Table of Contents

HK J Paediatr (New Series)
Vol 2. No. 2, 1997

HK J Paediatr (New Series) 1997;2:169-174

Personal Practice

Management of Short Stature in Childhood

LCK Low


Keyword : Chronic renal failure; Growth hormone deficiency; Turner Syndrome


Introduction

Physical growth and development is a sensitive index of the well-being of a child because linear growth represents the net expression of genetic, nutritional, environmental and hormone factors, and the effects of previous infections, infestations and diseases. Using the growth reference recommended by the World Health Organization(WHO), one can compare the growth, nutrition and state of health of children around the world. However, if one were to adopt the WHO reference for clinical use in Asia, a large number of children in the developing world would be regarded as growth retarded making the WHO reference impractical for clinical use in most developing countries.1 Hence, for the assessment of growth of children in a particular country, one has to use a growth reference standard constructed and based on measurements of normal children of that particular country.

In most developing countries where there has been recent improvements in health-care and socio-economic situation, a secular trend of increase in adult height over generations has been observed. For instance, the mean final height of Chinese women in China and Hong Kong has been increasing by 1.0cm to 1.3cm per decade.1,2 However, in some Western European countries, this secular trend of increase in adult height has levelled off over the past few decades implying that the potential final heights of 167.5 cm in females and 180.5cm in males have been reached in these countries.1 There is unlikely to be a single "gold" Chinese growth reference as there are geographic and socio-economical reasons to account for the differences in height of Chinese subpopulations in different parts of China, Taiwan, Hong Kong and some Asian countries. Ultimately, these subpopulations will reach similar mean adult height, but until then, local growth references must be updated regularly every ten years to facilitate the assessment of growth in different regions of China. Using an out-dated growth chart will result in a falsely low incidence of short stature in the population. Fortunately in Hong Kong, growth references were available in the 1960's and updated in 1980's3 and recently in 1993.4

Short stature is usually referred to as having a height for age below the third percentile or below two standard deviations from the reference mean. Using this definition, a large number, or 2.5% to 3% of normal children in the extreme end of the distribution, will be identified as being short and likely most of them do not need to be evaluated. Documentation of the growth velocity is equally important in children referred for assessment of short stature because an abnormal growth velocity in a previously normal child will warrant investigation even if the absolute height of the patient is still within the normal range. As growth velocity charts are not available in most Chinese populations, we have arbitrarily suggested that a growth velocity of less than 5 cm/year would be regarded as abnormal in prepubertal children between the ages of 3 to 10 years but a lower growth velocity value could be used during the one to two years before onset of puberty. It must be emphasized that short stature is common but organic growth failure is rare. It is our practice just to monitor the growth of children who are just below 2 SDS in height and have a normal growth rate and in good health. In children with heights between -2 SDS to -3 SDS, only screening tests (blood count, sedimentation rate, urinalysis, renal and liver function, thyroid function and bone age) will be done if the growth velocity is normal. In children shorter than -3 SDS and in children with an abnormal growth velocity, additional tests will be performed to look for growth hormone deficiency, pituitary dysfunction or other underlying systemic diseases where indicated.

In the following paragraphs, I will discuss some of the growth problems commonly encountered in Hong Kong and their management.

Growth Hormone Deficiency

The prevalence of growth hormone deficiency (GHD) has been estimated to be 27 in 100,0005 and organic causes account for 25% of the cases.6 Patients with untreated growth hormone deficiency have extreme short stature with final height SDS of -4 to -6 which can lead to severe handicap in adult life.7-8 Up till very recently, this is the only indication for which GH is provided free of charge by the Government and subsequently the Hospital Authority in Hong Kong. Growth hormone treatment has been shown to significantly improve final adult height. In older studies, the adult height in GH treated males with spontaneous puberty varied between -2.1 to -2.3 SDS while treated female patients reached an adult height SDS inferior to that observed in males.8 In a recent report, recombinant GH treatment in a dose of 0.5 to 0.7IU/Kg/week given daily by the subcutaneous route in GHD children resulted in a mean final adult height of -0.7 SDS.9 Although a positive dose response relationship has been shown during the first year of treatment, a positive influence of growth hormone dosage on final height has not been demonstrated so far. It has been shown that height SDS at the start of therapy, height SDS at the onset of puberty, the mid-parental height SDS and the duration of puberty were significantly correlated with final height. In patients with GHD and early puberty (commonly seen in patients after cranial irradiation), treatment with a gonadotropin releasing hormone analogue in addition to GH has been shown to improve the height prognosis in this group of patients. 10

