine atwild‐type andmutant mice, with a focus on the

ntal Medicine at the Academy of Sciences CR,Prague and a clinical teratologist involved in

terests are experimental and clinical teratology,

at the Institute of Experimental Medicine at thegy, and anatomy, and her field of interest is thehe has studied rudimentary structures duringorigin of developmental anomalies, and their

al Biology, UCSF, San Francisco, CA.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 319

in humans and mice, indicating thattooth anomalies and orofacial cleftingmay share common developmentalpathways. Because the study of toothdevelopment is central to understandingthe pathogenesis of dental anomalies,this review begins with an overview ofrecent studies in vertebrate animalmodels, which is followed by a surveyof dental anomalies with known orsuspected genetic causes.

LESSONS FROM ANIMALMODELS

Mouse Dentition: the Major ModelSystem

Most of our knowledge regarding thecellular and genetic basis of mammaliantooth development has come frommouse studies. Although mouse denti-tion is simpler than that of humans, thedevelopmental mechanisms are thoughtto be highly conserved between the two.Both humans and rodents have fewerteeth than the unreduced pattern of their

Figure 1. Comparison of the adult and emfunctional dentition in adult mouse. Right:upper incisor region, five to six small epcommonly give rise to the early bud of the uthree epithelial prominences predetermineincisor. During embryonic day (ED) 12.5–1primordia that do not progress beyond a bud shthickening (dashed line) is present in mandiblthe posterior part of the upper (R1, R2) and lomost conspicuous structures in the cheek regioMS rudiments cease growth due to epithelial apridges. The lowerR2 becomes incorporated in(M1) cap. The buds of the posterior molars (

mammalian ancestors, in which up tothree incisors, one canine, four premo-lars, and three molars may occur in eachdental quadrant. A few species, such assome insectivores, have retained the fullpattern of dentition. Humans have twoincisors, one canine, two premolars andthreemolars in the permanent dentition.The adult mouse dentition is muchmorereduced than in the human, consisting ofthree molars at the back of the mouthand one incisor at the front, separated bya toothless region called a diastema, ineach quadrant (Fig. 1). Another majordifference between mouse and humandentition is that mice have only a singleset of teeth, whereas in humans the firstset of teeth (primary or deciduous teeth)is replaced by a permanent set during

bryonic tootMouse embrithelial promipper incisor. Ithe origin of3.5, the uppape (D1–D5)e. Two large rwer (MS, R2n until ED 13optosis and arto the anterioM2, M3) dev

The adult mouse dentition ismuch more reduced than in thehuman, consisting of threemolars at the back of the

h pattern in themouse. Left:yonic tooth pattern. In thenences are integrated andn the embryonic mandible,the prospective functionaler diastema comprises five, while only a thin epithelialudimentary buds develop in) diastema, and these are the.5. The upper R1, R2, ande transformed into epithelialr part of the lower first molarelop at later stages.

mouth and one incisor at thefront, separated by a toothlessregion called a diastema, ineach quadrant (Fig. 1).Another major differencebetween mouse and humandentition is that mice haveonly a single set of teeth,

whereas in humans the firstset of teeth (primary or

deciduous teeth) is replaced bya permanent set during

childhood.

childhood. The mouse thereforeprovides a simplified model for toothformation in humans.

Beyond serving as a model forunderstanding mammalian tooth devel-opment in general, studying the devel-opment of the reduced dentition inmouse provides two advantages. First,the permanently renewing incisor servesas a model to study the role of stem cellsin organ regeneration [Harada et al.,1999; Seidel et al., 2010; Feng et al.,2011; Juuri et al., 2012; Lapthanasupkulet al., 2012; Biehs et al., 2013]. Second,the mouse embryonic jaws containrudimentary tooth primordia of teeththat were suppressed during evolution[Peterkova et al., 2002b; Hovorakovaet al., 2011] (Fig. 1). In the majority ofthe diastemal tooth primordia, develop-ment is arrested [Peterkova et al., 2003],such that the development of the mousediastema represents a model to studyhypodontia [Peterkova et al., 1995].Some of these rudimentary tooth pri-mordia may be rescued and can give riseto supernumerary teeth [Peterkovaet al., 2002a, 2006; Klein et al., 2006],which can model controlled toothregeneration [Peterkova et al., 2006,2009; Cobourne and Sharpe, 2010].

Teeth form through a series ofreciprocal interactions between epithe-lium (derived from oral ectoderm) andmesenchyme (derived from cranial neu-ral crest), which begin at mid‐gestation

320 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

in mouse embryos [Tucker and Sharpe,2004]. The interactions between oralepithelium and underlying neural‐crestderived mesenchyme are mediated bysecreted signaling molecules from themajor signaling families (FGF, TGF‐b,WNT, and HH), which lead to variousintracellular events, including expressionof transcription factors (e.g., membersof the Msx, Pax, and Runx families,discussed below) [Jussila and Thesleff,2012; Jheon et al., 2013].

As the epithelium and mesenchymeinteract, the developing tooth (toothgerm) progresses through several stages(Fig. 2). The first morphological sign oftooth development is a localized thick-ening of the oral epithelium. Next, thethickened (dental) epithelium invagi-nates into the underlying mesenchyme,forming a dental lamina and tooth buds,while the adjacent dental mesenchymecondenses around the forming toothbuds. Subsequently, the epitheliumaround the bud tip extends farther intothe mesenchyme, forming a cap andthen a bell stage tooth germ. The dentalepithelium (enamel organ) is surroundedby a layer of dental mesenchyme (dentalsac), and the enamel organ encloses themesenchymal papilla. The dental papillaarises from a small population of highlyproliferative mesenchymal cells in closeproximity to the inner dental epitheliumand the primary enamel knot [Rothovaet al., 2012]. Further epithelial morpho-genesis and expansion of the dental

Figure 2. Stages of development of thepithelium thickens and then invaginates intMesenchymal condensation occurs at the buda signaling center during tooth development atmorphogenesis is accompanied by the differedental epithelium and papilla mesenchyme, whprospective tooth crown. The matrix will ecrown, and this is followed by root developm

mesenchyme results in the formationof cusps. During the bell stage, cuspmorphogenesis continues and cytodif-ferentiation begins, as the epithelial cellsclosest to the dental mesenchyme be-come enamel‐producing ameloblasts,and the adjacent mesenchymal cellsbecome dentin‐producing odontoblasts[Ruch, 1995].

