The effect of hereditary disorders on tooth components: a radiographic morphometric study of two syndromes.

Abstract

The purpose of this study was to compare tooth components (enamel and dentin) in Familial Dysautonomia (FD) and Down syndrome (DS) in order to assess the extent to which each was affected.
The design was cross-sectional. The sample consisted of 20 FD patients and 45 DS patients. The control group comprised 250 healthy subjects. Mesio-distal crown width (CW), enamel and dentin thickness and pulp chamber dimensions were measured on standardized bitewing radiographs of mandibular second primary and first permanent molars. Statistical analyses were performed between groups using SAS programs.
CW was reduced in both hereditary disorders. In the DS group enamel height (EH) and dentin thickness were reduced. In FD enamel thickness in the primary and permanent molars as well as dentin height (DH) in permanent molars was increased.
In both syndromes the reduction in CW suggests reduced proliferation during tooth germ formation. However, the differences in enamel and dentin thickness suggest that ameloblasts and odontoblasts were affected differently in the later phases of cell function. In FD cell function is stimulated resulting in thicker enamel and dentin. In DS cell function is reduced resulting in thin enamel and dentin.

Full text

Page 1

The effect of hereditary disorders on tooth
components: a radiographic morphometric
study of two syndromes
Uri Zilbermana,*, Smith Patriciaa, Ari Kupietzkyb, Eliyahu Massc
aLaboratory of Bioanthropology and Ancient DNA, Faculty of Dental Medicine, Hebrew University,
Hadassah, Jerusalem, Israel
bDepartment of Pediatric Dentistry, Faculty of Dental Medicine, The Hebrew University, Hadassah,
Jerusalem, Israel
cDepartment of Pediatric Dentistry, The Maurice and Gabriela Goldschleger School of Dental Medicine,
Tel Aviv University, Tel Aviv, Israel
Accepted 24 February 2004
Introduction
Tooth formation starts at an early stage of embryo-
nic differentiation and is of limited duration. It
proceeds sequentially along the tooth row and so
provides data on different developmental stages
within an individual.1—3The final size of a tooth
represents the result of the combined effect of
genetic and environmental factors in the course
of dental development. However, the relatively
early age of tooth development means that they
are less affected than any other organ in the human
body by environmental factors and their morphol-
ogy is mostly a reflection of genetic factors.4—8
Both oral ectoderm and neural crest influenced
ecto-mesenchyme are involved in tooth formation.
Initiation and morphogenesis appear to be primarily
determined by the ectodermally derived enamel
organ, which also gives rise to the ameloblasts that
form the enamel matrix. The ecto-mesenchyme
Archives of Oral Biology (2004) 49, 621—629
KEYWORDS
Down syndrome;
Familial Dysautonomia;
Enamel;
Dentin;
Pulp;
Ectoderm;
Neural crest
Summary Objective: The purpose of this study was to compare tooth components
(enamel and dentin) in Familial Dysautonomia (FD) and Down syndrome (DS) in order to
assess the extent to which each was affected. Design: The design was cross-sectional.
Thesampleconsistedof20FDpatientsand45DSpatients.Thecontrolgroupcomprised
250 healthy subjects. Mesio-distal crown width (CW), enamel and dentin thickness and
pulp chamber dimensions were measured on standardized bitewing radiographs of
mandibular second primary and first permanent molars. Statistical analyses were
performed between groups using SAS programs. Results: CW was reduced in both
hereditary disorders. In the DS group enamel height (EH) and dentin thickness were
reduced. In FD enamel thickness in the primary and permanent molars as well as dentin
height (DH) in permanent molars was increased. Conclusions: In both syndromes the
reductionin CWsuggestsreduced proliferation duringtooth germ formation.However,
the differences in enamel and dentin thickness suggest that ameloblasts and odonto-
blasts were affected differently in the later phases of cell function. In FD cell function
is stimulated resulting in thicker enamel and dentin. In DS cell function is reduced
resulting in thin enamel and dentin.
? 2004 Elsevier Ltd. All rights reserved.
*Corresponding author. Tel.: þ972-2-6758584;
fax: þ972-2-6757451.
E-mail address: uri-z@inter.net.il (U. Zilberman).
0003–9969/$ — see front matter ? 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.archoralbio.2004.02.008

