Amelogenesis Imperfecta

Michael Aldred, Anna Talacko and Netasha Steyn Dorevitch Pathology,

Heidelberg, VIC, Australia

Synonyms

Hereditary brown hypoplastic enamel; Hereditary brown teeth; Hereditary

enamel aplasia; Heredi- tary enamel defects; Hereditary enamel dysplasia;
Hereditary enamel hypomineralization; Heredi- tary enamel hypoplasia;
Hereditary enamel matu- ration; Hereditary mineral hypocalcication

Denition

Amelogenesis imperfecta (AI) can be dened as a developmental defect of

enamel due to a defective gene affecting all or most of the teeth
ofboththedeciduousandpermanentdentitionsto some extent. The condition
can be inherited as an autosomal dominant, autosomal recessive, or X-linked
trait or present as sporadic cases which
mayrepresentdenovo(spontaneous)mutationsin one of the genes involved in
enamel matrix depo- sition and mineralization. The condition can also be
seen in association with a number of syn- dromes. Traditionally AI has been
classied according to the perceived phenotype. This assumes that all cases
can be neatly subdivided according to whether there is an enamel hypopla-
sia (reduction in quantity of enamel) or where mineralization is abnormal.
Where the degree of mineralization is severely affected, this has been
labelled a hypocalcication defect, and where the mineralization defect is
less marked, the term hypomaturation has been applied. However, there is
no clear-cut separation between these two categories. Furthermore, some
individuals have features of hypoplasia and hypominera- lization. For the
purposes of further discussion, the term hypomineralization will be used to
encompass both hypocalcication and hypomaturation. In an attempt to
avoid some of these classication dilemmas and paradoxes, more recently a
classication based upon the mode of inheritance as the primary
discriminator has been proposed, with the phenotype being
asecondarydiscriminator.Inautosomaldominant AI, the presenting individual
(proband) will prob- ably be aware of other family members similarly affected,
or this may become apparent during further discussion, sometimes including
examina- tionofothermembersofthefamily.Aclearlineof inheritance should be
able to be established in such families. Some geneticdisorders feature var-
iable expression whereby the clinical and/or radiographic features are not
uniform in all affected individuals. It is also possible that the phenomenon of
incomplete penetrance can occur whereby the condition appears to skip an
individ- ual who is not himself or herself obviously affected but passes on the
condition and therefore must have inherited and passed on the mutant gene.
It is not clear whether or not this applies in AI, but variable expression
certainly does.

Autosomal-recessive forms of AI are most likely to be identied where there is

consanguinity. This mayoccurincertaincommunitieswheremarriage
between,forinstance,rstcousinsisacceptedand even supported for family and
cultural reasons. It may also occur when the frequency of the mutant
geneinapopulationisrelativelyhighand/orthere is a limited gene pool such as
in some island communities. X-linked AI is characterized by dif- ferences in
the clinical appearances between males and females who inherit the mutant
gene (which is carried on the X chromosome). Males, by virtue of having only
one X chromosome, exhibit the condition to the fullest degree. The enamel
may be extremely thin (hypoplastic) which leads to spacing between the
teeth and either hard and shiny which indicates no signi- cant mineralization
defect or opaque/discolored implying hypomineralization to some degree (Fig.
1). In some families, the enamel in affected males is offull thickness, so there
is no spacing between the teeth. However, the enamel tends to be matt/
opaque/chalky in appearance with varying degrees of discoloration (Fig. 2).
Such a case would t with a hypomineralization phenotype. Where there is a
mineralization defect, the teeth may be prone to wear. The teeth are not
more likely to develop caries by virtue of the genetic defect itself. Females
exhibiting X-linked AI show vertical markings of the enamel, either grooves as
a result of hypoplasia or vertical bands of enamel of different color or a
combination of both (Fig. 3). This is a result of lyonization whereby one X
chromosome in each femalesomaticcellisinactivatedatacertainstage of
development in each tissue or organ. Presum-
ablythisoccursatanearlystageinmappingoutof the enamel organ so that
successive ameloblasts derived from cells under control of the normal or
mutant gene produce the vertical bands as they proliferate towards the
cervical margin of the crown. Some patients are seen with clinical appear-
ances typical of AI but without any obvious family history and no parental
consanguinity. It is important to consider in such patients the possibility of
uorosis. If this can be excluded, then a diagnosis of sporadic AI would be
reason- able as a working diagnosis. If this represents a spontaneous
mutation, then the possibility of this being passed onto future generations
needs to be considered in the longer term management of that patient which
should include a consideration of genetic counselling. Radio- graphs can
provide invaluablefurtherinformation in the assessment of patients with AI. A
dental panoramic radiograph may identify unerupted teeth. The failure of
eruption of some teeth in some individuals with AI presumably reects a
defect in the enamel organ caused by the mutant

