Genetic Etiology of Development Alterations Affecting the Number, Size, Form, Structure and Eruption of the Teeth

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Genetic Etiology of Development Alterations Affecting the Number, Size, Form, Structure and Eruption of the Teeth

   

Blanca Urzúa 1*, Ana Ortega-Pinto2 and Daniela Adorno-Farias2         

1Institute for Research in Dental Sciences, Faculty of Dentistry, University of Chile, Chile

2Department of Pathology and Oral Medicine, Faculty of Dentistry, University of Chile, Chile

*Corresponding author: Blanca Urzúa, Institute for Research in Dental Sciences, Faculty of Dentistry, University of Chile, Chile.

Citation: Urzúa B, Ortega A, Adorno D. (2020) Genetic Etiology of Development Alterations Affecting the Number, Size, Form, Structure and Eruption of the Teeth. J Oral Med and Dent Res. 1(2):1-14.

Received: October 11, 2020 | Published: October 26,  2020

Copyright© 2020 genesis pub by Urzua B, et al. CC BY-NC-ND 4.0 DEED. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International License., This allows others distribute, remix, tweak, and build upon the work, even commercially, as long as they credit the authors for the original creation.

DOI: https://doi.org/10.52793/JOMDR.2020.1(2)-09

Abstract

Teeth develop in the mammalian embryo via a series of interactions between the odontogenic epithelium and the neural crest-derived ectomesenchyme of the early jaw primordia. The molecular interactions required to generate a tooth are mediated by families of signaling molecules, which often act reiteratively in both a temporal and spatial manner. In humans, the process of odontogenesis lasts approximately 18 years, beginning in the 6th-8th week in the uterus and ending with the formation of the third molars in late adolescence. Each tooth passes through a series of stages that follow the same pattern, beginning with the formation of the bud, then cap and bell, followed by the deposit of enamel and dentin on the crown of the tooth. After the crown is formed, the development of the roots continues and finally the teeth emerge in the oral cavity, when about 2/3 of the roots have formed. Alterations in the indicated processes lead to a wide range of abnormalities that affect the number, size, shape of teeth and structural defects in mineralized tissues, as well as failures in dental eruption. The prevalence of these disorders may be as common as 2, 4% in hypodontia or extremely rare as 1 in 100,000 in dentin dysplasia. The spectrum of these anomalies, which may occur in isolation or as part of syndromes is variable; being very mild to severe and very severe. Most of the knowledge about mammalian odontogenesis comes from studies in animal models, mainly mouse. However, the murine dentition is not equal to human dentition, so there are a series of aspects of tooth development in our species that remain unanswered. In this context, the clinical and molecular genetics study of families with various dentition disorders is a valuable approach that will contribute to improve our knowledge of the phenotype-genotype correlations involved in these abnormalities.

Keywords

Odontogenesis; Alterations; Tooth development

Introduction

Normal Odontogenesis

Dental formation and development in humans occurs from the 6th week in utero to adolescence [1]. In this process, reciprocal interactions between the epithelium and mesenchyme play a key role, mediated by seven signaling pathways: WNT, BMP, FGF, SHH, EDA, TNF and NOTCH which affect gene expression networks regulated by transcription factors (TF) [2,3]. The initiation stage begins with the appearance of the dental lamina in which the TF Pitx2, Foxi3, Dlx2, Lef1, p63 are expressed associated with the acquisition of tooth destination and odontogenic potential in the oral epithelium. The dental lamina also expresses signaling molecules such as Shh, Bmp2, Bmp4, Bmp7, Fgf8, Fgf9, Wnt10a and Wnt10b which function as mediators of odontogenic potential from the epithelium to the mesenchyme [2,3]. Morphogenesis of the tooth in mammals begins in structures called placodes in the incisor and molar regions. In the placodal cells, which form the early signaling centers, genes like Pitx2, Foxi3 and signaling molecules like Shh, Wnt10, Bmp2 and Fgf20 are expressed determining the proliferation and growth of the placodal epithelium, which gives rise to the bud. This stage is critical in determining the number and position of the teeth to be formed. At the tip of the dental bud the primary enamel knot is formed, where some cells leave the cell cycle due to the localized expression of p21, signaling molecules and genes linked to signaling pathways. These signals stimulate the growth of the flanking epithelium, which originates the cervical loop, moving the morphogenesis phase from bud to cap [2,3]. The enamel knot matures and in the bell stage epithelial growth and folding determine the shape and size of the crown. In molars the appearance of secondary enamel knots is induced, which express the same signals as the primary knot, but determine the size, positions, and heights of the cusps. During cytodifferentiation, in the bell stage, enamel and dentin are synthesized at the epithelial-mesenchymal interface, by the interaction of the same signals present in dental morphogenesis [2,3]. The development of the root begins after the formation of the crown. The apical region of the dental organ elongates and originates the Hertwig's epithelial root sheath (HERS), which grows apically guiding the formation of the root(s) and determining their number, size and shape. The inner layer of the sheath interacts with the mesenchyme, producing laminin-5 and growth factors that induce the differentiation of odontoblasts that secrete root dentin. The cells from HERS control the formation of cementum by the cells of the dental follicle [4]. Abnormalities in the indicated processes lead to a wide range of abnormalities that affect the number, size, shape of teeth and structural defects in mineralized tissues, as well as failures in dental eruption. Abnormal dental phenotypes are within a spectrum of severities: normal variation, isolated dental anomalies, cosegregation with non-dental defects or are part of a more severe syndrome. All current evidence suggests that genetic, epigenetic and environmental factors contribute either individually or combined to produce this spectrum of anomalies [5,10].