The effectiveness of GH therapy in children with classical GHD is clear but the criteria for the diagnosis of GHD remain controversial. All the tests including GH levels to provocative tests, 24-hour spontaneous GH secretion, IGF-I and IGFBP-3, do not show strong discriminative power. Although clinicians employ screening or definitive provocative tests for growth hormone secretion, there is little scientific justification of such a distinction. Traditionally, the diagnosis of classical of GHD depends on auxology and evidence of hypothalamic-pituitary dysfunction together with subnormal GH responses (10-15 mIU/L) to two provocative stimuli. In our centre, the commonly used tests include L-dopa/propranolol test, clonidine test and insulin tolerance test. The clonidine stimulation test in our hands has a specificity of 77.9% and a positive predictive value of 34.6%.11 The false positive rate is 22.1% which is much higher than 12.5% obtained for the L-dopa-propranolol stimulation test.12 Using the analogy of testing for adrenal reserve when both cortisol and ACTH are measured, I see no reason why serum IGF-I and IGFBP-3 should not be measured together with GH testing for the diagnosis of GHD.

We have previously reported on our experience of GH therapy in GHD in Hong Kong.13 Of the 66 patients treated between 1978 and 1992, idiopathic GHD accounted for 53% of the cases. Between 1978 and 1985, patients received pituitary derived GH with a mean GH dosage of 0.17 IU/Kg/week due to a scarcity of supply. From late 1986, recombinant GH was introduced and since then patients have been treated with a dose of 0.5 IU/Kg/week divided in daily subcutaneous doses. The mean final height of this early treated cohort was -2.27 SDS with only 43% of the patients having an adult height in the normal range. This report highlighted the importance of early diagnosis and treatment with an appropriate dosage and the possibility of underascertainment of idiopathic GHD in our community. With increased community awareness and early diagnosis and treatment, the height prognosis of GHD patients in Hong Kong will be improved.

Pituitary GH was withdrawn in 1985 because of Creutzfeldt-Jakob disease and eight patients with GHD were treated with growth hormone releasing hormone given 3-hourly by a pulsatile infusion pump in dosages varying from 1 μg/Kg/pulse to 3 μg/Kg/pulse.14 Significant improvement in growth velocity was seen in 6 patients treated for 2 to 5 years.15-16 As no long-acting GHRH analogue is likely to be produced in the foreseeable future, subcutaneous GH therapy remains the practical treatment of choice. The recently described orally active peptidyl and non-peptidyl growth hormone releasing substances may be an alternative form of treatment in the future but these growth hormone releasing substances are ineffective in patients with organic disruption of the hypothalamic pituitary connection.17

Turner Syndrome

Turner Syndrome (TS) is a common cause of short stature in girls occurring in 1:2500 to 1:5000 female livebirths. Not all the patients have the somatic features of webbing of the neck, shield-like chest, cubitus valgus, lymphoedema, cardiac and renal anomalies but short stature is usually present. Up to 20% of the patients may show some degree of pubertal development. In our retrospective review of 203 Chinese patients with Turner Syndrome, the 45, X karyotype was observed in 42% of the patients.18 Contrary to previous findings, patients with 46,X,i (Xq) karyotype were found to be significantly shorter whereas children with the 45,X/46,XY and 46,X,del(Xq) karyotypes were significantly taller among the Chinese TS patients. Patients with TS who are disomic for Xp are significantly taller than patients who are monosomic for Xp, suggesting that karyotype can have a significant effect on the growth of these patients. The mean final height of Chinese TS patient was 142 cm as compared to 147 cm and 139 cm observed in Northern European and Japanese patients respectively. The mean height of Chinese girls with TS is -3.1 SD below the Hong Kong population mean normal, and thus shows a similar degree of growth retardation as compared to the normal population observed in TS girls of other ethnic groups.

The reasons underlying the growth failure of TS are not entirely clear but appear to be the result of an intrinsic skeletal dysplasia and ovarian dysgenesis may contribute to the disordered pubertal growth. Although conflicting results on GH secretion in TS have be reported, it is now generally accepted that prepubertal TS patients do not have abnormal growth hormone secretion and the variability observed may be partly explained by the existence of a different proportion of growth hormone isoforms, with a reduced amount of the 22K form which is the predominant GH isoform in normal girls.19 It is now recommended that provocative GH testing should only be performed on girls with TS whose growth is clearly abnormal relative to that expected for such patients.

With the exception of two studies, most of the trials of GH treatment in TS have not included a randomly selected untreated control group. In the absence of any data from randomized control trials, the issue of efficacy of GH treatment in girls with TS cannot be resolved.20 Most studies reported an improvement in final adult height over the individually predicated height varying from 3 cm to 8 cm.21-22 However, the response of the individual patients to growth hormone therapy is highly variable with no response in some and dramatic gain of nearly 18-20 cm in others. TS is now a licensed indication for GH therapy in Sweden, France, Japan and the United States of America. Gil is also given to TS patients in clinical trials in many different countries. The recommend Gil dosage is 1 IU/Kg/week in daily divided doses and consideration should be given to the addition of oxandrolone in a dosage of 0.0625 ,μg/Kg/day in TS girls over 9 years of age.21,23 There is no role for oestrogen as a growth promoting agent. I hope that free Gil will be available in all Hospital Authority Institutions for the treatment of patients with TS in the not too distant future. The local results based on the limited experience of a small number of TS treated with Gil (paid for by the parents) is encouraging.