Epithelial morphogenesis andgrowth of the dental mesenchymeduring the cap and bell stages arethought to be controlled and coordinat-ed by signals produced by the enamelknot, a morphologically distinct regionof the epithelium containing densely‐packed, non‐proliferating cells. Theprimary enamel knot forms at the centerof the tooth germ at the onset of thecap stage [Jernvall et al., 1994] and issubsequently eliminated by apoptosis[Lesot et al., 1996; Vaahtokari et al.,1996]. Secondary enamel knots form atthe cusp tips, and signals from themcontrol later aspects of cusp morpho-genesis [Jernvall et al., 1998].

In mouse and human, the upperincisors arise largely from the medialnasal process with a minor contributionof the maxillary facial process [Peterkovaet al., 1995; Hovorakova et al., 2006].The upper and lower molars arise fromthe first pharyngeal arch, which appearsto be molecularly patterned in terms oftooth location and identity before anymorphological signs of tooth develop-ment are evident. The mesenchyme of

e lower first molar in mouse. The oralo the neural crest‐derived mesenchyme.stage. The enamel knot appears and acts asthe cap stage. During the bell stage, toothntial growth of the interface between theich predetermines the form (cusps) of theventually mineralize, forming the toothent and tooth eruption.

the first pharyngeal arch initially hasubiquitous odontogenic potential, andthe odontogenic mesenchyme is speci-fied by its proximity to the oralepithelium, which is the source of theinductive signal. It is thought that FGF8from the lateral oral epithelium andBMP4 from the medial oral epitheliumdifferentially regulate the expression oftranscription factors (e.g., Dlx1, Dlx2,and Barx1 are expressed laterally, where-asMsx1 andMsx2 are expressed medial-ly) [Neubuser et al., 1997; Bei andMaas, 1998; Keranen et al., 1999;St Amand et al., 2000; Thomas et al.,2000]. These expression patterns havebeen proposed to represent an “odonto-genic homeobox code” that specifiestooth identity, analogous to homeoboxcodes found in other developmentalsystems [Sharpe, 1995].

The earliest marker for the locationof presumptive teeth is expression ofPax9, which results from antagonisticinteractions of FGF and BMP signaling

The earliest marker for thelocation of presumptive teethis expression of Pax9, whichresults from antagonistic

interactions of FGF and BMPsignaling. Fgf8 induces Pax9expression in first pharyngealarch mesenchyme, whereas

Bmp2 and Bmp4 inhibit thisinduction.

[Neubuser et al., 1997]. Fgf8 inducesPax9 expression in first pharyngeal archmesenchyme, whereas Bmp2 and Bmp4inhibit this induction [Neubuser et al.,1997]. Therefore, Pax9 is expressed onlyin regions where Fgf8 is present butBmp2 andBmp4 are absent. Interestingly,although Pax9 marks the sites of futuretooth development, in mouse studiesPax9 itself appears not to be necessary toposition teeth or initiate odontogenesis.Thus, in the mouse Pax9 mutant, teeth


develop normally up to the bud stage(E13.5) before arresting, indicating thatthis gene is critical for bud developmentbut not for tooth initiation [Peterset al., 1998]. The role of Pax9 in humanhypodontia is discussed below.

The expression of other genesindicates that, at the earliest stages oftooth development, the instructive in-formation resides in the epithelium.Sonic hedgehog (Shh) expression isrestricted to the emerging tooth pri-mordia. The restriction of Shh appears tobe due to repression by Wnt7b in thenon‐dental epithelium [Sarkar et al.,2000]. At the bud stage, the instructiverole shifts from the epithelium to themesenchyme; transcription factors suchasMsx1, Pax9, and Runx2 are expressedin the condensed dental mesenchyme[Thesleff, 2006]. These factors, all ofwhich are important in human toothdevelopment as well, promote theexpression of secreted signaling mole-cules including Bmp4, Fgf3, and Wnt5a,which act upon the epithelium andinduce the enamel knot.

Figure 3. Zebrafish tooth development.fertilization (dpf) (A) and 1‐month old (B). Veteeth not shown in (B). At 6 dpf, primary teeAlizarin stained and cleared preparation of thescheme shown in (A). Note keratinized pad ((anterior to left). E,F: One micrometer plastic5 dpf edar�/�mutant (F). Teeth 3V1, 4V1, 5V1,micrometer plastic cross‐section through an attinto the dentin (d). Scale bars C,E,F¼ 25mm

Zebrafish Dentition: An Up‐and‐Coming ModelIn recent years, animal models otherthan the mouse have emerged for theinvestigation of early development,organogenesis, and regeneration. Zebra-fish in particular have become a favoritelaboratory animal, as they are inexpen-sive to maintain, reproduce easily andabundantly, and have the vertebratebody plan. A vast array of genetic andmolecular tools has been developed forzebrafish, which have now been usedto model nearly every class of humandisease.

The zebrafish has no teeth on its oraljaws, but it has maintained sets of teethon the rearmost pharyngeal arch as aremnant of the once widespread oraltooth coverage in its remote ancestors.These pharyngeal teeth are continuouslyreplaced throughout life and havebeen well characterized in terms ofpatterning, structure and morphodiffer-entiation [Huysseune et al., 1998; Vander heyden and Huysseune, 2000; Vander heyden et al., 2000] (Fig. 3). A

A,B: Schematic representation of the pharyngentral tooth row, yellow; mediodorsal tooth row, octh 3V1, 4V1, and 5V1 are attached, and the first redentition of an 8 dpf zebrafish. Tooth 4V2 (arrowasterisk) opposing the teeth. D: SEM view of vecross‐sections through the pharyngeal dentition oand replacement tooth 4V2 are present in theWT;aching tooth in a one month zebrafish; note odont, D¼ 100mm, G¼ 50mm.

number of studies have addressed thegenetic and molecular underpinnings oftooth development and replacement(reviewed by Stock [2007]). Toothformation and replacement start early,well before many mutations becomelethal (at 48 and 80 hr post‐fertilization,resp.) [Borday‐Birraux et al., 2006]. Thiscircumvents the lethality encounteredwhen modeling craniofacial anomaliesand dental diseases in mouse models.Additionally, because mice do notreplace their dentition, dissecting themechanism of natural lifelong replace-ment in zebrafish represents a strategy forunderstanding tooth replacement inmammals that is not possible with themouse model.