gene. Such teeth may undergo resorption, possi- bly because the integrity of
the enamel is compromised. Where there is a mineralization defect, the
distinction between enamel and dentin is less obvious this may be seen in
extraoral radiographs such as a dental panoramic radio- graph; bitewing or
periapical radiographs will best illustrate this phenomenon. In some families,
taurodontismisalsoseen.Thismanifestsinmulti- rooted teeth as elongation of
the coronal pulp chambers at the expense of the roots, with dis- placement of
the furcation of the roots. In some such patients, the pulp chamber can also
appear wide in single-rooted teeth and is presumably a re ection of this trait.
Anterior open bite is seen in some individuals and families with AI. About 50
% of cases have been reported to be affected. The signicance of this nding
is as yet unclear.

Clinical Features

Incidence A study of school children in the USA found 1 in 14,00016,000

individuals to have amelogenesis imperfecta. In one part of Sweden, the
prevalence has been recorded as 1 in about 800. This variation may reect
dif- ferences in different populations and the fre- quency of the mutant
gene(s) in the relevant population as well as, perhaps, the assiduous- ness of
the examiner(s). Age AI may be identied in the deciduous dentition, but
this is more likely to occur where there is a known family history and the
parent(s) or carers are concerned about a child being affected. For unknown
reasons, the deciduous dentition is often less severely affected than the
permanent dentition; hence, in many cases, the condition may not be iden-
tied until the eruption of the permanent teeth, i.e., after the rst permanent
molars erupt at 6yearsofageandthepermanentincisors erupt at 78 years of
age. Sometimes the diagnosis may not be made until later depending upon
theperceptionofthepatientandfamilyandthe degree of severity of the
condition. Sex Thereisnosexpredilection inAI.However,as noted above, the
clinical manifestations may be different in different sexes in XAI. This might
lead to some heterozygous females not being recognized and an apparent
male predi- lection in one particular family. Site Both deciduous and
permanent dentitions will be affected. The deciduous dentition defects may
be more subtle than in the permanent

dentition. All teeth are affected to some degree though some may appear
clinically normal but may show evidence of radiographic changes (such as
where there is taurodontism) or if such teeth were examined microscopically.
Treatment Long-term treatment planning needs to be undertaken as the
condition will require treat- ment and re-treatment throughout life. Where
there is severe hypoplasia so that the crowns are smaller than normal or
where the teeth are subject to occlusal wear as a result of a mineralization
defect, placement of stainless steel crowns on the rst molars should be con-
sidered once these teeth are fully erupted. Acid-etch composite facings on
the labial aspectsofthemaxillarycentralandlateralinci-
sorscanimprovetheaesthetics,andthisshould reduce the possibility of teasing
which can be a signicant psychological problem for some
affectedchildren.Thisshouldnotbecarriedout too early; otherwise it will need to
be repeated after the crowns are fully erupted. In addition, treatment of too
young a child can compromise moisture control which is critical in successful
placement of such restorations. More denitive treatment can include
porcelain veneers on the anterior teeth as well as full crowns on premo- lars
and molars. Where there is marked hypo- plasia of the enamel, then crowns
may be necessary on the anterior teeth in addition to the premolars and
molars. Attention may need tobepaidtogingivalhealth;somefemaleswith XAI
havedifcultyinmaintainingoralhygiene because of plaque accumulation in
hypoplastic grooves at the gingival margin. If there is taurodontism and
endodontic treatment is required, navigation into the apical canals can pose a
problem in some patients. Outcome It is important to realize that
individuals with AI have a lifelong requirement for mainte- nance of their
dentition. This requires a signicant commitment of time on the part of the
individual and their family as well as the clinician, and there are considerable
nancial consequences. Macroscopy

Careful examination of a tooth specimen from a patient with AI is required.

Typically such a specimen would be an exfoliated deciduous tooth. The
assessment should include the shape of the crown and crown form as well as
any discoloration. The use of a sharp probe may demonstrate an ability to
indent the surface of the enamel if there is a signicant degree of
hypomineralization. In an extracted tooth, the root form should also be noted
(though this will not be relevant in an exfoliated tooth because the roots will
have been resorbed). Such a tooth might also be radiographed to provide
further information on the distinction or otherwise between enamel and
dentin in terms of radiodensity.