Development Alterations Affecting the Number of Teeth

Selective Dental Agenesis

Selective tooth agenesis or congenital absence of teeth corresponds to the lack of development of teeth in the Primary Dentition (PrD) and/or Permanent Dentition (PeD) [9,11]. It is classified as: anodontia, which refers to an absolute lack of development of teeth; hypodontia, denoting lack of development of one or more teeth; and oligodontia, indicating lack of development of six or more teeth, excluding third molars [9,11]. The lack of teeth in PrD has a prevalence of less than 1% [9].The primary teeth most frequently absent are the maxillary lateral incisors and mandibular incisors. The prevalence of agenesis in permanent teeth ranges from 3% to 10%, without considering third molars. If the third molars are considered, the prevalence is 20% [9].The teeth most affected by agenesis are third molars, then molars, second premolars and lateral incisors. Ethnic and gender differences have been reported, with the Asian population being the most affected and the female sex [10,12]. A large percentage of cases of primary hypodontia are inherited in autosomal dominant form, with incomplete penetrance and variable expressivity, whereas a minority has autosomal recessive or sex-linked patterns [12,16].The environment plays an important role and in some cases, multifactorial inheritance has been suggested [6,8].Genes involved in isolated dental agenesis are shown in table 1 [12,16].The genes associated with syndromic hypodontia are approximately 43, some of which overlap with genes involved in isolated hypodontia[15]. Agenesis has been associated with various syndromes [5], lip and palate fissures [17], colon cancer [18], breast [18,19], ovarian cancer [20] and the presence of tumors in general [21], suggesting that agenesis may have a prospective predictive value for neoplasms [21]. In addition, a study evaluating the impact of moderate to severe hypodontia on the quality of life and self-esteem of those affected revealed that this condition has a negative effect on quality of life, but not on self-esteem [22].

Hyperdontia

It corresponds to the development of an increased number of teeth, called supernumerary teeth (ST). ST are teeth or tooth-like structures in addition to the 20 primary teeth and 32 permanent teeth [9,23,24]. They appear in any region of the dental arch, as single or multiple teeth, can be uni or bilateral and may be associated with some syndrome [9]. Hyperdontia correlates positively with macrodontia and it is more frequent in males than females (2:1) [9]. The exact etiology of hyperdontia is not clear. Three hypotheses have been postulated: phylogenetic reversion, dichotomy of the dental bud and hyperactivity of the dental lamina [9,25]. Clinical complications related to ST include failure of eruption, rotation or displacement, dilacerations, root resorption, crowding, malocclusion, formation of cysts and fistulas, eruption in the nasal cavity and delayed root development of permanent teeth [9,23-25].In PrD the prevalence of hyperdontia fluctuates between 0.2% and 0.8%. In permanent dentition (PeD) it ranges from 0.1% to 3% (Caucasians), in the general population it is 0.5% to 5.3% and in Asians the prevalence is slightly higher [9]. 76-86% of hyperdontia cases involve single teeth, 12% involve two extra teeth and less than 1% may involve three or more teeth [9].Single tooth hyperdontia occurs more frequently in PeD, in the maxilla and in the anterior region. Conical mesiodens are the most common ST and occur more frequently in the maxillary incisor region, followed by maxillary and molar quarters, premolars, canines, and mandibular incisors [9].Supernumerary mandibular incisors are very rare and most of the extra teeth are unilateral. Multiple ST occurs more frequently in the mandible, in the premolar region followed by the molar and anterior regions [24]. An ST located in the anterior incisor region is called mesiodens, a fourth accessory molar is called distomolar or distodens. A paramolar is a posterior ST located lingual or buccally to a molar. Another classification divides them into supplemental type with normal shape and size or rudimentary type of smaller size and abnormal shape [24]. The ST of rudimentary type can be subclassified as conical of small size and rice form; Tuberculated in the form of barrel and with multiple cusps or tubers; Molariform teeth very similar to premolar or molar and odontomas that are malformations of disorganized dental tissue [9,24,25]. Relatively little is known about the genetic basis, etiology, and molecular mechanisms underlying ST formation. A small number of extra teeth is considered a common anomaly, however usually multiple ST have a genetic component and are thought to represent a third partial dentition [23-29]. Extra teeth show racial variation, exhibit sexual dimorphism and are prominent features in various developmental disorders [9]. ST are more frequent in relatives of affected patients than in the general population.This trait can be transmitted in an autosomal dominant form, with incomplete penetrance, in an autosomal recessive form or linked to the X chromosome [25-29]. Table 1 shows the genes, with literature evidence, involved in the formation of ST [9,25-29]. However, a recent article describes 101 candidate genes selected through bioinformatic programs and criteria [27]. The presence of ST can occur associated with syndromes so it is considered important in early diagnosis for the correct management and informed decision making about medical care and treatment in the long term. A recent study described 8 syndromes with strong evidence of association (Cleidocranial Dysplasia, Familial Adenomatous Polyposis, Trico-Rhino-Falangeal I, Rubinstein-Taybi, Nance-Horan, Opitz BBB/G, Oculo-Facio-Cardio-Dental and Robinow) and two syndromes with evidence suggestive of association with ST (Kreiborg-Pakistani and insulin-dependent diabetes mellituswith acanthosis nigricans) [30]. Interestingly, a recent study has shown that cells derived from ST are a promising source of mesenchymal stem cells for cellular therapy applicable to autoimmune diseases [31].

