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1 Received GH alone with late introduction of oestrogen therapy. 2 Received GH plus oxandrolone at a dose of 0.0625 mg/kg/day and late oestrogen therapy. 3 Received standard doses of GH of 0.9 IU/kg/wk; onset at age 11 yr. 4 Received adapted doses of GH up to 2.1 IU/kg/wk; onset at mean age of 10 yr for 4 yr, with late introduction of oestrogen therapy. 5 Approximate as calculated from SD score (Turner specific) provided by authors. 6 Duration of GH therapy was only 2.2 yr. 7 KIGS database: median values. Lyon height prediction [15] indicated a gain of 6.7 cm. GH plus oxandrolone at a dose of 0.05 mg/kg/day in 25% of patients and late oestrogen therapy in all. Guyda found a mean FH achievement of 150cm [18], compared to an untreated mean FH reported elsewhere of 142.9cm [15]. Also, Rosenfeld et al [10] reported a mean FH of 150.4cm, some 8.4cm above the PAH, in a group of 17 girls treated with GH alone and considers 150.0cm as a reasonable target for treatment. Since the publication of Guyda’s review, Johnston et al have reported the results of a randomised controlled trial which found a mean FH of 146.6 cm with 31% of 49 girls achieving this target [27]. In Glasgow, Scotland, Donaldson et al have found that 23 of 34 girls (68%) receiving GH treatment and reaching near-final/final height since 1993 have already exceeded this target of 150cm with a mean near-final/final height of 151.3cm [new data, unpublished], see figure for comparison with Scottish results reported by Chu et al [21]. When compared with this earlier data, the Glasgow group exhibits a significantly greater FH & TS height SDS following growth promoting treatment. As more is learned about the optimal treatment regimens of GH therapy with consistent prescribing over a prolonged period, height outcomes improve. While there is no doubt that the growth of groups of girls with TS is improved by GH therapy, there is considerable individual variation in response to treatment, with Guyda reporting lowest adult heights ranging from 131.5-145cm in five of the studies reviewed [18]. Factors affecting response to treatment While the optimal treatment regime is, as yet, unknown, the following factors have been identified as potential predictors of response – the first, age at start at treatment, is emerging from the literature as the primary predictive factor:
The relative influence of the following factors on FH remains unclear and both are currently under investigation as part of the UK Turner Study.
Figure — Near-final/Final heights attained by girls with TS treated at the Royal Hospital for Sick Children in Glasgow, 1994-2001 (dark bars) compared with previous data from Scotland 1988-1994 (pale bars)[21] Figure
Current UK practice Opinion as to best practice is constantly evolving and this is illustrated by the changing pattern of GH use in the UK over the past decade or so, reflecting the messages learned from previous research. The mean age of starting treatment has fallen significantly from 10.4 to 8.5 years. The starting dose has risen significantly from 26 to 45 mcg/kg/day and the frequency of injections has increased from 3 to 6-7 per week [19]. The regimen currently considered "best practice" is a dose of 50mcg/kg/day (1.4mg/m2/day) in daily injections, beginning when height falls below -2 SD or when the family identifies short stature as a problem and preferably by 8 years of age. Conclusions and recommendations There is a clear case for GH therapy in the treatment of TS. Groups of girls do well, with an increase in growth and improvement in final adult height. Some individuals, however, respond less well to treatment than others and the possible reasons for this also require further investigation. Questions remain over the best age at which to begin treatment and while this is largely dependent on the age at diagnosis, it would appear that starting earlier and, therefore, allowing a longer period of treatment is most advantageous. In order to have, as has been recommended, a substantial number of oestrogen-free years of GH treatment, it is recommended that GH should start no later that 8 years of age, unless the individual is particularly tall. Girls in whom the diagnosis is made later, i.e. in the mid teenage years, usually respond to GH poorly, and although each patient should be considered on her individual merits, GH should not be continued in the absence of a demonstrable response (2 cm/year or 50% increase in height velocity over 6-12 months). The optimal dose of GH has yet to be quantified but more rather than less GH seems to result in the most favourable results. Clinicians are cautioned, however, against adopting the high doses used by the French and Dutch groups until further controlled investigation is carried out and the safety issues examined. In addition, the financial implications of adopting such large doses as standard practice cannot be ignored. Intermittent therapy and incremental dose increases, as a means of counteracting the waning effect seen in response to GH over consecutive years of treatment, also require further investigation. Growth and height of the TS population is obviously improved by GH therapy but many unanswered questions remain. In the meantime, current UK best practice guidelines should be followed and any changes to treatment strategy should be made within the context of large scale, controlled, prospective studies.
