268 Australian Dental Journal, August, 1985

Volume 30. No. 4

Tooth size in 47,XYY males: evidence for a direct effect of the Y chromosome on growth*

Grant Townsend

Department of Dentistry, The Univer.siy of Adelaide

and

Lassi Alvesalo

Inslitute of Dentistr.v, Universiries of Titrku and Kuopio, Finland

ABSTRAC r-Mean values of deciduous and permanent tooth dimensions were compared between 47,XYY males and control subjects to clarify the role of the Y chromosome in dental development. Tooth siLe was generally larger in the 47,XYY sample, although the increase in size was not uniform throughout the dentition. The Y chromosome appears to have a direct effect on tooth size which may be due to a specific gene (or genes) or may be related to a more non-specific effect of heterochromatin on cellular activity.

(Received for publicairon November 1984.)

Introduction I t i \ well-established that human males tend, on

average, to have larger teeth than females, although the degree of Fexual dimorphism varies from tooth to tooth, being greatest generally in the canines. This difference in size has usually been attributed to differentially- balanced hormonal production between the sexes con- \equent upon the differentiation of either male or female gonads during the sixth or seventh week of embryogenesis rather than any direct effect of the sex chromosomes themselves. However, there is some evidence that the sey chromosomes do have a direct effect on the growth and development of both dental and osseous structures. Support for this idea has come from two types of studies: firstly, investigations involving normal populations where obserbed correlations between related individuals have been compared with theoretical values assuming sex linkage; and secondly, examination of individuals with various sex chromosome anomalies, for example, aneuploidies, where there is a loss or duplication of chromosomes other than an exact multiple of the haploid complement,

Correlative studies of normal relatives have indicated the existence of X-linkage for tooth size,' ' dental

' Ih i , *lud) wa \ wpportcd i n par1 hi thc National ALadciiir 01 tinland

development and skeletal maturation, ' although others have been unable to show its presence.' ' However, most investigators have tested for evidence of X-linkage alone, and i t is possible that a superimposed influence of the Y chromosome may have complicated analysis. For example, X-linkage would be expected to increase correlations between father-daughter and mother-\on pairs, whereas Y-linkage would revet-se Ihe ti-ends. In one of the few studies which have assessed both X and Y- linkage, Alvesalo6 analysed male and female cousin groups, as well as siblings, and found evidence that both X and Y chromosomes carried genes affecting tooth size but the influence of the chromosomes on the phenotype appeared to differ.

' Garn SM. Lewis AB. Kerewsky RS. ?(-linked inheritance of tooth size. J Dent Res 1965;44:439-41.

Lewis DW, Grainger RM. Sex-linked inheritance of tooth size: A family study. Arch Oral Biol 1967;12:539-44.

' Garn SM, Rohmann CG. X-linked inheritance of develop- mental timing in man. Nature 1962;196:695-6.

Townsend GC. Brown T. Inheritance of iooih size in Australian Aboriginals. Am J Phys Anthrop 1978;48:305-14.

' Potter RH, Rice JP, Dahlberg AA, Dahlberg T. Dental size traits within families: path analysis for first molar and lateral incisor. Am J Phys Anthrop 1983;61:283-9.

Alvesalo L. The influence of sex-chromosome genes on tooth sizein man. A genetic and quantitative study. Proc Finn Dent Soc 1971;67:3-54.

Australian Dental Journal, August, 1985

Tanner, Prader, Habich, and Ferguson-Smith' studied skeletal age in children with Klinefelter (XXY) and Turner (XO) syndromes. They found that the rate of skeletal maturation in XXY individuals and normal XY males was delayed compared with the rate of both XO individuals and normal XX females. The Y chromosome, therefore, produced retardation whether one or two X chromosomes were present, but without the Y chromosome neither one nor two X chromosomes produced an effect. Tanner and his colleagues concluded that genes on the Y chromosome were the cause of the normal sex differences in the rate of development, They favoured the concept of a direct chromosomal effect to the alternative explanation of hormonal influence because androgens normally cause an advance in maturation, not a delay. The skeletal age of 47,XYY boys has not been reported very often,' but in the few cases reported it appears to be either normal or retarded which lends further support to the theory of Tanner and his colleagues.

Another study of the influence of sex chromosomes on growth and development was reported by Gorlin, Redman and Shapiro.y Palatal form and maxillo-mandibular relationships were assessed in a series of patients with various X chromosome aneuploidies. The results indicated that the palate became progressively shallower with additional X chromosomes and that both maxilla and mandible became progressively longer, with the mandible showing greatest relative prognathism. The data also suggested that the Y chromosome influenced palatal and facial form but to a lesser degree.