While some developmental genesthat are expressed early in mammaliantooth development, such as pax9, are notexpressed during zebrafish tooth devel-opment [Jackman et al., 2004], manyparallels with mammalian teeth exist.The importance of Fgf signaling issimilar to that in the mouse. Over-expression of Fgf ligands in zebrafish

al dentition of a zebrafish at 6 days post‐hre; dorsal tooth row, green; replacementplacement tooth (4V2) is mineralizing. C:head) is more advanced compared to thentral teeth 2V–5V in a juvenile zebrafishf a 5 dpf wild‐type (WT) zebrafish (E) andonly 4V1 is present in themutant.G: Oneoblasts (od) sending processes (arrowhead)

Figure 4. Ectodermal dysplasia.Peg shaped incisors and multiplemissing teeth in a 13‐year‐old malewith X‐linked hypohidrotic ectoder-mal dysplasia.


embryos results in supernumerary pri-mary teeth [Jackman et al., 2013],whereas blocking Fgf signaling resultsin arrest of primary tooth formation[Jackman et al., 2004]. Downregulationof Bmp signaling likewise results insupernumerary teeth [Jackman et al.,2013]. Mutations affecting ectodysplasin(eda) or its receptor (edar) lead tohypodontia, as discussed below forhumans [Harris et al., 2008] (Figs. 3and 4).

Wnt signaling is a key event inreplacement and renewal of ectodermalappendages, and thus potentially also inthe replacement of primary by perma-nent teeth. Although several mutationsin components of the canonical Wntsignaling pathway do not affect toothnumber in zebrafish (AH personalobservations and [Wiweger et al.,2012]), Lef1 mutants display oligodontia[McGraw et al., 2011]. Whether theWnt pathway plays a role at the level ofinitiation of primary teeth or defectivetooth replacement needs to be clarified.

In addition to signaling moleculesand transcription factors, there arestructural similarities in the tissues andmatrices that constitute mammalian andzebrafish teeth. Thus, current studiesaim at understanding gene function incytodifferentiation or mineralization ofteeth [Go and Korzh, 2013; Verstraetenet al., 2013], or at elucidating the role ofparticular genes in rare diseases associat-ed with dental dysplasia [Bloch‐Zupanet al., 2011].

Initially, large‐scale forward geneticscreens were used to identify genesrelevant to craniofacial and tooth devel-opment, but new technologies areemerging. These include the rapid andtargeted introduction of mutations via

engineered endonucleases such as ZFNs(zinc finger nucleases) and TALENs(transcription activator‐like effector nu-cleases) (reviewed in Huang et al.[2012]). These techniques of reversegenetics hold great promise and willcontinue to increase the relevance ofzebrafish as a model for craniofacial anddental diseases.

HUMAN TOOTHDEVELOPMENTALANOMALIES

Genetic tooth anomalies can be dividedin three main ways. First, the type ofanomaly, whether of number, shape, orboth, must be determined. Theseanomalies can include too many teeth(hyperdontia), too few teeth (toothagenesis), or abnormalities of shapesuch as taurodontism (enlargement ofthe body and pulp of the tooth). Second,it is important to know if the anomaly issyndromic, that is, part of a conditionwith other features, or whether it isisolated. Third, the mode of inheritancemust be determined. Sporadic occur-rences of genetic anomalies are pre-sumed to be caused by recessive ormultifactorial inheritance, by new mu-tations, or by stochastic occurrences. Forthe remainder of this review, we willfocus on genetic causes of abnormaltooth development and the manifesta-tions of these abnormalities in termsof clinical care; disorders of toothmineralization are not discussed in thisreview.

Tooth Agenesis: Hypodontia,Oligodontia, and Anodontia

Hypodontia refers to the absence of oneto six teeth, excluding third molars,whereas oligodontia refers to the ab-sence of more than six teeth, excludingthird molars. Third molars are excluded,

Hypodontia refers to theabsence of one to six teeth,excluding third molars,

whereas oligodontia refers to

the absence of more than sixteeth, excluding third molars.

as these are missing in up to 20% ofpatients, making this a very commonfinding. Anodontia is the completeabsence of teeth in one or bothdentitions. Together, these are referredto as tooth agenesis.

Hypodontia can occur as a sporadicfinding, as part of a syndrome, or as anon‐syndromic familial form. There areover 80 syndromes that include hypo-dontia (see Online Mendelian Inheri-tance in Man, http://www.ncbi.nlm.nih.gov/omim), and some representa-tive syndromes are discussed below.Non‐syndromic familial hypodontiamay be inherited as an autosomaldominant [Alvesalo and Portin, 1969;Vastardis et al., 1996; Goldenberget al., 2000], autosomal recessive [Ah-mad et al., 1998; Pirinen et al., 2001], orsex‐linked trait [Erpenstein and Pfeiffer,1967; De Coster et al., 2009].

Missing teeth are more common inthe permanent dentition than in theprimary dentition, but there is a strongcorrelation between hypodontia inthe primary and permanent dentition[Matalova et al., 2008]. In the primarydentition, the prevalence varies from0.4% to 0.9% in Europe [Ravn, 1971;Jarvinen and Lehtinen, 1981] and is2.4% in Japan [Yonezu et al., 1997]. Inthe permanent dentition, the mostcommonly missing teeth in Caucasiansare the mandibular second premolars(4.2%), maxillary lateral incisors (2.3%),and maxillary second premolars (2.2%)[Polder et al., 2004]. Several researchershave reported a higher prevalence ofhypodontia among females, with afemale to male ratio of 3:2 [Brook,1975], but the reasons for this are notknown.

In individuals with congenitallymissing teeth in one region but crowd-ing in another, autotransplantation hasgood long‐term prognosis if the trans-planted tooth has completed half of itsroot formation [Paulsen et al., 1995].Endosseous implant replacement of themissing teeth is another popular andviable option.

A recent study found that 56%of the patients with isolatedhypodontia had a mutation inWNT10A, which is strongly

expressed in the dentalepithelium at the tooth

initiation stage and is requiredfor normal tooth development

beyond the bud stage.


Sporadic hypodontiaSporadic anodontia and oligodontia arerare, but sporadic hypodontia is arelatively common finding. As a generalrule, if only one or a few teeth aremissing, the missing tooth will be themost distal tooth of any given type. Forexample, if a molar is missing it is usuallythe third molar, if an incisor it is thelateral incisor and if a premolar it isusually the second premolar.

