(Acta Puediatr Jun 1992; 34: 222

- 235)

Pubertal Growth Andrea Prader, M.D. Department of’ Pediatrics, University of Zurich, Switzerland

Key Words

Pubertal growth, Pubertal spurt, Maturation, Growth hormone

Normal Growth Velocity The analysis of the dynamics of normal growth has to be based on longitudinal data. Cross-sectional data, which are much easier to obtain, give valuable reference values for height, weight etc. in relation to chronological age. They do not allow us, however, to extract true velocity values because velocity values based on cross-sectional data are blurred by the variability of the maturational tempo. This has been clearly demonstrated by Shuttleworth more than 50 years ago [I]. In Fig. 1 the pubertal spurts of 5 individuals with different timing of the spurt are shown. The resulting mean curve is flatter and broader than all the individual curves and is very different from the real dynamics of normal growth. Centering the individual curves on their mean age at peak height velocity (PHV) results in a true mean velocity curve, at least for the pubertal period. In the first Zurich longitudinal study of growth and development we have followed more than 200 Swiss children from birth to adulthood [3]. Using the method of Shuttleworth we have obtained a representative mean

Received November 29. 1991 Correspondence address: Andrea Prader, M.D., Department of Pediatrics. University of Zurich, Kinderspital Zurich. Steinwiesstrasse 75 CH-8032 Zurich, Switzerland

curve of height in distance and in velocity (Fig. 2). Before puberty the curves are nearly identical in both sexes. The velocity decreases first quickly and then more slowly and reaches a point of minimal prepubertal height velocity (MHV) which corresponds to the take off of the pubertal growth spurt. This declining velocity curve is interrupted by the midgrowth spurt at the age of 7 to 8 years. Like the pubertal spurt, the mid-growth spurt is not only seen in height, but also in all other growth parameters, like the length of the extremities, head circumference and in the shoulder and pelvic width. Surprisingly this small spurt has no or only a doubtful sex difference. In contrast the much more important pubertal spurt is highly sex dependent, being earlier and smaller in girls and later and bigger in boys. After a postspurt gradual decrease of velocity the end of growth is reached first in girls and then in boys. The sex difference of the pubertal spurt in time and intensity explains the sex difference of adult height of 13 cm in favour of the boys. The pubertal spurt occurs first in the extremities and later in the trunk, leading to the typical shift in body proportions with relatively longer extremities during puberty than before and after. There has been a suggestion of several small prepubertal spurts [4]. A careful study of published data and our own data does not

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support this concept. However, with improved methods to measure the lower part of the leg more precisely it is possible to detect minimal velocity changes of short duration. By using this method, called knemometry, spontaneous mini-growth-waves of a few weeks duration and the growth retarding effect of minor infections with subsequent catch-up growth, have been demonstrated [5]. Well established are the decreasing height during the day and the seasonal velocity changes. As I have mentioned the classical mean velocity curve is constructed by centering all individual velocity curves on the mean age of pubertal PHV. My associate The0 Gasser conceived the idea and developed the statistical methodology to center the individual velocity curves not only on the mean age of PHV but simultaneously also on the mean ages of many other characteristic points found in each individual curve, such as the minimal velocity before the mid-growth spurt and before the pubertal spurt and the points of maximal, minimal and zero acceleration [7]. The result of this new and sophisticated analysis is a structural average curve (Fig. 3) which represents the true mean velocity much better than the traditional one constructed according to Shuttleworth.

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Maturation and Growth As mentioned prepubertal girls and boys have nearly the same growth in distance and velocity. In contrast skeletal maturation is faster in girls than in boys during the whole prepubertal and pubertal period. This explains that they reach adult height earlier than boys and are shorter adults. It follows that the percent of adult height reached at any age is higher in girls than in boys. This explains that the characteristics of the pubertal growth period, like MHV, PHV and the radiological appearance of the sesamoid bone of the thumb, which occur later in boys than in girls in relation to chronological age, occur at the same time in both sexes if related to the percentage of adult height reached (Fig. 4). In both sexes M H V is reached at a mean height of 82.5% of adult height and PHV at 90%. The sesamoid bone of the thumb in the X-ray film of the hand appears at 89% of adult height. Menarche occurs when 95.3% of adult height is reached. The attainment of a certain percentage of adult height in relation to chronological age allows the prediction of adult height from height and age alone. This prediction has of course an error, which however is smaller in prepuberty than in puberty. This difference demonstrates that

Fig. 3: Structural average velocity (above) and acceleration (below) of height of boys (pointed lines) and girls (full lines). Data of the first Zurich longitudinal growth study. From Gasser et a1 [7].

