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Short stature
Endocrinology
Mini-symposium
Short stature
J. M. H. Buckler What do centile charts show?’
The child with short stature may have to face many problems in both practical and psychological terms during the growing years and ultimately as a fully grown adult. However the degree of upset which short stature imposes on the child and the family varies greatly, depending on their backgrounds and attitudes. Short stature in itself is not a disease but there may be a tendency to make it into one due to the attitudes of both the medical profession and society.
Centile charts show the spread of measurements within a particular population, which should, in theory, be appropriate for the individual being evaluated. The measurements of populations differ between races and countries, and between regions of a country, so it is not possible to obtain standards for all subgroups of a population. The standards of Tanner,2 despite being developed over 20 years ago from a population in the South of England, remain the best and the most widely used for Britain. However, it is necessary to make minor adjustments according to the origin of the individual3 There has been a secular trend over the years with advancement in the age of pubertal development (now no longer continuing) and an associated increase in height and weight. There is a need for more up-to-date standards, which hopefully will be available within the next few years. Centile charts show measurement spread within a population as it actually is, not necessarily as it ideally should be. With an increasing proportion of overweight members in the British population the weight distribution has become somewhat skewed upwards, and the opposite is seen in undernourished communities. But though these considerations affect interpretation when a child is first measured, they are less crucial subsequently, when serial measurements (if sufficiently accurate) will show whether there is a fall away from the particular centile which increases concern. Velocity centile charts2 make these deviations more obvious. It is important to realise that a fall away in a linear centile position will occur with velocities consistently less than the 25th centile. Growth rates vary in normal individuals between seasons and for other reasons, so to avoid these fluctuations, velocities should be based on increases in measurements over a full year, though it is not always appropriate to wait so long if shorter term changes are considered important.
What is normal growth? Whether growth is normal or not is difficult to define. The further a measurement is away from a particular centile range, the more likely is this to be ‘abnormal’. This is usually what triggers initial concern, but an outlying centile position in itself is seldom considered as the grounds for defining abnormality, even though some clinicians might use that criterion. What will be considered ‘normal’ will depend on the personality, attitudes and aspirations of the individuals, their families and society; on the measurements of other members of the family; on the child’s physique and other variables. The identification of a specific pathology is one means of defining ‘abnormality’, and this is clearly helpful in terms of prognosis and in choosing treatment regimens in those conditions for which there is an appropriate treatment. But the search for a treatment is not restricted to those individuals whose short stature can be labelled with a specific pathological diagnosis.
John M. H. Buckler, DM, FRCP, Senior Lecturer in Paediatrics, Academic Unit of Paediatrics (LGI), Department of Clinical Medicine, D Floor, Clarendon Wing, Leeds General Infirmary, Leeds LS2 9NS. Correspondence and requests for offprints to JMHB Currem Paediarrics 0 1992 Longman
(1992) 2, 125-130 Ltd
GroupUK
125
126
CURRENT
PAEDIATRICS
Most centile charts are based on cross-sectional data which are usually adequate in the prepubertal years, but the variability in the age of puberty makes longitudinal comparative standards essential for correct interpretation at that age.‘v4
Factors which influence growth patterns of individuals’ Most of the variation in size and growth pattern depend on variations which can be considered normal (Table 1). Hereditary factors are the most powerful influences in terms both of stature and physique and of the timing of growth phases. Though these are usually normal variants, pathological conditions affecting growth can, of course, also be inherited. The great variation in the age of puberty will cause a child’s height centile at a specific age to be higher or lower than previously, depending on whether puberty is earlier or later than average. To some extent ‘physiological age’, which becomes self-evident at puberty, has an effect in terms of greater or less growth potential at any chronological age and is indicated by bone age. It is important to recognize that there is an age when no further growth is possible, when puberty is completed and the epiphyses have fused, but the actual age will vary depending on when puberty occurred. Table 1 Factors influencing
?? Physiological
Table 2 Factors whose aberrations produce abnormal growth Adverse antenatal factors Abnormal genes and inheritance of pathologies Inadequate nutrition (a) Food intake - quantitative or qualitative (b) Inadequate digestion and absorption Chronic ill health e.g. asthma Adverse psycho-social factors Inappropriate hormone levels - notably: (a) thyroid (b) growth hormone (c) glucocorticoids (d) sex hormones
-I
or to placental insufficiency in the later stages of pregnancy. In these latter two groups subsequent growth usually shows catch up and a normal outcome. The degree to which growth, and intellectual development, can be influenced by environmental circumstances is controversial, but there is no question that extremes of emotional deprivation have a severely retarding effect on growth. There may however be more subtle ways in which the psyche is linked to growth. The adverse psychological effects of being small may themselves diminish growth whether this is natural or in response to treatment. Occasionally, however, the trauma associated with injection treatment may itself be the cause of unexpectedly poor growth response.
