Clinical Consideration in Tooth Development

PRESENTED BY : Dr. SHASHI BHAL MAURYA MDS FIRST YEAR

ORAL AND MAXILLOFACIAL PATHOLOGY AND MICROBIOLOGY

INTRODUCTION

• Teeth are specialized structural components of the craniofacial skeleton and are comprised of : enamel, dentin, and cementum.

• Developmental defects occur in each of these mineralized tissues, either alone (isolated), or in a combination (syndromic) with defects in other organs or tissues

Four signalling pathways, are repeatedly used throughout tooth development.

the bone morphogenetic proteins (Bmp), fibroblast growth factors (Fgf), sonic hedgehog (Shh), wingless-related (Wnt) pathways

Inactivation of any of these resulted in early tooth developmental arrest in mice.

E 11.5 – thickening of oral epithelium

Expression of key signaling molecules Bmp, Fgf, Wnt, Shh

Blocking each of these molecules results in tooth arrest in dental lamina or bud stage

Bmp and Fgf signaling is required for activation of expression of the Msx1 and Pax9

COMPLETE ANODONTIA

PARTIAL ANODONTIA

Kazhila C. Chinsembu ,Teeth are bones: Signature genes and molecules that underwrite odontogenesis Journal of Medical Genetics and Genomics Vol. 4(2),March 2012

Wnt signaling is required early in tooth germ formation and interference with signaling via addition of an antagonist results in retarded development and formation of smaller teeth; mutation of β-catenin causes formation of large, misshapen teeth buds and ectopic teeth.

E 11.5 – thickening of oral epithelium

Epithelium proliferates and invaginates into the neural crest cell derived mesenchyme

and forms BUD

E 13.5 – BUD clearly forms and surrounded by the condensing mesenchyme

Prior to the transition of bud to cap primary enamel knot forms at the tip of the tooth bud.And exihibits restricted expression of Bmp, Fgf, Wnt

ENAMEL KNOTBmp4 signaling from condensing mesenchyme and p21 from dental epithelium– induction of enamel

knot.

Plays central role in patterning of tooth crown by regulating growth and folding of the epithelium.

Addition of Bmp4 in oral epithelium

Upregulation of enamel knot marker such as p21

Overexpression of P21 –enlarged enamel knot and cuspal defects.Like Dense in Dente, Dense Evaginatus, Talons cusp

DENSE IN DENTE DENSE EVAGINATUS TALON CUSP

E 14.5 - high proliferation outside the enamel knot and low proliferation within the knot

Forming cap shape structure

If the shape of enamel knot is too small with mutation of Eda or Edaradd (Eda expression is regulated by Wnt)

Hypohidrotic Ectodermal DysplasiaCharacterized by presence of molars with reduced

cusps and peg like teeth.

If Wnt signaling blocked in early bell stage when the secondary enamel knot is forming --- again expression of Eda will reduced and molar forms with flattened cusps

Reducing tooth number• It can be due to—FUSION-fusion of existing tooth germ to form single compound tooth.Fusion observed in-

SMMCI (single median maxillary central incisor syndrome) Caused by failure in growth in midline, stimulated by a defect in SHH

signalling pathway (Nanni et al 2001)

Increase in tooth number

In the wild-type mouse mandible,• one incisor forms from each incisor placode,• three molars (M1, M2 and M3)forming from the molar placode.

1. One way increase number of tooth is to increase the number of placode.(Ectopic application of Shh has been shown to lead to formation of ectopic tooth germs).

2. SPLITTING OF TOOTH GERM (GEMINATION): Rabbit molars were halved two miniature molars formed (Glasstone 1952)

3. Multiple teeth have been shown to arise from the molar field in mice where β-catenin has been overexpressed (Jarvinen et al. 2006; Liu et al. 2008).a) In mice - a) molar region was explanted in to kidney capsule three molars forms.

b) Molar region explanted into β-catenin mouse 40 teeth forms (Jarvinen et al.2006).

The initial tooth buds form normally, but the dental epithelium then starts to undergo further budding and invaginations, leading to the formation of additional enamel knots and additional teeth and leads to the formation of ODONTOMA.

4. Similar overproduction has been described in Epfn mutant mouse (Nakamura et al. 2008).

5. In human patients with a mutation in APC (is a Wnt modifier) supernumerary teeth and odontomas are observed (Fader et al. 1962; Wolf et al. 1986; Wang et al. 1998)

Changing the complexityComplexity of tooth- Altered by addition or removal of tooth.