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Pubertal growth ( 1 19) 225 growth and maturation are largely independent of each other. In conclusion girls are more mature than boys from birth on as demonstrated by the faster skeletal maturation and the faster growth of height if height is expressed in percentage of adult height. In this perspective the earlier puberty and the earlier end of growth of girls compared to boys is only the logical continuation of a basic sex difference in tempo of maturation beginning in the perinatal period. Fig. 5 shows the time relation between the pubertal growth spurt and the appearance of the pubertal signs [8]. In both sexes the first pubertal signs and the appearance of the sesamoid bone occur after the beginning of the pubertal spurt, between MHV and PHV, axillary hair at PHV, and menarche and voice changes after PHV. In the majority of boys the 3 ml testicular stage is found before any other signs of puberty. The distance between the start and the end of the pubertal development of the male genitalia is remarkably short, namely only 2y2 years, reflecting the rapid effect of testosterone on the development of the male genitalia. The overall pattern of the pubertal growth spurt and the development of puberty is practically identical in both sexes. There are of course remarkable variations of individual items in relation to other items inside of the pubertal period which I am not going to discuss because I wish to

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concentrate on pubertal growth and not on puberty in general. And there is, as you know, a large variability in the timing of the whole period of pubertal growth and puberty, i.e. a large variability of the maturational tempo with a large difference between early and late maturers. Pediatricians usually believe that early maturers will be short adults and late maturers tall adults. This is based on the experience with children suffering from precocious puberty who show acceleration of growth and bone age and stop growing at an early age before reaching normal adult height. However, this is an abnormal situation. In the normal children of our study we found no correlation between final adult height and age of puberty if we consider the total group of children [9]. Only if we compare groups of early and late maturers there is a small difference in the girls but not in the boys, late girls being statistically 3 cm taller as adults than early girls, a barely signlficant difference [lo]. Other authors have found a small difference in boys but not in girls [l 13 or similar small differences in otherwise selected groups of children [12]. In conclusion final height and time of puberty of normal children are not or very little correlated. This indicates again that the two developmental phenomena growth and maturation are largely independent of each other. The small or even questionable

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Fig. 5 : Relation between adolescent growth and sexual development in the first Zurich longitudinal growth study [9]. S = amearance of the sesamoid bone. attainment of99 percent of adult height.

226 ( 120) Prader influence of the timing of puberty on adult height must be kept in mind when we discuss the possibility to improve final adult height by postponing puberty artificially using LHRH agonists for a limited period of time [ 13, 141. Constitutional Variants of Normal Growth The marked variation of height and of maturation allow us to identify certain constitutional variations of growth and of maturational tempo. The two variants of growth are constitutional or familial tall stature and constitutional or familial short slature. The two variants of maturational tempo are constitutional or familial accelerarion q f growth, bone age and puberty, and constitutional or .familial de1a.v of groM?h, hone age and puberty. On the standard percentile chart of height the growth curve of constitutional tall stature lies on or above the top percentiles and that of constitutional short stature on or below the lowest percentiles. The growth curve of constitutional acceleration crosses upwards through the percentiles, that of constitutional delay downwards through the percentiles. The vague terms “constitutional” or “familial” are based on the experience that usually some family members have the same course of growth and maturation

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but that there is not a simple Mendelian hereditary pattern but rather the irregular pattern characteristic of multifactorial traits. Family history, good health of the child and the typical growth curve allow the diagnosis of these variants before puberty. The normal variants of maturation demonstrate that normal growth does not always follow the same percentile or remain in the same percentile channel. If growth follows the same percentile it may safely be assumed to be normal. If it does not it may be normal or abnormal and a closer look at the child is necessary. The described normal variants of height and of maturation are rarely seen in their pure forms. More frequent are the combinations of tall-early, tall-late, short-early and short-late. Indeed the most frequent growth problem in pediatric practice is the normal and healthy boy with the short-late type of growth and maturation. Statistically this pattern is of course just as frequent in girls as in boys. However, the psychosocial impact is more severe in boys. This explains why physicians see boys with the short-late type of growth and maturation much more frequently than girls. We have analysed in our longitudinal study

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Fig. 6 : Height velocity of children becoming tall adults (full line) and short adults (pointed line) in the first Zurich longitudinal growth study. From Gasser et al [7].

