Tooth Agenesis

Tooth Agenesis: Newer Concept

Meena Kulkarni * / Tripti Agrawal ** / Supriya Kheur ***

Developmental disturbances involving the oral cavity affect the growth and development of a child. Tooth
agenesis may be associated with a number of documented syndromes or may present as an isolated entity.
The presence or absence of teeth is decided by the influence of various genes and their signaling pathways.
These syndromes appear due to chromosomal defects or due to mutations in the genes responsible for
organogenesis. Identification of these mutations helps understand the underlying defect and plays an impor-
tant role in their treatment strategies. This is a comprehensive review of literature on syndromic and non-
syndromic forms of dental agenesis and an attempt in enlisting various syndromes associated with dental
agenesis.
Keywords: Tooth agenesis, non syndromic, syndromic, children
J Clin Pediatr Dent 36(1): 65–70, 2011

INTRODUCTION Tooth  agenesis  can  hamper  child’s  normal  growth  and

D
evelopmental disturbances affecting the oral tissues development. It will have its effect on the overall craniofa-
are manifested in many ways. They can be broadly cial and psychosomatic development of the child. Tooth age-
classified  in  two  categories—those  involving  hard nesis  can  alter  esthetics,  cause  malocclusion  along  with
tissues and the ones involving soft tissues. The spectrum of speech defects and thereby adversely affect the child’s per-
developmental pathologies affecting teeth includes variation sonality. This paper analyzes the molecular events involved
in shape, size, eruption pattern and number. Tooth agenesis in partial and complete anodontia. 
can  lead  to  partial  or  complete  Anodontia  (Ana-Absence,
Dontia-Teeth),  though  it  is  an  established  fact  that  a  few Molecular Basis of Tooth Development
teeth, by evolution, are congenitally absent (eg. 3rd molars). First step in the process of tooth development is the for-
Global literature has reported a wide range in the frequency mation of tooth bud. The developing tooth buds are formed
of congenitally missing teeth as 1.6% to 9.6%. The congen- in  the  developing  jaw  bones  as  early  as  8th  week  of
itally missing primary teeth are uncommon but when they do intrauterine life. Tooth bud formation takes place due to the
occur,  maxillary  lateral  incisor  is  the  one  frequently continuous proliferation of basal cells of the oral ectoderm
reported.  which leads to the formation of epithelial thickenings ( pri-
The presence or absence of one or more teeth is decided mary epithelial band).1 The epithelial thickening during the
by a complex series of events in an individual. The interplay tooth development contains genetic determinants for initiat-
between  various  genes  and  their  signaling  pathways  are ing  signals  that  regulate  the  number  and  position  of  the
responsible  for  the  morphologic  character  and  positioning future teeth. The oral ectoderm contains “Instructional sig-
different  teeth  in  human  dentition.  Mutations  in  closely nals” for tooth development and perhaps the pattern of entire
linked polygenic system, most often transmitted in different dentition. In short, these signaling pathways lay down a blue
patterns with incomplete penetrance and variable expressiv- print for the entire dentition. The homeobox gene constitutes
ity lead to various malformations Graber et al.1-5 a  large  family  of  genes  that  specify  correct  positioning  of
body parts during the embryonic development. An overview
of  these  genes  and  their  potential  role  help  us  to  better
* Meena  Kulkarni,  Prof.  and  HOD,  Department  of  Oral  Pathology  and understand the events of tooth genesis. All members of this
Microbiology, Dr. DY Patil Dental College and Hospital. family share a common code of 60-amino acid DNA binding
** Tripti  Agrawal,  MDS  II  year,  Department  of  Oral  Pathology  and sequence. The homeobox genes are widely expressed during
Microbiology, Dr. DY Patil Dental College and Hospital.
embryonic  development  (Dlx,  Pax,  Msx).2 Four  major  sig-
*** Supriya  Kheur,  Reader,  Department  of  Oral  Pathology  and
Microbiology, Dr. DY Patil Dental College and Hospital. naling pathways and their inhibitors control tooth formation;
a fine balance between them determines the numbering and
Send  all  correspondence  to  Dr.  Tripti  Agrawal,  Department  of  Oral
patterning of human dentition. They are Bmp, Fgf, Wnt and
Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital,
Pimpri Pune- 18,  Shh signaling pathways.6,7 
The  tooth  formation  also  relies  on  epithelial  ectomes-
Phone: 09503042421.
enchymal interaction. It has been reported that genes impli-
triptiagrawal29@gmail.com cated  in  the  epithelial  mesenchymal  interaction  during