Chronic Renal Failure

Since 1996, the Hospital Authority approved the use of GH in the treatment of patients with chronic renal failure and hence the local experience is limited. Growth retardation is one of the important long-term consequences of chronic renal failure in childhood. The cause of this growth failure is multifactorial and include chronic acidosis, renal osteodystrophy, anaemia, energy and protein malnutrition, and secondary growth hormone resistance. The growth hormone binding protein concentration has been found to be low in children with chronic renal failure.24 Probably as a consequence the serum concentration of IGF-1 in uraemic children is low and the increased levels of insulin like growth factor binding protein 3 may reduce the availability of free active IGF-1. 25 Over the past few years, non-controlled studies and two placebo-controlled studies26-27 have shown that growth hormone can significantly increase the growth velocity of uraemic children before and during dialysis without advancing skeletal maturation excessively suggesting an improvement in adult height potential in these children. However, it must be emphasized that no long-term data on final adult height of uraemic patients treated with growth hormone, are available at this point in time. In order to have a full-benefit of growth hormone treatment, children with chronic renal failure must be in good metabolic control and have adequate nutrition intake.

In the United States, the Food and Drug Administration has only approved the use of growth hormone in children with chronic renal insufficiency before transplantation. Although transplantation usually accelerates linear growth, this enhanced growth is not sustained partly because of glucocorticoid and immunosuppressive treatment. Several recent studies have examined the effect of growth hormone treatment in children with functioning renal allografts and who were maintained on low doses of glucocorticoid and other immunosuppressive agents and an increased growth rate with growth hormone therapy has been documented. However a rise in the serum creatinine concentration and a decrease in creatinine clearance have been found in a significant proportion of such children treated with growth hormone.28 Although most studies have reported no difference in the rate of allograft rejection between growth hormone treated and untreated renal graft recipients, careful monitoring should be continued as long as the patients continue to receive growth hormone treatment.

β-Thalassaemia Major

β-thalassaemia major is a common inherited haematological disorder among Southern Chinese. About 350 patients are receiving treatment in our public hospitals. With regular transfusion and iron chelation therapy with desferrioxamine, prolonged survival is now possible. In our recent retrospective survey of 71 patients with transfusion dependent β-thalassaemia, 27% of the boys and 32% of the girls were found to have a height below the 3rd percentile.29 About 60% of both the boys and girls had an upper to lower segment ratio below the 10th percentile for age. The abnormal body proportion has been shown to be due to platyspondyly and is seen in patients with or without growth retardation. Platyspondyly has been observed in patients treated with transfusion but without chelation. Similarly, platyspondyly has also been reported in regularly-transfused patients with low serum ferritin concentration as a result of chelation. Abnormal puberty is present in a significant proportion of children and the lack of a pubertal growth spurt in our patients has been found to be detrimental to adult height attainment. Delay puberty will obviously worsen the body disproportion in adolescents with β-thalassaemia major.

Although growth retardation is common, we could document subnormal GH response to insulin induced hypoglycaemia in 5 of 41(12%) thalassaemic patients with short stature, all but one of whom were above 9 years of age.30 There is likely to be an increase in the incidence of subnormal GH secretion with age. We have found that the serum growth hormone binding protein levels are normal whereas the serum IGF-I and IGFBP-3 concentrations are low in patients with β-thalassaemia major.31 We found no difference in the serum IGF-I levels in our patients (both pubertal and prepubertal) with or without growth failure and this would suggest that the growth failure in thalassaemia may not be specifically related to the GH-IGF-I axis.30-31

In eight short thalassaemic children with impaired GH secretion, GH therapy at a dose of 0.2 IU/kg three times per week resulted in only modest improvement in growth response with only two patients achieving a growth velocity 2 cm/year above the pre-treatment. We have shown that GH therapy at a subcutaneous dose of 0.14 IU/kg/day resulted in dramatic improvement in growth velocity in 13 of 15 short prepubertal non-GH deficient thalassaemic children from a pre-treatment value of 3.6±0.7 cm/yr to 8.0±1.2 cm/yr after one year without a significant advancement in bone age.32 There was also a significant rise in serum IGF-I concentration with GH therapy and this rise was sustained throughout the treatment period. Our patients have finished 5 years of treatment with 3 patients remaining on treatment.33 Although the short term response was good, we are uncertain at present whether GH therapy in non-GH deficient short thalassaemic children will improve their final height. We did not notice any unwanted metabolic or hormonal responses in any of our patients during treatment.34