Both genetic and environmentalfactors may contribute to sporadichypodontia [Schalk‐Van Der Weideet al., 1993; Vastardis, 2000]. In termsof environmental influences, develop-ment of the permanent teeth may beaffected by various factors such as traumato the jaws, surgical procedures on thejaws, early extraction of the primaryteeth, chemotherapy and radiation ther-apy [Schalk‐Van Der Weide et al., 1993;Nasman et al., 1997]. Currently, little isknown about the genetic etiologies ofsporadic hypodontia, although thesemay be similar to those that causefamilial non‐syndromic hypodontia.Mutation in PAX9 has been associatedwith both sporadic (or low‐penetrancefamilial) hypodontia and oligodontia[Pawlowska et al., 2010].

Familial, non‐syndromic hypodontiaIn familial hypodontia, the inheritancein the majority of families is autosomaldominant with incomplete penetranceand variable expressivity. Mutations inseveral genes have been found to causefamilial hypodontia. It is also thoughtthat many cases of familial hypodontiamay represent a complex, multifactorialcondition.

A missense mutation in MSX1 onchromosome 4 was the first mutationfound to be associated with non‐syndromic hypodontia. The mutationwas found in all affected members of afamily with missing second premolarsand third molars. Some also had missing

A missense mutation inMSX1 on chromosome 4 wasthe first mutation found to be

associated with non‐syndromichypodontia. The mutationwas found in all affectedmembers of a family withmissing second premolars

and third molars.

maxillary first premolars, mandibularfirst molars, one or both upper lateralincisors or a single lower central incisor.All had normal primary dentitions[Vastardis et al., 1996].

Subsequently, a second gene—PAX9 on chromosome 14—was foundto be involved in hypodontia. A frameshift mutation in PAX9 was identifiedin a family with autosomal dominanthypodontia that had missing permanentmolars [Stockton et al., 2000]. Someindividuals were missing the maxillaryand/or mandibular second premolars aswell as central incisors. Since then anumber of mutations and polymor-phisms have been identified in thehuman PAX9 region with variableforms of oligodontia that mainly affectthe molars [Nieminen et al., 2001;Frazier‐Bowers et al., 2002; Das et al.,2003; Mostowska et al., 2003a,b, 2006].

More recently, hypodontia associ-ated with AXIN2 mutations has beenidentified to affect awider range of toothtypes. In a four‐generation Finnishfamily, 11 members were found to bemissing at least 8 permanent teeth alongwith an increased risk of developingcolorectal neoplasia [Lammi et al.,2004]. AXIN2 is a component of theWNT signaling pathway.

Mutations in two genes that cancause ED, EDA andWNT10A, can alsocause isolated hypodontia; the syn-dromic effects of mutations in thesegenes are discussed later in this review.EDA mutations have recently beenlinked to non‐syndromic hypodontia,which typically includes missing man-dibular and/or upper incisors and canine[Yang et al., 2013]. A recent studyfound that 56% of the patients withisolated hypodontia had a mutation inWNT10A, which is strongly expressedin the dental epithelium at the tooth

initiation stage and is required fornormal tooth development beyond thebud stage [van den Boogaard et al.,2012].

Syndromic hypodontia

Van der Woude syndrome. VWS(OMIM #119300) is characterized byparamedian lip pits and sinuses, conicalelevations of the lower lip, cleft lip and/or cleft palate (CP), and hypodontia.Adhesions between maxilla and mandi-ble (syngnathia) have been reported[Leck and Aird, 1984]. At times, VWScan be identified solely based on lip pits[Soni et al., 2012]. VWS is the mostcommon clefting syndrome and occursin approximately 2% of the populationwith facial clefts [Rintala and Ranta,1981; Schutte et al., 1996]. The preva-lence of VWS is up to 1 in 40,000 stillborn or live births [Burdick, 1986].

VWS is inherited in an autosomaldominant fashion and is caused bymutations in the interferon regulatoryfactor 6 (IRF6) gene [Kondo et al.,2002]. However, there is some geneticheterogeneity in VWS [Wong et al.,2001]. IRF6 mutations also cause popli-teal pterygium syndrome (PPS), whichin addition to the craniofacial findings ofVWS consists of genital abnormalities,webbing of fingers, toes, and behindknees, and other occasional features[Lees et al., 1999].

Lip pits are the most commonmanifestation of VWS. The occurrencehas been reported in up to 88% of theaffected individuals [Janku et al., 1980].

Three genetic loci have beenassociated with ARS so far.FOXC1 and PITX2 encodetranscription factors and arelocated on chromosomes 6p25

and 4q25, respectively.


VWS is underdiagnosed because lowerlip pits are often missed, leading toundetected submucous CP [Lam et al.,2010]. In CP patients with lower lipsinuses, the incidence of hypodontia was77.8% [Ranta and Rintala, 1982].

Hypodontia is frequently seen inVWS, and a close association betweenVWS and congenital absence of secondpremolars has been shown [Schneider,1973; Calzavara Pinton et al., 1989;Oberoi and Vargervik, 2005a]. There is atendency toward greater maxillary hy-poplasia in VWS, particularly in themostsevere cleft type (bilateral CLP). Inaddition, the highest incidence of miss-ing teeth is also seen in VWS with themore severe cleft type [Oberoi andVargervik, 2005a].

Ectodermal dysplasia. There are morethan 150 clinically distinct inheritedsyndromes in which ED is present.ED consists of variable defects in themorphogenesis of ectodermal deriva-tives including skin, sweat glands, hair,nails, and teeth. Many of the EDsyndromes have non‐ectodermal mani-festations, which are not discussed herein detail. Patients with ED can havehypodontia or anodontia, with theanterior teeth usually conical or peg‐shaped (Fig. 4); the alveolar ridge isdeficient and patients tend to havehypoplastic maxillae with anterior cross-bite and low face height withoverclosure.

The ED syndromes can be inheritedin an autosomal dominant, autosomalrecessive, or X‐linked form. The mostcommon form of ED is X‐linkedhypohidrotic ED, or XLHED (OMIM305100) and is caused by mutations inthe gene encoding ectodysplasin‐A(EDA), which is a member of theTNF signaling pathway. TNF signalingthrough EDA activates NFKB1, which isknown to play an important role inodontogenesis [Ohazama and Sharpe,2004]. Affected males show severeoligodontia or anodontia in both pri-mary and permanent dentition. Anaverage of nine permanent teeth developin individuals with classic XLHED,typically the canines and first molars[Lexner et al., 2007]. Teeth are often

smaller than average and have an alteredmorphology. Anterior teeth tend to beconical in shape. Dental radiographsare helpful in determining the extentof hypodontia. Taurodontism is morecommon in the molars of individualswith XLHED.