Developmental Alterations Affecting Tooth Size and Morphology

Abnormalities in tooth size and shape result from disturbances in the morpho-differentiation stage of development, i. e. during cup-to-bell stages [6].

Size

The variation in the size of the teeth is a trait that has normal distribution in human populations, it is variable between ethnicities and sexes. The presence of physically smaller teeth than normal is called microdontia and the presence of larger than average teeth is called macrodontia [9,23-24]. Typically, in either of the two arches only a few teeth are altered in size. Differences in size cannot be considered in isolation, because microdontia is strongly associated with hypodontia and macrodontia with hyperdontia. Women have a higher frequency of microdontia and hypodontia and men have a higher prevalence of macrodontia and hyperdontia [6,9,24]. The generalized microdontia is infrequent and observed mainly in Down syndrome, pituitary dwarfism and other hereditary disorders. The isolated microdontia is more frequent, affecting the maxillary lateral incisors that can present crown in the form of rice and root of normal length. The prevalence is 0.8% to 8.4% and the trait is inherited in an autosomal dominant form with incomplete penetrance [6-10]. Generalized macrodontia is rare and usually only a few teeth are abnormally large in size. It is associated with pituitary gigantism, otodental syndrome, XYY men and pineal hyperplasia with hyperinsulinism. Isolated macrodontia occurs more frequently bilaterally in incisors, canines and less frequently in second premolars and third molars. A prevalence of 0.1 to 4.3% has been reported [6-10].

Morphology: There are many genetic-based morphological variations of the teeth.

Gemination: Is defined as a single enlarged tooth or united tooth (double) in which the tooth count is normal when the anomalous tooth counts as one [6,10].

Fusion: Corresponds to a single enlarged tooth or two united teeth in which the tooth count reveals an absent tooth when the anomalous tooth counts as one. Gemination or fusion appears in both dentitions, more frequently in the anterior maxillary region (gemination) and mandibular (fusion), being more affected the incisor and canine teeth. The prevalence of double tooth in primary dentition is 0.5 to 2.5%, while in the permanent it is 0.3 to 0.5% [6,10].

Accessory cusps: Such as Carabelli's cusp, which is located on the palatine surface of the mesiolingual cusp of deciduous or permanent upper molars. It occurs in 90% of Caucasians and is rare in Asians. The talon cuspalis an additional cusp located on the surface of an anterior tooth, from the cemento-enamel junction to the incisal margin, are frequent in permanent central and lateral incisor teeth. Dens evaginatus is a cusp-like elevation located in the central cleft of the buccal cusp of incisor or premolar teeth, with a frequency of 1 to 4% in Asians and rare in Caucasians [6-10]. Dens invaginatus (Dens in dente) corresponds to an invagination of a portion of the enamel organ that results in enamel-dentin deeper into the pulp chamber. It has a prevalence ofless than 0.1% and the lateral incisors are the most frequently affected teeth. Shovel- shaped teeth are incisors that have prominent lateral margins and have been described as a frequent variation in natives of America [6-10].

Taurodontism: Corresponds to the enlargement of the body and pulp chamber of a multi-root tooth, with apical displacement of the cameral floor. It affects PeD more frequently, can be uni or bilateral, with a prevalence varyingbetween 0.5 and 46%, and it can occur in isolation or as part of numerous syndromes [6-10,32].

Globodontia: Is a condition in which teeth are shaped like a globe. This rare abnormality is associated with otodental syndrome; it is inherited in an autosomal dominant form, with an unknown prevalence [9,33].

Lobodontia or wolf teeth:  Corresponds to an uncommon autosomal dominant abnormality in which teeth are shaped like wolf teeth. The estimated prevalence is 1: 1,000,000 [9, 34-35].