The Journal of Clinical Pediatric Dentistry Volume 36, Number 1/2011 65

Tooth Agenesis

mouse odontogenesis also serve as potential candidates for molecules.  Research  led  to  the  understanding  of  Wnt/ 

tooth agenesis in humans. 8 β-catenin  pathway  in  tooth  development.  It  is  known  that
this pathway is found to be mutated or hyperactivated in var-
Genes: Potential Role in Odontogenesis ious types of cancers (e.g. colorectal cancers). It is shown to
Over  expression  of  Bmp1  in  transgenic  mouse  or  func- promote self-renewal and proliferation of various stem cells.
tional  inactivation  of  FGFR2b  or  Shh  results  in  arrest  of It  also  regulates  distinct  cell  fate  decision  in  neural  crest
tooth  development  in  the  bud  stage  itself.  When  the stem  cells  which  play  a  pivotal  role  in  odontogenesis. The
inhibitors or mediators of these signaling pathways are per- Wnt  pathway  regulates  multiple  developmental  processes
turbed more teeth are formed with abnormal shape. Defec- including craniofacial development and may play a role in
tive  ameloblast  or  odontoblast  differentiation  and  reduced cleft lip/palate and other defects of craniofacial development
amount  of  matrix  deposition  may  also  be  manifested. such as tooth agenesis.9
(Tables 1 and 2) Shh is a crucial signaling molecule acting during organo-
The  members  of  Fgf  family  ligand,  namely  Fgf3  and genesis, patterning of limb, development of gut, tooth initi-
Fgf10, derived from mesenchyme, promote the proliferation ation and tooth morphogenesis. The tooth defect results from
of incisor epithelial stem cell niche. Consistently, downreg- mid-facial fusion defect. Disturbance in Shh signaling path-
ulation of Fgf10 leads to hampered growth of incisors.6 way leads to defective growth and development of maxillary
The  name  Wnt  was  derived  from  Drosophila  wingless arch resulting in the premature fusion of left and right parts
and  mouse  Int1  in  late  1980s  and  early  1990s.  The  Wnt of the dental lamina, leading to fusion of incisor buds.10
 proteins  are  a  family  of  secreted  growth  factors  which  in A  study  conducted  by  X.  P.  Wang  et al (2005)  showed
association with specific receptors act as repressors or acti- that Shh signaling pathway genes Ptc1, Ptc2 and Gli1 were
vators  of  target  genes  which  encode  various  cell  signaling down  regulated  in  Runx2  muted  lower  molars.  But  the
expression  was  unaffected  in  upper  molars.11 Nonsense
mutations in Msx have been demonstrated in non-syndromic
Table 1. Abnormalities caused by mutation in transgenic mice
affecting tooth formation.6
tooth agenesis.12,13 Msx mutations also result in mild maxil-
lary anterio-posterior hypoplasia.14 A study conducted by S.
TOOTH PHENOTYPE GENES INVOLVED
Pirinen  et al 1996  concluded  that  palatal  displacement  of
Initiation stage arrest Msx1, Msx2, Dlx1, Dlx2, Fgf8, Lhx6/ canine is genetic and is related to genetic incisor-premolar
Lhx7, Pitx2, Gil2, P63, Dkkl. hypodontia  and  peg  shaped  incisors.15 M.  L.  Klein  et  al
Bud stage arrest Pax9, Lef1, Max1, Runx2, Barx1, (2006) have concluded that novel mutation in the initiation
Bmpr1a, Fgfr2b, Shh, Noggin.
codon of Pax9 (belongs to paired ox gene family and named
Supernumerary teeth Apc, Sp6, Lrp4, IFT88/ Polaris, Gas1, on the basis of presence of a DNA binding paired domain)
Qsr2, Sproty 2, 4.
has been responsible for non-syndromic oligodontia. It acti-
vates the tooth bud to cap transition, and is usually associ-
Table 2. Abnormalities caused by mutation in transgenic mice ated with missing permanent molars, all second premolars,
affecting tooth matrix6
upper first premolars but hypodontia in primary dentition is
Table 2a. ENAMEL DEFECT very rare.10,16
TOOTH PHENOTYPE GENES INVOLVED
Syndromes: Their Myriad Expressions
Enamel hypoplasia Msx2, Lama3, Enamelin, Mmp20, Sp3,
Sp6, Smoothend, Connexin43, Agenesis can occur in isolated cases or can be associated
Periostin, Amelex. with variety of syndromes.
No Enamel Gdnf, Eda, Follistatin, Ameloblastin. Over  200  syndromes  exhibit  cleft  lip/cleft  palate  along
with tooth agenesis as a part of their phenotype and many of
Ectopic Enamel Wnt3, Sprouty2, 4.
their  causative  genes  have  now  been  identified.  The  Msx
mutation  causes  a  wide  spectrum  of  phenotypes  ranging
Table 2b. DENTIN DEFECT
from  Witkop  syndrome  to  non-syndromic  hypodontia.
TOOTH PHENOTYPE GENES INVOLVED Mutations  in  Ectodysplasin  are  well  known  to  cause  Ecto-
Dentinogenesis Dspp, Msx2. dermal  dysplasia  (HED).  Shh  gene  causes  developmental
imperfecta disorders  ranging  from  only  mild  microcephaly  or  dental
Dentin defect Sp3. defects  to  very  severe  autosomal  dominant  syndromic
Abnormal dentin Sp6  phenotypes.
structure The  Shh  downstream  transcription  factor  GLI3  causes
Pallister-Hall  syndrome.  The  Homebox  gene  Pitx2  is
Table 2c. ROOT DEFECT expressed in the oral epithelium at the site of tooth formation
TOOTH PHENOTYPE GENES INVOLVED and is necessary for the maintenance of the balance of Bmp4/
Short Root Shh.
Fgf8 expressed in oral epithelium. Mutation in these genes is
responsible  for  some  cases  of  Reiger  syndrome,  together
Lacking Root Nfi-c/ CTF
with  Pax  gene  family.  Along  with  severe  oligodontia  this