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forms the dental sac and dentin—pulp complex.
Crown size is determined by two phases: the early
stage, the determination of the volume of the
dentin—pulp complex, is characterized by comple-
tion of dentin—enamel junction (DEJ) in the crown
and the dentin cementum junction in the root. The
thickness of enamel and dentin is determined bythe
amount of tissue laid down by the ameloblasts and
odontoblasts, while cementum proliferation is asso-
ciated with the recruitment of additional cells
throughout life.9Enamel thickness is defined early
in life, whereas dentin thickness increases through-
out life by secondary (physiological) and tertiary
(reactive) apposition, and pulp size is inversely
affected by this phenomenon since dentin apposi-
tion reduces the size of the pulp.10
Individuals with hereditary disorders such as
Down syndrome (DS) and Familial Dysautonomia
(FD)haveremarkablysmallteeth.Thisphenomenon
has been related to an overall impairment of normal
development.11—14However, while FD primarily
affectsthenervoussystem,DS(Trisomy21),exhibits
general growth retardation. In view of our under-
standing of the contribution of various tissues on
tooth development, each of these conditions may
affect a different phase of tooth development.
FD, also known as Riley Day syndrome (MIM
#223900) is an autosomal recessive disorder that
mainly affects children of Jewish Ashkenazi origin,
with an incidence of 1 in 3700 live births, which
corresponds to a carrier frequency of 1 in 32 among
Ashkenazi Jews.15,16It is classified as a hereditary
sensory and autonomic neuropathy type III17and is
the most common and widely recognized of the
congenital sensory neuropathies.18,19FD affects
the development and survival of sensory, sympa-
thetic and parasympathetic neurons. It is a devas-
tating and debilitating disease, present from birth,
with a variety of symptoms, including gastrointest-
inal dysfunction, vomiting crisis, recurrent pneumo-
nias, altered sensitivity to pain and temperature,
and cardiovascular instability.18,20There is a pro-
gressive neuronal degeneration throughout life, and
survival statistics indicate that the probability of
reaching 30 years of age is only 50%.21One of the
most distinctive features of the disease is impaired
pain perception due to the progressive neuropathy.
ThediagnosisofFDisbasedon:absenceoffungiform
papillae on the tongue, absence of axon flares after
injection of intradermal histamine, decrease or
absent deep tendon reflexes, absence of overflow
emotional tears and Ashkenazi Jewish ancestry.19
The clinical features of FD are due to a striking
progressive depletion of unmyelinated sensory and
autonomicneurons.22TheFDgenecoded‘‘DYS’’was
mapped to chromosome 9q31-q33.23In FD patients,
neuralcrestdysfunctionisbelievedtoberesponsible
for the wide range of dysautonomic changes.8Tooth
componentsinFDpatientshavebeenshowntodiffer
from those of normal healthy controls.14
DS (MIM #190685) is caused by trisomy of the 21st
chromosome. It is a relatively common anomaly
(one in every 600—700 live births), and is the best
known example of the severe growth and develop-
ment abnormalities associated with an extra chro-
mosome.Thedisorder
features, general body size, mental and systemic
development.24The dental characteristics asso-
ciated with DS include antero-posterior shortened
palate,25
microdontia of permanent dentition,
while some primary teeth are larger,12,13altered
crown morphology26and shape,27taurodontism28
and hypodontia.29Other body features that may
affect the oro-facial complex in DS are the altered
development and morphology of bone. Rib growth
cartilage in DS fetuses showed an increase in the
hypertrophic portion with a concomitant decrease
in the proliferating and resting zone.30This abnorm-
ality may represent an early manifestation of an
abnormal cartilage maturation pattern, which
appears postnatally in long bones, leading to dimin-
ished growth rates. Bone mineral density in DS is
reduced compared to healthy population,31—34due,
probably, to their muscular hypotonia.32,33
The purpose of this study was to compare the
severity and pattern of change in tooth components
of FD individuals with those of children with a
different genetic disorder that is also characterized
by reduced tooth size. In order to determine the
effect of these conditions at different stages of
tooth development on the two tissues involved,
we measured crown size, enamel and dentin thick-
ness in the early developing mandibular second
primary molars and later developing mandibular
first permanent molars. Our basic hypothesis was
that crown size can be partitioned into two phases:
an early proliferative stage represented by the
volume of the tooth at the DEJ and a latter stage
of cell function represented by enamel and dentin
thickness.
affects,amongother
Materials and methods
Routine diagnostic bitewing radiographs of 20
patientsdiagnosedwithFDand45patientswithcyto-
geneticallydeterminedDSwerestudied.Thecontrol
group consisted of 250 healthy children and adoles-
centsandcomprised132malesand118femalesaged
3—16 years. The FD group included 14 males and
6 females aged 5—22 years and the DS group consis-
ted of 20 females and 25 males aged 3—27 years.
622 U. Zilberman et al.

