8 Growth disorder in the Ullrich-Turner syndrome MICHAEL

B. R A N K E

In 1938 Henry H. Turner described a disorder in seven females characterized by sexual infantilism, pterygium colli, cubitus valgus and short stature. As early as 1930, however, Otto Ullrich had recognized the same disorder as a specific entity. The disorder, which to current knowledge is caused by the complete or partial absence of one of the X chromosomes, is commonly termed Turner syndrome. Only in German literature is the term UllrichTurner syndrome used. Otto Ullrich had not only independently described the syndrome but had also speculated that lymphangiectasia during prenatal development might cause some of the abnormalities characteristic of the disorder. Since there is modern evidence for the correctness of this assumption, it seems justifiable to name the syndrome after both physicians, although there is a certain arbitrariness about the naming of syndromes. Ullrich-Turner syndrome (UTS) is a not uncommon disorder (approximately 1 : 2500 liveborn females). It is characterized by three main clinical features (Ranke, 1989): (1) abnormal external appearance and abnormalities of some internal organs; (2) malformation of the ovaries, and (3) short stature. Deviation of the appearance and abnormalities of internal organs varies. In some cases the characteristic features allow the diagnosis prima vista and as early as in the neonatal phase. In other cases the symptoms are subtle and need to be looked for. Gonadal dysgenesis progresses with age, thus allowing a fraction of patients to enter puberty (Hibi et al, 1991) and even allowing fertility in rare cases. Short stature is the most constant finding in UTS. The aim of this chapter is to describe the normal pattern of growth in UTS during development and to discuss some aspects of attempts to promote growth in UTS.

GROWTH IN UTS

Short stature is the most constant feature in UTS. It is present both in patients with the 45,X karyotype, which is found in about 60% of all cases, and in patients presenting with a great variety of other chromosomal abnormalities. We have suggested that growth in UTS can be classified into four phases (Ranke et al, 1983, 1988). (1) There is intrauterine growth Baillidre' s Clinical Endocrinology and Metabolism--

Vol. 6, No. 3, July 1992 ISBN 0-7020-1620-9

603

Copyright © 1992, by Bailli~re Tindall All rights of reproduction in any form reserved

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retardation. In children born near term, the average length is approximately 3 cm less than in normal children. (2) There is probably close to normal growth during infancy and early childhood (Karlberg et al, 1991). (3) There is considerable loss in height during later childhood. From about 3 to 12 years of age, children with UTS lose approximately 15 cm in height as compared with normal girls. (4) Since puberty does not occur, the total growth phase is prolonged. However, there is only a minor additional loss in height during this phase, which has probably very little to do with the fact that puberty does not occur (Massa et al, 1990).

Prenatal growth Accurate data on the whole course of growth before birth in UTS are not available. A substantial number of fetuses bearing the UTS karyotype are spontaneously aborted (Waeburton et al, 1981). In future, the increasing number of prenatal diagnoses through amniocentesis may allow prenatal growth to be followed by sonography. In addition, this method allows the recognition and follow-up of severely affected cases (lymphoedema). There are a number of reports about the size at birth of children born after the 30th 5

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ULLRICH--TURNER SYNDROME

week of gestation (Brook et al, 1974; Lenko et al, 1979; Ranke et al, 1983). These data show that in newborns at term (38th-42nd week) the average length is reduced by about 3 cm and the body weight by about 500g. About one-third of liveborn neonates are small for gestational age. Due to lymphoedema, weight at birth, which is the more accurately measurable parameter, may be too high. There is no evidence for size at birth being associated with the underlying karyotype (Figure 1). Postnatal

growth

Postnatal growth in UTS has been described in a number of studies (Brook et al, 1974; Lenko et al, 1979; Ranke et al, 1983, 1991; Bernasconi et al, 1991; Lippe and Frane, 1991; for review see Naeraa and Nielsen, 1990). Usually the data reported are based on retrospective analyses mixing longitudinal and cross-sectional data. Since cases with karyotypes other than 45,X are relatively infrequent, there are no comprehensive studies of growth in patients with such specific karyotypes (Figure 2). The study of growth in UTS is also influenced by the bias introduced through the timing of its discovery in afflicted patients. The diagnosis may be made prenatally, at birth, during childhood, at adolescence or during adult life, with karyotype, HEIGHT