Female carriers have variable,milder phenotypic expressions resultingfrom X chromosome inactivation. Theymay have hypodontia or anodontia andabnormally shaped teeth. Sixty to eightypercent of carriers have some degree ofhypodontia [Cambiaghi et al., 2000]. InXLHED, both primary and permanentdentitions are affected [Clauss et al.,2008].

Odonto‐onycho‐dermal dysplasia(OMIM 257980) is an autosomal reces-sive ED syndrome caused by mutationsin WNT10A [Adaimy et al., 2007].These patients present with dry hair,severe hypodontia, smooth tongue, naildysplasia, hyperhidrosis of palms andsoles, and hyperkeratosis. As mentionedabove, WNT10A mutations are also acommon cause of isolated hypodontia.

Oral‐facial‐digital syndrome type I. OFDsyndrome type 1 (OMIM 311200) is adevelopmental disorder characterized bymalformations of the face, oral cavity,digits, central nervous system, and kid-neys. The prevalence of OFD1 is 1 in50,000 to 1 in 250,000 live births. OFD1is an X‐linked disorder caused bymutations in the gene OFD1. Thisgene is important for formation of acellular organelle known as the primarycilium. OFD1 affects only females, as thiscondition is lethal in males. Althoughclinical features overlap with other typesof OFD (of which there are at least 9), X‐linked dominant inheritance and poly-cystic kidney disease are specific toOFD1.

The typical oral manifestations ofOFD1 are seen in the tongue, palate, andteeth. The tongue is lobed and is bifid ortrifid with nodules (hamartomas orlipomas); this is seen in at least a thirdof patients with OFD1. Ankyloglossiadue to a short lingual frenulum iscommon. Cleft hard or soft palate,submucous CP, or highly arched palateoccur in more than 50% of affected

patients. Alveolar clefts and accessorygingival frenulae are common. Thesefibrous bands are hyperplastic frenulaeextending from the buccal mucousmembrane to the alveolar ridge, result-ing in notching of the alveolar ridges.Dental abnormalities include missingteeth, extra teeth, enamel dysplasia,and malocclusion [Al‐Qattan, 1998;Toriello and Franco, 2007]. The lowerlateral incisors are missing in 50% ofindividuals, and this is associated withfibrous bands in the region.

Rieger syndrome. Rieger syndrome(OMIM 601542) is an autosomal domi-nant disorder characterized by malfor-mations in the anterior chamber of theeye, umbilical anomalies, and hypodon-tia. Its prevalence is 1 in 200,000. Whenthe ocular abnormality is combinedwithother craniofacial, dental, and develop-mental somatic anomalies, it is giventhe name Axenfeld‐Rieger syndrome(ARS; OMIM 180500). Glaucoma isfound in 50% of the cases [Shields et al.,1985]. Craniofacial, dental, and umbili-cal anomalies are also regularly reportedin connection with ARS [Childers andWright, 1986; Dressler and Gramer,2006]. Characteristic craniofacial fea-tures are maxillary hypoplasia, hyper-telorism, and telecanthus. Othersystemic features like anomalies of thepituitary gland, middle ear deafness,heart defects, hypospadias, short stature,and mental retardation were diagnosedin several ARS patients [Shields et al.,1985; Ozeki et al., 1999].

Three genetic loci have been asso-ciated with ARS so far. FOXC1 andPITX2 encode transcription factorsand are located on chromosomes 6p25and 4q25, respectively [Tumer and


Bach‐Holm, 2009]. A third locus forARS was mapped to chromosome13q14 but the gene has not yet beenidentified. Therefore ARS is consideredas a morphologically and geneticallyheterogeneous disorder.

A third locus for ARS wasmapped to chromosome

13q14 but the gene has not yetbeen identified. ThereforeARS is considered as amorphologically and

genetically heterogeneousdisorder.

Dental features include hypodon-tia/oligodontia of primary and perma-nent dentition. The most commonlymissing teeth are lower second premolarsand subsequently the central incisorsand upper second premolars [Dressleret al., 2010]. The missing teeth in theanterior maxilla are thought to causeunderdevelopment of the premaxilla.Other dental abnormalities includehyperplastic upper labial frenulum,peg‐shaped front teeth, and small teeth,enamel hypoplasia, conical‐shapedteeth, shortened roots, taurodontism,and delayed eruption.

Holoprosencephaly. Holoprosencephaly(HPE; OMIM # 236100), which occurswith a frequency of 1 in 16,000 livebirths and 1 in every 200 spontaneousabortions, is a an etiologically heteroge-nous condition with teratogenic andgenetic factors [Hall et al., 1997]. HPE iscaused by impaired midline cleavage ofthe embryonic forebrain. HPE is themost common defect of the forebrainand mid‐face in human [Wallis andMuenke, 2000]. The most severe formis cyclopia, and the mildest phenotype isa single upper central incisor. Several locifor HPE have been mapped. HPE3is caused by mutations in the Sonichedgehog (SHH) gene, which wasdescribed above in the context of tooth

development [Lami et al., 2013]. Bothrecessive and dominant inheritance ofHPE has been reported [Cohen andGorlin, 1969].

The HPE spectrum is commonlyassociated with solitary median maxil-lary control incisor (SMMCI), a raredental anomaly that can occur in either aprimary or permanent dentition. It canbe an isolated dental finding or occurin association with other recognizedsyndromes or specific chromosomalabnormalities [Nanni et al., 2001]. Thespectrum of defects is extremely variable,as some individuals can present with thefull HPE spectrum, some may have onlymild symptoms such as SMMCI, andothers may have no symptoms at all [El‐Jaick et al., 2007]. Sometimes SMMCI isthe most easily recognizable anomalyassociated with HPE [Hall et al., 1997].All HPE patients have SMMCI, but notall SMMCI patients have been diag-nosed with HPE [Kopp, 1967]. Severalsyndromes have been associated withSMMCI, including ED, Duane retractionsyndrome, velocardiofacial syndrome,CHARGE syndrome, VACTERLassociation, and HPE [Oberoi andVargervik, 2005b].