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Only radiographs with minimal or no distortion
and minimal or no overlapping between the prox-
imal surfaces were selected for the study.
All radiographs were coded, and the examiner
was unaware as to which group the radiographs
belonged to. The measured teeth were the man-
dibular second primary and first permanent molars.
Only intact teeth without restorations or marked
attrition were measured. The measurements were
performed using a digital caliper on a light table
with the use of a magnifying glass, as was previously
described.35The results were in mm. Six measure-
ments were taken on each tooth crown (Fig. 1).
Enamel height (EH), dentin height (DH) and pulp
height (PH) were measured parallel to the long axis
of the tooth, one millimeter mesial to the central
fossa on the same line. This line was chosen for
reproducibility reason and for the fact that attrition
on enamel affects mainly tooth cusps and not
the central fossa. Pulp width (PW) was measured
perpendicular to the long axis of the tooth on the
widest part of the pulp. Mesial enamel width (EW)
and maximal crown width (CW) were measured on
the widest mesio-distal length of the tooth on a
line perpendicular to the long axis of the tooth.
Each measurement was performed separately. All
measurements were also expressed as a ratio of
mesio-distal CW, in order to minimize the effect
of external tooth size and possible errors due to
magnification on each variable. The same examiner
performed all measurements.
Measurement accuracy and reliability
When taken by experienced personnel dental radio-
graphs provide an easily reproducible two-dimen-
sional representation of the maximum diameters of
the crown, enamel, dentine and pulp cavity, whose
accuracy can be easily verified by repeated radio-
graphs.35Enamel as measured from radiographs
represents its maximal thickness, given that all
the levels of enamel from buccal to lingual are
projected on two dimensions.36The mesial EW is
in fact the maximal enamel thickness measured
from tooth slices.35The occlusal enamel measured
from radiographs is in the same range of dimensions
obtained from tooth slices and naturally broken
teeth.37Pulp chamber dimensions measured on
radiographs show the maximal size.38
In order to test the reliability of measurements
taken from radiographs, 10 randomly chosen teeth
were re-measured. The range of variation found
betweenmeasurementstakenondifferentaccepted
radiographs was 2—5% and averaged 3.2%. Variation
was least for CW measurements and greatest for EH.
Statistical analysis
All data were transferred to a computer and statis-
tically analyzed using the SAS package.39In cases
where both right and left teeth were measured the
mean value was used. A previous study on FD and
controls showed that sexual dimorphism in CW and
tooth components was insignificant in comparison
to the differences between groups.14Therefore,
in this study, males and females were grouped
together for analysis.
Univariate ANOVA was performed, using each
variable as dependent variable and health status
as independent variable, in order to determine the
influence of FD or DS on tooth components. The
procedure used was the post-hoc, multiple compar-
isons for means, with a ¼ 5%. Multifactorial discri-
minant analysis was performed to determine the
distance between the controls and the two syn-
dromes. The procedure used was the biplot-multi-
variate analysis of variance.40
Results
A total of 175 mandibular second primary and 160
mandibular permanent first molars were computed
in the control group. They were compared to the FD
group (11 second primary and 9 first permanent
molars) and DS group (29 second primary and 41
first permanent molars). One way analysis of var-
iance (ANOVA, REGWR procedure. Post-hoc, a ¼ 5%)
Figure 1
enamel height, DH: dentin height, PH: pulp height, EW:
enamel width, PW: pulp width, CW: crown width.
The measurement of crown components. EH:
The effect of hereditary disorders on tooth components623