normal growth
Which short stature children need investigating? age -
notably at puberty
Although it is obvious that extremes of undernutrition will slow growth as a whole, there is a tendency for variation in thinness or fatness within an arbitrarily ‘normal’ range to have a minor effect on growth patterns. Obese children tend to go into puberty earlier than normal and grow faster at that age; thin children and those involved in certain kinds of competitive sport such as gymnastics and ballet dancing tend to be delayed in puberty and shorter in stature at that time. In general, however, moderate variations in exercise have little relationship to growth patterns. Table 2 lists the more common abnormal conditions linked with poor growth. Though numerically these only account for a minority of short children, yet these are factors responsible for a high proportion of the severely short statured subjects and include many for which there is an unequivocally appropriate treatment. Intrauterine growth retardation frequently reflects long-term adverse antenatal influences, including genetic ones, and is often a pointer to subsequent ongoing poor growth. Such low birth weight babies are small in all respects and are to be distinguished from those where the low weight is due to prematurity
Some pointers to aid in identification of potential growth problems are shown in Table 3. Many of these have been considered already. Although in many cases of short stature, height and weight centile positions correspond, a marked disparity between the two makes some underlying pathology more likely. Situations where the weight is at a lower centile level than the height suggest undernutrition - whether due to inadequate food intake or failure to absorb the food. (Note, however, Table 3 Clinical aids to identification problems
and evaluation
of short stature
Low height centile positions Fall-off in height centile position with time - prolonged low height velocity centile (except at pubertal age range) Disparate height-weight centile relationships Inappropriate height centile for the family (parents and siblings) Abnormal appearance: e.g. (a) Evidence of specific syndromes (Down, Turner) (b) Body disproportion (e.g. bone dysplasias, hypothyroidism) inappropriately small size at birth Clinical evidence of chronic disease or the effects of its treatment Marked deviation in the age of sexual development
SHORT STATURE
that delayed puberty gives the false impression of underweight as the weight drifts down further from the standard centile than does the height.) If the weight is at a higher centile position than the height, this is a pointer to endocrine causes or other specific conditions of obesity. The association with short stature is an aid in distinguishing those obese children where there is a pathological cause for obesity from the large number of obese children where these is no such underlying pathology, in whom the stature is usually above what would otherwise be expected. Knowledge of the family growth pattern is important as an indication of whether an inherited mechanism for the short stature is likely, of either a normal or pathological nature, as well as identifying a possible link with early or delayed pubertal development within the family (the age of the menarche being a good pointer to this in women). The mid-parental height centile is a guide to where the child’s height centile might be expected, although if one parent is tall and the other short the child might take after either. Many chronic diseases may in themselves be sufficient to explain short stature, although sometimes linked with other factors such as treatment (notably with large dose corticosteroids), undernutrition, potentially reversible hormonal suppression, or psychological disturbance. Conversely, basically good health, general well being, plenty of energy and little time off school are features which contribute to reassurance.
Predictions of ultimate height Although a child’s current short stature is usually the major cause of concern, it might well be accepted if there was a prospect of more reasonable stature as an adult. Predictions of ultimate height are, however, imprecise, particularly for those at the extremes of tallness or shortness, or of advanced or retarded physiological development. It is usually considered that systems incorporating bone age are the best, and in Britain the Tanner Whitehouse System (TW2) is usually the favoured one.‘j This is more appropriate for British (and probably other European) subjects than those based on American standards incorporating the Greulich-Pyle method of bone age assessment.’ Much depends on the assessment of bone age which is very subjective and, though usually corresponding well to physiological development, does not always do so, as for example in some exogenously obese children or in some children markedly delayed in puberty. Sometimes when puberty is under way assessment of its staging may be almost as good an index of growth potential as the apparently more precise methods incorporating bone age.4 In pathological conditions, prediction of the outcome with or without treatment is often very imprecise. Where short stature is associated with marked bone age retardation, such as most endocrine causes
127
of poor growth, the theoretical increased growth potential is frequently not achieved even on appropriate treatment. Bone age estimations may be difficult or impossible where the appearance of the bone is markedly abnormal, such as bone dysplasias or diseases. For some conditions centile charts have been produced, e.g. Down and Turner syndromes and achondroplasia; extrapolation of a centile position to the adult height is a useful guideline, although without bone age estimations cannot incorporate a factor for ‘physiological age’.
Investigational aids The need for investigation and its nature depends on the initial and ongoing clinical assessment. The range of possible investigations is vast and it is inappropriate to consider these in depth here. Bone age evaluation by the TW2 method is helpful diagnostically as well as in predicting theoretical growth potential. Bone age is only an adjunct to the other aspects of evaluation, for there is no precise dividing line between the deviations due to physiological and to pathological causes. The most reliable interpretations require good radiological technique and an experienced assessor, preferably the same one if there are serial observations.* Investigation for specific chronic diseases will be indicated from the basic history and assessment. A check on whether the food intake is adequate in quantity and quality is a sensible initial assessment in a short child who is markedly underweight, particularly if anaemic. If the diet is adequate, tests for malabsorption are indicated, particularly in the presence of suggestive symptoms and signs. Conversely, if there is a degree of obesity, hormonal studies are more likely to be forthcoming. Skinfold measurements are simple and helpful, both initially and over the course of time, to indicate what the ‘weight’ and weight changes actually represent. Not all children whose weight is at a higher centile than height are obese, for this also occurs in those whose physique is stocky or with proportionately short limbs; conversely, long-limbed individuals and those delayed in puberty may appear underweight but are not necessarily thin on the basis of skinfold measurements. It is important always to bear in mind the possibility of adverse psychosocial circumstances contributing to or causing poor growth, but it is often difficult to evaluate this adequately and it may require considerable insight and the assistance of experienced supportive staff. Emotional deprivation can closely mimic other disorders and even overlap them in terms of clinical signs and symptoms and results of investigations, e.g. coeliac disease or hormonal insufficiencies. In the absence of a positive outcome to these basic lines of investigation a skeletal survey may be needed to exclude bone dysplasias, particularly in children with body disproportion. In short stature girls chro-
128
CURRENT
PAEDIATRICS
mosome analysis is important to exclude Turner syndrome, for though the full picture is obvious clinically, a proportion of girls with this condition may only show short stature and, at the appropriate age, delayed or incomplete pubertal development, particularly those in whom the karyotype is not the classical 45X0.