66 The Journal of Clinical Pediatric Dentistry Volume 36, Number 1/2011

 Tooth Agenesis

syndrome  is  characterized  by  cleft  lip/  palate  and  cranio - (glycine 637 to serine substitution in type III collagen).25 But
facial malformation. the  Ehlers-Danlos  syndrome-dermatosparaxis  type  is  char-
Van der Woude syndrome is the most common syndromic acterized by extensive skin bruising and short stature. Muta-
form of cleft palate and is caused by the mutation of IRF6 tions  for  this  syndrome  is  recorded  in  the  pNPI  gene  (i.e.
gene. The translocation mutation in locus 1q32-q42 has been Absence of activity of procollagen I N-proteinase). 26 
recorded  for  this  syndrome.8 Mutation  in  FGFR1  causes Syndromes  expressing  phenotypic  pattern  of  severe
severe  developmental  disturbances  including  Kallmann growth retardation are Aarskog syndrome, Ellis-van Creveld
Syndrome.16 Hypodontia features in a number of other syn- syndrome  and  Johanson-Blizzard  syndrome. Aarskog  syn-
dromes, such as Down’s syndrome which is characterized by drome is an X-linked recessive disorder. The person suffer-
mental  retardation  and  characteristic  facies.  Trisomy  in ing from this syndrome is recognized soon after birth and is
chromosome  21  is  mapped  as  the  cause  and  characteristic characterized  by  proportionate  short  stature  along  with
feature of this syndrome. severe  dental  agenesis.27,28 Short  limbs,  postaxial  poly-
Mental  retardation  and  dental  agenesis  together  is dactyly, nail hypoplasia and cardiac defects are the diagnos-
expressed  in  a  few  other  syndromes,  out  of  which  Ruben- tic features of Ellis-van Creveld syndrome. Mutations of the
stin-Taybi  is  not  very  infrequent. This  syndrome  is  caused EVC1 and  EVC2 genes,  on  chromosome  4p16  are  mapped
by  the  mutation  in  16p13.3  and  is  characterized  by  dental for this syndrome.29 Johanson-Blizzard syndrome is charac-
agenesis, mental retardation, broad thumbs/ toes and facial terized  by  beak-like  nose,  abnormal  hair  patterns,  aplastic
dysmorphism.  Laurence-Moon  syndrome  caused  by  muta- nasal alae, hypotonia and growth retardation. Translocation
tion in gene 20p12 is also found to be associated with dental mutation in chromosome 15q15-q21 is recorded for this syn-
agenesis  and  mental  retardation. The  other  features  of  this drome.30 
syndrome  are  spastic  paraplegia  and  pigmentary  retinopa- Some  of  less  commonly  encountered  syndromes  are
thy.8 Hallermann-Streiff syndrome and Seckel syndrome. Haller-
Severe  skull  deformity,  midface  hypoplasia  and  syn- mann-Streiff  syndrome  characterized  by  short  stature  and
dactyly together are characters of Apert Syndrome; which is bird-like face is also associated with dental agenesis. It is a
an autosomal dominant disorder with the locus of mutation dominantly inherited disorder due to mutations in the con-
at FGFR2 on chromosome 10q. Along with supernumerary nexin  43  gene  GJA1.31 Seckel  syndrome  is  associated  with
teeth and severe skull malformation, dental agenesis is also severe  growth  retardation,  microcephaly  and  beak-like