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dysmorphology, short stature, delayed puberty or even infertility being the presenting symptom. In addition, the numbers investigated are smaller than in growth studies designed to define normal growth in a population. Thus, even though postnatal growth in UTS is probably the best described of all known syndromes, there remain uncertainties about the natural history of growth (Table 1). Table 1. Height, bone age (TW2-RUS, GP) and height velocity in UTS. Age (years) 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 >20

Mean height* (cm)

Mean height§ (cm)

Mean bone age (TW2-RUS)t (years)

Mean bone age (GP)$ (years)

77.30 (2.6) 85.10 (3.5) 91.55 (3.8) 97.25 (4.0) 102.50 (4,2) 107.35 (4.4) 111.90 (4.6) 116.20 (4.8) 120.30 (5.0) 124.20 (5.1) 127.95 (5.3) 131.45 (5.4) 134.65 (5.5) 137.55 (5.7) 140.10 (5.8) 142.20 (5.9) 143.90 (5.9) 145.00 (6.0) 146.3 (6.1)

74.9 (3.7) 83.1 (4.3) 88.3 (4.7) 92.7 (5.4) 97.8 (4.0) 102.3 (5.1) 105.3 (4.6) 112,5 (4.9) 116.7 (4.6) 119.8 (4.6) 123.0 (6.6) 128.1 (6.0) 131.3 (6.3) 134.2 (5.9) 138.3 (5.8) 139.1 (5.2) 139.2 (3.8) 142.8 (3.7) 143.2 (4.5)

1.10 1.90 2.90 3.90 4.90 5.90 6.90 7.90 8.90 9.90 10.85 11.75 12.55 13.25 13.80 14.30 14.70 15.00 --

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7.80 (1.9) 6.45 (1.6) 5.70 (1.4)

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4.85 (1.2) 4.55 (1.1) 4.30 (1.1) 4.10 (1.0) 3.90 (1.0) 3.75 (0.9) 3.50 (0.9) 3.20 (0.8) 2.90 (0.7) 2.55 (0.6) 2.10 (0.5) 1.70 (0.4) 1.10 (0.3)

--

Values in parentheses are standard deviations. TW2; Tanner-Whitehouse 2 method; RUS, radius-ulna score. * From Ranke et al (1988). t Interpolated from Ranke et al (1991). $ Interpolated from Ranke ct al (1991) and Rochiccioli et al (1991). § From Lyon et al (1985). As in the normal population, growth can be described in terms of distant height and height velocity. G r o w t h f r o m birth to adulthood can be considered as a model which divides it into three components. In UTS, the components of infancy, childhood and puberty are different from the normal. During the early postnatal years growth was formerly assumed not to be essentially different from normal children. H o w e v e r , the detailed analysis of longitudinal data show reduction in growth beginning from birth (Karlberg et al, 1991). G r o w t h velocity declines continuously, leading to a progressive loss in height during childhood. Since the oestrogen-related pubertal growth phase is absent, a pubertal growth spurt is also absent. G r o w t h continues along the childhood c o m p o n e n t of the model. But the total growth phase is prolonged and, in this way, the relative deviation of height from normality diminishes. It reaches the m a x i m u m around the age of 14 years. Adult height is not reached before the end of the teens. F r o m