Investigation and interpretation of growth hormone status There is considerable controversy about the value and method of growth hormone (GH) testing. In those children whose short stature is due to a severe deficiency of GH production, the levels of GH in the blood under any circumstance are low, less than 7 mu/l. To confirm such unequivocal cases with testing is of value and the use of tests may help hold in check indiscriminate prescription of GH. Blood levels above 20 mu/l effectively exclude GH deficiency. Frequently, however, levels fall between 7 and 20 mU/l which many consider represents ‘partial deficiency’. These dividing levels are, however, arbitrary. Response undoubtedly varies from one test to another, from day to day, from hour to hour, and in relation to fasting or feeding, to preceding exercise or level of activity and to physical or emotional stress, and, though most laboratories participate in quality control, there may still be minor differences in interand intra-laboratory estimates. It is often recommended to undertake two tests rather than diagnose partial deficiency on the basis of one alone. Low or borderline response to standard testing can also occur in the presence of various clinical states. This apparent GH deficiency may be misleading, for although it may truly coexist with other pathologies, these may be the primary cause of growth failure. Frequently appropriate treatment of these other states will result in a spontaneous outpouring of GH, whose suppression is therefore potentially reversible. Assessment of GH status in the presence of such conditions should therefore be deferred until these problems have been corrected. Such conditions are hypothyroidism, notably primary, for secondary may well coexist with GH deficiency; coeliac disease; glucocorticoid excess, usually iatrogenic; psychological causes and severe emotional deprivation. Pubertal delay often suppresses GH release, though not to unequivocally low levels. To exclude partial deficiency in prepubertal children from the age of about 10 years upwards, it is recommended that a priming course of sex hormones should be administered over 3 days prior to testing.
Tests of growth hormone release9 Two physiological circumstances are consistently linked with outpouring of GH, severe exercise and sleep, and these can be used as the basis of tests, blood samples being taken at appropriate times in
relation to these states. Exercise if adequate is a useful outpatient screening procedure to exclude GH deficiency, but a poor GH response is not sufficient evidence to diagnose deficiency and further testing would be indicated. Recently, highly sensitive assays for estimating urine GH levels have been developedlO in a few centres and overnight urine collection provides an excellent alternative to blood tests, correlating well with the corresponding plasma mean level. The method is non-invasive and evaluates a physiological state and avoids the inconvenience and discomfort of repeated blood sampling. There are many pharmacological tests for growth hormone release.’ In the UK the most widely used stimuli are insulin hypoglycaemia, glucagon, arginine infusion and clonidine. Though there has been an awareness of the potential risks of the insulin hypoglycaemia test for a long time, these have been highlighted recently following a further fatality. The value of this test must therefore be questioned now, for it has little to recommend it in preference to other tests. Its main advantage over other tests was that it provided a means also of testing the pituitary adrenal axis, but glucagon also achieves this. GH deficiency may arise from dysfunction of either the hypothalamus or the anterior pituitary. The recent availability of growth hormone releasing hormone (GHRH) provides a test which theoretically distinguishes these aetiological sites. If GHRH can be developed as a possible therapeutic agent in the future, this information would be valuable in identifying those patients for whom this treatment could be appropriate.
Treatment of short stature There are several aspects of short stature in itself which might warrant consideration of treatment. Severe short stature imposes practical problems in day to day living. Psychological and emotional difficulties vary greatly in their severity from individual to individual, dependent particularly on the attitudes of the family and society. Short stature children may suffer from teasing and bullying, from an inability to compete successfully in sports and from being treated according to the age they appear to be rather than the age they actually are. They may question why they are different and whether there is something fundamentally wrong. Aims and forms of management The most obvious aim is to end up with an acceptable adult stature, hopefully achieving this by an early improvement in growth rate thus alleviating also the current problems. This is managed best where a pathology can be identified for which there is a specific treatment which will also correct other clinical features associated with the condition. Such primary
SHORT STATURE
causes of poor growth would include inadequate or inappropriate feeding, malabsorption syndromes, inappropriate hormone levels, severe psychosocial deprivation and specific chronic diseases, but response will clearly depend on how possible or complete is the treatment regimen. Such an ideal outcome is not always possible, and if treatments which improve the immediate growth rate do not improve ultimate height, or are even detrimental to it, a better ultimate outcome would probably be achieved by no medical therapeutic action whatsoever. If, however, the more immediate psychological problems are so severe that they cannot be alleviated without hormonal therapy, a carefully evaluated compromise may be acceptable. This is well illustrated by the cumulative problems of pubertal delay in a child already of short stature. The adverse psychological effect can be devastating and to initiate the process of puberty with a 3-month course of gonadotrophin or gonadal steroids may be well justified. Where a specific treatable deficiency is not present, alternative forms of medical treatment are possible. Every effort should be made to achieve an optimal state of nutrition. There is always a place for identifying practical problems and providing an answer to these. Limb lengthening procedures for short limbed forms of bone dysplasias, where the treatment will lessen the disproportion, are beneficial in certain circumstances. However, the implications of such major protracted and restricting procedures will require careful evaluation and considerable social and psychological support. Other non-specific forms of medical treatment are controversial. Except in the circumstances illustrated above, there is little justification for the use of hormones to improve immediate growth rates which would, by excessively accelerating bone maturation, lead to reduction in ultimate stature - perhaps also producing other unacceptable clinical changes. Oxandrolone, a weakly anabolic agent, has been recommended for short term treatment to improve height velocity and this is sometimes effective without adverse long-term consequences. However, the most rewarding approaches are often aimed at improving the morale and self esteem of the individual, his overall attitude and that of his family and friends to his shortness, and helping him to recognise that he is fundamentally normal and his short stature is not a disease as such. This may break a vicious cycle whereby the psychological upset and stress are potentiating the poor growth.