Most of the variation in traits related to tooth size and shape present continuous distribution coincident with a multifactorial model of inheritance, present ethnic variation and association with several hereditary disorders. Genes involved in some of these anomalies are described in table 1 [6-10]. Carabelli cusp, talon cusp, Dens evaginatus and Shovel shaped incisors have relevance in forensic genetics, population genetics and in association with syndromes. Dens invaginatus, gemination and fusion may favor the development of caries, pulpitis and periodontal problems. In addition, they can cause crowding, delayed eruption or ectopic eruption. Taurodontism has anthropological importance and may be associated with syndromes. Globodontia causes malocclusion, increased endodontic lesions and it is a diagnostic feature of otodental syndrome. [6-10,35]

Alterations Affecting the Structure of Dental Hard Tissues

Hereditary Enamel Defects, Amelogenesis Imperfecta (AI)

A heterogeneous group of developmental disorders altering the structure, chemical composition and appearance of the enamel can affect all or almost all primary or permanent teeth, in isolation or as part of syndromes [9,36]. AI are grouped into four clinical phenotypes: hypoplastic, hypocalcified, hypomature and hypomature/hypoplastic with taurodontism. The consideration of secondary enamel traits and inheritance pattern in these four phenotypes categorizes them into 14 different subtypes [9,37]. The estimated frequency of AI in the population ranges from 1 in 8,000 to 1 in 14,000 [9,36-37]. Table 1 summarizes the genetic etiology of the various types of isolated and syndromic AI [37]. Patients with AI present enamel fractures, dentin hypersensitivity, altered masticatory function, need for frequent replacement of obturations, loss of vertical dimension and high prevalence of dentomaxillary abnormalities requiring orthodontic resolution [9,38-39]. The aesthetic aspect of their teeth generates a high psychosocial impact on them; problems of aesthetic dissatisfaction, self-perception and low self-esteem, higher levels of social avoidance, anguish and complex about their teeth, greatly limiting their social life and interaction with their peers [39]. In addition, AI is also associated with other genetic disorders and syndromes. It has been reported that AI is associated with 23 autosomal dominant syndromes, 45 autosomal recessive inheritance syndromes and 12 chromosome X-linked inheritance conditions, increasing the list of genes possibly involved in AI [40]. Hereditary defects of dentin. These defects include two entities: Dentinogenesis Imperfecta (DI) and Dentin Dysplasia (DD) [5,9,36].

Dentinogenesis Imperfecta

Is an autosomal dominant disease characterized by severe hypomineralization and altered dentin structure, caused by mutations in the dentin sialo-phosphoprotein (DSPP), from which sialo-dentin protein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are formed, playing important roles in tissue mineralization [5,9,36]. The recent proposed classification, based on molecular analysis of the DSPP gene, includes three types of DI: mild form (previously considered DD type II), moderate (before DI type II) and severe (before DI type III) [41]. Epidemiological data indicate that DGI has a prevalence of 1: 6,000 to 1: 8,000 [5,9,36], and it is caused by genetic variants of the DSPP gene, the main non-collagenous protein in the dentin matrix [5,9,36]. Teeth are small, colored blue-gray or amber and opalescent. The enamel is detached from the underlying hypomineralized dentine that is exposed and rapidly wears through attrition. Radiographically, bulbous crowns are observed due to cervical constriction, short and thin roots, tooth mobility, total or partial pulpal obliteration, and increased periodontal disease in the absence of caries [36,41]. Association of DI with several syndromes such as Osteogenesis Imperfecta, Ehlers-Danlos and Goldblatt and Schimke immuno-osseous dysplasia has been described [36].

Dentin Dysplasia

Is a hereditary defect characterized by normal-looking crowns and short roots in both dentitions.Pulp cavities are small in size and associated with periapical radiolucencies and obliterated pulp chambers [36,41]. The most up-to-date classification distinguishes one clinical entity; dysplasia of the root dentin, formerly called DD type I. This defect is extremely rare, with a prevalence of 1: 100,000 and affects both dentitions [41]. DD is inherited in an autosomal dominant form, with complete penetrance, although cases with autosomal recessive inheritance have also been described [42]. Table 1 shows the genes involved in DD [35,36,41]. Clinically, teeth look normal, the first sign of disease is tooth mobility leading to premature exfoliation, roots are short or absent, fused, with a conical apical aspect (taurodonts) and the pulp is replaced by dentin-like mineralized tissue. Periapical lesions and periodontal disease are frequent [36,41].

Defects of Enamel and Dentin Development of Uncertain Etiology

In this group are included enamel development defects (EDD) such as hypoplasias and opacities, regional odontodysplasia, molar incisive hypomineralization (MIH), molar incisive malformation (MIM) and dental fluorosis. Evidence of the genetic component implied in these conditions has begun to accumulate, and for now they respond to a model of continuous distribution of multifactorial etiology [6-10,43,44].

