Journal of
Dental Research
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Effect of X-Chromosome Aneuploidy on Jaw Growth
Robert J. Gorlin, Robert S. Redman and Burton L. Shapiro
J DENT RES 1965 44: 269
DOI: 10.1177/00220345650440012201
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It is now increasingly evident that chromosomal abnormalities underlie a
goodly proportion of congenital abnormalities, between 5 and 15 per cent of
children with congenital abnormalities showing evidence of chromosomal
deletions or aberrations. Since dentofacial defects are particularly common
in developmental abnormalities, and to an extent not in accordance with
the concept of stage-specificity, the possible chromosomal basis of dentofacial
defects represents a problem in its own right and, when the chromosomal type
is known, provides new indications as to the role of chromosomes in controlling developmental timing.
-S. M. G.
Effect of X-Chromosome Aneuploidy on Jaw Growth
ROBERT J. GORLIN, ROBERT S. REDMAN, and BURTON L. SHAPIRO
Division of Oral Pathology, School of Dentistry, University of Minnesota, Minneapolis, Minnesota
This report represents but an initial probe into a subject that holds great promise for
future study. It is our sincere hope that this communication will stimulate further inquiry.
Loss or duplication of chromosomes other than the exact multiple of the haploid complement is referred to as "aneuploidy." This may involve either the sex chromosomes
(X and/or Y) or the autosomes (non-sex chromosomes). Deletion of one of the autosomes
in both man and Drosophila appears to be lethal. Several distinct syndromes result from
triplication of chromosomes in the 13-15, 18, and 21 groups, but we shall not discuss these
here. We shall limit ourselves for the most part to consideration of syndromes that arise
because of a gain or loss of X chromosomes.
Surprisingly, these symptom complexes are not as rare as one might suppose. In newborns, the XXY or Klinefelter syndrome is present in 0.3 per cent, the XO chromatinnegative Turner syndrome is present in 0.03 per cent, and the XXX syndrome is present
in 0.13 per cent.' In individuals institutionalized for mental retardation, the incidence
rises to 1.0, 0.05, and 0.4 per cent, respectively.2 These institutions form, then, a ready
source of these fascinating patients for study. Since the marked addition of extra X
chromosomes (XXXX, XXXXY, and XXYY syndromes) appears to be associated with
more severe mental retardation, these individuals are concentrated in this population.
However, these syndromes are far less common than the XXY, XO, and XXX symptom
complexes. Possibly the most efficient way to screen such a population for purposes of
carrying on growth studies is by means of buccal smears for study of Barr bodies. The
Barr body represents the tightly coiled or inactive X chromosome, and, since all X chromosomes in excess of one are thought to be "essentially inactive," there is one less Barr body
than the number of X chromosomes. For example, individuals with XO (Turner syndrome)
This investigation was supported in part by USPHS Research Grant DE-1770 from the National Institute
of Dental Research, National Institutes of Health, Bethesda, Md.
269
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270 GORLIN, REDMAN, AND SHAPIRO
SuPPlement to No. I
and XY (normal male) constitutions should have 0 Barr bodies; XX (normal female),
J. dent. Res.
XXY (Klinefelter syndrome), and XXYY should have 1; XXX and XXXY should have
2; and XXXX and XXXXY should have 3. However, Barr bodies are not necessarily
visible even when present. In females, for example, only about 25 per cent of exfoliated
buccal mucosal cells manifest a Barr body.
Obviously, familiarity with the phenotype of the specific aneuploidy will aid in diagnosis,
but not all the conditions have a characteristic clinical appearance. This certainly appears
to be true in the cases of the XXX, XYY, and, possibly, the XXXX and XXXXX syndromes. Moreover, patients with the XXY syndrome do not develop many of the stigmata
until puberty, and prepubertal diagnosis is therefore seldom made. Since prepuberty is a
very critical period for growth study, a screening for these individuals during this period is
desirable. However, with the aid of buccal smears one can readily isolate such a group for
study. Then, once such a group is separated on this initial screening, further confirmation
may be carried out by karyotype study of the chromosomes.
Before we discuss the studies we have carried on and our attempts to establish norms
for our measurements, it might be well to discuss the salient aspects of several of these
syndromes.
XO SYNDROME (TURNER'S SYNDROME, GONADAL DYSGENESIS OR AGENESIS, OVARIAN
SHORT STATURE SYNDROME, GENITAL DWARFISM).-The syndrome described by Turner' in
1938, consisting of adult short stature (usually 50-58 in.), primary amenorrhea, infantile
uterus, infantile vagina and breasts, ovarian agenesis, pterygium colli, cubitus valgus, and
low nuchal hair line, is now well recognized as a distinct entity. Other changes often
present include lymphangiectatic edema of the hands and feet, which usually disappears
by the second year; spadelike chest and widely separated hypoplastic, sometimes inverted,
nipples; epicanthal folds; ptosis of lids; renal anomalies; mental retardation; coarctation
of the aorta; congenital deafness; clinodactyly; deformation of nails and ears; pigmented
nevi; and, rarely, cutis laxa' (Figs. 1 and 2).
In patients near the age of puberty or older, the urinary gonadotropins are elevated
and the 17-ketosteroid level is depressed. If hormonal therapy is not instituted, a generalized osteoporosis, similar to that in postmenopausal women, occurs.