Microscopy

Iffacilitiesareavailable foragroundsectiontobe prepared, this is best orientated

in the sagittal plane but certainly in the longitudinal axis of the tooth. In
ground sections when there is an enamel hypoplasia, the enamel will be
thinner than normal (Fig. 4). The prism structure may be altered so that the
surface of the enamel does not have prisms orientated at an angle to the
surface but instead has a rather amorphous appearance. The dentin will
typically appear normal (though there are isolated reports of subtle dentin
defects in some patients with AI which have not been fully explained). More
usually ground section facilities will not be available, and a tooth will be
decalcied and sectioned. In this instance, the mineral salts of the enamel
will be lost. Any residual enamel matrix will be identiable. A small amount of
enamel matrix may be seen innormalteethafterdecalcication.InAI,ifthere
were exclusively a hypoplastic defect, then no enamel matrix would be seen.
Where hypominer- alization is a feature, a considerable amount of enamel
matrix may be present. Because the out- line of the enamel will not usually
be visible in suchsections(unlessitcanbeenvisagedbyvirtue of any remaining
surface covering such as dental

plaque), itis important that this be evaluatedmac- roscopically prior to

sectioning.

Immunophenotype

Not relevant

Molecular Features

A number of genes are involved in enamel forma- tion. These may be genes
encoding production of an enamel protein or genes involved in the miner-
alization process. The identication of the amelogenin gene on the X
chromosome (and also the Y chromosome in males, which does not appear to
be of clinical signicance) provided the rst clue to the mapping of XAI.
Subsequently a range of mutations in the amelogenin gene have been found
in such families. Another gene on the long arm of the X chromosome has
been impli- cated in another family; this gene has not yet been cloned, and
there are no genes in this region yet known to be involved in enamel
development. In autosomal forms of AI, several genes have been mapped or
mutations identied in candidate genes. Mutations in the enamelin gene on
chro- mosome 4q21 have been identied in autosomal dominant AI as well as
families with autosomal recessive AI. As the phenotype in these families has
been variable, it is reasonable to assume that different mutations in different
parts of any gene involved in enamel production can produce a range of
phenotypes, even within the same fam- ily. Autosomal dominant AI families
with a hypocalcication phenotype in Brazil and Korea have been mapped to
8q24.3, and muta- tionsinthefam83Hgeneweresubsequentlyiden- tied.
Families with the tricho-dento-osseous syndrome (TDO) comprising
amelogenesis imperfecta, curly hair, and bone changes have been found to
have mutations in the DLX3 gene on chromosome 17q21.3-q22. Mutations in
this gene have also been found in some families with autosomal dominant AI
with taurodontism without the extraoral manifestations of TDO. Mutations in
the kallikrein-4 (KAL4) gene have been identied in autosomal-recessive AI of
a so-called pigmented hypomaturation type. Jalili
syndrome,anautosomalrecessiveconditionchar- acterized by AI and cone-rod
dystrophy, has been mapped to chromosome 2q11.2, and mutations in the
CNNM4 gene have subsequently been reported. The MMP20 gene, located on
the long arm of chromosome 11 at position 11q22.3, has been known to be
involved in normal enamel formation, and a mutation in this gene has been
identied in one family with autosomal recessive AI (pigmented
hypomaturation type). Autosomal recessive AI has also been mapped to
chromo- some 15q21.3 with mutations in the WDR72 gene being found in
such families. Such studies illustrate that mutations in a number of genes in
various chromosomal locations can lead to enamel defects with or without
extraoral manifes- tations. Furthermore, as yet unidentied genes may also
cause AI.

Differential Diagnosis

The chief differential diagnosis to be considered

inrelationtoAIisuorosis.Wherethereisaclear family history of the condition in
successive gen- erations, a diagnosis of uorosis can be reason- ably
excluded. A single case with no other family membersaffectedcanbemore
difcult toresolve, though any suggestion of horizontal banding is more
typical of uorosis than AI.

References and Further Reading

Aldred, M. J., & Crawford, P. J. (1995). Amelogenesis imperfecta Towards a

new classication. Oral Diseases, 1,2 5. Aldred, M. J., Savarirayan, R., &
Crawford, P. J. (2003). Amelogenesis imperfecta: A classication and cata-
logue for the 21st century. Oral Diseases, 9, 19 23. Cameron, A. C., &
Widmer, R. P. (Eds.). (2008). Hand- book of pediatric dentistry (3rd ed., pp.
246254). Edinburgh: Mosby-Elsevier. Online inheritance in man.
http://www.ncbi.nlm.nih.gov/ omim search amelogenesis imperfecta.
Accessed 1 August 2012. Pindborg,J.J.
(1970).Pathologyofthedentalhardtissues. Philadelphia: WB Saunders.