Developmental Alterations Affecting the Eruption of the Teeth

Dental eruption is a temporally and locally regulated process that requires bone resorption and deposition. It corresponds to the movement of a tooth from its site within the alveolar bone to its functional position in the oral cavity [10,45,46]. Among the alterations in the chronology of eruption are: 1) Early dental emergence, which occurs when a tooth erupts before the third month of life (natal or neonatal tooth), is very rare and has genetic influence; 2) Late eruption of the primary dentition, which occurs when no tooth has erupted at the 13th month of life; 3) Early eruption in PeD, corresponding to eruption before full root formation, more frequent when the temporal tooth is prematurely lost; 4) Late PeD eruption, which occurs due to loss of the temporary tooth with insufficient root development of the permanent successor, temporal ankylosis or late formation of the permanent germ; 5) Primary eruption failure (PEF) is the localized failure of PeD eruption without any other systemic condition present [9,10]. It affects permanent molars uni or bilaterally that are completely formed and do not reach the occlusal plane due to a primary defect in the mechanism of eruption. There are isolated PEF types with familial and non-familial forms [45,46].The prevalence of alterations of the eruption is variable. Natal or neonatal teeth occur in about 1:3,000 children, mainly affecting the incisors. Failure of eruption of first and second molars is rare, with an estimated prevalence of 0.01% for the permanent first molar and 0.06% for the second molar [9,45,46]. PEF is an autosomal dominant disorder due to mutations in the parathyroid hormone receptor 1 (PTH1R) gene. However, an analysis of the molecular mechanisms of the eruption process reveals other obvious candidate genes (Table 1) [10,45,46]. As in other dental disorders, eruption abnormalities are also associated with syndromes. Natal teeth are observed in Ellis-Van-Creveld, Congenital Pachyonyquia type 1 and Hallermann-Streiff syndromes. Generalized delayed eruption of both dentitions is present in Down's syndrome, gingival fibromatosis, hypothyroidism, and childhood hypopituitarism. Delayed eruption of PeD is associated with Creidocranial dysplasia, among other syndromes. [45,46].

PROCESS / ANOMALY

GENE NAME

GENE NAME

GENE NAME

1. TOOTH DEVELOPMENT

ACTBA

FGF2

P63

1.1. Odontogenesis in General

ACTRIIA

FGF20

PAX3

 

ACVR1

FGF3

PAX6

 

ACVR1B

FGF4

PAX9

 

ACVR2A

FGF5

PDGFA

 

ACVR2B

FGF6

PDGFC

 

ALX1

FGF7

PDGFRA

 

AXIN2

FGF8

PDGFRB

 

BARX1

FGF9

PITX2

 

BMP2

FGFR1

PRRX1

 

BMP4

FGFR2

PRRX2

 

BMP5

FGFR3

PRX1

 

BMP6

FOXI3

PRX2

 

BMP7

FST

PTCH1

 

BMPR1A

GAS1

PTHR1

 

BMPR1B

GLI1

RUNX2

 

BMPR2

GLI2

RUNX3

 

CAVI

GLI3

SHH

 

CBLB

HOXA2

SHOX2

 

CDKN1A

HOXD10

SMAD2

 

DKK1

IFT88

SMAD6

 

DKK4

IGF1R

SMO

 

DLX1

IKKA

SOSTDC1     

 

DLX2

IKKR

SP6

 

DLX3

IRAK3

SPRY2

 

DLX5

IRF6

SPRY4

 

EDA

LEF1

TAB2

 

EDAR

LHX6

TBX10

 

EDARADD

LHX8

TFAP2A

 

EGF

LTBP3

TFAP2C

 

EGFR

MET

TGFA

 

EPHB3

MSX1

TGFB3

 

ERBB2

MSX2

TGFBR2

 

ERBB3

NOG

TP73L

 

ERBB4

NR2F1

TRAF6

 

EVC

NTRK3

WNT10A

 

FGF1

OSR2

WNT10B

 

FGF10

P21

-

2. NUMBER OF TEETH

 

 

 

2.1. Non-syndromic Tooth Agenesis

 KDF1

EDARADD

NFATC3

 

AXIN2

FAM65

PAX9 (STHAG 3)

 

BMP2

GREM2 (STHAG 9)

SMOC2

 

BMP4

HYD2 (STHAG 2)

TSPEAR

 

CDH23

KREMEN1    

WNT10A (STHAG 4)

 

DKK1

LRP6 (STHAG 7)

WNT10B (STHAG 8)

 

EDA (STHAG X1)

LTBP3 (STHAG 6)

-

 

EDAR

MSX1 (STHAG 1)  

-

2.2 Syndromic Tooth Agenesis

ADAMTS2

GJA1

P53

 

ANTXR1

GLI3

P63

 

APC

GRHL2

PAX3

 

AXIN2

HOXB1

PHGDH

 

BCOR

IFT121

PITX2

 

COL1A1

IFT122

POLR3A

 

COL1A2

IKBKG

POLR3B

 

COL3A1

IKKγ

PORCN

 

CREBBP

IRF6

PRX1

 

CXORF5 

JAG1

PRX2

 

DLX1

KDM6A

PVRL1

 

DSP

KIF3A

RECQL4

 

DTDST      

KMT2D

RIEG2

 

EDA

KREMEN1

RSK2

 

EDAR 

KRT17

SHH

 

EDARADD

LHX6

SLC25A21

 

ERCC8

LHX8

SMAD2

 

EVC1    

LTBP3

SMO

 

EVC2   

MKKS      

TBX22

 

EYA1

MMP1

TBX3

 

FAP2B   

MMP13

TCOF1   

 

FGD1

MMP20

TFAP2B

 