Etiology -1) Diet- diet dependent changes of dental pattern seen in both carnivores and rodents (Evans et al

2007)

2) Formation of additional enamel knot- overstimulation of Eda signaling pathway

3) NUMBER of cusp depends on both cusp size and tooth size.• Larger tooth –more space to develop additional cusp• If cusp is smaller – more cusp can be be fitted in (Cai et al 2007)• Eg. Small molar (artificially created ) by recombining a small number of

mesenchymal cells with tooth epithelium number of cusp generated was reduced(Hu et al 2006)

Mineralization:epithelial mesenchymal interaction

After the disappearance of the secondary enamel knot signalling centres, cells of the tooth organ terminally differentiates-

• Inner enamel epithelium cells – Ameloblastoma• Dental pulp mesenchyme- Odontoblast

Tgfb1, Fgfs, and Bmp2

Induce polarization of Odontoblast (Begue-et al

1994)

The later stages of tooth development are characterized by the formation of the mineralized tissue: dentin,cementum and enamel. Dentin and cementum have significant similarities with bone.

(Linde & Goldberg, 1993),

ENAMEL: Inherited enamel defect known as Amelogenesis imperfecta.

Ameloblast secretes two major class of proteins- Nonglycosylated –amelogennin – 90%of enamel matrix Glycosylated – Tuftelin

• Ameloblastin• Enamelin

Enamelin (ENAM) – main candidate responsible for autosomal inherited form of Amelogenesis Imperfecta.Amelogenin (AMLEX) mutation leads to X-linked Amelogenesis Imperfecta.Also occurs due to mutation in Enamelysin and Kallikrein (KLK4).

DENTINDentinal defects are classified into

dentin dysplasia type 1 and type 2 dentinogenesis imperfecta type 1, type 2 and type 3

Dentinogenesis imperfecta universally designated as Osteogenesis imperfecta with Dentinogenesis imperfecta.

Occurs due to mutation in type1 collagen.

Dentin dysplasia type 1 and type 2 Dentinogenesis imperfecta

Mutation in DSPP, COL1A1 AND COL1A2

Root formation

Expression of Bone Morphogenetic Proteins and Msx Genes during Root Formation

Journal of Dental Research, Mar2003, Vol. 82 Issue 3, p172-176, 5p, 3 Color Photographs, 1 ChartColor Photograph; found on p174

trauma to the calcified portion of the tooth germ which alters the angulation of the tooth during root formation leads to .Dilaceration

.(NEVILLE)

 The formation of ectopic enamel requires the presence of differentiated ameloblasts apical to the CEJ. In humans, Hertwig's epithelial root sheath (HERS) or its residues, the epithelial rests of Malassez have been implicated as the likely sources of ectopic ameloblasts.

Shivani sharma et al Enamel pearl on an unusual location associated with localized periodontal disease: A clinical report, J Indian Soc Periodontol. 2013 Nov-Dec; 17(6): 796–800

If cells of the epithelial root sheath remain adherent to the dentin surface, they may differentiate into fully functioning ameloblasts and produce enamel. Such droplets of enamel called Enamel pearls,

Mass of ectopic enamel located inthe furcation area of a molar tooth.

Genetic defects occurring late in tooth developmentDLX3 mutation causes the deformation in multirooted tooth known as TAURODONTISM

(Bull like shape).

HYPOPHOSPHATASIA is a bone disorder caused by mutation in ALPL (alkaline phosphatase).

Histological examination of pt with hypophophatasia

Shows lack of both cellular and acellular cementum formation.

References… NEVILLE, ALLEN, BOUQUOT Oral and Maxillofacial Pathology third editionShafer’s text book of oral and maxillofacial pathology seventh editionOrban’s oral histology and embryology 13th edition.Aswathy Raj,Deepa.M.S, Ahmed Hasan Farooqi GENETICS AND TOOTH ANOMALIES - AN

UPDATEOral & Maxillofacial Pathology Journal Vol. 4 No. 1 Jan - June 2013 Hattab FN, Yassin OM, Al-Nimri KS. Talon cusp in the permanent dentition associated with

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Danker E, Harari D, Rotstein I. Dens evaginatus of anterior teeth. Literature review and radiographic survey of 15,000 teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:472-76

Thaleia Kouskoura1 Natassa Fragou1 Maria Alexiou1 Nessy John2 Lukas Sommer2,The genetic basis of craniofacial and dental abnormalities, Schweiz Monatsschr Zahnmed Vol. 121 7/8/2011

Johannes G Dauwerse1, Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome, NATURE GENETICS, VOLUME 43 | NUMBER 1 | JANUARY 2011 .

Current knowledge of tooth development: patterning and mineralization of the murine dentition Javier Catón and Abigail S. Tucker Department of Craniofacial Development and Orthodontics, King’s College London, Floor 27, Guy’s Tower, Guy’s Hospital,London, UKJ. Anat.(2009)214 pp502–515.

Teeth are bones: Signature genes and molecules that underwrite odontogenesis Kazhila C. Chinsembu Journal of Medical Genetics and Genomics Vol. 4(2), pp. 13 - 24, March 2012

Jan C-C. Hu, James P.,Developmental biology and genetics of dental malformations Orthod Craniofacial Res 10, 2007; 45–52

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