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Table 1
Measurements of tooth components.
Second primary molars First permanent molars
ControlsFDDSControlsFDDS
EHMean
N
S.D.
Minimum
Maximum
0.961.16
10
0.18
0.94
1.42
0.92
28
0.16
0.73
1.53
1.66 1.74
9
0.17
1.45
2.00
1.42
41
0.18
0.87
1.72
175160
0.15
0.64
1.64
0.40
0.64
2.78
DH Mean
N
S.D.
Minimum
Maximum
2.832.58
11
0.47
1.72
3.14
2.27
28
0.46
1.33
2.91
3.30 3.64
9
0.48
2.91
4.17
2.85
39
0.33
2.36
3.57
175160
0.38
2.08
3.92
0.52
2.03
4.92
PHMean
N
S.D.
Minimum
Maximum
1.10 0.97
11
0.34
0.50
1.51
1.52
28
0.59
0.69
2.55
1.69 0.99
9
0.63
0.38
2.16
1.81
39
0.87
0.64
3.89
175160
0.40
0.33
2.28
0.60
0.47
3.55
EWMean
N
S.D.
Minimum
Maximum
0.83 0.76
11
0.10
0.60
0.90
0.88
26
0.13
0.75
1.37
1.321.29
9
0.11
1.18
1.50
1.22
41
0.18
0.76
1.53
175160
0.10
0.59
1.16
0.29
0.62
2.12
PWMean
N
S.D.
Minimum
Maximum
5.00 4.78
11
0.43
4.14
5.38
4.54
28
0.35
4.03
5.42
4.574.08
9
0.43
3.30
4.59
4.38
39
0.51
3.39
5.32
175160
0.41
3.93
5.87
0.49
3.35
6.02
CWMean
N
S.D.
Minimum
Maximum
10.25
175
0.49
9.07
11.44
9.96
10
0.59
8.87
10.75
9.77
28
0.37
8.79
10.60
11.39
160
0.73
9.61
12.96
11.05
9
0.51
10.30
11.73
11.11
41
0.74
9.70
12.27
EH1Mean
N
S.D.
0.09 0.12
9
0.02
0.09
28
0.02
0.14 0.16
9
0.01
0.13
41
0.01
175160
0.01 0.03
DH1Mean
N
S.D.
0.28 0.27
10
0.03
0.23
28
0.05
0.29 0.33
9
0.04
0.26
39
0.03
175160
0.040.04
PH1Mean
N
S.D.
0.110.10
10
0.03
0.15
28
0.06
0.150.09
9
0.06
0.16
39
0.08
175 160
0.040.05
EW1Mean
N
S.D.
0.080.08
10
0.01
0.09
26
0.02
0.120.12
9
0.01
0.11
41
0.02
175160
0.010.02
PW1Mean
N
S.D.
0.49 0.48
10
0.03
0.46
28
0.03
0.400.37
9
0.03
0.39
39
0.04
175160
0.030.05
The data for the FD was taken from a previous report.14Note: EH, enamel height; DH, dentin height; PH, pulp
height; EW: enamel width; PW, pulp width; CW, crown width; EH1, EH/CW; DH1, DH/CW; PH1, PH/CW; EW1, EW/
CW; PW1, PW/CW.
624U. Zilberman et al.