Buccal smear reveals a chromatin-negative pattern (0-3 per cent) in most of these
patients.* Only 45 chromosomes are present,5 loss of an X chromosome producing XO.
Variants have been described having deletions, ring forms, isochromosomes,6 and mosaicism.7 The cause of the so-called male Turner syndrome is not known. One case has been
reported with the XO complement,8 but several others have been reported as XY.9 The
XO syndrome has been reported in twins,7 and there has been one report of XO syndrome
in a child and the D1 trisomy in a sibling.10 The palmar axial triradius is higher than
normal in about 20 per cent of XO patients.7' 11 The parents of an affected child are not
older than normal at time of conception.
Oral andlor facial anomalies. Two of the most constant oral findings in XO syndrome
appear to be high-palatal vault4' 5, 7,12-15 and hypoplastic mandible.4' 6, 7,]5-15 Cleft palate has
also been noted.7' 19 The mouth has been described as small with the corners pulled down by
the pterygium colli, producing the characteristic "sphinxlike" visage.'
Asymmetry of the skull and facial bones has been noted,4 , 21 as well as asymmetry
of the gingiva. 22
*
Mosaics commonly have an intermediate value (8-12 per cent) on buccal smear.
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F1(;. 1.-TJiner sviilrome (X(O). Note shield chest, w widespread( nipples, welbhedl neck with 1ow-set ears,
lun slight ctlluittls valgus.
Fi,. 2.-' urner s- nIrome (XO)). Note ptosis of eyelid and retrognathit
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272 GORLIN, REDMAN, AND SHAPIRO
J. dent. Res. Supplement to No. .1
In isolated cases, the teeth have been found to be prematurely erupted, the first permanent molars erupting between 1' and 4 years,'7 crowded,23 and with abnormally short
roots.20 Microdontia has also been mentioned.24
Recent evidence would suggest that the XO syndrome is present in about 10 per cent
of embryos aborted before the 8th week in utero.5 26
XXX, XXXX, AND XXXXX SYNDROMES ("SUPER FEMALE"). A number of cases of
XXX syndrome have been described in which there were 44 autosomes and 3 X chromosomes. Two sex chromatin bodies were found on buccal smear. Although a specific clinical
picture was assumed by Jacobs et al.,27 later investigators have found no constant physical findings.20 31 A combination of this syndrome and trisomy 18 has been described.A
Single cases of XXXX syndrome 33 34 and XXXXX syndrome35 have been recorded also.
The latter child had an associated heart anomaly, Mongoloid obliquity of the eyelids,
iris coloboma, and simian palmar creases.
Several patients with XXX syndrome have been oligophrenic, with secondary amenorrhea. Some have had small heads and have been underdeveloped with infantile genitalia,36
while others have been normally developed. All children produced by XXX mothers have
been found to be normal.
Oral and/orfacial anomalies.-Little mention has been made of oral and/or facial anomalies in this syndrome. Johnston et al.36 noted high palatal vault, malocclusion, and pegshaped incisors, but we suspect there are no characteristic oral anomalies.
XXY SYNDROME (KLINEFELTER SYNDROME, "CHROMATIN-POSITIVE SYNDROME," MEDULLARY GONADAL DYSGENESIS, SEMINIFEROUS TUBULAR HYALINIZATION WITH GYNECOMASTIA).-Though described by Klinefelter et al.37 in 1942, recent interest in this syndrome
has been stimulated by the finding in 1956 by Bradbury et al.30 that males with the syndrome are chromatin-positive and by Jacobs and Strong39 in 1959 that they have 47
chromosomes with an XXY pattern. Mental deficiency affects about 25 per cent of patients with XXY syndrome, and they constitute about 1 per cent of mentally retarded
institutionalized males, or about 0.2-0.3 per cent of the general male population." 40
Klinefelter's syndrome is probably the most frequent cause of male hypogonadism.
The clinical picture may vary, but most patients with XXY syndrome have small
testes and, after the age of puberty, aspermatogenesis, variable gynecomastia, elevated
urinary gonadotropins, and low or normal 17-ketosteroid levels. Most have a smaller penis
than normal. Usually, a eunuchoid build, female escutcheon, paucity of body hair, abundant head hair, and lack of acne are noted.41 42 The span is greater than the height by 1.5
inches and the lower segment/upper segment (pubis-sole/crown-pubis) ratio is increased.
Multiple cutaneous angiomas are common.43 Social, and especially sexual, behavior is
often deviant.44 Bony anomalies such as radio-ulnar synostosis, pseudo-epiphyses, kyphoscoliosis, osteoporosis, and hyperostosis frontalis interna may also be noted. Inguinal
hernia and varicose veins are common. Testicular biopsy demonstrates characteristic
tubular hyalinization.45 There may be a higher rate of neoplasia suffered by patients with
XXY syndrome.
Oral and/or facial anomalies. Severe oral anomalies have not been reported to be
associated with the XXY syndrome, although cleft palate with cleft lip has been noted.46
XXXXY, XXXY, AND XXYY SYNDROMES. Other variants of Klinefelter syndrome,
including the XXXY47 48 and XXXXY (Figs. 3-5) syndromes, have been observed, arising
from non-disjunction in both the first and second meiotic divisions of oogenesis or from
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|~ ~ ~ ~ ~ ~ ~ ~ ~I1|
~ ~ f '. !VNCENT2 ,1 l i 1
Fw.. 3.-lMinefelter syn drome variant (XXXXY). Note the eunuchoid huild, infantile genitalia, genie
valgum, severe acrocyanosis, and lack of hody hair. (Courtesy D)r. H. Schade.)
lFi.. 4. -Klinoefelter sy ndrome variant (XXXX Y). JPrognathism was extremely marked in this patient.