Tooth anomalies associated with cleft lipand palate. It has long been recognizedthat hypodontia is associated with cleftsof the lip and palate. Studies have foundthat hypodontia is present in approxi-mately 80% of children with non‐syndromic clefts [Shapira et al., 1999],and the prevalence of hypodontia in-creases markedly with the severity ofthe cleft [Ranta, 1986]. The teeth mostfrequently missing on the cleft side werethe upper permanent lateral incisors;these were absent in 74% of all cleftpatients, followed by maxillary andmandibular second premolars. The teethmost often missing on the non‐cleft sidewere the maxillary second premolars,followed by the maxillary lateral incisorsand mandibular second premolars. In-terestingly, congenital absence of boththe maxillary lateral incisors and secondpremolars was found more frequently insiblings of patients with clefts as well[Eerens et al., 2001].

Hypodontia outside the cleft regionis more frequent in cleft individuals thanin non‐cleft individuals [Shapira et al.,1999], and, in general, hypodontiaoccurs about 10 times more frequentlyon the cleft side, with left predominance.This is consistent with the side prefer-ence for unilateral cleft lip and palate.Additionally, the prevalence of hypo-dontia (excluding third molars) has beenreported as 50% in Pierre Robinsequence, which comprises a triadof micrognathia, glossoptosis, and CP.In these cases, there is an increasedfrequency of hypodontia in thelower jaw compared to individualswith isolated cleft lip and palate [Ranta,1986].

In addition, these individuals canhave other anomalies related to the shapeand size of individual teeth, or thepresence of additional teeth. A recentmeta‐analysis concluded that patientswith cleft lip and palate experience notonly more tooth agenesis, but alsosupernumerary teeth and anomaloustooth morphology in comparison tonon‐cleft patients [Tannure et al., 2012].The most frequently undersized teethare upper lateral incisors, and while thereis evidence that other teeth in cleftpatients have higher levels of agenesisand dysmorphology than in non‐cleftpatients, the data are conflicting. In cleftpatients, a high occurrence of a super-numerary lateral incisor (40–73%) hasbeen detected in the primary dentition[Bohn, 1950; Hansen and Mehdinia,2002].

From an embryological point ofview, it has been shown using 3Dreconstructions that the location of thefusion of the medial nasal and maxillaryfacial outgrowths transiently appears as afurrow on the mesenchymal aspect ofthe developing lateral incisor germ inhumans until prenatal week 8. Thisimplies that the upper incisor germ takesits origin partially from the maxillaryoutgrowth (Fig. 5) [Hovorakova et al.,2006]. This complex origin at a criticalplace of fusion of facial processes canexplain the developmental vulnerabilityand resulting anomalies of the upperlateral incisor [Hovorakova et al., 2006].Complete orofacial clefts of the lip and

Figure 5. Dual developmental origin and duplication of the upper lateral incisor.A:The supernumerary lateral incisor in a patient after the operation of a left‐sided cleft lipand palate.B: Scheme showing the dual developmental origin of the upper lateral incisorand its disturbance associated with a jaw cleft. The upper lateral incisor develops by aphysiological fusion (arrow) of two parts, one originating from the dental epithelium ofthe medial nasal (green) and one originating from the dental epithelium of the maxillary(orange) facial outgrowth. In cleft patients (A), the lateral incisor duplication adjacent tothe cleft area has been explained by the non‐fusion of both incisor subcomponents as aresult of the non‐fusion of the medial nasal and maxillary processes (A, B). The increasingextent of hypoplasia of the facial outgrowth tissues determines the formation of two, one,or no lateral incisor, respectively. The lowest level of tissue insufficiency of the facialprocesses might result in the lateral incisor anomalies even in an intact jaw (without cleft).Dash‐and‐dotted line represents midline. i1, i2, and c: upper deciduous central incisor,lateral incisor, and canine, respectively.


alveolus result from the failure of thefusion of the medial nasal and maxillaryprocesses. Consequently, the fusion ofthe dental epithelia is also absent and thetwo incisor subcomponents remainseparate, such that a duplication of thelateral incisor occurs in the cleft area (Fig.5). It has been proposed that the numberof lateral incisors, even in normalindividuals, depends on whether both,one, or no incisor subcomponent is ableto give rise to a functional tooth[Hovorakova et al., 2006].

Delayed Formation and Eruptionof Teeth

The permanent teeth usually replace theprimary teeth between the ages of 6–12years. However, eruption times for thepermanent teeth can vary considerably.The lower incisor shows the leastvariability and the lower second premo-lar the greatest in timing of eruption.When two primary teeth are fused, it islinked with the absence of permanentteeth.

Several syndromes have delayedformation and eruption of teeth, includ-ing Apert syndrome [Kaloust et al.,1997], cleidocranial dysplasia, Dubowitz

syndrome, Goltz syndrome, progeria,Menke syndrome and oculofaciocardio-dental (OFCD) syndrome [Oberoi et al.,2005]. Two of these syndromes arediscussed below as examples.

In Apert syndrome, there are delaysin both development and eruption, andthere can also be ectopic eruption andabnormalities in incisor and molar shape[Kaloust et al., 1997]. Erupting teethremain buried in thickened gingivaltissues for long periods of time. Thealveolar swellings of the maxillary archare characteristic of the syndrome andhave been shown to contain excessivemucopolysaccharides, predominantlyhyaluronic acid [Peterson and Pruzansky,1974]. Activating mutations in genesencoding receptors for FibroblastGrowth Factors, which were discussedabove in the context of tooth develop-ment, cause Apert syndrome. However,it is not clear how these mutationscontribute to the characteristic dentaland gingival findings in Apert syndrome[Kaloust et al., 1997].

OFCD syndrome (OMIM 300166)is an X‐linked condition with charac-teristic ocular, facial, cardiac, and dentalfindings in affected females and pre-sumed lethality in affected males. The

most typical dental anomaly is canineradiculomegaly (enlarged roots). Other

OFCD syndrome (OMIM300166) is an X‐linked

condition with characteristicocular, facial, cardiac, anddental findings in affected

females and presumed lethalityin affected males. The mosttypical dental anomaly iscanine radiculomegaly

(enlarged roots).

findings include delayed dental develop-ment and eruption, oligodontia, re-tained primary teeth and variable rootlength. Mutations in the BCOR genehave been found in this condition [Nget al., 2004].

Delayed tooth eruption has alsobeen found in the upper jaw of patientswith orofacial clefts. Eruption of thepermanent upper lateral incisor, which isalso sometimes absent in patients withcleft lip and palate, and the permanentsecond molar is retarded in patients withcleft lip and palate. In contrast, earliereruption has been found in the perma-nent and deciduous maxillary canine,first and second premolars. The delay oracceleration of tooth eruption in cleftpatients might be a consequence of theaffected bones and teeth [Peterka et al.,1996].