FGF10

MMP9

TGFB

 

FGFR1

MSX1

TGFB3

 

FGFR2

NECTIN1

TSPEAR

 

FGFR3

NEFL

UBR1

 

FLNA

NEMO

WNT10A

 

FLNB

NF-KB

WNT5A

 

FOXC1

NSD1      

-

 

FUZ

OFD1

-

2.4 Supernumerary Teeth (ST)

APC

FGF4

PAX6

 

BMPR1A

FGFR2

PAX9

 

CDH1

FOXN1

PAXSEY

 

CHD8

GAS1

PDGFRB

 

COL3A1

GCM2

PLOD

 

CRE1

GLA

PTPN11

 

CREBBP

GSK3B

R-SPONDIN2

 

CTNNB1

IFT88

RECQL4

 

EDA

IKBKG

ROR2

 

EDAR

IL11RA

RUNX2

 

ERTM

LPR4

SATB2

 

EVC

LPR5

SOSTDC1

 

EVC

LPR6

SOX2

 

EVC2

MNX1

SPRY2

 

EYA1

MSX1

SPRY4

 

FAM20A

NEMO

TNXB

 

FAM20B

NHS

TRPS1

 

FGF10

OFD1

-

 

FGF3

OSR2

-

3. Shape of the Teeth

 

 

 

 

ANKRD11

EVC

PCNT

 

AXIN2

EVC2

RECQL4

 

BCOR

FGF3

SMARCAL1

 

CACNA1S

GREM2

SMOC2

 

CREBBP

IKBKB

SOSTDC1

 

DLX3

IKBKG

TRAF6

 

EDA

IKKA

WNT10A

 

EDAR

IKKR

WNT5A

 

EDARADD

IKKγ

-

4. TOOTH STRUCTURE

 

 

 

ENAMEL

ACP4

ENAM

MMP20

4.1 Non-syndromic Amelogenesis Imperfecta

AMBN

FAM20A

ODAPH

 

AMELX

FAM83H

RELT

 

AMTN

GPR8

SLC24A4

 

CLDN16

ITGB6

SP6

 

CLDN19

KLK4

STIM1

 

CNNM4

LAMA3

TP63

 

COL17A1

LAMB3

WDR72

4.2 Syndromic Amelogenesis Imperfecta

AIRE

FAM20C

OCRL1

 

ALDH3A2

FGF23

PDZD7

 

ATR

FOXC1

PEX1

 

CLDN16

GALNS

PEX6

 

CLDN19

GALNT3

PITX2

 

CNNM4

GLB1

ROGDI

 

COL17A1

GPR98

SLC10A7

 

COL7A1

HSD17B4

SLC13A5

 

CREBBP

KIND1

SLC4A4

 

DLX3

LAMA3

TBCE

 

ERCC8

LAMB3

TP63

 

EVC1

LAMC2

TRPM

 

EVC2

LTBP3

OCRL1

 

FAM20A

NHS

PDZD7

DENTIN

 

 

 

4.3 Dentinogenesis Imperfecta

DSPP

 

 

4.4 Dentin Dysplasia

MT1-MMP

NOTUM (Mouse)

SMOC2

 

SSUH2

VPS4B

-

5 TOOTH ERUPTION

 

 

 

5.1 Failure Primary Eruption

ALPL

IDS

PORCN

 

ASB

IKBKG

POSTN

 

CA2

IL11RA

PTH1R

 

CCL2

IL6ST

PTH1R

 

CICN5

LAD3

PTHLH

 

CLCN7

LEMD3

RANKL

 

COL1A1

LONP1

RANKR

 

COL1A2

MiR-31

SATB2

 

CSF1

NSD1

SFRP1

 

CTSC

OLEKHM1

SLC4A2

 

CTSK

OPG

TCIRGI,

 

DMP1

OSTM1

TNFa

 

FGF23

POLR3A

VEGF1

 

Table 1: List of genes associated with developmental defects that alter the number, size, shape, structure and eruption of the teeth.Those genes in which mutations have been described in mouse models or human beingsare annotated. Note that some genes are involved in isolated and syndromic developmental disorders. This table is based on references [6,10,14-16,23,28,32,37,40,45-51].

Conclusions

The presence of dental development abnormalities in patients, not only generates diverse clinical complications, but also impacts the aesthetic aspect of their teeth and produces a high psychosocial impact on them; problems of aesthetic dissatisfaction, self-perception and low self-esteem, higher levels of social avoidance, anguish and complex about their teeth, greatly limiting their social life and interaction with their peers. In addition, most of the alterations in tooth development can occur in isolation or associated with syndromes, therefore the presence of any of these abnormalities in patients can be used preventively as a possible marker of syndromic association, which should be exhaustively studied.

Acknowledgement

We would like to thank the support to this publication of Project NºFIOUCh C19-02 (Research Fund in Dentistry, Faculty of Dentistry of the University of Chile).

Conflict of Interest

The authors deny any conflicts of interest related to this manuscript.