Growth Hormone treatment Who should receive growth hormone?
There is little question about the appropriateness and efficacy of the use of GH in those children who are unequivocally deficient. Careful attention should be given, however, to ensuring correct dosage of the
129
other hormones in those with multiple pituitary hormone deficiencies if the best growth response is to be achieved. In addition to GH deficiency, GH has recently been approved for use in Turner syndrome. Despite the fact that most girls with this condition are not GH deficient, GH treatment (in rather larger dosage than for GH deficiency) does improve their height velocity and probably ultimate stature, though confirmation of this is awaited. GH treatment has been suggested in many other short stature conditions but with conflicting reports of its value, and its use is highly controversial. If used in high enough dosage, height velocity will increase in the majority of children in the early stages of treatment whatever the cause of their short stature. The level of response is seldom maintained, however, and whether ultimate height is benefited remains to be seen. Trials are underway of its use in chronic renal insufficiency and juvenile chronic arthritis, among others, but a continuing high level of disease activity (or high dosage steroid treatment) inhibits a response to treatment. Until more data is forthcoming regarding the long-term outcome of GH treatment, its use in ‘short normals’, those with intra-uterine growth deficiency, non-GH-deficient children and other states should probably be restricted to centres where well monitored trials can be undertaken. Regimen
of growth hormone
treatment
GH nowadays is usually administered by daily subcutaneous injection. Most children can receive their injections at home, either administered by themselves or by their parents after a short period of instruction and supervision. The response to the same total dosage is greater if the injections are given daily rather than less frequently. The standard recommended dose for GH deficiency is of the order of 0.550.7 unit/kg per week or about 12 unit/m2 per week, but higher doses up to 1.0 unit/kg per week are used in Turner syndrome. Treatment should be started early, in GH deficiency as soon as the diagnosis is made. and in Turner syndrome preferably before 5 years as response is greater in the earlier years. The duration of treatment depends on: (a) the response - for it is clearly inappropriate to continue treatment if an acceptable height velocity is not maintained; (b) the acceptability of the stature achieved; (c) the remaining growth potential based on bone age. Side effects during treatment are uncommon if the injection is given correctly and the site moved around to avoid lipoatrophy. There are now preparations produced by four pharmaceutical companies which are equally effective. Multidose preparations, stable in solution, are now available. These are more convenient and take up less space in the refrigerator. Pen devices have recently been developed which, after familiarisation with the technique, are welcomed by
130 CURRENT PAEDIATRICS most families in terms of convenience, ease of injection and allow a smaller injection volume.
2.
Conclusion 3.
There is little doubt about the hardship suffered by individuals with extreme short stature in terms of difficulties of day-to-day living, psychological stress, embarrassment and feelings of imperfection. The early identification of treatable causes and the initiation of appropriate treatment offer the possibility of great benefits. In those for whom no such specific treatment is available, support can still be provided, through direct aids to daily living, and counselling of individuals and those with whom they live and work. For the multitude of less severely short statured children in whom there is no treatable pathology, emphasis usually should rather be directed towards maintaining their morale and their consciousness of worth and ‘normality’ than to developing false confidence through hormone treatment.
References 1. Tanner JM. Use and abuse of growth standards. In: Falkner F and Tanner JM, eds. Human growth: A
4. 5.
6.
7.
8. 9. 10.
comprehensive treatise. Vol. 3, 2nd ed. New York, London: Plenum Press, 1986: 95-109. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity; British children 1965. Arch Dis Childh 1966; 41: 454-471. Eveleth PB, Tanner JM. Worldwide variation in human growth. 2nd edn. Cambridge: Cambridge University Press, 1990. Buckler J. A longitudinal study of adolescent growth. London: Springer-Verlag, 1990. Falkner F, Tanner JM, eds. Human growth. A comprehensive treatise. 2nd ed. Vol. 3. New York, London: Plenum Press, 1986. Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR, Goldsmith H. Assessment of skeletal maturity and prediction of adult height (TW2 Method), 2nd ed. London: Academic Press, 1983. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. Stanford; Stanford University Press, 1959. Buckler JMH. How to make the most of bone ages. Arch Dis Childh 1983; 58: 761-763. Hughes IA. Handbook of endocrine investigations in children. (Revised reprint) London: Wright, 1989. Walker JM, Wood PJ, Williamson S, Betts PR, Evans AJ. Urinary growth hormone excretion as a screening test for growth hormone deficiency. Arch Dis Childh 1990; 65: 89-92.