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the subgroups tall, short, early and late by comparing the mean velocity of the children in the lower and the upper third of adult height and of children in the lower and the upper third of age at PHV [lo].

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Fig. 6 shows the height velocity of tall and of short children. The difference between mean adult height is 15.5 cm in the boys and 12.7cm in the girls. The tall children gain more height mainly by a higher growth velocity in the prepubertal period. MHV and PHV are also somewhat increased in the tall children but the real pubertal growth spurt, i.e. the difference between PHV and MHV is practically identical. It is concluded that tall adult stature is mainly caused by more prepubertal growth and not by a stronger growth spurt. Fig. 7 gives the height velocity of early and late maturers. The difference between the mean age of PHV is two years in the boys and 2.2 years in the girls. Early maturers grow faster in prepuberty, have an earlier pubertal spurt and reach a higher PHV. However, as in tall and short children the real pubertal spurt (difference between PHV and MHV) is identical. It is interesting to compare the pubertal growth of children with chronic diseases with that of normal late maturers. Fig. 8 compares the mean PHV centered velocity curve of boys with chronic renal failure studied in Heidelberg with the mean of our total group of normal boys and with our sample of late maturers [15]. In these patients prepubertal growth is

228 ( 122) Prader very strong. This is evident by the sex difference in growth and maturation and by the correlation of height with midparent height (Fig. 9). The strong correlation between the child’s height and his parents’ height is not only seen in normal children but is also found in certain groups of children with abnormal growth [16], as for instance in girls with Turner syndrome. The influence of the sex chromosomes is not only documented by the sex difference of normal growth and maturation but also by the fact that XO Turner girls are shorter than normal X X girls and that XXY Klinefelter boys are taller than normal XY boys and XYY boys even taller than the XXY Klinefelter boys. Appearently the lack of an X chromosome in girls decreases height and each Y in boys present increases height. In numerical or structural abnormalities of the autosomes short stature is a frequent finding. Environmental influences on growth and maturation are documented by the negative effect of malnutrition, of frequent infections and low social class as well as by the secular trend which increases height and accelerates puberty in periods of good socio-economic conditions and decreases height and delays puberty in periods of poor socio-economic conditions. We know little how the genetic and environmental influences are mediated. We

very poor and the pubertal spurt is markedly delayed as you would expect. Furthermore MHV and PHV are much lower than in the two control groups. However, the true growth spurt (difference between MHV and PHV) is again about normal. This illustrates and extends the general rule shown by Shuttleworth and many subsequent authors, that the absolute values of MHV and PHV are higher in tall and in early maturing children and lower in short and in late maturing children and even more so in children with a chronic disease, whereas the true spurt remains about the same. However, the absolute amount of pubertal growth (adult height minus height at MHV) drops markedly the more puberty is delayed. This experience again raises doubts about the effect of delaying puberty artificially in short children in order to increase their final adult height. Genetic, Environmental and Endocrine Influences I have pointed out that the two developmentaf phenomena growth and maturation are two largely independent multifactorial traits. It is therefore not surprising that the regulation of growth and maturation is extremely complex. Let me discuss briefly some genetic. environmental and endocrine influences. Without any doubt the genetic influence is

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Pubertal growth ( 123) 229 know of course that hormones and growth stimulating peptide factors modulate growth to a large extent and that endocrine diseases frequently cause abnormalities of growth and maturation. I will discuss briefly some relevant aspects of our knowledge and some interesting experiments of nature. Growth hormone (GH) is important for growth and it has been shown that normal short children secrete less GH than tall children suggesting a difference in the physiological set point of the GH regulation. Estrogens and androgens stimulate the secretion of GH. If given as a priming dose to prepubertal children the GH peak values in the GH provocative tests will increase. If prepubertal children are treated with estrogens or androgens, even in very small doses, their growth velocity accelerates which is partly mediated by an increased secretion of GH. During puberty the spontaneous GH secretion is markedly higher than in prepuberty. This is mainly due to higher amplitudes in the pulsatile secretion of GH. GH deficiency leads to a decrease of growth velocity and to a delay of skeletal and pubertal maturation. This corresponds largely to the experimental effect of GH and IGF I on growth, on cartilage cells and on sex steroid producing cells. The pubertal growth spurt is caused by the increase of the sex steroid secretion in the maturing gonads and the related increase in growth hormone secretion. Without gonadal maturation there is no pubertal growth spurt. Nevertheless normal adult height can be reached without gonadal maturation at the expense of eunuchoid body proportions. In other words gonadal steroids cause the pubertal growth spurt and modulate body proportions but do not influence adult height. Some years ago we compared the effect of testosterone on growth in patients with isolated gonadotropin deficiency, anorchia and GH deficiency [lq. The effect on growth in patients with gonadotropin deficiency or anorchia, who have a normal GH secretion, is much stronger than in patients who are deficient in GH even if GH is replaced in a dosage sufficient to stimulate prepubertal