Intrauterine Growth Retardation (UGR)

It is now accepted that the maternal uterine environment exerts the dominant influence on the size of babies at birth. There are three distinct categories of IUGR infants: those secondary to chromosomal, genetic, syndromal, infective or teratological causes; those who represent the lower extreme of normal; those who have been subjected to chronic nutritional or oxygen deprivation due to placental dysfunction. Apart from complications encountered in the neonatal period, these children have now been shown to have a nearly sevenfold increased risk for hypertension, noninsulin dependent diabetes mellitus, cardiovascular and cerebrovascular disease and short stature in adult life. Many definitions have been used for defining infants with IUGR and it is desirable to have a universally accepted definition like a birth length of -2SD after adjusting for gestation and gender. The rate of catch-up growth in infancy and childhood of IUGR infants depends firstly on the definition used, secondly on the rate of catch-up growth in the first six months of life and thirdly on the incidence of growth faltering between 6 and 18 months of life which is commonly seen in developing communities around the world.35 Using the Swedish growth reference, we have found that 75% of a cohort of IUGR Chinese children born in 1967 were below 2SDS at 2 years. In a study of postnatal growth in Hong Kong IUGR children delivered between 1988 and 1993, 35% of the children were short at 12 months of age.36 We have also followed the growth of IUGR babies recruited in 1995. Our study revealed that catch-up growth was detectable after two weeks of life with 79% of the infants achieving a height within the normal range by 5 months of age, a rate of catch-up similar to the Swedish cohort reported by Karlberg and co-workers.37

Worldwide, between 10% to 30% of IUGR children fail to show catch-up growth and they attain a final height that is far below their genetic potential (161.9±8.0 cm in boys and 147.6±7.2 cm in girls).38 The American National Co-operative Group reported significant short-term growth response to GH but it must be noted that only 124 of 270 patient started on GH remained on treatment. In another report, a dose dependent increase in height SDS was observed after 2 years of GH treatment in 230 short IUGR children of 1.1, 1.7 and 2.5 SDS (for three treatment groups using 0.1, 0.2 and 0.3 IU/kg/day respectively) compared with an increase of 0.14 SDS in the control group.39 Contrasting results on the rate of bone maturation and therefore height prediction during GH treatment of short IUGR children have been reported. However, long-term follow-up studies, with assessment of final height are required before any reliable conclusions can be drawn on the value of GH treatment in children with IUGR.

Other Causes of Short Stature

Constitutional delay of growth and sexual maturation is a common cause of short stature especially in boys. There has been no long-term benefit from the use of growth hormone and the short-term effects have been found to be no better than oxandrolone, at a fraction of the cost.40 In a national survey of physician recommendation on GH use in non GHD children, Cuttler et al. reported that the decision to recommend treatment rested on a combination of medical, social and perceptual factors.41 Only 2.1% of the doctors thought that short stature seldom impaired emotional wellbeing. A strong family wish and reduction in GH cost would increase their likelihood of recommendation of GH treatment. However, recent studies have shown that short stature in childhood and adolescence is not associated with clinically significant psychosocial morbidity. No psychological benefits or negative effects have been demonstrated in short non-GHD children after 3 and 5 years of GH treatment. Short stature is perceived as a stigma by parents and doctors and not by the patients.42

The efficiency of growth hormone in improving the final height of non-growth hormone deficiency short children is far from clear. Although GH can improve the growth velocity of short children without GHD in short term trials, the height gain is transient, casting doubt on the efficacy of short-term GH treatment.43 The number of studies reporting on the final height of such children treated with growth hormone is limited. The consensus of most of these authors is that growth hormone treatment of non-growth hormone deficiency short children will result in an average net gain in final height standard deviation score of about 0.5-0.8 (3-5 cm).44 However, a more encouraging response has also been reported. Until data on a randomized controlled trial is available, growth hormone treatment on short children without growth hormone deficiency will remain controversial.

Conclusions

Short children with growth hormone deficiency should benefit from growth hormone treatment and in this clinical situation, the benefits clearly outweigh the burden and cost of treatment. Growth hormone therapy is likely to be effective in improving the final adult height of girls with Turner syndrome even if the results of the randomized placebo controlled trials are not available. It is also safe and effective in improving growth in children with chronic renal failure before transplantation but long-term results on final height is still awaited. Growth hormone therapy has not been proven to be effective in other conditions associated with short stature. Growth hormone treatment should be prescribed and supervised by a paediatric endocrinologist. Although growth hormone therapy appear very safe, paediatricians should remain vigilant and maintain careful monitoring for short-tern and long-term biochemical, physical and psychological adverse events even after growth hormone treatment has been discontinued. There is a need for properly designed growth promoting studies in Chinese children.

Acknowledgement

The author would like to thank Ms Jessica Cheng for her help in the preparation of the manuscript.


References

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