References

  1. Townsend G, Bockmann M, Hughes T, Brook A. (2012) Genetic, environmental and epigenetic influences on variation in human tooth number, size and shape. Odontology. 100(1):1-9.
  2. Thesleff I. (2014) Current understanding of the process of tooth formation: transfer from the laboratory to the clinic. Aust Dent J. 59 Suppl 1:48-54.
  3. Balic A, Thesleff I. (2015) Tissue Interactions Regulating Tooth Development and Renewal. Curr Top Dev Biol. 115:157-86.
  4. Li J, Parada C, Chai Y. (2017) Cellular and molecular mechanisms of tooth root development. Development. 144(3):374-84.
  5. Bailleul-Forestier I, Molla M, Verloes A, Berdal A. (2008) The genetic basis of inherited anomalies of the teeth. Part 1: Eur J Med Genet. 51(4):273-91.
  6. Klein OD, Oberoi S, Huysseune A, Hovorakova M, Peterka M, et al. (2013) Developmental disorders of the dentition: an update. Am J Med Genet C Semin Med Genet. 163C(4):318-32.
  7. Cobourne MT, Sharpe PT. (2013) Diseases of the tooth: the genetic and molecular basis of inherited anomalies affecting the dentition. Wiley Interdiscip Rev Dev Biol. 2(2):183-212.
  8. Brook AH, Jernvall J, Smith RN, Hughes TE, Townsend GC. (2014) The dentition: the outcomes of morphogenesis leading to variations of tooth number, size and shape. Aust Dent J. 59 Suppl 1:131-42.
  9. Neville BW, Damm DD, Allen CM, Chi A. (2015) Oral and maxillofacial pathology. 4th Edn. USA. Editorial Saunders. Cap 22.
  10. Frazier-Bowers S, Siddharth RV. (2017) Genetic Disorders of Dental Development: Tales from the Bony Crypt. Curr Osteoporos Rep. 15:9-17.
  11. Al-Ani AH, Antoun JS, Thomson WM, Merriman TR, Farella M. (2017) Hypodontia: An Update on Its Etiology, Classification, and Clinical Management. Biomed Res Int. 2017:9378325.
  12. Galluccio G, Castellano M, La Monaca C. (2012) Genetic basis of non-syndromic anomalies of human tooth number. Arch Oral Biol. 57(7):918-30.
  13. Olley R, Xavier GM, Seppala M, Volponi AA, Geoghegan F, et al. (2014) Expression analysis of candidate genes regulating successional tooth formation in the human embryo. Front Physiol. 5:445.
  14. Yin W, Bian Z. (2015) The Gene Network Underlying Hypodontia. J Dent Res. 94(7):878-85.
  15. Ye X, Attaie AB. (2016) Genetic Basis of Nonsyndromic and Syndromic Tooth Agenesis. J Pediatr Genet. 5(4):198-208.
  16. Yamaguchi T, Hosomichi K, Yano K, Kim YI, Nakaoka H, et al. (2017) Comprehensive genetic exploration of selective tooth agenesis of mandibular incisors by exome sequencing. Hum Genome Var. 4:17005.
  17. Phan M, Conte F, Khandelwal KD, Ockeloen CW, Bartzela T, et al. (2016) Tooth agenesis and orofacial clefting: genetic brothers in arms? Hum Genet. 135(12):1299-1327.
  18. Küchler EC, Lips A, Tannure PN, Ho B, Costa MC, et al. (2013) Tooth agenesis association with self-reported family history of cancer. J Dent Res. 92(2):149-55.
  19. Bonds J, Pollan-White S, Xiang L, Mues G, D'Souza R. (2014) Is there a link between ovarian cancer and tooth agenesis? Eur J Med Genet. 57(5):235-9.
  20. Iavazzo C, Papakiritsis M, Gkegkes ID. (2016) Hypodontia and ovarian cancer: A systematic review.J Turk Ger Gynecol Assoc. 17(1):41-4.
  21. Yin W, Bian Z. (2016) Hypodontia, a prospective predictive marker for tumor? Oral Dis. 22(4):265-73.
  22. Hashem A, Kelly A, O'Connell B, O'Sullivan M. (2013) Impact of moderate and severe hypodontia and amelogenesis imperfecta on quality of life and self-esteem of adult patients. J Dent. 41(8):689-94.
  23. Lu X, Yu F, Liu J, Cai W, Zhao Y, et al. (2017) The epidemiology of supernumerary teeth and the associated molecular mechanism. Organogenesis. 13(3):71-82.
  24. Fleming PS, Xavier GM, DiBiase AT, Cobourne MT. (2010) Revisiting the supernumerary: the epidemiological and molecular basis of extra teeth. Br Dent J. 208(1):25-30.
  25. Subasioglu A, Savas S, Kucukyilmaz E, Kesim S, Yagci A, et al. (2015) Genetic background of supernumerary teeth. Eur J Dent. 9(1):153-8.
  26. Lagronova‐Churava SV, Spoutil F, Vojtechova S, Lesot H, Peterka M, et al. (2013) The dynamics of supernumerary tooth development are differentially regulated by Sproutygenes. J Exp Zool B Mol Dev Evol. 320(5):307-20.