(Courtesy ofl )r. H. Schade.)
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!;j: #; I:X
274 GORLIV,
VIV!)8N1.1
kEJ)lAIAN,
IdnRO
.7. dent. Res.
Supplement lo
No. 1
mitotic non-disjunction of 1)oth X chromosomes in an XXV zygote, which itself arose
from meiotic non-clisjunction. A imiosaic, XXXY XXXXY, has also been reported:0 4
These individuals seem to have miore sexvore (cInital alterations than those with Klinefelter's sx ndronie. Patients withl the XXXXY sy-ndrome are severelNi retarded mentall-.
The intelligence quotients have ranged between 20 and 53, the vast majority being below
35. Though the patients are phenotvpic all>x males, the penis is drastically reduced in size
and the postpubertal testes are minute. Failure of descent of the testes appears to occur
in about one-third of the patients, far more commnionly thaLn has been noted in the XXY
syndronme. Furthermore, the destruction or albsenc e of tubules in the XXXXY syndrome
is fear greater than that observed in the XXY syndrome. The scrotum is hypoplastic o
rufdilmlenltran in the majorit> of cases.
1c;. 5.KMlinefelter syndlr(omc vaiolat (XXX\X). Note similar facialt fC'l1tLdreS seenr1 ini patient in Figtre 4.
Skeletal anomalies airc conlmot. IThex include unilateral
or
bilateral proximal radtio-
ulnar sx nostosis; bilateral prolongation of radii with overgrowth of the ulnar head and
widening of the radial head LSSOdiatuec with cubitus valgus, clinoclac tx lx of the fifth finger
associated with a small, cube-shaped middle phalanx (seen in about 10 per cent of 21
trisomics); abnormal ossification (centers andI pseunlo-epiph ss, uc)Xa ValIgaL; genu valguni,
pes planus, lordosis, sc oliosis, hernia, chest (leformiit>, absence of fr-ontal sinuses, decreased
bone age andtiuscular tone, and retarded motor development. Other anomalies have included epicanthus, ocular- hypertelorismi, Brushf-iell spots, strabismus, rn-opia, alternating
esotropia, increased numbers of cutaneous nevi, al)sence of faciscl or both- hair, and acrocvanosis. Abnormal (leriatogltyphics have been recorded, such as increased numbers of
arches on fingerprints andl simi'an palmer c reases. In addition to mental retardation,
there are disproportionately long extremities and scant> pubic hair6dO.
Oral ando/r Jacial an()mtlies.- Oral anomalies hLve Includedl cleft
palate,50-4
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man-
1'."o. 44, 1905
X-CCHROMOTSOME ANEUPLOIDY ON JA W GROWTII 275
dibular prognathismj 51 55 and genesis of upper central incisors.? Patients with an
XXYY pattern have been noted to have mandibular prognathism 559 (Fig. 6).
XYY SYNDROME1. U-Onx a few cases of this syndrome have been reported. The clinical
features have included obesity, neurodermatitis umbilical hernia,60, 61 and undescended
testes "2 but it is unlikely that there is a typical phenotype.
Oral and/or facial anomalies.--In one case,60' 61 the features were noted to be large and
coarse, and there wxas a `cystic lesion of the mandible." The microscopic nature of this
lesion was not discussetl.* No mention was made of oral or facial changes in the second
cause.2"
....
ie
1. 6. Klinefelter syndrome variant (XXYY) .The most notexxorthy feature shoxxn is the parognlathism
PHENOTYPE XND THE1 LYONS HYPO1IIIVSIS IN ow thatt we have briefly considered the
general anti oral characteristics of several of the X- and Y-chromoscome aneuploid states,
let us look ait them critically in view of the Lyon hypothesis.
If, as Ly'on originally contended, one of the X chromosomes remains tightly coiled and
essentially inalctive, then, theoretically, we should have no differences between the phenotytpes of the} normall female (XX) aind the individual with Turner's syndrome (XO).
Neither should we expect any' difference in phenotype between the normal male (XY)
and the individual with Klinefelter's syndrome (XXY). Moreover, since it has been
asserted that all X chromosomes in excess of one are inactive, we should expect no difference in phenoty pe aImong XX, XXX, XXXX, and XXXXX states and, correspondingly,
among XY, XXXY, and XXXXY individuals.
Even a superficial consideration of the hypothesis in light of what has been noted
clinically- would suggest that this aspect of the original Lyon hypothesis is not tenable.
From the limited number of cases of X-chromosome aneuploidy' available to us for study
over the last few years, we were struck by the change in jaw form in individuals with
* W e have had opportunity to see the roentgenograms of the jaw in this patient. It seems unlikely that
the cyst was related to the syndrome.