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our data we concluded that about three-quarters of the difference of adult height to the normal population is lost during childhood. The pattern of height development described by various large series is surprisingly similar. The variability of height for a given age appears to be very similar (one standard deviation amounts to approximately 4.7% of a given mean for age) to that found in normal children (Lyon et al, 1985). Fewer height velocity data have been published since they are more difficult to collect (Ranke et al, 1983, 1991) (Table 1). Based on our earlier data we assumed that there was a continuous decline in height velocity to the end of growth (Ranke et al, 1983). In a recent study involving 738 observations, we have been able to show that there are two minor growth spurts: one during the prepubertal (adrenarche?) and one during the pubertal period (Ranke et al, 1991) (Figure 3). The latter, which was also shown by others (Schober et al, 1987), is present despite the absence of recognizable thelarche. These different findings are probably the result of the composition of the sample investigated. It can, however, be assumed that the factors regulating growth in normal children play a role in the growth process of UTS. Normal standards and growth charts have been devised for UTS. They allow the illustration and expression of height and height velocity data in terms of standard deviation scores (SDS), thus allowing meaningful evaluation of spontaneous and modified growth. Adult height in UTS

Data on adult height in patients never treated with substances influencing growth are difficult to collect, therefore debate on the subject persists. Applying the Infancy-Childhood-Puberty model, it may be possible to predict the range of final height from the data collected during childhood and adolescence within a population (Karlberg et al, 1991). The reported adult height varies between publications (Table 2). The mean adult stature in UTS patients of Caucasian origin approaches approximately 142-147 cm. Comparing reports of the adult height in UTS, there appears to be a difference of 20 cm between mean normal female adult height and adult height in UTS within a given population (Brook et al, 1974; Lenko et al, 1979; Sybert, 1984; Lyon et al, 1985; Ranke et al, 1988, 1991; Naeraa and Nielsen, 1990; Bernasconi et al, 1991; Lippe and Frane, 1991). Variation of adult height is similar to that observed in the normal population. There is a Table 2. Adult height (age > 19 years) in UTS. Study Japan: Hibi et al (1991) USA: Lippe and Frane (1991) Italy: Bernasconi et al (1991) Lyon et al (1985) Denmark: Naeraa and Nielsen (1990) Germany: Ranke et al (1988)

n

Mean height (cm)

45 90 62 138 76 44

136.7 (6.9) 142.3 (6.0) 142.7 (6.4) 142.9 (6,7) 146.8 (6,8) 146.9(7,2)

Values in parentheses are standard deviations.

ULLRICH--TURNER SYNDROME

609

positive correlation between the adult height reached and parental height (Brook et al, 1977; Massa et al, 1990; H. Chavez-Meyer and M. B. Ranke, unpublished observations). The issue of whether or not patients with different karyotypes grow in an identical or different mode is still not settled, although some recent results oppose such an assumption (Naeraa et al, 1991; Ranke et al, 1991) (Figure 2). The main reason for this ongoing uncertainty is the small number of untreated patients who can be followed up to the end of growth. Although empirical data from untreated adult patients with different karyotypes will probably not be available, there is some evidence supporting the assumption that there may be a link between karyotype and growth. In a very recent study (H. Chavez-Meyer and M. B. Ranke, unpublished observations), we investigated the correlation of patient and parental height in a very large sample of patients from birth to 17 years of age. When dividing the patients into groups, i.e. those with 45,X and those with non-45,X karyotype, there was a different pattern of correlation between the groups with UTS and the normal population. Whereas the correlation between height of UTS with maternal or paternal height was similar in magnitude and not different from the normal population, the correlation to paternal height was not present in 45,X UTS and was lower than between normal father-daughter height relationship. However, there is a significant correlation to maternal height with a magnitude higher than between normal father-daughter height relationship. This finding is in line with the suggestion that in 45,X UTS the paternal X chromosome is predominantly lost (Connor and Loughlin, 1991). If the activation of an X chromosome has a quantitative impact on growth development, the functional prevalence of a maternal or paternal X chromosome should have a bearing on growth (even if its magnitude may be small) as long as parental size is not extreme. The issue of the effect of parental height on height in UTS, in particular on adult height, will be of importance if attempts are made to calculate the 'target' height in UTS. Bone age