The dentition provides a unique model system for studying developmental events occurring from very early in fetal life to adolescence. Human dental development begins with the formation of the deciduous incisors at about four weeks in ufero, followed by the other deciduous and permanent teeth which each pass through a series of well-defined developmental stages beginning with soft tissue proliferation then subsequent crown and root calcification. Final crown morphology is determined well before emergence and does not change thereafter, apart from the effects of attrition or restorative procedures. Therefore, by studying final crown size and shape and applying knowledge of the timing and sequence of odontogenesis, one can attempt to elucidate retrospec-

269

. Tanner JM, Prader A, Habich H, Ferguson-Smith MA. 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 1959;2:141-4.

Buhler EM. A synopsis of the human Y chromosome. Hum Genet 1980;55:145-75.

" Gorlin RJ, Redman RS, Shapiro BL. Effect of X-chromosome aneuploidy on jaw growth. J Dent Res 1965;44:269-82.

'I' Alveralo L. Osborne RH, Kari M. The 47,XYY male, Y chromorome, and tooth size. Am J Hum Genet 1975;27:53-61.

" Alvesalo L , Kari M. Sizes of deciduous teeth in 47,XYY males. Am J Hum Genet 1977;29:486-9.

tively the nature of any disturbance in early growth that affected crown formation.

Previous reports of tooth size in 47,XYY males have indicated that both permanent and deciduous teeth are larger than However, as the incidence of the 47,XYY aneuploidy is low (about 1/1OOO) the number of individuals studied to date is still small. This report provides a further description of tooth size in 47,XYY males, including a larger sample than previously available. Mesiodistal and buccolingual tooth diameters of both deciduous and permanent teeth are compared with normal controls to gain more information about the role of the Y chromosome in dental development.

Materials and methods The 47,XYY sample consisted of 21 Caucasian boys

and young adults all confirmed by cytogenetic tests to be 47,XYY. Measurements were recorded from dental casts collected as part of a longitudinal growth study in Finland of individuals with sex chromosomal abnormal- ities. The control group was comprised of 150 normal Caucasian males, none of whom had a history of serious medical problems.

Mesiodistal and buccolingual diameters of deciduous and permanent teeth were recorded by one investigator (G.T.) to an accuracy of 0.10 mm according to the definitions of Seipel" and Moorrees and othersn3 using a dial caliper with ground tips. Teeth which had not fully erupted or showing evidence of attrition were excluded and measurements were not attempted where dental caries, restorations or dental plaque obscured a dimension. Measurements were obtained for teeth on both sides of the dental arch but, as no statistically significant differences were noted between sides, values were averaged from right and left measurements for use in the final analysis. I f a tooth was missing, the measurement from its antimere, if present, was used.

Descriptive statistics were determined, including mean values, standard deviations and coefficients of variation. Estimates of skewness and kurtosis were calculated t o assess the form of distributions. The significance of differences between mean values was tested by Student's r test. Twenty dental casts, selected at random, were remeasured to assess the magnitude of experimental errors. The standard deviation of a single determination (DahlbergI4) averaged 0.08 mm indicating that experimental errors were small and unlikely to bias tooth measurements.

Seipel CM. Variation of tooth position. Svensk Tandlak Tidskr 1946;39,Suppl.

' I Moorrees CFA, Thomsen SO, Jensen E, Yen PKJ. Mesiodistal crown diameters of the deciduous and permanent teeth in individuals. J Dent Res 1957;36:39-47.

Dahlberg G. Statistical methods for medical and biological students. London: Allen and Unwin, 1940.

270 Australian Dental Journal, August, 1985

TMLL I Crown diameters of deciduous teeth in 4 7 , X Y Y males and male control subjects

47,XYY Controls

n X SD n 'L SD Toot h

Maxilla di' di' dc dm' dm'

Mandible di, di dc dm I dm2 Maxilla di' di' dc dm' dm' Mandible di , di, dc dm I dm,

3 5 7 5 8

1 2 6 3 5

3 5 9 8 8

2 2 6 6 6

6.58 5.41 7.25t 7.73t 9.697

4.35 5.10 6.23- 8 .32

10.65t

5.18 5.11 6.63t 9.39t

l0.58t

4.20 4.73 5.93 7.98t 9.70t

0.10 0.30 0.28 0.59 0.51

- -

0.28 1.16 0.55

0.37 0.33 0.43 0.51 0.40

- -

0.39 0.43 0.43

Mesiodistal 27 42 54 40 42

17 36 5 3 43 43

30 42 54 48 50

16 34 51 49 48

Buccolingual

6.48 0.44 5 . 2 3 0.32 6.88 0.32 7.11 0.41 8.94 0.40

4.00 0.31 4.57 0.37 5.87 0.32 7.84 0.40

10.02 0.47

4.95 0.29 4.82 0.39 6.24 0.37 8.81 0.42

10.04 0.44

8.88 0.48

'Mean value significantly greater at p<0.05. ?Mean value significantly greater at p<0.01.