Mini-symposium
Short stature
J. M. H. Buckler What do centile charts show?’
The child with short stature may have to face many problems in both practical and psychological terms during the growing years and ultimately as a fully grown adult. However the degree of upset which short stature imposes on the child and the family varies greatly, depending on their backgrounds and attitudes. Short stature in itself is not a disease but there may be a tendency to make it into one due to the attitudes of both the medical profession and society.
Centile charts show the spread of measurements within a particular population, which should, in theory, be appropriate for the individual being evaluated. The measurements of populations differ between races and countries, and between regions of a country, so it is not possible to obtain standards for all subgroups of a population. The standards of Tanner,2 despite being developed over 20 years ago from a population in the South of England, remain the best and the most widely used for Britain. However, it is necessary to make minor adjustments according to the origin of the individual3 There has been a secular trend over the years with advancement in the age of pubertal development (now no longer continuing) and an associated increase in height and weight. There is a need for more up-to-date standards, which hopefully will be available within the next few years. Centile charts show measurement spread within a population as it actually is, not necessarily as it ideally should be. With an increasing proportion of overweight members in the British population the weight distribution has become somewhat skewed upwards, and the opposite is seen in undernourished communities. But though these considerations affect interpretation when a child is first measured, they are less crucial subsequently, when serial measurements (if sufficiently accurate) will show whether there is a fall away from the particular centile which increases concern. Velocity centile charts2 make these deviations more obvious. It is important to realise that a fall away in a linear centile position will occur with velocities consistently less than the 25th centile. Growth rates vary in normal individuals between seasons and for other reasons, so to avoid these fluctuations, velocities should be based on increases in measurements over a full year, though it is not always appropriate to wait so long if shorter term changes are considered important.
What is normal growth? Whether growth is normal or not is difficult to define. The further a measurement is away from a particular centile range, the more likely is this to be ‘abnormal’. This is usually what triggers initial concern, but an outlying centile position in itself is seldom considered as the grounds for defining abnormality, even though some clinicians might use that criterion. What will be considered ‘normal’ will depend on the personality, attitudes and aspirations of the individuals, their families and society; on the measurements of other members of the family; on the child’s physique and other variables. The identification of a specific pathology is one means of defining ‘abnormality’, and this is clearly helpful in terms of prognosis and in choosing treatment regimens in those conditions for which there is an appropriate treatment. But the search for a treatment is not restricted to those individuals whose short stature can be labelled with a specific pathological diagnosis.
John M. H. Buckler, DM, FRCP, Senior Lecturer in Paediatrics, Academic Unit of Paediatrics (LGI), Department of Clinical Medicine, D Floor, Clarendon Wing, Leeds General Infirmary, Leeds LS2 9NS. Correspondence and requests for offprints to JMHB Currem Paediarrics 0 1992 Longman
(1992) 2, 125-130 Ltd
GroupUK
125
126
CURRENT
PAEDIATRICS
Most centile charts are based on cross-sectional data which are usually adequate in the prepubertal years, but the variability in the age of puberty makes longitudinal comparative standards essential for correct interpretation at that age.‘v4
Factors which influence growth patterns of individuals’ Most of the variation in size and growth pattern depend on variations which can be considered normal (Table 1). Hereditary factors are the most powerful influences in terms both of stature and physique and of the timing of growth phases. Though these are usually normal variants, pathological conditions affecting growth can, of course, also be inherited. The great variation in the age of puberty will cause a child’s height centile at a specific age to be higher or lower than previously, depending on whether puberty is earlier or later than average. To some extent ‘physiological age’, which becomes self-evident at puberty, has an effect in terms of greater or less growth potential at any chronological age and is indicated by bone age. It is important to recognize that there is an age when no further growth is possible, when puberty is completed and the epiphyses have fused, but the actual age will vary depending on when puberty occurred. Table 1 Factors influencing
?? Physiological
Table 2 Factors whose aberrations produce abnormal growth Adverse antenatal factors Abnormal genes and inheritance of pathologies Inadequate nutrition (a) Food intake - quantitative or qualitative (b) Inadequate digestion and absorption Chronic ill health e.g. asthma Adverse psycho-social factors Inappropriate hormone levels - notably: (a) thyroid (b) growth hormone (c) glucocorticoids (d) sex hormones
-I
or to placental insufficiency in the later stages of pregnancy. In these latter two groups subsequent growth usually shows catch up and a normal outcome. The degree to which growth, and intellectual development, can be influenced by environmental circumstances is controversial, but there is no question that extremes of emotional deprivation have a severely retarding effect on growth. There may however be more subtle ways in which the psyche is linked to growth. The adverse psychological effects of being small may themselves diminish growth whether this is natural or in response to treatment. Occasionally, however, the trauma associated with injection treatment may itself be the cause of unexpectedly poor growth response.