Bone age determinations are helpful in the evaluation of the growth process. The determination of bone age, either by the method of Greulich and Pyle (1952) or by the Tanner-Whitehouse 2 (TW2) method (Tanner et al, 1975), is prone to subjective error, and structural abnormalities in UTS cause additional difficulties. In UTS bone age is retarded and progresses in a different pattern to that of normal girls (Brook et al, 1974; Ranke et al, 1983, 1991; Rochiccioli et al, 1991). Although data in infancy and early childhood are scarce, bone age appears to progress at a rate of less than i year per year. During childhood (up to the age of 12 years) bone age progression corresponds to normality. Thereafter this rate progresses slowly (Table 1) and this must be borne in mind when bone age is taken into consideration during treatment for growth promotion. Normative data for length of metacarpophalangeal bones, established from X-ray films of the hand (Chavez-Meyer and Ranke, 1991), may allow the study of acral growth in UTS. It is felt that normative, longitudinal data on the natural course of bone age development

610

M. B, RAN~CE

in UTS are needed before bone age can safely be considered when predicting adult stature during the course of spontaneous and medically-altered growth in UTS.

Other auxological parameters There is only limited information about other anthropometric parameters in UTS. Weight in relation to height tends to increase with age due to increases in adipose tissue and muscle (Ranke et al, 1988). Head circumference is normal. There is some shortness of extremities, expressed by a slight increase of the rump/leg length (Neufeld et al, 1978). Further research is needed to document other auxological parameters. Within the context of the multifaceted discussion on treatment of short stature in UTS, the question of whether or not it is possible to correctly predict the course of growth and, in particular, adult height has generated great interest. There are several suggestions. 1.

2.

3.

Since there is some correlation between parental height and adult height in UTS, as in normals, a target height and target range can be calculated on the basis of parental height. The formula suggested (Lenko et al, 1979), and modified by us for the German UTS population (mean UTS height 146.3cm) (Ranke, 1988), is: target height (cm)=[height of father (cm) + height of mother (cm)] + 2 × 0.63 + 39.5 cm (+ 5 cm). This equation needs to be empirically validated and possibly modified on the basis of detailed knowledge of the karyotype (e.g. origin of X chromosome). Several attempts have been made to try and predict adult height in individuals more accurately (Frane et al, 1989; Karlberg et al, 1991; Naeraa et al, 1991). One model is to plot the growth of an individual girl with UTS on a UTS-specific growth chart and to extend this line, following the individual percentile, to a 'projected final height'. In practice the height SDS for age, based on UTS-specific height data, is calculated and is taken as the height SDS at the end of growth. The validity of this approach of predicting adult height is supported by empirical evidence (Lyon et al, 1985; Frane et al, 1989). In the author's view, it appears to be quite a sound approach if it can be assumed that growth follows the channel of targeted height during childhood in UTS (Rosenfeld et al, 1988; Frane et al, 1989) and that individual influences on a child's growth (e.g. parental height) are already expressed within the deviation of height from the disease-specific mean for a given age. Since height prediction models in normal children take bone age into consideration, it may be assumed that the height SDS for bone age can be used as a more accurate indicator for adult height. The height SDS for bone age is termed the 'index of potential height (IPH)'. It has also been found to be a fairly accurate means of predicting adult height (Joss, 1991; Karlberg et al, 1991; Naeraa et al, 1991). Since bone age in UTS deviates systematically from chronological age, in the author's view a better prediction of IPH over projected height only seems likely if the patient's bone age deviates from the UTS pattern.