a  marked  feature  of  this  syndrome.17 Another  syndrome facies.  On  the  basis  of  genetic  mutation  this  syndrome  is
associated  with  skull  deformity, Acanthosis  Nigricans  and divided into three types.
severe scoliosis is Crouzonodermoskeletal syndrome. Point
mutation in the FGFR3 gene on chromosome 4p is noted.18 Mutations in Seckel syndrome-32
ADULT  syndrome  is  an  uncommon  syndrome,  featuring Seckel 1- 3q22.1-q24
dental agenesis, ectrodactyly, nail dysplasia, breast hypopla- Seckel 2- 18p11.31-q11.2
sia. Mutation of chromosome 3q27 is reported in this syn- Seckel 3- 14q23
drome.19, 20
Most commonly encountered features with dental agene- Some  of  the  syndromes  frequently  associated  with  skin
sis are the presence of cleft lip/ palate and marked skeletal pigmentation  are  Goltz-Gorlin  syndrome  and  McCune-
disorders. Few like Cleft lip/ palate syndrome or Ectodermal Albright syndrome. Dental agenesis and skin pigmentation
dysplasia  syndrome,  Coffin-Lowry  syndrome  and  Hay- along  with  polyostotic  fibrous  dysplasia  is  a  well  docu-
Wells syndrome are reported with these features. Cleft lip/ mented feature of McCune-Albright syndrome. Mutation in
palate syndrome presents with dental agenesis in association chromosome number 20q13.2 causes this syndrome.8 Goltz-
with syndactyly, ectodermal dysplasia and cleft  lip/ palate. Gorlin syndrome is reported to be caused due to heterozy-
The  defect  in  this  syndrome  is  in  the  genetic  locus  as  a gous  loss-of-function  mutations  in  the  PORCN  gene.  This
translocation mutation in 11q23-q24.8  Another form of ecto- syndrome  expresses  itself  as  linear  skin  pigmentation,  fat
dermal  dysplasia  syndrome  is  X-linked  translocation  from herniation and syndactyly.33
Xq12-Xq13.1.21,22 Hay-Wells  syndrome  is  associated  with Organ  malformation  is  a  rare  manifestation  well  docu-
the mutation in p63 causing the amino acid substitution of mented in the medical literature and directly affects the life
sterile alpha motif (SAM) domain which results in the defec- expectancy of the patient. Alagile syndrome, Branchio-oto-
tive  protein  interaction.23 Coffin-Lowry  syndrome  is  an  X- renal syndrome, Rieger syndrome and Rothmund-Thomson
linked disorder with a mutation in Xp22.2 which is respon- syndrome are a few rare syndromes associated with the mal-
sible for the major skeletal disorder.24 formation of an entire organ or a part of it and is associated
Syndromes  associated  with  dental  agenesis  express  a with dental agenesis. Mutation in short arm of chromosome
wide variety of phenotypic patterns ranging from skin pig- 20 is responsible for Alagile syndrome. The main feature of
mentation,  neuropathies,  hypermobility  of  joints,  limb  and this syndrome is cardiac and ocular anomalies, characteris-
organ malformations to growth retardation. Explanation for tic  facies  along  with  dental  agenesis.34 Branchio-oto-renal
the Ehlers-Danlos syndrome-hypermobility type is intracel- syndrome  is  associated  with  mutated  gene  on  8q13.3,
lular  retention  of  type  III  collagen  mutations  of  COL3A1 14q23.1  and  19q13.3.  The  characteristic  features  of  this