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growth. This experience demonstrates that the effect of testosterone on growth depends largely on the presence of a normal GH secretion. It is less well known but clinically evident that the androgenic effect (stimulation of body hair) of testosterone also depends on the presence of a normal GH secretion [18]. The mid-growth spurt is possibly caused by the adrenarche, i.e. the increase of the secretion of adrenal androgens seen at this age period. This is supported by the growth pattern of patients with congenital adrenal hypoplasia who experience no adrenarche and whose growth, in our limited experience, is first normal and then falls off around the time when normal children undergo the adrenarche, even if the cortisone deficiency is replaced physiologically. On the other hand boys with anorchia or girls with pure gonadal dysgenesis, whose adrenals are intact, show normal growth and skeletal maturation during the whole prepubertal period. The experience with these two endocrine defects suggests that normal growth and skeletal maturation in prepuberty depend possibly on the adrenarche after the age of 7 and d o certainly not depend on the low gonadal steroid production normally present in prepubertal children. If this assumption is correct it is difficult to explain on an endocrine basis the prepubertal delay of growth and maturation seen in normal late maturers and in children with gonadotropin deficiency. An interesting experiment of nature are the XY girls with testicular feminisation or androgen insensitivity. Their growth follows more or less the male pattern of growth and in the timing and height of the pubertal growth spurt [19], in spite of the fact that they are androgen insensitive. Their growth spurt is apparently caused by the estrogens derived from the androgens. On the other hand this condition demonstrates that the male pattern of growth and maturation does not depend on the presence of androgens. Catch-up growth as seen after the correction of a growth inhibiting condition is another amazing and insufficiently explained phenomenon of growth. The velocity of catch-up

230 (124) Pruder growth may be three times faster than normal and yet there is no clinical or laboratory evidence of an abnormally high concentration of growth promoting hormones or factors. Indeed, we do not know what causes the catch-up growth and how it is regulated. It is also interesting that catch-up growth is age dependent, allowing a full compensation of growth and maturation in young children but only a partial one in older children. This experience suggests an age dependent responsiveness of the target cells. This corresponds to the discussed fact that the total amount of pubertal growth is smaller in late maturers than in early maturers. The responsiveness of target cells is probably a major factor in growth regulation. A well known example of an abnormally low response of the chondrocytes is the short stature seen in the various forms of bone dysplasia. The form of the velocity curves seen in catch-up growth is very different from the form of the normal pubertal growth spurt. Catch-up growth is extremely rapid in the beginning and slows down with time. In contrast the pubertal growth spurt increases slowly to its peak and decreases slowly again. Under hormonal replacement therapy with GH in GH deficiency, with thyroxin in hypothyroidism or with gonadal steroids in hypogonadism the resultant acceleration of growth has the typical form of catch-up growth. This is because we usually start replacement therapy with the full physiological replacement dosage. In contrast spontaneous puberty is caused by a slow increase of endogenous gonadal steroids. If we give gonadal steroids to agonadal or hypogonadal children, for instance in girls with Turner syndrome, we should try to copy the spontaneous pubertal spurt, beginning with extremely low amounts of gonadal steroids and increasing the dosage slowly over a time period of 2 years.

Conclusions

most interesting aspects of the developing child. 2) The sex difference of growth and maturation is visible during the whole growth period and not only in puberty. It is only partly explained by endocrine factors. 3 ) Growth and maturation are two different, largely independent multifactorial variables. 4) Final adult height depends mainly on prepubertal growth and very little on the timing of puberty. The pubertal spurt, PHV and MHV in tall and in short children, as well as in early and late maturers is quantitively similar. 5 ) The growth velocity curve of catch-up growth, seen after removal of growth inhibiting pathological factors and in the beginning of replacement therapy in full dosage with GH, thyroxin and gonadal steroids is very different from the normal pubertal growth spurt. 6 ) In spite of the remarkable progress of our knowledge we are still far away from understanding fully the regulation of growth and maturation. In relation to therapeutic management my analysis suggests the following: I ) The dosage of sex steroid replacement therapy in order to induce normal pubertal development should begin with the smallest amount possible and be slowly increased over a period of about two years. If the full replacement dosage is given from the start the resulting growth acceleration is of the catchup type and not of the pubertal spurt type. 2) The dosage of GH replacement therapy in GH deficient children should be increased during puberty, irrespectively whether puberty is spontaneous or artificially induced. 3) Artificial suppression of puberty in order to increase final adult height is theoretically of questionable value because of the decreasing potential of pubertal growth with increasing age. It should only be undertaken if puberty is precocious in relation to skeletal maturation or if GH is given at the same time.