Abnormalities in Tooth Size,Shape, and Form

Abnormalities in tooth size and shape arethought to result from disturbances inthe morphodifferentiation (cap‐bell)stage of development. About 5% ofthe population has a significant “toothsize discrepancy” due to disproportion inthe size of upper and lower teeth. Themost common abnormality is a variationin size of the upper lateral incisors andsecond premolars. In patients with


hypodontia, the most common abnor-mality is a peg‐shaped upper lateralincisor.

There is very often a discrepancybetween tooth size and jaw size. Thecombination of microdontia and normaljaw size is accompanied by the presenceof tremata (free spaces between teeth).Similarly, a shorter jaw in the mesio‐distal direction with teeth of normal sizeresults in orthodontic anomalies. Thisdisproportion is most pronounced in theupper jaw of cleft patients, where thepermanent teeth have normal mesio‐distal dimension, while the upper jawarch is significantly shorter [Peterkaet al., 1996].

Sometimes, tooth germs may fuseor germinate during development [Gut-tal et al., 2010], resulting in teeth withseparate pulp chambers joined at thedentin or teeth with a common pulpchamber, respectively. It is often difficultto differentiate between the two, but if alateral incisor is missing it is most likelybecause of fusion of the central andlateral incisor primordia.

Taurodontism (OMIM 272700) ischaracterized by a large pulp chamberand is most commonly seen in molars.The word “taurodontism” was first usedto describe the teeth of Neanderthalsand another group of prehistoric hu-mans, the Heidelbergs [Keith, 1913].Taurodontism causes constriction of thecementoenamel junction, thus elongat-ing the pulp chambers vertically creatingan apically displaced pulp. There issignificant variation among modernday populations. The prevalence hasbeen reported as 0.5% in Japanese[Daito, 1971], 0.57–3.2% in whiteAmericans [Blumberg et al., 1971;Witkop, 1976], 4.3% in African Amer-icans [Jorgenson et al., 1982], 8% inJordanians [Darwazeh et al., 1998], 33–41% in certain African populations[Shaw, 1928], and 46.4% in young adultChinese [Macdonald‐Jankowski and Li,1993]. Taurodontism is thought to bea polygenic trait, and both autosomaldominant and recessive inheritance havebeen suggested.

A taurodontic tooth is thought toresult from a disturbance in growth ofHertwig’s epithelial root sheath. Based

on this hypothesis, there may be anassociation between taurodontism andhypodontia, as both conditions may beattributed to defects in the growth ofdental epithelium [Hu and Simmer,2007]. Taurodontism has been describedtogether with isolated [Stenvik et al.,1972; Seow and Lai, 1989; Schalk‐VanDer Weide et al., 1993] and syndromichypodontia in many syndromes, includ-ing 18p11.3 deletion [Kantaputra et al.,2006], Smith–Magenis syndrome [To-mona et al., 2006], tricho‐dento‐osseoussyndrome [Hart et al., 1997; Wrightet al., 1997; Price et al., 1999; Islamet al., 2005], Klinefelter’s syndrome[Komatz et al., 1978; Hillebrand et al.,1990; Yeh and Hsu, 1999], Williamssyndrome [Axelsson et al., 2003],McCune–Albright syndrome [Akintoyeet al., 2003], Down syndrome [Alpozand Eronat, 1997] and Ellis van Creveldsyndrome [Hunter and Roberts, 1998].It has also been described in individualswith cleft lip and palate. An autosomaldominant hypoplastic/hypomatureamelogenesis imperfecta (AI) associatedwith taurodontism (OMIM 104510) hasbeen mapped to the distal‐less homeo-box (DLX3) locus [Dong et al., 2005].More recently, taurodontism has beenlinked with Laurence–Moon/Bardet–Biedl syndrome (LM/BBS) and there-fore should be included as a minorcriterion in diagnosing LM/BSS [An-dersson et al., 2013]. Lastly, there may bea common genetic etiology betweenVWS, hypodontia, and taurodontism[Nawa et al., 2008]. The frequency oftaurodontism in VWS subjects wasalmost 50% [Nawa et al., 2008].

Supernumerary Teeth

A supernumerary tooth is an additionaltooth that can be found in any region ofthe dental arch. Supernumerary teethresult from disturbances during theinitiation and proliferation stages ofdental development. The most commonsupernumerary tooth that appears is inthe maxillary midline and is calledmesiodens. The prevalence of supernu-merary teeth is between 0.3% and 0.8%in primary dentition and 1.5% and 3.5%in permanent dentition [Brook, 1974].

A male to female ratio of 2:1 is found inpopulations with single supernumeraryteeth [Kantor et al., 1988] whichincreases to 3:1 for multiple supernu-merary teeth [Gibson, 1979]. Althoughinherited forms are rare, a familialinheritance has been reported that canbe autosomal dominant with incom-plete penetrance, autosomal recessive[Cassia et al., 2004] or sex‐linked patternof inheritance [Burzynski and Escobar,1983].

Greater than 90% of supernumerar-ies will occur in the upper jaw, andapproximately 25% of the maxillaryanterior supernumerary teeth erupt,but more commonly they are impactedand require extraction. Supernumeraryteethmay be unilateral or bilateral, singleor multiple, and may be found in one orboth jaws. Multiple supernumeraryteeth are rare in non‐syndromic individ-uals, so such a finding should prompt areferral to a medical geneticist. Anincreased prevalence of supernumeraryteeth can be found in cleft lip and palatepatients, and there are over 20 syn-dromes with supernumerary teeth, themost common being cleidocranial dys-plasia and Gardner syndrome [Mooreet al., 2002]. The frequency of supernu-merary teeth in individuals with unilat-eral cleft lip and/or palate was found tobe 22.2% [Scheiner and Sampson,1997], with males affected twice as oftenas females in the permanent dentition.

There are various hypotheses re-garding the etiology of supernumeraryteeth. According to one, a supernumer-ary tooth is created as a result ofdichotomy of the tooth bud [Liu,1995]. Another theory is thatsupernumeraries are formed as a resultof local, independent conditioned hy-peractivity of the dental lamina [Liu,1995; Scheiner and Sampson, 1997].Sometimes, supernumerary teeth can beinterpreted as atavisms, if they appear atlocations where teeth were suppressedduring evolution [Smith, 1969; Peter-kova et al., 2006].