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. The method of Bayley and Pinneau (1952), based on Greulich-Pyle bone age ratings, was also used to predict final height in UTS. In the case of UTS, where height is more reduced than bone age, prediction gave fairly good results (Zachmann et al, 1978; Naeraa et al, 1991). It is felt that, of these methods, which are on the whole not very precise in predicting individual adult height (a quality shared by prediction methods for normal variations of growth), 'projected final height' is currently the most robust one, provided good UTS standards are available. PATHOGENESIS OF SHORT STATURE IN UTS The reason for short stature in UTS is at present not known. Most investigators, including the author, believe that a disorder at the tissue level is primarily responsible for short stature. Some, however, favour the idea of hormones being partly the cause. In particular, a disorder of the growth hormone (GH)-insulin-like growth factor (IGF) axis has been discussed. There is no doubt that the response of growth hormone to provocative tests is frequently found to be poor and that the amount of growth hormone secreted spontaneously is frequently subnormal. Spontaneously secreted growth hormone at pubertal age is definitely below the levels found in normal girls during puberty (Buchanan et al, 1987; Ranke et al, 1987). Likewise low or subnormal IGF-1 levels have been found during that period (Cuttler et al, 1985; Ross et al, 1985; Ranke et al, 1987). This, however, has to be attributed to the absence of oestrogen and to mild obesity, since the conditions can be reversed by oestrogen administration and/or reduction in weight (Schober et al, 1987). The serum levels of the growth hormonedependent IGF-binding protein (IGFBP-3), which is highly correlated with spontaneous growth hormone secretion, were found to be within the normal range (Ranke et al, 1989). Recently it has also been shown that age-matched girls, with or without low growth hormone secretion, grow at similar rates, with or without exogenous growth hormone (Massa et al, 1990). Thus, there is no convincing evidence that a genuine disorder of the growth hormone axis is involved in the pathogenesis of the growth disorder in UTS (Ranke et al, 1987; Van Vliet, 1988). GROWTH PROMOTION IN UTS

Attempts to improve growth rates in UTS by the administration of anabolic steroids, oestrogens and growth hormone are still being made in a multitude of studies. Evaluation of the growth response to treatment

The goal of treatment for short stature in a child is to normalize its height in relation to the normal population. Thus, during treatment an evaluation

612

M.B. RANKE

must be made as to whether or not the mode of treatment applied is in accordance with such a goal. It is obvious that an increase in height velocity as such does not allow one to judge whether the goal has been approached. It is certain that only UTS-specific data on spontaneous height velocity allow a meaningful evaluation of the growth process during treatment. The extent of growth is not only determined by height velocity but also by the tempo of growth (e.g. slow growth may result in higher stature than fast growth). The effect of treatment must therefore be evaluated by taking into consideration a parameter that indicates a change in the tempo of growth. During normal growth, bone age development is taken as this indicator since the relationship between height and bone age determines the tempo of and the potential for growth. Spontaneous bone age development in UTS is different from its normal counterpart (Brook et al, 1974; Ranke et al, 1979, 1991). This is partly a result of the absence or diminution of ovarian steroids. However, in UTS other factors may play a role and alterations of bone age through treatment may be different from the normal at different stages of development. Since bone age ratings are often prone to errors in judgement and rather difficult to evaluate in UTS due to structural abnormalities of the bones, they should be used with caution. From the patient's point of view, height in relation to the normal population is of significance. Treatment should therefore attempt to allow both growth within normal limits in childhood and within the normal adult range. Thus, in order to evaluate a mode of treatment, the questions to be asked are whether the mode improves height compared with disease-specific standards or whether it really normalizes height. Treatment with anabolic steroids

Anabolic steroids are derivatives of testosterone. The structure of testosterone is changed in order to conserve the anabolic effect and to reduce the androgenic effect of the precursor molecule. With respect to growth auxology it is assumed that in children the anabolic effect of androgens (testosterone/anabolic steroids) is expressed by the promotion of longitudinal bone growth, whereas the androgenic effect is expressed by an advancement of bone maturation. Anabolic steroids can improve shortterm growth (Johanson et al, 1969; Joss, 1988), but if substances with a relatively high androgenic potency are used, particularly at higher dose levels, there can be a negative effect on growth due to the advancement of bone age. In recent years, oxandrolone was the anabolic steroid given preference in attempts to promote growth. This compound has a very high anabolic to androgenic ratio of potency and does not produce any of the side-effects caused by some anabolic steroids. The therapeutic range of the drug may nevertheless be rather narrow and androgenic side-effects have occasionally been observed in dosages as low as 0.125 mg/kg body weight. The mechanism of oxandrolone and its effect on growth is not fully known. It is assumed that there is a direct effect on the target tissue level and that it does not activate the G H - I G F axis directly. However, there are suggestions that growth hormone secretion can be augmented by oxandrolone. The