My analysis may be summarised as follows: I ) Growth and maturation are among the

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References 1.

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Shuttleworth FK. Sexual maturation and the physical growth of girls aged six to nineteen. Monographs of the Society for Research in Child Development. 12th ed. Washington, 1937, National Research Council, 2-No 5. Tanner JM. Growth at adolescence, 2nd ed. Oxford, 1962, Blackwell Scientific Publications. Prader A, Largo RH, Molinari L et al. Physical growth of Swiss children from birth to 20 years of age. Helv Paediatr Acta (Suppl) 1989; 52. Butler GE, McKie M, Ratcliffe SG. The cyclical nature of prepubertal growth. Ann Hum Biol 1990; 17: 177-198. Hermanussen M. The measurement of short-term growth. In Tanner JM ed: Auxology 88. 1989 Smith-Gordon, Nishimura, p49-61. Prader A. Physiologisches, pathologisches und manipuliertes Korpenvachstum. Monatsschr Kinderheilkd 1986; 134: 292-301. Gasser T, Kneip A, Ziegler P et al. A method for determining the dynamics and intensity of average growth. Ann Hum Biol 1990; 17: 459474. Prader A, Largo RH, Wolf C. Timing of pubertal growth and maturation in the first Zurich longitudinal study. Acta Paediatr Hung 1984; 25: 155159. Largo RH, Gasser T, Prader A et al. Analysis of the adolescent growth spurt using smoothing spline functions. Ann Hum Biol 1978; 5 : 421434. Molinari L, Gasser T, Largo RH et al. Short, tall, early and late children in the first Zurich longitudinal growth study. In preparation. Hags U, Taranger J. Height and height velocity in

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early, average and late maturers followed to the age of 25: a prospective longitudinal study of Swedish urban children from birth to adulthood. Ann Hum Biol 1991; 18: 47-56. Tanaka T, Suwa S, Yokoya S et al. Analysis of linear growth during puberty. Acta Paediatr Scand (Suppl) 1988; 347: 25-29. Hibi 1, Tanaka T, Tane A et al. The influence of gonadal function and the effect of gonadal suppression treatment on final height in growth hormone treated GH-deficient children. J Clin Endocrinol Metab 1989; 69: 221-226. Stanhope R, Brook CGD. The effect of gonadotrophin releasing hormone analogue on height prognosis in growth hormone deficiency and normal puberty. Eur J Pediatr 1988; 148: 200-202. Schaefer F, Seidel C, Binding A et al. Pubertal growth in chronic renal failure. Pediatr Res 1990; 28: 5-10. Brook CGD, Gasser T, Werder EA et al. Height correlations between parents and mature offspring in normal subjects and in subjects with Turner’s and Klinefelter’s and other syndromes. Ann Hum Biol 1977; 4: 17-22. Aynsley-Green A, Zachmann M, Prader A. Interrelation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism. J Ped 1976; 1989: 992-999. Zachmann M, Prader A. Anabolic and androgenic effects of testosterone in sexually immature boys and its dependency on growth hormone. J Clin Endocr 1970; 30: 85-95. Zachmann M, Prader A, Sobel EH et al. Pubertal growth in patients with androgen insensitivity. J Ped 1986; 108: 694-699.

DISCUSSION Dr. Prader Dr. Tanaka, Tokyo, National Children’s Hospital: I’d like to comment on the timing of puberty and the final height. We analyzed 500 normal children longitudinally and got the same results as you showed-there is no correlation between final adult height and age of puberty if we considered the total group of children. But we found that those who matured earlier were taller before puberty than the slower maturer; there is a significant difference in height between the slower maturer and earlier maturer before puberty. So, when we took the groups of same height

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level before puberty we found a very significant positive correlation between the time of puberty and final height in each group. It means that if the height in the prepubertal period is the same, the timing of the puberty is a very important factor to the final height. That is our rationale in the use of gonadal suppression therapy in children. Dr. Prader: Well, partly I know your papers and you have found as we have that in a large group of normal children there is no correlation between the age of puberty and final height. But if you take specific groups, early maturers and late maturers, then the late maturers tend to be taller, that is what you