  27. Kim YY, Hwang J, Kim HS, Kwon HJ, Kim SA, et al. (2017) Genetic alterations in mesiodens as revealed by targeted next-generation sequencing and gene co-occurrence network analysis. Oral Dis. 23(7):966-72
  28. Bae DH, Lee JH, Song JS, Jung HS, Choi HJ, et al. (2017) Genetic analysis of non-syndromic familial multiple supernumerary premolars. Acta Odontol Scand. 75(5):350-54.
  29. Takahashi M, Hosomichi K, Yamaguchi T, Yano K, Funatsu T, et al. (2017) Whole-exome sequencing analysis of supernumerary teeth occurrence in Japanese individuals. Hum Genome Var. 4:16046
  30. Lubinsky M, Kantaputra PN. (2016) Syndromes with supernumerary teeth. Am J Med Genet A. 170(10):2611-6.
  31. Makino Y, Yamaza H, Akiyama K, Ma L, Hoshino Y, et al. (2013) Immune therapeutic potential of stem cells from human supernumerary teeth. J Dent Res. 92(7):609-15.
  32. Yang J, Wang SK, Choi M, Reid BM, Hu Y, et al. (2015) Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds. Mol Genet Genomic Med. 3(1):40-58.
  33. Enright S, Humphrys AK, Rea G, James JA. (2015) Globodontia in the Otodental Syndrome: A Rare Defect of Tooth Morphology Occurring with Hearing Loss in an Eight-Year-Old. Dent Update. 42(10):927-32.
  34. Skrinjaric T, Gorseta K, Skrinjaric I. (2016) Lobodontia: Genetic entity with specific pattern of dental dysmorphology. Ann Anat. 203:100-7.
  35. Bloch-Zupan A, Sedano H, Scully C. (2012) Dento Oro Craniofacial anomalies and Genetics. Ed. Elsevier.
  36. Seow WK. (2014) Developmental defects of enamel and dentine: challenges for basic science research and clinical management. Aust Dent J. 59 Suppl 1:143-54.
  37. Smith CE, Poulter JA, Antanaviciute A, Kirkham J, Brookes SJ, et al. (2017) Amelogenesis Imperfecta; Genes, Proteins, and Phatways. Front Physiol. 26(8):435.
  38. Malik K, Gadhia K, Arkutu N, McDonald S, Blair F. (2012): The interdisciplinary management of patients with amelogenesis imperfecta- restorative dentistry. Br Dent J. 212(11):537-42.
  39. Pousette Lundgren G, Karsten A, Dahllof G. (2015) Oral health-related quality of life before and after crown therapy in young patients with amelogenesis imperfecta. Health Qual Life Outcomes. 13(1):197.
  40. Wright JT, Carrion IA, Morris C. (2015) The molecular basis of hereditary enamel defects in humans. J Dent Res. 94(1):52-61.
  41. de La Dure-Molla M, Philippe Fournier B, Berdal A. (2015) Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification. Eur J Hum Genet. 23(4):445-51.
  42. Jaouad IC, El Alloussi M, Laarabi FZ, Bouhouche A, Ameziane R, et al. (2013) Inhabitualautosomalrecessive form of dentin dysplasia type I in a large consanguineous Moroccan family. Eur J Med Genet. 56(8):442-4.
  43. Jeremias F, Pierri RA, Souza JF, Fragelli CM, Restrepo M, et al. (2016) Family-Based Genetic Association for Molar-Incisor Hypomineralization. Caries Res. 50(3):310-8.
  44. Kuchler EC, Tannure PN, de Oliveira DS, Charone S, Nelson-Filho P, et al. (2017) Polymorphisms in genes involved in enamel development are associated with dental fluorosis. Arch Oral Biol. 76:66-69.
  45. Wise GE, Frazier-Bowers S, D'Souza RN. (2002) Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med. 13(4):323-34.
  46. Frazier-Bowers SA, Simmons D, Koehler K, Zhou J. (2009) Genetic analysis of familial non-syndromic primary failure of eruption. OrthodCraniofac Res. 12(2):74-81.
  47. Vogel P, Read RW, Hansen GM, Powell DR, Kantaputra PN, Zambrowicz B, Brommage R. (2016) Dentin Dysplasia in Notum Knockout Mice. Vet Pathol. 53(4):853-62.
  48. Xiong F, Ji Z, Liu Y, Zhang Y, Hu L, et al. (2017) Mutation in SSUH2 Causes Autosomal-Dominant Dentin Dysplasia Type I. Hum Mutat. 38(1):95-104.
  49. Xu H, Snider TN, Wimer HF, Yamada SS, Yang T, et al. (2016) Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption. Matrix Biol. 52-54:266-83.
  50. Yang Q, Chen D, Xiong F, Chen D, Liu C, et al. (2016) A splicing mutation in VPS4B causes dentin dysplasia I. J Med Genet. 53(9):624-33.
  51. Gene expression in tooth (WWW database). Tooth and Craniofacial Development Group of the Developmental Biology Programme, Institute of Biotechnology, University of Helsink
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