The Journal of Clinical Pediatric Dentistry Volume 36, Number 1/2011 67

Tooth Agenesis

 syndrome  are  branchial  cysts,  structural  ear  defects  and CONCLUSION

renal hypoplasia.35 This is a comprehensive review of literature on the relation-
Rieger syndrome is found to be associated with mutation ship  of  alterations  in  the  genetic  signaling  mechanism  and
on  4q25  and  undefined  mutation  on  13q14  and  16q24. anodontia. We are just beginning to uncover the myth of this
Hypoplastic iris, umbilical hernia and anal stenosis are the cellular  phenotype  transition  that  plays  an  important  role
features of this syndrome.36 Mutation in 8q24.3 leads to phe- during development and homeostasis. Human tooth agenesis
notypic features like dermatosis, bone defects, scalp defects is probably caused by several independent defective genes,
and  hypogonadism  which  are  collectively  known  as  Roth- acting alone or in combination with other genes, leading to
mund-Thomson syndrome.37 specific phenotypic patterns. 
Charcot-Marie-Tooth disease is characterized by progres- Biologists have taken huge leaps that will take us a long
sive  late  onset  neuropathy  and  is  an  autosomal  dominant way in detecting the loci that contribute to dental agenesis.
condition.  It  occurs  due  to  mutations  in  the  NF-L  gene Further research in characterizing the unique syndromic and
(NEFL);  the  neurofilament  light  chain  (NF-L)  is  a  major non-syndromic  forms  will  help  us  to  establish  molecular
constituent  of  intermediate  filament.24 Fanconi  renotubular relationship between various signaling genes and their path-
syndrome occurs due to mutation in 15q15.3, and is charac- ways responsible for tooth agenesis. These insights will sig-
terized by retarded growth, rickets and hypophosphatemia.8 nificantly add to our knowledge of complex cellular events
Missense mutations or small deletions in the X-linked gene, that give rise to molecular development strategies that con-
FLNA  leads  to  Frontometaphyseal  dysplasia  characterized trol the pattering of the human dentition.
by frontal hyperostosis and metaphyseal dysplasia.38,39 A day is not too far where this knowledge can be applied
Dental  agenesis  and  limb  malformation  are  common  to in  experimental  and  clinical  trials  to  develop  tooth  buds
Moebius syndrome, Oral-facial-digital syndrome, Pseudox- using  stem  cells.  Hope  is  on  the  horizon  to  create  teeth  in
anthoma elasticum syndrome, Rapp-Hodgkin syndrome and vitro to replace the missing teeth.
Larsen  syndrome.  These  syndromes  are  usually  detected
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