232 ( 126) Prader said, In our experience we have found this only in girls and only in a small amount. I know that in the Swedish longitudinal study it has been found only in boys and again only a small difference. You found a large difference, and you find it in both sexes. Dr. Tanaka: I found that in the early matuier group there is a signlficant correlation of the time of puberty and the final height. Also in the late puberty group and also in the normal puberty group there is a significant correlation in each group. Dr. Prader: But if you take early maturers and then you find a difference in that group, you said those who grow less in prepuberty will be shorter in the final end than those who grow more in prepuberty. Is that what you said? Because I suppose that there is hidden in the small and early group not just the early. But let’s find the points where we agree. No correlation between the time of puberty and final height in general, but I mention that if you examine certain specific groups only then a difference may come out. Dr. Tanaka: But between early and late there is no difference in the final height. Dr. Prader: Between early and late maturers. there is no difference in final height between groups, only within groups. Dr. Tanaka: Yes. Dr. Prader: I assume that in this group you have short-early and tall-early. Dr. Tanaka: Right. Dr. Prader: And there, of course, you find this difference because the short early will be shorter as adults than the tall early. You see, the tall early grow faster than the short early in prepuberty and therefore, because most of a girl’s height is reached during prepuberty you will find a difference in adult height. We have not analyzed our groups in this way but we can do it. Hopefully we may find the same results. Dr. Murata from Tokyo: I have three questions. The typical age of menarche of the Japanese female is between 12 years and 12 years and 6 months. It seems that in the case of girls in Zurich, the typical age of menarche is between 13 years and 13 years and 6

months. Do you still have the secular trend of change or is it stabilized in’zurich? Sometimes menarche occurs before peak height age statistically or on average, but in principal how do you assess the relationship between the height growth and onset of menarche? Is there a relationship between the two? Dr. Prader: Concerning the question of timing of puberty and a final height, I don’t think there is any correlation, but the amount of growth between take-off age spurt and the final height age I think is different whether the maturation is accelerated or decelerated. The age of menarche is earlier in Japan than in Switzerland. I accept this as a fact. So I don’t think I can discuss this any more. But the secular trend in Switzerland is stabilized. I cannot fully answer the second question, only partially. If we take the statistics of height of young men when they are recruited for the army, then the secular trend in Switzerland is still going on. However, if we look at the difference between the first Zurich and the second Zurich longitudinal study we do not see the secular trend, so we have reasons to believe that in young children it has stabilized but in the older generation, that means young men nowadays, it is still going on. Of course that is still possible, but we have not analyzed this any further so I cannot give you a definite answer. And then the next question was the relation between peak height velocity and menarche, the age relation. Now, we have never seen a girl who had menarche before peak height velocity, never. Not one in our longitudinal study. So this seems to be rather a stable correlation, it occurs relatively shortly after peak height velocity and never before, whereas the other pubertal signs vary inside the pubertal block, at menarche much less. The same is true when menarche is correlated with bone age more than all the other pubertal signs. Now, did you have another question or did I answer all the three questions? Dr. Murata: The third question, whether the final height is tall or short is not related to the age or timing of puberty as you said. I agree with you and to explain this, between

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Pubertal growth (127) 233 the take-off age of pubertal spurt and age of the final height, there is the amount of growth and this is rather identical in older subjects regardless of the early maturer or late maturer, or is it different? Dr. Prader: The pubertal spurt, taken as the difference between peak height and takeoff age, is always similar. But the amount of total growth after take-off or peak height velocity depends on age so the growth potential diminishes with age. Again, the growth spurt in itself does not diminish. We have seen that in the boys with chronic renal deficiency, but the total amount of growth diminishes markedly because the whole spurt is on a lower basis and the older the child is, the lower it is. Dr. Matsuo from Keio University: My question concerns the relationship between childhood height and adult height. You show the correlation of the data between childhood height and adult height is better in boys. Did I understand correctly? Dr. Prader: I did not discuss this aspect. It was in one of the slides but 1 didn’t discuss this aspect. There is some controversy. Various authors have found better correlations in boys and others have found it better in girls. So, I left this out because this is not a very clear area. Dr. De Felice, National Children’s Medical Research Center, Tokyo: I would like to ask you, Dr. Prader, about differences, if there are any, between children with celiac disease and control group children. Second question, did you have any data about psychosocial short stature and pubertal growth pattern and lastly, did you have any data about differences in small-for-weight newborn and appropriatefor-age newborns in spite of the pubertal growth spurt? Dr. Prader: These are three questions. Celiac disease compared to controls. Well, we have done this and many have done this at a certain age when the diagnosis is mad. Of course, after treatment, there is not much use to compare them. But certainly before treatment patients with celiac disease are short and upon treatment they show a typical catch-