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276 GORLIN, REDMAN, AND SHAPIRO
J. dent. Res.
Supplement to No. 1
altered numbers of X chromosomes, the palate seeming to become progressively shallower
and wider and the absolute relationship between the mandible and the maxilla becoming
more prognathic, especially after puberty, as the number of X chromosomes increases
from 1 to 4. However, these were only clinical impressions. We realized the necessity for
absolute standards, and, considering the apparent inconsistency with the Lyon hypothesis,
it was necessary to construct new hypotheses concerning the X chromosome and jaw
growth. These were as follows:
1. Genes on the X chromosome have a strong effect on palatal form, the palate altering
progressively with the addition of each X chromosome, being relatively high and narrow
in XO individuals and wide and shallow in those with an XXXXY complement.
2. Genes on the X chromosome have an effect on mandibular growth relative to maxillary growth, the mandible progressing from retrognathic in XO individuals to severely
prognathic in XXXXY individuals.
In order to test these hypotheses, the pairings were put in the null hypothesis form.
Thus it was hypothesized that
XO = XY, XX = XXY, XXX = XXXY, XXXX = XXXXY, etc.,
for mean palatal index and maxillo-mandibular relationships.
JAW MEASUREMENTS. Critical estimation of palatal form and various palatal indices
have been studied for a variety of reasons for many years. In discussion of anthropometry,
most texts of physical anthropology have included some type of palatal index. Talbot62
and Channing and Wissler63 measured palatal width and height in both apparently normal
and insane individuals. Neither study, however, found significant differences between the
groups. Korkhaus64 designed a three-dimensional orthodontic caliper or symmetrograph
in 1928. In 1938, Sedgewick and Brawley65 designed their own instrument for measuring
palatal height, width, and length, but no application of their instrument was made. In
1948, Lundstrdm66 modified Korkhaus' instrument and employed it to measure jaw size
in twins. Lebret,67 in 1962, used the Korkhaus symmetrograph in a study concerned with
palatal growth changes and published tracings of palatal shape and selected dimensions.
Since previous investigators have employed a variety of instruments in determining
palatal indices, often choosing different anatomical reference points, it was felt that a
palatal index was needed which could be determined by use of an instrument relatively
easy to use directly on the patient as well as on jaw casts. Accordingly, one was designed,
and fixed points were chosen for measurement.
The instrument and choice of reference points have been described previously.68 A horizontal plane was established by contacting three reference areas: the lingual cervical lines
of the two maxillary first permanent molars, and the tip of the labial interdental papilla
between the two maxillary central incisors. Palatal width was considered to be the distance
between the two maxillary first molars. Palatal height was measured from the established
horizontal plane to the posterior boundary of the hard palate in the mid-line. The palatal
index was then defined as
Palatal index = Palatal height X 100.
An index such as this made it "possible to convey an exact idea of the proportion which
one measurement bears to another, and thus something of the form of the structure concerned, in a single numerical expression."668
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Vol. 44, 1965
X-CHROMOSOME ANEUPLOIDY ON JAW GROWTH 277
For measurement of maxillo-mandibular relationship, we turned to the work of Reidel,69
the most nearly valid survey with regard to sample size. Utilizing cephalometric (lateral
head) roentgenograms, he measured the angles formed by lines drawn from the sella turcica
to the nasion to the most receded points on the alveolar portions of the maxilla (point A)
and mandible (point B). The S-N-A angle (sella-nasion-point A) gives a reliable indication of the relationship of the maxilla to the cranium; the S-N-B angle, of the mandible
to the cranium; and the difference of the two angles, S-N-A minus S-N-B, or A-N-B, of
the maxilla to the mandible. Reidel established the means and standard deviations of
these angles for adults and for children aged eight to eleven years. Unfortunately, he made
no distinctions with regard to sex.
To establish our standards, palatal measurements of presumably normal individuals
were made in 123 adult females and 101 adult males (aged fifteen to forty-two years) and
in 41 boys and 33 girls (aged ten to twelve years). Norms and standard deviations were
established for each of these groups.
TABLE 1
MEAN PALATAL INDICES
Mean
Phenotype
Normal female .XX
Normal female .XX
Normal male .XY
Normal male .XY
Turner syndrome (female).
Turner syndrome (female).
Klinefelter syndrome.
Klinefelter syndrome.
Klinefelter syndrome .
Klinefelter syndrome ......
Genotype
Age
Palatal
Index
S.D.
No.
SE.
39.0
27.5
43.1
27. 7
51.3
45.3
50.5
30.5
7.04
XO
XO
XY
XXY
XXXY
XXXXY
Adult
10-12 years
Adult
10-12 years
Adult
10-12 years
Adult
Adult
Adult
5 years
3.80
9.06
6.00
5.22
12.51
123
33
101
41
5
4
2
2
1
1
0.6
0.7
0.9
0.9
2.6
25.0
17.9*
..........
..........
7.2
.........
.........
* First molars not present; index is an approximation.
Several patients having the XO and XXY syndromes were readily available for study,
and these formed our first group. One of the authors (R. J. G.) then contacted several
confreres who had reported unusual cases of X-chromosome aneuploidy to obtain jaw
casts and cephalograms. Several were forthcoming. (In addition, screening of 3,500 mentally retarded individuals is now being carried out at Faribault State Hospital, Faribault,
Minnesota, to give us another group for study.)
Palatal indices were established for all patients who had X-chromosome anomalies and
who had sufficient teeth to make valid measurements. In addition, cephalometric roentgenograms were made for five of them.