normal growth
Which short stature children need investigating? age -
notably at puberty
Although it is obvious that extremes of undernutrition will slow growth as a whole, there is a tendency for variation in thinness or fatness within an arbitrarily ‘normal’ range to have a minor effect on growth patterns. Obese children tend to go into puberty earlier than normal and grow faster at that age; thin children and those involved in certain kinds of competitive sport such as gymnastics and ballet dancing tend to be delayed in puberty and shorter in stature at that time. In general, however, moderate variations in exercise have little relationship to growth patterns. Table 2 lists the more common abnormal conditions linked with poor growth. Though numerically these only account for a minority of short children, yet these are factors responsible for a high proportion of the severely short statured subjects and include many for which there is an unequivocally appropriate treatment. Intrauterine growth retardation frequently reflects long-term adverse antenatal influences, including genetic ones, and is often a pointer to subsequent ongoing poor growth. Such low birth weight babies are small in all respects and are to be distinguished from those where the low weight is due to prematurity
Some pointers to aid in identification of potential growth problems are shown in Table 3. Many of these have been considered already. Although in many cases of short stature, height and weight centile positions correspond, a marked disparity between the two makes some underlying pathology more likely. Situations where the weight is at a lower centile level than the height suggest undernutrition - whether due to inadequate food intake or failure to absorb the food. (Note, however, Table 3 Clinical aids to identification problems
and evaluation
of short stature
Low height centile positions Fall-off in height centile position with time - prolonged low height velocity centile (except at pubertal age range) Disparate height-weight centile relationships Inappropriate height centile for the family (parents and siblings) Abnormal appearance: e.g. (a) Evidence of specific syndromes (Down, Turner) (b) Body disproportion (e.g. bone dysplasias, hypothyroidism) inappropriately small size at birth Clinical evidence of chronic disease or the effects of its treatment Marked deviation in the age of sexual development
SHORT STATURE
that delayed puberty gives the false impression of underweight as the weight drifts down further from the standard centile than does the height.) If the weight is at a higher centile position than the height, this is a pointer to endocrine causes or other specific conditions of obesity. The association with short stature is an aid in distinguishing those obese children where there is a pathological cause for obesity from the large number of obese children where these is no such underlying pathology, in whom the stature is usually above what would otherwise be expected. Knowledge of the family growth pattern is important as an indication of whether an inherited mechanism for the short stature is likely, of either a normal or pathological nature, as well as identifying a possible link with early or delayed pubertal development within the family (the age of the menarche being a good pointer to this in women). The mid-parental height centile is a guide to where the child’s height centile might be expected, although if one parent is tall and the other short the child might take after either. Many chronic diseases may in themselves be sufficient to explain short stature, although sometimes linked with other factors such as treatment (notably with large dose corticosteroids), undernutrition, potentially reversible hormonal suppression, or psychological disturbance. Conversely, basically good health, general well being, plenty of energy and little time off school are features which contribute to reassurance.
Predictions of ultimate height Although a child’s current short stature is usually the major cause of concern, it might well be accepted if there was a prospect of more reasonable stature as an adult. Predictions of ultimate height are, however, imprecise, particularly for those at the extremes of tallness or shortness, or of advanced or retarded physiological development. It is usually considered that systems incorporating bone age are the best, and in Britain the Tanner Whitehouse System (TW2) is usually the favoured one.‘j This is more appropriate for British (and probably other European) subjects than those based on American standards incorporating the Greulich-Pyle method of bone age assessment.’ Much depends on the assessment of bone age which is very subjective and, though usually corresponding well to physiological development, does not always do so, as for example in some exogenously obese children or in some children markedly delayed in puberty. Sometimes when puberty is under way assessment of its staging may be almost as good an index of growth potential as the apparently more precise methods incorporating bone age.4 In pathological conditions, prediction of the outcome with or without treatment is often very imprecise. Where short stature is associated with marked bone age retardation, such as most endocrine causes
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of poor growth, the theoretical increased growth potential is frequently not achieved even on appropriate treatment. Bone age estimations may be difficult or impossible where the appearance of the bone is markedly abnormal, such as bone dysplasias or diseases. For some conditions centile charts have been produced, e.g. Down and Turner syndromes and achondroplasia; extrapolation of a centile position to the adult height is a useful guideline, although without bone age estimations cannot incorporate a factor for ‘physiological age’.
Investigational aids The need for investigation and its nature depends on the initial and ongoing clinical assessment. The range of possible investigations is vast and it is inappropriate to consider these in depth here. Bone age evaluation by the TW2 method is helpful diagnostically as well as in predicting theoretical growth potential. Bone age is only an adjunct to the other aspects of evaluation, for there is no precise dividing line between the deviations due to physiological and to pathological causes. The most reliable interpretations require good radiological technique and an experienced assessor, preferably the same one if there are serial observations.* Investigation for specific chronic diseases will be indicated from the basic history and assessment. A check on whether the food intake is adequate in quantity and quality is a sensible initial assessment in a short child who is markedly underweight, particularly if anaemic. If the diet is adequate, tests for malabsorption are indicated, particularly in the presence of suggestive symptoms and signs. Conversely, if there is a degree of obesity, hormonal studies are more likely to be forthcoming. Skinfold measurements are simple and helpful, both initially and over the course of time, to indicate what the ‘weight’ and weight changes actually represent. Not all children whose weight is at a higher centile than height are obese, for this also occurs in those whose physique is stocky or with proportionately short limbs; conversely, long-limbed individuals and those delayed in puberty may appear underweight but are not necessarily thin on the basis of skinfold measurements. It is important always to bear in mind the possibility of adverse psychosocial circumstances contributing to or causing poor growth, but it is often difficult to evaluate this adequately and it may require considerable insight and the assistance of experienced supportive staff. Emotional deprivation can closely mimic other disorders and even overlap them in terms of clinical signs and symptoms and results of investigations, e.g. coeliac disease or hormonal insufficiencies. In the absence of a positive outcome to these basic lines of investigation a skeletal survey may be needed to exclude bone dysplasias, particularly in children with body disproportion. In short stature girls chro-
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mosome analysis is important to exclude Turner syndrome, for though the full picture is obvious clinically, a proportion of girls with this condition may only show short stature and, at the appropriate age, delayed or incomplete pubertal development, particularly those in whom the karyotype is not the classical 45X0.