ULLRICH--TURNER SYNDROME

613

discrepancies between these findings may be related to the dose given. It has been shown by several investigators that, in patients with UTS, oxandrolone improves the short-term growth rates without unduly advancing bone maturation (Danowski et al, 1966; Urban et al, 1979; Schoenberger et al, 1982; Joss and Zuppinger, 1984; Muritano and Job, 1985; Crock et al, 1991). As a rule, doses of the order of 0.1 mg/kg body weight have been applied. It is our experience that an increase in height velocity can also be achieved at a dose level of 0.05mg/kg body weight. Reports about the long-term results of such treatment are controversial. Some authors found a difference when comparing the adult height of the treated group with the controls (Joss and Zuppinger, 1984; Crock et al, 1991), whereas others did not (Rosenbloom and Frias, 1973; Sybert, 1984; for review, see Joss, 1988). The reason for this discrepancy probably lies in the experimental design of the studies. Nevertheless, one cannot avoid drawing the conclusion that longterm treatment with oxandrolone may improve the final height of these patients by a few centimetres. Treatment with oestrogens

Since oestrogens are causally related to the normal pubertal growth spurt of girls on the one hand, and are lacking in UTS on the other, it was assumed that oestrogen replacement during pubertal age would benefit growth. However, in earlier studies the effects of such replacement doses were not found to be advantageous (Sybert, 1984). The increase in growth velocity was usually greater than that compensated for by an inappropriate advancement of bone maturity. The latter is applied in preventing excessive height in girls. Ross and colleagues were the first to observe very low doses of oestrogen to have a growth-promoting effect in UTS without resulting in undesirable advancement in bone maturity (Ross et al, 1986). Subsequently, several groups of investigators tried to promote growth with very low doses of oestrogens. These studies, in which a variety of oestrogen preparations were used at dosage levels equivalent to approximately 50-100ng/kg BW ethinyloestradiol, showed similar growth rates above basal levels during the first year (Ranke et al, 1986; Kastrup et al, 1988). However, the study of Kastrup et al (1988) clearly indicated that the rate of bone age progression exceeded the normal levels. It is therefore highly questionable whether this approach can be beneficial in the long run or whether it is in fact disadvantageous in terms of the patient's final height. Treatment with growth hormone

When pituitary human growth hormone became available, a few patients with UTS were treated with it (Hutchings et al, 1965; Tzagournis, 1969; Tanner et al, 1971). The results of these trials were largely disappointing. With the recent availability of growth hormone produced by the recombinant technique in abundant amounts it has been possible to conduct carefully designed studies with the aim of re-evaluating this therapy (Raiti et al, 1986; Rosenfeld et al, 1986, 1988, 1991; Singer-Granick et al, 1986;

614

M.B. RANKE

Takano et al, 1986, 1991; Rongen-Westerlaken et al, 1988; Holland et al, 1991; Nilsson et ~il, 1991; Rongen-Westerlaken and Wit, 1991; Sippell et al, 1991; Stahncke et al, 1991; Toublanc et al, 1991). In contrast to the observations made when pituitary human growth hormone was used; the growth rates in recent studies using recombinant growth hormone were, without exception, reported to be higher than those spontaneously observed in Turner syndrome. Although the response depends on the growth hormone dose, it is, nevertheless, much lower than that observed with true growth hormone deficiency (Ranke et al, 1979) (Figure 4). Growth rates are relatively low, HV [ o m / y r ]

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Figure4. Heightincrement during (a) firstand (b) secondyearof growthhormonetherapyfrom recent studies compared with patients with growth hormone deficiency. particularly during treatment after the first year, an observation also made in the treatment of children with growth hormone deficiency. The cause for the observed changes in the results with growth hormone is a matter of speculation. It is assumed to be partly due to the fact that the total dosages applied at present are comparatively higher, and partly to a possible increase of the specific activity of the new growth hormone preparations. In addition to this, the bioavailable growth hormone dose is increased by the number of injections given. Based on the experiences with growth hormone deficiency, a five- to tenfold higher growth hormone dose is required in UTS to achieve the same increase in height velocity as observed in growth hormone deficiency during the first and second years of treatment. In combination with oxandrolone, considerably higher growth rates have been observed (Nilsson et al, 1991; Rosenfeld et al, 1986, 1988, 1991; Sippell et al, 1991; Stahnke et al, 1991). This is probably a result of the different mechanisms of action of the two drugs. The effect of long-term treatment of growth hormone (with Or without