3. Treatment of non-GHD children outwith licensed indications Introduction With the current availability of biosynthetic GH, increasing numbers of patients with short stature (non-GHD and Turner syndrome) have been treated with GH in order to try and improve both short-term growth and final adult height. The recent BSPED audit estimated that 22% of the approximately 2400 known patients aged 0-16 years currently receiving GH in the United Kingdom are being treated outwith licensed indications (a). Doses of GH used in non-GHD children are usually higher than GHD patients, although within the recommended range, in order to achieve a faster height velocity. Small for gestational age (SGA) children have received even higher doses of GH (1). However, side-effects of treatment with GH, which include an increased incidence of diabetes (2) must be weighed against any potential benefits of therapy. Although we can attempt to review the current status of information regarding the use of GH in unlicensed indications, unfortunately unambiguously clear evidence of benefit is lacking. Many of the studies to date involve small numbers of patients, treated in an uncontrolled manner for short periods of time, and numbers of patients followed to final height are small. In addition, few studies have included a control group, and fewer still a placebo arm. Investigation of other potential benefits of GH therapy to the patient; physical, social and psychological are rarely included. Idiopathic Short Stature (ISS) This group is a heterogeneous one, made up of patients with familial short stature (FSS) and constitutional delay of growth and puberty (CDGP). The demonstration of a spectrum of GH secretion (3), with arbitrary cut-offs of GH deficiency would appear to indicate that almost all short children will respond to GH therapy, but require larger doses to produce lesser growth responses than that seen in GH deficiency (4). There have been a number of studies, which indicate that short but otherwise normal children will improve short-term height velocity in a dose dependent manner with GH therapy. Although the role of GH therapy in these patients is to improve both short-term height velocity, and adult height, there is currently little data to indicate that these patients are disadvantaged as a result of their short stature (5), or gain any psychological benefit from treatment (6). One study with a degree of randomisation showed an overall improvement in growth rate, although, as expected, less than that seen in GH deficiency (7). This study also indicated a potential improvement in final adult height, based on bone age. Long-term final adult height data has been summarised in 413 patients from 11 studies with ISS (8). Most patients were male, and the mean duration of GH therapy exceeded five years. The overall mean final height gain over predicted adult height was only +0.4 SDS or 2.7cm, although another, more recent study has indicated improved results (5.9cm in girls and 5.0cm for boys) (9), possibly due to earlier institution of GH therapy. Caution must be exercised in consideration of average increases in stature when recommendations are being made, as there are clearly marked inter-individual variations in treatment efficacy. Within each clinical trial there have been ISS patients who respond well and those who grow slowly with identical GH treatment regimens. This variability in response is not yet understood, and may in part be due to the fact that the diagnostic label ISS constitutes many subcategories which cannot be separated out with current techniques. Therefore, although GH cannot be routinely recommended for ISS patients, allowance needs to be made to consider GH treatment for certain subgroups when diagnostic methods improve.