Vol. 34 No. 2 April 1992

up growth. But of course I do not know how growth would be in a celiac patient whose disease is never treated. There we have no experience. The second question was psychosocia1 dwarfism. This is a condition I know well from the literature, mainly from papers from the United States, but in our experience in Zurich, we have about one patient every five years and there is always a lot of discussion so we have very little experience. And, of course, the diagnosis is difficult and I am quite sure depends on catch-up growth when you remove the bad psychosocial influences and then only you are sure that this is psychosocial short stature, but my experience is so limited I cannot answer this. The last question was how do small-fordates grow later up to adult height. I cannot answer this fully but a few things are quite clear. There are a number of papers showing that many of the short for age at birth will show a catch-up growth during the first year of life. Not all, but quite many. And then there is a clear-cut result and we can confirm this if we take a large group of normal children and compare adult height with birthweight. Those with a low birthweight have a lower adult height, those with a larger birthweight have a higher adult height. So there is no doubt that adult height also depends on birthweight. Of course in such a group there are many different groups, smallfor-dates, for what reason, etc. So what 1just said is all I can tell you. Dr. Hasagawa from Tokyo: I have a question about individual difference of growth. After the infancy and before puberty, what percentage of the normal children show the shift from 1 percentile line to either the higher or lower percentile line by jumping more than two lines? Dr. Prader: Shown on one slide, the group of constitutional acceleration of growth, bone age and puberty will cross upwards through their percentiles and the group of the delay will cross downwards, but of course many abnormal conditions will cross downwards too. Does this answer your question or not completely? Dr. Hasagawa: Not completely. What

234 ( 128) Prader percentage of children cross upward? Dr. Prader: I cannot give you the figure. Are you talking about prepuberty or about infancy? Dr, Hasagawa: After infancy and before puberty. Dr, Prader: I cannot give you an exact figure. We have never analyzed how many. Dr. Yoshizawa, National Children’s Medical Research Center, Tokyo: Is it observed meaningfully the fluctuation, especially the growth of arm length or leg length and body height between mid-growth point and pubertal spurt? Dr. Prader: You mean how do the proportions between trunk and extremities change? The extremities accelerate more in an earlier stage of puberty than the trunk and therefore children at a certain stage have relatively much longer legs than they have at prepuberty or in adult age. Dr. Yoshizawa: We can observe the fluctuation of growth body height, leg lengths, or perhaps arm lengths also from between mid-growth spurt and pubertal spurt. Dr. h d e r : The extremities grow faster than the trunk in that period of time. Is that what you wanted to know? Dr. Yoshizawa: Have you ever observed that fluctuation? Dr. Prader: No, the mid-growth spurt is visible in total height, in the extremities, in the trunk and in all other parameters. There is a question; I have mentioned that some people feel that there is more than one prepubertal spurt which would fluctuate. Now we do not believe this but it is controversial. Our opinion is that those authors who have found this have a specific design on how to analyze, and that design automatically gives that result. We have written a letter to the editor to stimulate that controversy. One other thing I could say about the length of extremities is that the relative lengths of extremities is more in tall children or tall adults than in short children. And of course in Turner syndrome, we have just discussed this, Dr. Ranke and I find that typically short children have relatively shorter extremities than normal or tall children. So