Results Estimates of skewness and kurtosis, calculated where

sample sizes permitted, indicated that tooth measurements were normally distributed and could therefore be described in terms of mean values and standard deviations. Comparisons of mean diameters of deciduous tooth crowns between 47,XYY males and control subjects are presented in Table 1. Although the sample size for 47,XYY was small there was a clear trend for deciduous teeth in 47,XYY boys to be larger than in controls for both mesiodistal and buccolingual dimensions. Statisti- cally significant differences were noted for canines and molars, but not for incisors. This result may merely reflect the small sample size for deciduous incisors, but warrants further investigation. Coefficients of variation are not reported for deciduous tooth diameters because of the small sample sizes available.

Table 2 presents comparisons of tooth diameters, together with coefficients of variation, in the permanent dentition. Mean values for all tooth dimensions, except the buccolingual dimension of the maxillary canine, were larger in 47,XYY males than controls, 18 of a possible 28 comparisons being significant at p<0.05. The average percentage increase in the size of permanent teeth in the 47,XYY group compared with controls was 4.6 per cent, ranging from a slight decrease in size for the buccolingual dimension of the maxillary canine to a 10.2 per cent increase for the mesiodistal dimension of the maxillary second premolar. Percentage increases were generally

smallest for canines (about 2 per cent) and largest for first molars (about 7 per cent). Coefficients of variation were generally smaller in the 47,XYY group than controls (27 to 28 comparisons), but no statistical tests were performed on the coefficients.

Discussion There are a number of approaches by which the role

of the chromosomes on somatic growth may be clarified. For instance, experimental studies of animals with chromosomal aneuploidies provide one means of in- vestigating the nature of growth disturbances during early foetal life, but extrapolation to man remains a problem. Studying the relationship in humans between the number of sex chromosomes and various morphological traits, such as stature, has also proved valuable but the super- imposed influences of hormonal and nutritional effects operating prior to and during adolescence need to be taken into account. Quantitative analysis of tooth morphology in individuals with sex chromosome abnormalities is another approach which has certain advantages.

Family studies have shown that tooth size variability has a strong genetic basis, estimates of heritability being about 60 per cent.'5 The final size of each tooth reflects

' ' Townsend GC. Heritability of deciduous tooth size in Australian Aboriginals . Am J Phys Anthrop 1980;53:297-300.

Australian Dental Journal, August, 1985 27 1

T w i t 2 C r o w diamerers oJpermanenr reerh in 4 7 , X Y Y males and male conrrol suhjecrs

47,XYY Controls

n \ SD c v n X SU I oo[h

~

hl il \ I 1 I t3 I ' I ' c I'hl Phl' 1L1' hl ' hlandible I I, c' Phl Phl . h l , M. Maxilla I ' 1: c' Phl' PM: M' M: hlandible I, I : C P M , PM, hl I M,

18 18 14 13 I I 10

T

I4 I 6

16 10 8

I 2 3

15 I 2 12 15 14 I2 4

9 9

I I I2 1 1 13 5

9.33t 7.04 8.24 7.501- 7.461-

I I .49t 10.66

5.791- 6.291- 7.25' 7.47 7.65*

12.27t 11.87'

7.63. 6.80 8.56 9.85. 9.93'

12.35t 11.90

6.57. 6.8St 8.03 8.45 8.94

I I .sot 11.41'