Results
In making comparisons, an obviously important limitation is the small size of the
samples not only of the affected individuals but of the normal children as well. For this
reason, a rigorous statistical analysis of our results at this time would be premature.
Table 1 is a summary of the mean palatal indices for the normal and abnormal X-chromosome groups. Table 2 is a summary of the comparisons of the mean palatal indices.
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TABLE 2
SUMMARY OF COMPARISONS OF MEAN PALATAL INDICES
Phenotype and Sample
paCson-
Genotype
Phenotype
>
XX
XX
XX >
XX
XY
Normal female
Normal female
Normal female
Normal male
Normal female (10-12 years)
Normal male (10-12 years)
Normal male
Normal female
Normal male
Normal female
Normal male
Normal male (10-12 years)*
Genotype
Normal male
Normal male (10-12 years) ........
Turner syndrome .................
..
Turner syndrome
Turner syndrome (10-12 years) ....
Turner syndrome (10-12 years).....
Klinefelter syndrome ..............
Klinefelter syndrome ..............
Klinefelter syndrome ..............
Klinefelter syndrome ..............
Klinefelter syndrome ..............
Klinefelter syndrome (5 years)*
.....................
....
XY
XY
XO
XO
XO
XY
XY
XXY
XXY
XXXY
XXXXY
>
>
>
XX
XY
XY
XX
XY
XX
XY
XY
_
>
<
<
<
<
* Closest age group available for comparison.
TABLE 3
CEPHALOMETRIC ANALYSIS OF PATIENTS WITH EXCELLENT OCCLUSION*
CHILDREN
(8-11 YR.)
ADULTS
PLANES AND LANDMARKs
Mean Angle
(In Degrees)
Relative antero-posterior position of maxilla (angle
82.01
S-N-A).
Relative antero-posterior position of mandible (angle
.79.97
797
S-N-B)
S--)...... :..................................
to mandible (difference of angles
Relation of maxilla
S-N-A and S-N-B, or angle A-N-B) ....... ....... + 2.04
S D
Mean Angle
(In Degrees)
S.D
.D.
80.79
3.85
3.60
360
802
78.02
3.06
36
1.81
+ 2. 77
2.33
3.89
* Adapted from R. S. REIDEL, Angle Orthodont., 22:143, 1952.
TABLE 4
CEPHALOMETRIC ANALYSIS OF INDIVIDUALS WITH X-CHROMOSOME ANEUPLOIDY
Phenotype and Age Group
Genotype
Angle
SAN-A
Angle
(In Degrees)
Klinefelter syndrome (adult) .XXY
(adult) . .XO
(adult) . .XO
(age 10-12 years) .XO
XO
(age 10-12 years)
Turner syndrome
Turner syndrome
Turner syndrome
Turner syndrome
85.0
71.5
72.0
82.2
79.0
85.5
69.2
66.5
79.0
74.0
A-N-B
tinon
Angle
ClassificaClos of
Occlusion
-0.5
+2.3
+5.5
+3.2
+5.0
I
II
II
I
II
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Vol. 44, 1965
X-CHROMOSOME ANEUPLOIDY ON JAW GROWTH 279
Table 3 gives the cephalometric angles selected from Reidel's tables to show maxillomandibular-cranial interrelationships in people with "excellent occlusion." Table 4 lists
the same angles for the individuals with X-chromosome anomalies.
Discussion
The results were, without exception, consistent with the hypothesis that the number of X
chromosomes influences palatal form, the palate becoming progressively shallower with the
addition of each X chromosome. But the data also suggested that the Y chromosome has
a similar, although lesser, influence. For example, the XO index was greater than the
mean XY index for both children and adults, and the XXY index was less than the XX
index.
It is not surprising that the Y chromosome is implicated in somatic growth, since it
was shown by Tanner et al.70 in 1959 that children with the XXY syndrome exhibit a
male pattern of skeletal maturation of the carpal bones, while those with the XO syndrome manifest the more rapid carpal bone maturation of the female.
The cases that were measured cephalometrically are also too few for statistical analysis.
Nevertheless, a distinct trend may be noted. The XXY patient has a prognathic profile,
although the teeth are in Class I relationship. Three of the four XO patients have both
the maxilla and the mandible in a retrognathic relationship to the cranium, and the XXY
patient has both arches in a prognathic relationship to the cranium.
These findings are consistent with the hypothesis that the X chromosome has an effect on
mandibular growth relative to maxillary development. They also suggest that the hypothesis
might be broadened to include an effect upon the development of both arches relative
to the cranium, with the lesser effect being upon the maxilla.
In the XXXXY syndrome the jaw growth which results in severe prognathism occurs
at puberty, though it is present to some degree in earlier years. Several patients need to
be followed through the pubertal growth period before definitive ascertainment of deviant
growth may be made.
Another problem which should be investigated is the effect of X-chromosome aneuploidy
on tooth form. Garn and Rohmann71 have suggested an X-chromosome influence on the
formation of mandibular premolars and molars. They found that tooth development was
more alike in sister-sister siblings than in brother-brother or sister-brother siblings and
suggested that since sisters are the only sibling pairs carrying an intact paternal X chromosome in common, the gene overlap effects the similarity in tooth development.