the relative length of the extremities is dependent on the total height and age. Dr. Tachibana from Kanagawa: You said that the pubertal growth spurt first starts in the extremities and then in the trunk. I have carried out a longitudinal study and this is based on school statistics. Children want to cheat when the measurements are taken because they like longer extremities but there was a significant individual difference. Did you see significant individual difference in terms of this? And in case of pubertal spurt there must be an influence of the sex steroid and why there is this difference in terms of the timing, in terms of the extremity growth and the trunk growth, is there any difference in the sensitivity to the sex steroid influence between extremities and the trunk to cause this difference in the timing of growth? Dr. Prader: As I mentioned, there are so many aspects of descriptive growth which we cannot explain. And of course, an interesting experiment is of those patients who have no puberty who continue to grow and to get what we call eunuchoid proportions. The extremities become longer in relation to total height than in normal people. So you could draw conclusions to answer your question from that. The lack of growth of gonadal steroids increases the relative lengths of extremities. I think such things could be discussed at length. Dr. Ranke: Professor Prader, could you perhaps comment on the basis of your understanding of the growth process? How the strategies to improve height in situations like Turner syndrome and any other growth disorder with respect to the timing and use of growth hormone, sex steroids or perhaps anabolics should be on the basis simply theoretically if you should take an approach what to use and what not to use? Dr. Prader: I think I would agree with what you have said today and what has been said by others. The induction of puberty should be more or less at the correct age and it should be with very small doses. One should imitate normal puberty. We have recently published a paper on that concerning Turner syndrome by using the transdermal estrogen

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Pubertal growth (129) 235

therapy. Now about growth hormone, I believe it was also you who said that it should be given early. That is certainly true in growth hormone deficiency, no one would doubt this. Whether it is true for the Turner syndrome, how I could answer that would be purely on a theoretical basis. If you regard it as a pharmacologic therapy and this probably then it is most likely as you have already said, that you probably get better results the earlier you begin and the longer you give this therapy, but otherwise I cannot give miracle answers. Dr. Yokoya: My question is regarding mid-growth spurt. In many of your slides, you clearly showed us the presence of mid-growth spurt but I thought that the data was based on the statistical findings. My question is whether we can always observe such a growth spurt in individual children, or how many children have such a mid-growth spurt?

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Dr. Prader: Well, it is difficult to be sure in the individual child because it needs, of course, a relatively narrow placement of measurements. I had the same question as you have and I have put some pressure on our statisticians to give me a good answer. We feel that most normal children show this midgrowth spurt and that is the reason I have mentioned it is found not only in the total height but in all other body dimensions, even in small dimensions like the diameter of the elbow for instance, statistically this is absolutely clear-cut physically. I am surprised myself and of course we have no real explanation. I mean the adrenarche is a possible explanation but we do not know. Dr. Yokoya: But if you can measure body size very frequently, do you think that all normal children have growth spurts? Dr. Prader: That is what I believe.

(Actu Paediutr Jpn 1992; 34: 236

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Characteristics of Pubertal Growth in Japanese Children from the Standpoint of Skeletal Growth Mitsunori Murata, M.D. Department qf Pediutrics, Tokilo Women k Medical College Duini Hospital, Tokyo

Since the end of the 2nd World War, Japan has seen quite rapid socioeconomical development. With this development the physical size of Japanese children has increased, but the final size, especially the stature, is still shorter than that of Americans or Europeans. Bone maturation velocities were compared among Japanese and Chinese children and adolescents aged 7 to 18 (in 1986) and English TW2-subjects, using the TW2 method. Asian children and adolescents may have a different tempo of skeletal maturation during pubertal growth from that of English children and adolescents. This, probably genetic, difference in the tempo of skeletal maturation, especially that of RUS, between Japanese and English during pubertal growth may be one of the main causes of the fmal difference in the stature of the two groups. Key Words Pubertal growth, Bone age, Skeletal maturation, Japanese children

Introduction Since the end of the 2nd World War, Japan has seen quite rapid socioeconomical development. With this development the physical size of Japanese children has increased, but the final size, especially the stature, is still shorter than that of Americans or Europeans. We have very interesting results from the investigation of skeletal growth in children and adolescents aged from 7 to 18 years in 1986. using the TW2 bone age estimation method. Because this investigation was done in order to compare the physical size and activities of Japanese and Chinese children Recei\,ed hovember 29. 1991 Correspondence address: Mitsunori Murata. M.D.. Department of Pediatriecs. Tokyo Women's Medical College Daini Hospital, 2-1-10 Nishi-ogu. Arakawa-ku, Tokyo 116. Japan

and adolescents in 1986, the differences of skeletal maturity and physical size between Japanese and Chinese children and adolescents are also discussed in this paper.

Subjects and Methods In order to select subjects with normal physical fitness, only subjects with height and weight in the range of the mean rt 2SD in each age group were selected. The subjects were about 100 boys and girls each in age group from 7 to 18 years old in 1986 in the Tokyo metropolitan area, as shown in the Table 1. According to the instruction of Tanner's Textbook [I], X-ray photographs of the left hand of these subjects were taken, and the bone age in each subject was estimated by the TW2 method [l]. The 50th percentile value of the total score of 3 types of bone age estimation method (20-