0.44 0.48 0.42 0.27 0.25 0.40 0.32

0.32 0.33 0.37 0.31 0.31 0.40 0.35

0.39 0.46 0.39 0.46 0.52 0.50 0.26

0.33 0.39 0.31 0.59 0.53 0.47 0.29

Mesiodistal 4.8 I04 6.9 95 5.1 82 3.6 74 3.4 74 3.5 81 3 .o 65

5.6 100 5.2 I02 5.1 87 4.2 76 4.0 79 3.3 72 3.0 54

Buccolingual 5.1 81 6.8 71 4.5 81 4.6 76 5.3 83 4.1 98 2.2 69

5.0 78 5.7 78 3.8 73 7 .O 74 6.0 78 4.1 92 2.5 67

8.76 6.85 8.04 7.07 6.77

10.65 10.31

5.47 6.04 6.99 7.19 7.29

1 I .42 10.94

7.34 6.57 8.62 9.47 9.50

11.76 11.81

6.18 6.44 7.92 8.13 8.64

10.83 10.72

0.53 0.55 0.43 0.39 0.44 0.50 0.57

0.32 0.35 0.40 0.46 0.46 0.59 0.65

0.52 0.57 0.55 0.56 0.60 0.55 0.72

0.45 0.42 0.53 0.54 0.53 0.49 0.60

c v ~

6.0 8. I 5.4 5.6 6.5 4.6 5.5

5.8 5.8 5.7 6.4 6.2 5.2 5.9

7. I 8.7 6.3 5.9 6.3 4.6 6.1

7.3 6.5 6.6 6.6 6. I 4.5 5.6

'Mean value significantly greater at p<O.OS. W e a n value rignificantly greater at p < O . O I .

the amount of cellular activity which has occurred during its period of formation. Furthermore, the stability of crown form, once mineralization is complete, overcomes the problem of additional environmental factors altering phenotype. Assuming that the cellular activity of developing teeth germs reflects cellular activity in other tissues, we may use the dentition to infer the nature of general disturbances in growth from very early in foetal Life.

The Y chromosome is an acrocentric chromosome with a long arm (4) and a short arm (p) on either side of the centromere. For many years no structural or regulatory genes could be assigned to the Y chromosome and i t has only been in the last few years, with the advent of new cytogenetic and immunological methods, that any genetic loci have been specified. A testis-determining gene has

been identified,I6 together with a locus involved in spermat~genesis.~'

The results of this study confirm that the extra Y chromosome does have an influence on tooth size in 47,XYY males, but is this a direct chromosomal effect or an indirect response resulting from, for example, altered hormonal levels? Whilst i t is impossible to rule out hormonal effect, hormonal levels in 47,XYY males generally appear to be comparable with matched

for example, both plasma testosterone and urinary androgen secretion seem normal." Also, the increase in tooth size in 47,XYY individualst is evident not only in the permanent teeth but also in the deciduous teeth which develop very early, before or about the time at which the gonads differentiate. Furthermore, studies

' * Miller OJ, Siniscalco M. Report of the committee on the genetic constitution of the X and Y chromosomes. Cytogenet Cell Genet 1982;32:179-90.

'. Tiepolo L , Zuffardi 0. Localization of factors controlling spermatogenesis in the non-fluorescent portion of the human Y chromosome long arm. Hum Genet 1976;34:119-24.

'' Owen DR. The 47,XYY male: a review. Psych Bull 1972;78:209-33.

l o Polani PE. Errors of sex determination and sex chromosome anomalies. In: Ounsted C , Taylor DC, eds. Gender differences: their ontogeny and significance. Edinburgh: Churchill Livingstone, 1972.

212 Australian Dental Journal, August, 1985

the amount of heterochromatin present in a cell regulates cellular division."

The concept that the Y chromosome may exert its effect by modifying cell division has been proposed before; for example, Mittwochl' has suggested that the Y chromosome may regulate the velocity and extent of growth of the primitive gonad. Also, Barlon" has postulated that the influence of heterochromatin i n reducing the rate of cell division could account for the effects of altered sex chromosome complements on pheno- typic characters such as fingerprints, intelligence quotient, and birth-weight. The observation that 4 7 , X Y Y individuals seem to show delayed emergence of' teeth is also consistent with such a theory."'

Turning specifically to the results of the present study, it is interesting to note that the increase in tooth size in 4 7 , X Y Y males was not uniform throughout the dentition. Alvesalo, Osborne, and Kari,"' in an earlier study based on a smaller sample, also noted that the size of the canines, which generally show greatest sexual dimorphism in normal groups, was only slightly affected if at all in 47,XYY males. They suggested that this might reflect their developmental and genetic independence in relation to other teeth. However, there was a trend in this study for the earlier-forming permanent teeth, for example, first molars and central incisors, to be more affected than later- forming teeth. I f we postulate that direct genetic effects and superimposed hormonal influences both contribute to final phenotype, perhaps the later-forming teeth, which tend to show greater dimorphism (excluding third molars), normally reach their maximum size potential whereas earlier-forming teeth still have some potential for sizc increase which is manifested in the presence of an additional Y chromosome. The tendency for tooth dimensions to be less variable in the 4 7 , X Y Y males than normal controls is also of interest, since variability is normally increased in subjects with genetic abnormalities. The result might be due to sampling effects, but is worthy of further investigation.