615

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oxandrolone) on adult height has not yet been firmly established. However, the results of Rosenfeld et al (1991) indicate that there is a significant trend towards an increase in adult stature after more than 5 years of treatment. With growth hormone, the patients tend to continue to grow at greater than UTS-specific height velocities, without an undesirable advancement of bone maturation. Many patients in this as well as other studies have already exceeded the height projected at the start of therapy; some did so as early as 3 years after treatment (Rosenfeld et al, 1988; Nilsson et al, 1991; Takano et al, 1991; Toublanc et al, 1991). On the whole, the patients in Rosenfeld's study are, at any investigated age, significantly taller than children with UTS who grow spontaneously (Table 3) (Rosenfeld et al, 1991). The reason for the efficacy of growth hormone, even though given in doses which compare with substitution therapy in growth hormone deficiency and which are not in the pathological range, is not fully understood. We have suggested that the change in the ratio of IGF-1 to IGFBP-3 in favour of IGF-1 may be part of the answer (Ranke et al, 1989). Table 3. Height after 5 years of treatment with growth hormone. Age (years)

n

< 14 14-15 15-16 > 16

25 9 9 22

Height (cm) 141.5 148.7 148.1 149.8

(9.1) (7.1) (4.5) (5.4)

Norm (cm) (Lyon et al, 1985) 14 yrs: 15 yrs: 16 yrs: Adult:

132.6 135.8 138.6 142.9

(6.2) (6.4) (6.5) (6.7)

Values in parentheses are standard deviations. From Rosenfeld et al (1991).

Risks of growth-promoting therapy The potential risks of growth-promoting therapies are posed by the following: (1) the specific factors related to UTS; (2) the specific side-effects of the drugs used; (3) the dosage and duration of the drugs used; and (4) a combination of these factors. At present, we know rather little about the spontaneous outcome of patients with UTS since there are no data available on UTS in adult life. Impaired glucose tolerance and a tendency towards high biood pressure (even without cardiac failure) are well-documented abnormalities in UTS (Wilson et al, 1988; for review, see Chiumello et al, 1991). High doses of G H may increase the risk of developing diabetes mellitus. Although recent studies have shown that the negative effects of growth hormone on glucose tolerance were transient (Wilson et al, 1988; Sippell et al, 1991; Stahnke et aI, 1991), the long-term risks cannot be predicted. Oxandrolone has been in use for decades and appears to be fairly safe when given in low doses. However, its potential hazards when given over long periods of time are by no means established. Since the dose-risk potential may be age dependent, care must be taken in the treatment of younger patients.

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CONCLUSION At present, it can be claimed with some certainty that growth hormone and/or oxandrolone can increase height velocity in UTS. Growth hormone therapy in this syndrome cannot be considered to be substitutive, as it is in growth hormone deficiency. It is highly probable that growth hormone (with or without oxandrolone) improves adult stature. The modalities of such a treatment need to be optimized, especially the timing of the start of therapy and the dosage. It is probably legitimate to state (and it may well be economically sound) that a growth disorder must be treated as soon as it is recognized. Since height impairment due to UTS can be assumed at birth, growth-promoting therapies could even be introduced immediately after birth in detected cases. In attempting to improve height, even if 'very low' doses are given, oestrogen should be administered with great caution and should probably never be given without additional growth hormone. Despite the promising results reported recently, our main responsibility lies in not harming patients through treatment. All forms of treatment discussed here are still in the experimental stage and need to be carried out under conditions which provide maximum safety to the patients. Even though short stature is a severe problem in UTS, personal and social attitudes towards height need to be considered and must be respected in every individual case. Therapies to improve height have to be designed within the context of providing total patient care.

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