The diagnosis of a supernumerarytooth is confirmed by radiographicexamination if abnormal clinical signsare found. Periapical and occlusal radio-graphs are commonly used in the incisor

Figure 6. Cleidocranial dysplasia(CCD). A: Panoramic radiograph and(B) cone beam CT images of a 14‐year‐old boy with CCD showing themultiple retained primary teeth andmultiple impacted permanent teethand supernumerary teeth.

Dental anomalies are presentin 30–75% of patients withGardner syndrome, and mayinclude impacted or uneruptedteeth, hypodontia, abnormal

tooth morphology,supernumerary teeth,

hypercementosis, compoundodontomas, dentigerous cysts,fused molar roots, long andtapered molar roots, and

multiple caries.


region. Three‐dimensional cone beamCT is valuable as it shows the position ofthe supernumerary in all three dimen-sions, thereby enabling the correctbuccal or palatal approach during re-moval and direction of force applicationfor orthodontic alignment [Liu et al.,2007].

Some of the problems associatedwith supernumerary teeth include fail-ure of eruption, displacement [Howard,1967], crowding, and formation ofdentigerous cysts [Awang and Siar,1989]. Root resorption of adjacent teethis a rare occurrence as well [Hogstromand Andersson, 1987].

Cleidocranial dysplasiaThe best‐known syndrome associatedwith supernumerary teeth is cleidocra-nial dysplasia (CCD). CCD (OMIM#119600) is an autosomal dominantskeletal dysplasia associated with claviclehypoplasia and dental abnormalities andhas a prevalence of 1 in 1,000,000. It iscaused by mutations in RUNX2, whichencodes a transcription factor thatactivates osteoblast differentiation. Onethird of CCD cases are sporadic andrepresent new mutations [Otto et al.,2002].

Individuals with CCD have growthretardation with moderate short stature,delayed fontanelle closure with parietaland frontal bossing, midface hypoplasia,hypertelorism, low nasal bridge, brachy-dactyly and hearing loss. They may haveCP or a narrow, high palate.

Dental manifestations are found inmore than 90% of individuals with CCDand include delayed eruption of decid-uous and permanent teeth, supernumer-ary teeth, retention cysts and enamelhypoplasia (Fig. 6) [Golan et al., 2003].Formation and eruption of the decid-uous teeth are usually normal. Onesuggested explanation for the delayed ornon‐eruption of many permanent andsupernumerary teeth is the lack ofcellular cementum in the apical regionof impacted teeth [Manjunath et al.,2008]. While CCD patients at a youngerage display relatively normal jaw pro-portions and morphology of the mandi-ble, CCD patients at an older age displayshort lower face height, acute gonial

angle, anterior inclination of the man-dible, and mandibular prognathism; dueto maxillary hypoplasia, individuals withCCD tend to have a Class III malocclu-sion [Ishii et al., 1998].

Because of challenges in dentalmanagement of these individuals withCCD, comprehensive orthodontic andsurgical treatment is required. Addition-ally, there is a wide variation insupernumerary tooth development,including asymmetrical developmentof supernumerary teeth in the upperand lower jaw [Soni et al., 2012]. Delayof physiologic root resorption resultsin prolonged retention of the primaryteeth, and the eruption of the perma-nent teeth is delayed and many fail toerupt [Shaikh and Shusterman, 1998].The presence of supernumerary teeth isnot pathognomic for CCD; in fact, somepatients may have no supernumeraryteeth or even missing teeth [Richardsonand Deussen, 1994].

Recent advances in dentistry, suchas dental implants, allow better treat-ment options and outcomes for individ-uals with CCD. As an example, dentalimplants can be used not only for

orthodontic tooth movement with re-duced side effects, but also for replacingteeth that cannot be brought into thearch orthodontically. With the advance-ments in three‐dimensional imaging,Cone Beam Computed Tomography(CBCT) is now routinely used indiagnosis and treatment planning [Liuet al., 2007].

Gardner syndromeGardner syndrome, a variant of familialadenomatous polyposis (FAP; OMIM#175100), is a rare autosomal dominantcondition characterized by gastrointesti-nal polyps, multiple osteomas, and skinand soft tissue tumors including acharacteristic retinal lesion. Approxi-mately 10% of FAP individuals areaffected by Gardner syndrome [Ram-aglia et al., 2007]. Gardner syndromeand FAP are caused bymutations inAPCat 5q21 [Groden et al., 1991; Kinzleret al., 1991]. APC is a multidomainprotein that plays a major role in tumorsuppression by antagonizing the WNTsignaling pathway [Barth et al., 1997].

Dental anomalies are present in 30–75% of patients with Gardner syndrome,and may include impacted or uneruptedteeth, hypodontia, abnormal toothmorphology, supernumerary teeth, hy-percementosis, compound odontomas,dentigerous cysts, fused molar roots,long and tapered molar roots, andmultiple caries [Butler et al., 2005;


Madani and Madani, 2007; Basaran andErkan, 2008]. Osteomas occur in 68–82% and are generally located in theparanasal sinuses andmandible [Dawlatlyet al., 1997; Madani and Madani, 2007].They can also affect the skull and longbones [Cankaya et al., 2012]. In themandible, central or lobulated osteomascan be observed; central osteomas arecharacterisctically near the roots of theteeth, and lobulated types arise formthe cortex and most commonly at themandibular angle [Wesley et al., 1987].Often the general dentists or orthodont-ists are the first health care professionalsto suspect the diagnosis and refer to theoromaxillofacial surgeon [Cankaya et al.,2012].

CONCLUSION

Dental anomalies are seen as eitherisolated findings or in individuals withcraniofacial developmental abnormali-ties, and in both cases they can pro-foundly affect the life of the affectedindividual. Studies of tooth develop-ment in animal models together withgenetic studies of patients are improvingour understanding of the causes of dentalanomalies, and are laying the foundationfor future biologically based treatments.

ACKNOWLEDGMENTS

This work was supported by the NIH(DP2‐OD00719 and R01‐DE021420to O.D.K.), the California Institute ofRegenerativeMedicine (RN2‐00933 toO.D.K.), and by the Grant Agency ofthe Czech Republic; CZ:GA 9CR:GAP305/12/1766.

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Developmental Disorders of the Dentition: An Update tooth review.pdfin humans and mice, indicating...

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