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for each tooth component showed significant differ-
ences between FD, DS and control groups (Table 1).
Mesio-distal crown diameter (CW) of second pri-
mary and first permanent molars in children with
both syndromes was smaller than that of the control
group (Table 1). In FD EH and dentin thickness was
significantly greater than that of the controls in the
permanent molars and PH was reduced. In the
primary molars, EH was also increased relative to
the other groups, and PH decreased, although DH
showed no significant difference. The ratio of EH to
CW was greater in both primary and permanent
molars of individuals with FD than in controls or DS.
In DS permanent molars EH and width and dentin
thickness were reduced, absolutely and relatively.
In DS primary molars dentin thickness was reduced
and PH was greater, both absolutely and relatively
than that of the controls and FD groups.
If these changes were related to age or function,
then a similar trend would be expected in all tooth
components. The results demonstrate that this is
notthe case. ThisisexemplifiedbyFigs.2and3that
show biplot representations of the multivariate
analysis of variances for second primary and first
permanent molars. The biplotis a graphic devicefor
approximate display of various features of a matrix
of multivariate means for several samples. It is
especially revealing in principal component analy-
sis, where the biplot can show inter-unit distances
and indicate clustering of units as well as display
variances and correlations of the variables. Each
group can be graphically determined as a confi-
dence circle for samples. The center is the mean
of the analyzed group and the radius is the simul-
taneous distance from the mean. The level of sig-
nificance chosen was a ¼ 2:5%. The size of each
circle depends on the group size–—the smaller the
group, the larger the circle. Overlapping circles
mean that the distances between groups are not
significant statistically. The vectors represent vari-
ables. Vectors perpendicular to the line connecting
two circles centers represent variables that make
the difference between groups. Vectors parallel
to the line connecting between two centers repre-
sent variables that are similar in both groups.
From the biplot one may learn what sort of linear
Figure 2
abbreviations similar to Table 1.
Biplot of second primary molars. N: control group, FD: Familial Disautonomia, DS: Down syndrome. Vectors
The effect of hereditary disorders on tooth components625

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combination of the given variables will show up the
relatively large sample differences, among all sam-
ples or between some given pair of samples.
As observed in Figs. 2 and 3, FD and DS groups
differ significantly from the control group (N). The
main variables contributing to the difference
between DS and N groups in primary molars are
enameldimensionsandCW andin permanent molars
pulp dimensions and CW. Between FD and N groups
pulp dimensions and DH in primary molars and
enamel dimensions and DH in permanent molars
showed the greatest differences. DS differ from FD
in DH, pulp and CW in primary molars and in enamel
thickness,DH,andpulpandCWinpermanentmolars.
Discussion
The growth pattern of the molar teeth in the human
embryo is characterized by a rapid increase in
dimensions of the tooth germ, from the beginning
of the cap stage to the initiation of calcification on
the mesio-buccal cusp. Thereafter, there is a gra-
dual deceleration in growth as cell differentiation
proceeds at the interphase between the enamel
organ and dental sac until the outline of the DEJ
is completed. Once this is achieved any further
increase in crown size is dependant on the amount
of enamel laid down by the ameloblasts, and not by
mitotic activity.2
Figure 3
similar to Table 1.
Biplot of permanent first molar. FD: Familial Disautonomia, DS: Down syndrome. Vectors abbreviations
626U. Zilberman et al.