On the basis of available evidence, i t does seem that the Y chromosome has a direct effect on tooth size and, by inference, also on somatic growth in general. Nevertheless, experimental studies involving manipulation of hormone levels in animals have clearly shown that testicular hormones also influence sexual dimorphism in tooth size." I b Probably, as Ounsied and Taylor" haLe suggested, both factors normally operate for full expression of the male gender syndrome. Whilst the genetic effect may be due to a specific gene (or genes) located on the Y chromosome, it may be related to a more non-specific effect of heterochromatin on cellular activity.

Address for reprinis: G . Townsend.

Senior Lecturer in Oral Anatomy, Department of Dentistry,

The University of Adelaide, Adelaide, S.A. , 5 0 0 0 .

of the teeth of patients with complete testicular femini- zation syndrome have shown that the permanent teeth of these individuals are as large as in normal males and definitely larger than in normal females.'" Affected individuals have the normal male karyotype (46 ,XY)t and almost normally functioning testes, but they are pheno- typically females with an external appearance very similar to normal females. Since this syndrome results from an inability of target organs to react to androgens, the results strongly suggest that the Y chromosome does have a direct effect on dental development.

Whether the genetic effect might be the result of specific genes on the Y chromosome or heterochromatin remains unclear. Alvesalo and De La Chapelle" have suggested on the basis of examining the dentition of individuals with deletions of parts of the Y chromosome that there may be a growth-promoting gene in the region of the long (4) arm, near the centromere. However, the Y chromosome is still largely heterochromatic; that is, genetically inert. Heterochromatin tends to replicate its DNA late during the synthetic phase of the cell cycle and it is possible that

tApart irom d tendenc) to hc ta l l in staturc. the malority 01 1 7 . Y Y Y male, are phenotypically normal and therefore most c a m are probahlr never recog- nized. However. some 4 1 . X Y Y males shou hehavioural problem\ including drcrcaaed tolerance to frustration, impulswenes*, and aggrerslrener\. %\era1 \tudies haw indicated a relatively high frequency of these men in prison, This disorder 15 thought to arhe from Y chromatid nondi$Juncllun iiallurc of \eparation) during the second meiotic di\ ision of spermatogeneris. Sexual development of 41 .XYY malei is often normal and they appear to be fertile

Testicular feminization I\ an heredttary condition in u hich individual, uho have the normal male harotype (46.XY) \hou a phenot)pic \ex re\ercal. Normall) the presence of a Y chromosome in human5 causes the dc\elopment of teste, Urom the undiiierenuated embryonic gonad. folloacd h ) dc.relopmen1 o i inale external genitalia. Although testes are pre\enl and normal amouni\ 01 androgens appear to he produced in indi\wduals ulth tr\liculai feminization. the androgens fad to masculimze the rxlrrnal geniialia uhich appear to be phenotypically female

Hamerton probides a detailed d e w i p t i o n of thex and other *c\ chromo5omal ahnormahties in man (Hammerton 11 . Human c!togeneuc\ Vol 2. Neu York Academic Pre\\. 1971 I

'" Alvesalo L , Varrela J . Permanent tooth sizes in 46,XY females. Am J Hum Genet 1980;32:736-42.

'' Alvesalo L. De La Chapelle A . Tooth sizes in two males with deletions of the long arm of the Y-chromosome. Am J Hum Genet 1981;45:49-54.

:: Polani PE. Chromosomer and chromosomal mechanisms in the genesis of maldevelopmenr. In: Connolly K J . Prechtl HFR. eds. Maturation and development: biological and psychological perspectives. Clinics in Developmental Medicine No. 77/78. London: Heinemann. 1981.

:' Mittwoch Ursula. Differential growth of human foetal gonads with respect to sex and body 5ide. Ann Hum Genet 1976;40: 133-8.

'' Barlou P . The influence of inactive chromosomes on human development. Anomalous sex chromosome complements and the phenotype. Humangenetik 1973;17: 105-36.

I ' Heller NH. Blecher SR. Reverse, hormone-dependent sex difference in molar tooth mass in pubertal mice. Arch Oral Biol 1982;27:325-9.

I4 Lorber M, Alvo G, Zontine WJ. Sexual dimorphism of canine teeth of small dogs. Arch Oral Biol 1979;24:585-9.

*' Ounsted C. Taylor DC. The Y chromosome message: a point of view. In: Ounsted C, Taylor DC, eds. Gender differences: their ontogeny and significance. Edinburgh: Churchill Livingstone, 1972.