Furthermore, what influence does the Y chromosome have on the sexual dimorphism
of tooth formation? Hunt* has suggested that sex could be ascertained in 70 per cent of
cases on the basis of cuspid-tooth development. If the Y chromosome has the same effect
on the tooth as it has on bone, then we might test the hypothesis that the teeth of an XO
individual would be sexed as female and those of XXY, XXXY, and XXXXY individuals
as male.
Each X-chromosome aneuploidy lends itself to extensive investigation. For example,
the chromosome spectrum of gonadal dysgenesis alone contains at least eight known
karyotypic abnormalities: X-chromosome monosomy (XO); mosaicism of X-chromosome
monosomy (XX/XO, XXX/XO); deletion of part of one X chromosome (Xx); mosaicism
for an X-chromosome deletion (XX/Xx); X isochromosomy; mosaicism for X isochro*
Personal communication, 1963.
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280 GORLIN, REDMAN, AND SHAPIRO
J. dent. Res.
Supplement to No. I
mosomy; mosaic combinations of the above (XX/XO/Xx); ring chromosomes; etc. Investigation of the effect of each of these anomalies on jaw form should provide additional
needed information.72
It is possible that a major gene in a polygenic system resides on the X chromosome
and that there is a somewhat additive effect of X chromosomes. Or several genes whose
combined action produces palatal development are on the X chromosome and act similarly.
One may hypothesize additional mechanisms.
The brilliant concept of "dosage compensation" regarding males and females, as put
forward by Muller75 in 1947-48 in his Harvey lecture, is partially explained by the Lyon
hypothesis. However, the difference in phenotype among several aneuploid states, which
should theoretically be identical, certainly suggests some dosage effect in these polysomic
states.
In any case, if our preliminary findings are confirmed by additional measurements,
then it would seem that a relationship between palatal shape and number of X chromosomes does in fact exist. However, if this hypothesis is correct, then a modification of the
Lyon hypothesis73 along the lines suggested by Russell74 would appear to be more compatible with our findings.
Summary
and children were measured for palatal form
adults
A series of normal male and female
A series of patients with various X-chrointerrelationships.
and maxillo-mandibulo-cranial
the sizes of the samples used are
Though
measured.
similarly
mosome aneuploidies were
too small for valid statistical analysis, the results suggest that (a) the palate becomes progressively shallower with the addition of each X chromosome as one proceeds from the
XO to XXXXY syndromes; (b) both the mandible and the maxilla become progressively
longer with the addition of each X chromosome as one proceeds from XO to XXXXY
syndromes; (c) the greater relative progression is exhibited by the mandible; (d) both
palatal form and maxillo-mandibular relations are also affected by the Y chromosome in
a manner similar to that of the X chromosome, but to a lesser degree. If these results are
substantiated by the findings in large samples, then a modification of the Lyon hypothesis
along the lines suggested by Russell would appear to be more compatible with the data.
References
1. GUSTAVSON, K. H., and AKESSON, H. 0. Mental Deficiency and Aberrant Sex Chromatin, Lancet, 3:724,
1961.
2. MACLEAN, N., et al. A Survey of Sex Chromosome Abnormalities among 4,514 Mental Defectives, Lancet,
1:293-96, 1962.
3. TURNER, H. H. A Syndrome of Infantilism, Congenital Webbed Neck and Cubitus Valgus, Endocrinology, 23:566-74, 1938.
4. OBERMAN, J. W. The Prepubertal Diagnosis of Ovarian Agenesis and Its Relationship to Status BonnevieUlirich, J. Pediat., 47:48-59, 1955.
5. FORD, C. E., et al. A Sex Chromosomal Anomaly in a Case of Gonadal Dysgenesis (Turner's Syndrome),
Lancet, 1: 711-13, 1959.
6. VAHARU, T. Gonadal Dysplasia and Enlarged Phallus in a Girl with 45 Chromosomes plus "Fragment,"
Lancet, 1: 1351, 1961.
7. LEMLI, L., and SMITH, D. W. The XO Syndrome: A Study of the Differentiated Phenotype in 25 Patients,
J. Pediat., 63:577-88, 1963.
8. BLOISE, W., et al. Gonadal Dysgenesis (Turner's Syndrome) with Male Phenotype and XO Chromosomal
Constitution, Lancet, 2:1059-60, 1960.
9. STEIKER, D. D., et al. Turner's Syndrome in the Male, J. Pediat., 58:321-29, 1961.
Downloaded from jdr.sagepub.com at PENNSYLVANIA STATE UNIV on March 6, 2014 For personal use only. No other uses without permission.
Vol. 44, 1965
X-CHROMOSOME ANEUPLOIDY ON JAW GROWTH 281
10. THERMAN, E., et al. The D Trisomy Syndrome and XO Gonadal Dysgenesis in Two Sisters, Amer. J.
hum. Genet., 13:193-204, 1961.
11. PENROSE, L. S. Finger-prints, Palms and Chromosomes, Nature, 197:935-37, 1963.
12. GRUMBACH, M. M., et al. Chromosomal Sex in Gonadal Dysgenesis (Ovarian Agenesis), J. din. Endocr.,
15:1161-93, 1955.
13. JACKSON, W. P. U., and SOUGIN MIBASHAN, R. Turner's Syndrome in the Female, Brit. med. J., 2:36871, 1953.
14. WADE, W. G., et al. A Case of Gonadal Dysgenesis or the Ulirich-Turner Syndrome with Androgenic
Manifestations, Arch. Dis. Childh., 31:354-57, 1956.