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Regulation of tooth size has long been known to
be polygenic, and influenced by genes on both the X
and Y chromosomes6,41—44and their absence or
duplication grossly affects tooth size and enamel
thickness. The X chromosome has a role in the
determination of tooth shape and enamel apposi-
tion and the Y chromosome has been related to
larger tooth size in males and especially in the
canine tooth.45—51The X amelogenin gene has been
mapped to the short arm and is now considered to
be the source of the genomic defect for X-linked
Amelogenesis Imperfecta52which may also affect
other ectodermal derived tissues.
Our understanding of the processes involved in
the regulation of tooth development is rapidly
increasing and many hundreds of genes appear to
be involved.5,8,53—55
The limitedduration
sequence of events leading to development of the
teeth, means that examination of the different
components of teeth in the living can provide infor-
mation on the timing and extent of abnormalities in
early stages of development since the form, size
and even number of teeth is affected in many
different syndromes.7,11In this paper, we have
attempted to distinguish between the different
stages of tooth development defined by the DEJ
and enamel and dentin thickness implicated in FD
and DS, both of which show reduced crown size.
A number of studies have shown that the later
developing teeth in DS are the most severely
affected, in keeping with the general deceleration
in growth and development.26Townsend12reported
that in the primary dentition only the second molars
showed any reduction in size although all perma-
nent teetharesmaller. Thishas been attributed toa
transitory acceleration in mitotic activity in early
life prior to the characteristic retardation in growth
that has been reported in the second trimester56
and is expressed in the reduced size of the primary
second molars and all permanent teeth.26,27
The biplot analysis highlights the differences
found between the three groups, demonstrating
the distinct behavior of the tooth components in
the two syndromes, as summarized in Table 2.
Reduction in enamel thickness of DS patients has
and‘‘irreversible’’
previously been described by Zilberman57and by
Bell et al.58on extracted mandibular permanent
incisors. The increased severity of the defect
observed on the permanent molars may be due to
their later timing and rate of development. The
durationofenamelapposition inthe primarysecond
molar is shorter than that of the first permanent
molar and starts earlier. In the primary second
molar enamel formation begins at 6 months in utero
and crown formation is complete at 12 months (a
total of 15 months), while in the first permanent
molar enamel formation begins at birth and the
crown is completed at 2.5—3 years (a total of
30—36months).Therateofrecruitmentandenamel
apposition ofthe ameloblasts in the primaryteeth is
faster than that of the permanent molars. In the
permanentmolarsbothrecruitmentandapposition,
determinedbythe cross-striation intervalinenamel
varies. It is small close to the DEJ, 2—3 mm per day,
and increases toward the surface to 5—6 mm per
day, in the final stages of amelogenesis.59
In the DS sample, the reduction in crown size in
primary second molars is mainly due to the reduc-
tion in proliferation shown by the reduced dimen-
sions of the dentin and pulp, while in permanent
molars both proliferation and apposition of enamel
and dentin are affected. The reduction in enamel
and dentin thickness of the permanent first molars
takes place within the context of the overall decel-
eration ofbody growth observedin DS patients after
the age of 2 years.23
In FD patients despite the reduction observed in
crown size both enamel and dentin were thicker
than in the DS group, suggesting hyperfunction of
both ameloblasts and odontoblasts. Since enamel
is laid down only over a restricted period of time,
this suggests that ameloblastic activity was either
accelerated or prolonged. We hope to be able to
clarify this in the future through examination of the
ultrastructure of exfoliated primary teeth.
In conclusion, the results showed that these two
hereditary disorders differ significantly in their
effect on tooth formation. DS was associated with
reduced activity of the ameloblasts and odonto-
blasts, while FD was associated with increased
activity of both components. This study showed
Table 2
Summary of the effects of DS and FD on tooth components.
Tissue Tooth componentCell division (proliferation) Function (apposition)
DSFDDS FD
Ectodermal
Ecto-mesenchymal
Enamel
Dentin—pulp
complex height
Reduced ReducedReduced
Reduced
Increased
Increased in M1
Not affected
The effect of hereditary disorders on tooth components627

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that the use of standard roentgenographs can pro-
vide valuable information on the contribution of
different phases in tooth formation to the external
expression of growth insults in the dentition.
Acknowledgements
The authors would like to thank Dr. Einot Israel from
the Department of Statistics, Hebrew University,
Jerusalem for the biplot analysis. This study was
supported in part by a grant from the Israel Sciences
Foundation no. 032-5302.
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