Investigation and interpretation of growth hormone status There is considerable controversy about the value and method of growth hormone (GH) testing. In those children whose short stature is due to a severe deficiency of GH production, the levels of GH in the blood under any circumstance are low, less than 7 mu/l. To confirm such unequivocal cases with testing is of value and the use of tests may help hold in check indiscriminate prescription of GH. Blood levels above 20 mu/l effectively exclude GH deficiency. Frequently, however, levels fall between 7 and 20 mU/l which many consider represents ‘partial deficiency’. These dividing levels are, however, arbitrary. Response undoubtedly varies from one test to another, from day to day, from hour to hour, and in relation to fasting or feeding, to preceding exercise or level of activity and to physical or emotional stress, and, though most laboratories participate in quality control, there may still be minor differences in interand intra-laboratory estimates. It is often recommended to undertake two tests rather than diagnose partial deficiency on the basis of one alone. Low or borderline response to standard testing can also occur in the presence of various clinical states. This apparent GH deficiency may be misleading, for although it may truly coexist with other pathologies, these may be the primary cause of growth failure. Frequently appropriate treatment of these other states will result in a spontaneous outpouring of GH, whose suppression is therefore potentially reversible. Assessment of GH status in the presence of such conditions should therefore be deferred until these problems have been corrected. Such conditions are hypothyroidism, notably primary, for secondary may well coexist with GH deficiency; coeliac disease; glucocorticoid excess, usually iatrogenic; psychological causes and severe emotional deprivation. Pubertal delay often suppresses GH release, though not to unequivocally low levels. To exclude partial deficiency in prepubertal children from the age of about 10 years upwards, it is recommended that a priming course of sex hormones should be administered over 3 days prior to testing.
Tests of growth hormone release9 Two physiological circumstances are consistently linked with outpouring of GH, severe exercise and sleep, and these can be used as the basis of tests, blood samples being taken at appropriate times in
relation to these states. Exercise if adequate is a useful outpatient screening procedure to exclude GH deficiency, but a poor GH response is not sufficient evidence to diagnose deficiency and further testing would be indicated. Recently, highly sensitive assays for estimating urine GH levels have been developedlO in a few centres and overnight urine collection provides an excellent alternative to blood tests, correlating well with the corresponding plasma mean level. The method is non-invasive and evaluates a physiological state and avoids the inconvenience and discomfort of repeated blood sampling. There are many pharmacological tests for growth hormone release.’ In the UK the most widely used stimuli are insulin hypoglycaemia, glucagon, arginine infusion and clonidine. Though there has been an awareness of the potential risks of the insulin hypoglycaemia test for a long time, these have been highlighted recently following a further fatality. The value of this test must therefore be questioned now, for it has little to recommend it in preference to other tests. Its main advantage over other tests was that it provided a means also of testing the pituitary adrenal axis, but glucagon also achieves this. GH deficiency may arise from dysfunction of either the hypothalamus or the anterior pituitary. The recent availability of growth hormone releasing hormone (GHRH) provides a test which theoretically distinguishes these aetiological sites. If GHRH can be developed as a possible therapeutic agent in the future, this information would be valuable in identifying those patients for whom this treatment could be appropriate.
Treatment of short stature There are several aspects of short stature in itself which might warrant consideration of treatment. Severe short stature imposes practical problems in day to day living. Psychological and emotional difficulties vary greatly in their severity from individual to individual, dependent particularly on the attitudes of the family and society. Short stature children may suffer from teasing and bullying, from an inability to compete successfully in sports and from being treated according to the age they appear to be rather than the age they actually are. They may question why they are different and whether there is something fundamentally wrong. Aims and forms of management The most obvious aim is to end up with an acceptable adult stature, hopefully achieving this by an early improvement in growth rate thus alleviating also the current problems. This is managed best where a pathology can be identified for which there is a specific treatment which will also correct other clinical features associated with the condition. Such primary
SHORT STATURE
causes of poor growth would include inadequate or inappropriate feeding, malabsorption syndromes, inappropriate hormone levels, severe psychosocial deprivation and specific chronic diseases, but response will clearly depend on how possible or complete is the treatment regimen. Such an ideal outcome is not always possible, and if treatments which improve the immediate growth rate do not improve ultimate height, or are even detrimental to it, a better ultimate outcome would probably be achieved by no medical therapeutic action whatsoever. If, however, the more immediate psychological problems are so severe that they cannot be alleviated without hormonal therapy, a carefully evaluated compromise may be acceptable. This is well illustrated by the cumulative problems of pubertal delay in a child already of short stature. The adverse psychological effect can be devastating and to initiate the process of puberty with a 3-month course of gonadotrophin or gonadal steroids may be well justified. Where a specific treatable deficiency is not present, alternative forms of medical treatment are possible. Every effort should be made to achieve an optimal state of nutrition. There is always a place for identifying practical problems and providing an answer to these. Limb lengthening procedures for short limbed forms of bone dysplasias, where the treatment will lessen the disproportion, are beneficial in certain circumstances. However, the implications of such major protracted and restricting procedures will require careful evaluation and considerable social and psychological support. Other non-specific forms of medical treatment are controversial. Except in the circumstances illustrated above, there is little justification for the use of hormones to improve immediate growth rates which would, by excessively accelerating bone maturation, lead to reduction in ultimate stature - perhaps also producing other unacceptable clinical changes. Oxandrolone, a weakly anabolic agent, has been recommended for short term treatment to improve height velocity and this is sometimes effective without adverse long-term consequences. However, the most rewarding approaches are often aimed at improving the morale and self esteem of the individual, his overall attitude and that of his family and friends to his shortness, and helping him to recognise that he is fundamentally normal and his short stature is not a disease as such. This may break a vicious cycle whereby the psychological upset and stress are potentiating the poor growth.