15. WILKINS, L., and FLEISCHMAN, W. Ovarian Agenesis, J. clin. Endocr., 4:357-75, 1944.
16. COSTILLO, E. B., et al. Syndrome of Rudimentary Ovaries with Estrogen Insufficiency and Increase in
Gonadotropins, J. cdin. Endocr., 7:385-93, 1947.
17. SILVER, H. K., and DODD, S. G. Gonadal Dysgenesis, Bonnevie-Ullrich-Turner Syndrome with Elevated
Urinary Gonadotropins in a Nine Year Old Child, Amer. J. Dis. Child., 94:702-7, 1957.
18. TURNER, E. K. A Case of Probable Ovarian Agenesis with Turner Syndrome in a Female Child Aged
Seven Months, Med. J. Aust., 1:39-42, 1954.
19. ALBRIGHT, F., et al. A Syndrome Characterized by Primary Ovarian Insufficiency and Decreased Stature: Report of Eleven Cases, with a Digression on Hormonal Control of Axillary and Pubic Hair, Amer.
J. med. Sci., 204:625-48, 1942.
20. SILVER, H. K., and KEMPE, C. H. Ovarian Agenesis (Congenital Aplastic Ovaries) in Child, Amer. J.
Dis. Child., 85:523-30, 1953.
21. WARNER, E. N. A Survey of Mongolism, with a Review of One Hundred Cases, Canad. med. Ass. 1., 33:
495-500, 1935.
22. SANDBERG, A. A., et al. XYY Genotype: Report of a Case in a Male, New Engl. J. Med., 268:585-89,
1963.
23. SCHNEIDER, R. W., and MCCULLAGH, E. P. Infantilism, Congenital Webbed Neck and Cubitus Valgus
(Turner's Syndrome), Cleveland cdin. Quart., 10:112-25, 1943.
24. SOLDBERG, M. B., et al. Three Unusual Endocrinopathies with Associated Ovarian Pathology. I. Ovarian
Agenesis. II. Precocious Puberty. III. Virilism, J. cdin. Endocr., 7:11-29, 1947.
25. CARR, D. H. Chromosome Studies in Abortuses and Stillborn Infants, Lancet, 2:603, 1963.
26. CLENDENEN, T. M., and BENIRSCHKE, K. Chromosome Studies on Spontaneous Abortions, Lab. Invest.,
12:1281-92, 1963.
27. JACOBS, P. A., et al. Evidence for the Existence of the Human "Super Female," Lancet, 2:423-25, 1959.
28. DECARLI, L., et al. Trisomie Condition of a Large Chromosome in a Woman with Mongoloid Traits,
Lancet, 2:130-31, 1960.
29. FRASER, J. H., et al. The XXX Syndrome Frequency among Mental Defectives and Fertility, Lancet, 2:
626-27, 1960.
30. JACOBS, P. A., et al. Abnormalities Involving the X Chromosome in Women, Lancet, 1: 1213-16, 1960.
31. STEWART, J. S. S., and SANDERSON, A. R. Fertility and Oligophrenia in an Apparent Triple-X Female,
Lance!, 2:21-23, 1960.
32. UCHIDA, I. A., and BOWMAN, J. M. XXX-18 Trisomy, Lancet, 2:1094, 1961.
33. McKuSICK, F. A. On the X Chromosomes of Man, Quart. Rev. Biol., 97:69-175, 1962.
34. CARR, D. H., et al. The XXXX Sex Chromosome Complex in Two Mentally Deficient Females, Canad.
med. Ass. J., 84:131-36, 1961.
35. KESAREE, N., et al. A Phenotypic Female with 49 Chromosomes, Presumably XXXXX, J. Pediat., 63:
1099-1113, 1963.
36. JOHNSON, A. W., et al. The Triple X Syndrome, Brit. med. J., 2:1046-51, 1961.
37. KLINEFELTER, H. F., JR., et al. Syndrome Characterized by Gynecomastia, Aspermatogenesis without
A-Leydigism and Increased Excretion of Follicle-Stimulating Hormone, J. cdin. Endocr., 2:615-27, 1942.
38. BRADBURY, J. T., et al. Chromatin Test in Klinefelter's Syndrome, J. cdin. Endocr., 16:689, 1956.
39. JACOBS, P. A., and STRONG, J. A. A Case of Human Intersexuality Having a Possible XXY Sex Deter-
mining Mechanism, Nature, 183:302-3, 1959.
40. MOSIER, H. D., et al. The Frequency of the Positive Sex Chromatin Patterns in Males with Mental Deficiency, Pediatrics, 25:291-97, 1960.
41. STEWART, J. S. S. Klinefelter's Syndrome: Clinical and Hormonal Aspects, Quart. J. Med., 28:561-72,
1959.
Downloaded from jdr.sagepub.com at PENNSYLVANIA STATE UNIV on March 6, 2014 For personal use only. No other uses without permission.
282 GORLIN, REDMAN, AND SHAPIRO
J. dent. Res.
Supplement to No. 1
42. STEWART, J. S. S. Medullary Gonadal Dysgenesis (Chromatin Positive Klinefelter's Syndrome), Lancet,
1:1176-78, 1959.
43. RHODE, R. A. Chromatin-Positive Klinefelter's Syndrome: Clinical and Cytogenetic Studies, J. chron.
Dis., 16:1139-50, 1963.
44. MOSIER, H. D., et al. Sexually Deviant Behavior in Klinefelter's Syndrome, J. Pediat., 57:479-83, 1960.
45. DELHANTY, J. D. A., et al. Triploid Cells in a Human Embryo, Lancet, 1: 1286, 1961.
46. LEON, N., et al. The Effects of Chorionic Gonadotropins in Klinefelter's Syndrome, J. clin. Endocr., 19:
1667 79, 1959.
47. CARR, D. H., et al. An XXXY Sex Chromosomal Complex in Klinefelter's Subjects with Duplicate Sex
Chromatin, J. cdin. Endocr., 21:491-505, 1961.
48. FERGUSON-SMITH, M. A., et al. Primary Amentia and Microorchidism Associated with an XXXY Sex
Chromosome Constitution, Lancet, 2:184-87, 1960.
49. HARNDEN, D. G. A Human Skin Culture Technique Used for Cytological Examinations, Brit. J. exp.
Path., 41:31-37, 1960.
50. FRASER, J. H., et al. A Case of XXXXY Klinefelter's Syndrome, Lancet, 2:1064-67, 1961.
51. DAY, R. W., et al. An XXXXY Male, J. Pediat., 63:589-98, 1963.
52. MILLER, 0. J., et al. A Family with an XXXY Male, a Leukemic Male and Two 21-Trisomic Mongoloid
Females, Lancet, 2:78-79, 1961.
53. BARR, M. L., et al. The XXXXY Sex Chromosome Abnormality, Canad. med. Ass. J., 87:891-901,1962.
54. SCHERZ, R. G., and ROECKEL, I. E. The XXXXY Syndrome, J. Pediat., 63:1093-99,1963.
55. SCHADE, H., et al. Ein Patient mit XXXXY-Chromosomen, Med. Welt., 16:869-76, 1963.
56. CARR, D. H., et al. A Probable XXYY Sex Determining Mechanism in a Mentally Deficient Male with
Klinefelter's Syndrome, Canad. med. Ass. J., 84:873-78, 1961.
57. ELLIS, J. R., et al. A Male with XXYY Chromosome, Ann. hum. Genet., 25:145-52, 1961.
58. MULDAL, S., et al. "Double Male" A New Chromosome Constitution in the Klinefelter Syndrome, Acta
endocr. (Kbh.), 39:183-203, 1962.
59. VAGUE, J., et al. Syndrome de Klinefelter, debilite mental, discrete atrophie cerebrale, caryotype XXXX,
Ann. endocr. (Paris), 22:988-92, 1962.
60. HAUSCHKA, T. S., et al. An XYY Man with Progeny Indicating Familial Tendency to Non-Disjunction,
Amer. J. hum. Genet., 14:22-30,1962.
61. SANDBERG, A. A., et al. An XYY Human Male, Lancet, 2:488-89, 1961.
62. TALBOT, E. S. The Etiology of Osseous Deformities of the Head, Face, Jaws and Teeth, p. 72. Chicago, Ill.:
W. T. Keener Co., 1894.
63. CHANNING, W., and WISSLER, C. The Hard Palate in Normal and Feebleminded Individuals, Amer. J.
Insan., 61:4, 1905.
64. KORKHAUS, G. A New Orthodontic Symmetrograph, Int. J. Orthodont., 16:655-68, 1930.
65. SEDGEWICK, H. J. O., and BRAWLEY, R. E. Palatometer, Amer. J. Orthodont., 24:673-74, 1938.
66. LUNDSTR6x, A. Tooth Size and Occlusion in Twins, Basle: S. Karger, 1948.
67. LEBRET, L. Growth Changes of the Palate, J. dent. Res., 41:1391-1404, 1962.
68. SHAPIRO, B. L., et al. Measurement of Normal and Reportedly Malformed Palatal Vaults. I. Normal
Adult Measurements, J. dent. Res., 42:1039, 1963.
69. REIDEL, R. The Relation of Maxillary Structures to Cranium in Malocclusion and in Normal Occlusion,
Angle Orthodont., 22:142-45, 1952.
70. TANNER, J. M., et al. Genes on the Y Chromosome Influencing Rate of Maturation in Man. Skeletal Age
Studies in Children with Klinefelter's (XXY) and Turner's (XO) Syndromes, Lancet, 2:141, 1959.
71. GARN, S. M., and ROHMANN, C. G. X-Linked Inheritance of Developmental Timing in Man, Nature,
196:695-96, 1962.
72. BECKER, K. L., et al. The Chromosomal Spectrum of Gonadal Dysgenesis, Proc. Mayo Clin., 38:490-96,
1963.
73. LYON, M. F. Sex Chromatin and Gene Action in the Mammalian X-Chromosome, Amer. J. hum. Genet.,
14:135-48, 1962.
74. RUSSELL, L. B. Genetics of Mammalian Sex Chromosomes, Science, 133:1795-1803, 1961.
75. MULLER, H. J. Evidence of the Precision of Genetic Adaptation, Harvey Lect. Ser., 43:165-229, 1947-48.
Downloaded from jdr.sagepub.com at PENNSYLVANIA STATE UNIV on March 6, 2014 For personal use only. No other uses without permission.