Growth Hormone treatment Who should receive growth hormone?
There is little question about the appropriateness and efficacy of the use of GH in those children who are unequivocally deficient. Careful attention should be given, however, to ensuring correct dosage of the
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other hormones in those with multiple pituitary hormone deficiencies if the best growth response is to be achieved. In addition to GH deficiency, GH has recently been approved for use in Turner syndrome. Despite the fact that most girls with this condition are not GH deficient, GH treatment (in rather larger dosage than for GH deficiency) does improve their height velocity and probably ultimate stature, though confirmation of this is awaited. GH treatment has been suggested in many other short stature conditions but with conflicting reports of its value, and its use is highly controversial. If used in high enough dosage, height velocity will increase in the majority of children in the early stages of treatment whatever the cause of their short stature. The level of response is seldom maintained, however, and whether ultimate height is benefited remains to be seen. Trials are underway of its use in chronic renal insufficiency and juvenile chronic arthritis, among others, but a continuing high level of disease activity (or high dosage steroid treatment) inhibits a response to treatment. Until more data is forthcoming regarding the long-term outcome of GH treatment, its use in ‘short normals’, those with intra-uterine growth deficiency, non-GH-deficient children and other states should probably be restricted to centres where well monitored trials can be undertaken. Regimen
of growth hormone
treatment
GH nowadays is usually administered by daily subcutaneous injection. Most children can receive their injections at home, either administered by themselves or by their parents after a short period of instruction and supervision. The response to the same total dosage is greater if the injections are given daily rather than less frequently. The standard recommended dose for GH deficiency is of the order of 0.550.7 unit/kg per week or about 12 unit/m2 per week, but higher doses up to 1.0 unit/kg per week are used in Turner syndrome. Treatment should be started early, in GH deficiency as soon as the diagnosis is made. and in Turner syndrome preferably before 5 years as response is greater in the earlier years. The duration of treatment depends on: (a) the response - for it is clearly inappropriate to continue treatment if an acceptable height velocity is not maintained; (b) the acceptability of the stature achieved; (c) the remaining growth potential based on bone age. Side effects during treatment are uncommon if the injection is given correctly and the site moved around to avoid lipoatrophy. There are now preparations produced by four pharmaceutical companies which are equally effective. Multidose preparations, stable in solution, are now available. These are more convenient and take up less space in the refrigerator. Pen devices have recently been developed which, after familiarisation with the technique, are welcomed by
130 CURRENT PAEDIATRICS most families in terms of convenience, ease of injection and allow a smaller injection volume.
2.
Conclusion 3.
There is little doubt about the hardship suffered by individuals with extreme short stature in terms of difficulties of day-to-day living, psychological stress, embarrassment and feelings of imperfection. The early identification of treatable causes and the initiation of appropriate treatment offer the possibility of great benefits. In those for whom no such specific treatment is available, support can still be provided, through direct aids to daily living, and counselling of individuals and those with whom they live and work. For the multitude of less severely short statured children in whom there is no treatable pathology, emphasis usually should rather be directed towards maintaining their morale and their consciousness of worth and ‘normality’ than to developing false confidence through hormone treatment.
References 1. Tanner JM. Use and abuse of growth standards. In: Falkner F and Tanner JM, eds. Human growth: A
4. 5.
6.
7.
8. 9. 10.
comprehensive treatise. Vol. 3, 2nd ed. New York, London: Plenum Press, 1986: 95-109. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity; British children 1965. Arch Dis Childh 1966; 41: 454-471. Eveleth PB, Tanner JM. Worldwide variation in human growth. 2nd edn. Cambridge: Cambridge University Press, 1990. Buckler J. A longitudinal study of adolescent growth. London: Springer-Verlag, 1990. Falkner F, Tanner JM, eds. Human growth. A comprehensive treatise. 2nd ed. Vol. 3. New York, London: Plenum Press, 1986. Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR, Goldsmith H. Assessment of skeletal maturity and prediction of adult height (TW2 Method), 2nd ed. London: Academic Press, 1983. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. Stanford; Stanford University Press, 1959. Buckler JMH. How to make the most of bone ages. Arch Dis Childh 1983; 58: 761-763. Hughes IA. Handbook of endocrine investigations in children. (Revised reprint) London: Wright, 1989. Walker JM, Wood PJ, Williamson S, Betts PR, Evans AJ. Urinary growth hormone excretion as a screening test for growth hormone deficiency. Arch Dis Childh 1990; 65: 89-92.