Children born Small for Gestational Age (SGA) In approximately 15% to 20% of short children, post-natal growth failure appears to be related to reduction in pre-natal growth velocity (intra-uterine growth retardation, IUGR), resulting in children who are small for gestational age (SGA). The precise definition has, however, varied between different investigators, making comparison difficult, and these are also a heterogeneous group, often including specific dysmorphic syndromes such as Silver-Russell syndrome (SRS). A number of studies have reported that GH increases height velocity in short children with SGA, and pooled data from five separate European trials has shown that GH can normalise height in short prepubertal children with SGA when given at doses of 33, 67, 100 mcg/kg/day (1, 2 or 3mg/m2/day) over 2 years (10). An analysis of the combined data from three randomised GH trials in short pre-pubertal children with SGA has demonstrated a GH dose-dependent response during the first 2 years of therapy (11). In addition, it appears evident that younger children receiving higher doses appear to benefit most over the short term (1). High-dose (2mg/m2/day) discontinuous GH therapy (two years-on, two years-off) has been shown to be equivalent to four years continuous low-dose GH (1mg/m2/day) in terms of overall height increment. There is, however, a paucity of final height data on substantial numbers of patients from these randomised trials. Ranke et al. (12) assessed 720 SGA patients treated with GH in the KIGS database, of whom 50% were considered to be GH-insufficient using their criteria. Of this cohort, sixteen patients who have received GH at a median dose of 36mcg/kg/day have gained 1.0 SD score in final height. Lower doses (18mcg/kg/day) had a limited effect on final height in patients with SGA and GH-insufficiency compared to an untreated group (13). Noonan syndrome Phenotypic similarities between Noonan and Turner syndrome have lead to the assumption that treatment with GH might have the same effect on short-term growth and final height. Prospective trials have only treated for short periods (14), and consequently much of the longer-term data is based on only small numbers, or from retrospective analyses using national and international databases. These show short-term improvements in height velocity during initial GH therapy, which slows with continuing treatment, but few patients have been followed to final height (15). Recent analysis of United Kingdom patients treated with GH entered in the KIGS database (N = 66) has shown them to be short both compared to normal and Noonan children (16). During the first year of GH therapy (mean dose 33mcg/kg/day) height velocity increased from a pre-treatment mean (SD) of 4.8 (1.1) to 7.2 (1.7) cm/year. As with other studies, there was a waning of the effect of GH over ensuing years, and if assessed by a change in Noonan reference standards, final height (N=10) was increased by a mean of 3.1 cm, with only 2 patients increasing their predicted final height by 5 cm or more. Skeletal dysplasias Although individuals with skeletal dysplasias show a GH-resistant pattern, therapy with GH (either on its own or in combination with surgical limb lengthening) has been attempted to try and improve their height. There are a number of published trials in achondroplasia and hypochondroplasia, although patient numbers are small, with no control groups. A review of these studies (17) indicated that in both of these conditions GH therapy for 1 or 2 years appears to increase height velocity over pre-treatment values, with no evidence (at least in achondroplasia) that disproportion is worsened. Adult height data (both from trials and databases) are currently unavailable. Conclusions In all these patient groups, GH therapy has resulted in a short-term improvement in height velocity, although as expected, not as great as that seen in patients with GH deficiency. There is usually a waning of effect with continued use of GH, but despite this many studies have indicated that predicted adult height may be increased. Actual adult height data are either very limited or restricted by trial design (for example, results shown in comparison with historical data). Although the role of GH therapy in these patients is to improve both short-term height velocity, and adult height, there is currently little data to indicate that these patients are disadvantaged as a result of their short stature, or gain any psychological benefit from treatment. As a result, the Lawson Wilkins Pediatric Endocrine Society of North America has considered that it is inappropriate to treat these children with GH outside of controlled clinical (18). However in clinical practice, there still remains a small number of children with either dysmorphic syndromes (diagnosed or undiagnosed), and/or those with extreme short stature and extremely poor growth, where GH could be considered outwith licensed indications. In these children the following guidelines might be appropriate:
4. Management of short stature in chronic renal failure and post-transplant Introduction The prevalence of chronic renal failure (CRF) in childhood has been estimated to be 55 per million child population. The predominant cause is renal dysplasia with obstruction or reflux. At any time in the UK there are approximately 750 children in end-stage renal failure (ESRF), of whom half are transplanted. Of the remainder, one third are haemodialysed and two thirds are on peritoneal dialysis (1). Epidemiology of growth retardation Growth retardation has been reported to occur in up to 50% of children with CRF. The age of onset of CRF is the most important factor that influences growth: children with congenital nephropathies are particularly severely affected as growth in the first two years of life is principally dependent on nutrition, which is very difficult to maintain because the infant with CRF is anorexic and frequently vomits (2). After this age, when the role of growth hormone (GH) becomes more important, the rate of growth can be normal, although catch-up is rare (3). Growth may also be adversely affected at the time of puberty, which may be delayed, with an abnormal pubertal growth spurt (4). Growth retardation increases with the severity of CRF: children who have needed dialysis have a worse height prognosis than those on conservative management, and those on prolonged dialysis fare the worst of all (5), although improvement of dialysis adequacy, assessed by measurement of weekly creatinine clearance, has a beneficial effect on growth (6). Successful renal transplantation can normalise growth in some children, but corticosteroid therapy may adversely affect growth even in children with well functioning transplants, particularly at the time of puberty (7,8). Pathophysiology of growth failure in CRF and post transplant The pathogenesis of growth failure is multifactorial, but the most important cause is inadequate intake of calories and protein leading to malnutrition. Water, electrolyte and acid-base imbalances are other causes, as many children with congenital developmental renal anomalies have severe tubular losses of sodium, water and bicarbonate. The part played by renal osteodystrophy in poor growth is controversial (2). Another possible cause for poor growth in CRF is endocrine disturbance. There is resistance to growth GH, as circulating GH levels are normal or high, and bioavailability of insulin-like growth factor 1 (IGF-1) is low. The causes of these findings may be abnormalities of the GH and IGF-1 receptors, or increased binding of IGF-1 by IGF binding proteins, which are increased in CRF due to decreased renal clearance. After transplantation poor growth may be due to the use of steroid therapy as immunosuppression, as steroids depress GH secretion and interfere with the action of IGF-1 both peripherally and by inhibition of circulating IGF-1 (7,8). Current data on Ht SDS in CRF and post transplant Over the last 10 years most published data suggests that there has been very little change in the prognosis for height in children with CRF, on dialysis and post transplant. In 1996, 50% of children with CRF under the age of 5 years in the North American Paediatric Renal Transplant Co-operative Study (NAPRTCS) had a height standard deviation score (Ht SDS) below the normal range (9) - a figure very similar to 10 years previously (10). Mean Ht SDS at the initiation of dialysis was -2.0 in Holland (5) and -1.9 in the NAPRTCS database (11), with a continuing decline in Ht SDS while on dialysis (5). Similarly for children with renal transplants, the NAPRTCS database gave a mean Ht SDS of -2.1 (12) and the Dutch -2.6, with no change to final height (5). However, not all centres have such gloomy results: the Finnish group report a mean Ht SDS of -1.3 (1.2) in 21 children at the start of dialysis and -0.8 (1.0) after 9 months of peritoneal dialysis. Only 1 child was given GH. Growth was related to dialysis adequacy as estimated by weekly creatinine clearance (6). At Great Ormond Street Hospital, the mean Ht SDS at 3 years of age of 81 children presenting with a GFR of <20ml/min/1.73m2 before the age of 2 years was -1.4 (0.7) in those who were managed conservatively, -1.4 (1.5) in those who were dialysed and -0.8 (0.9) in those who received a transplant. Only 5 of these children received GH and none for longer than 2 years. The mean Ht SDS continued to improve over the 13 years of the study. It is not clear why these results are better, but may be related to aggressive nutritional management (2,6). Improvement in height in transplant patients is well described in young children (12,13), but is said to be rare during the pubertal years (12). However catch-up growth can be seen in puberty if an alternate day prednisolone regimen post transplant is introduced early: the mean Ht SDS in 59 pubertal patients at transplant was -1.8 (0.2) and increased to -1.0 (0.2) at 3 years with such a regimen, without the use of GH (14). Treatment of growth failure in CRF The most important aspect of the management of growth in CRF is provision of an adequate intake of protein and calories. This may necessitate the use of enteral feeding, which should be considered as soon as there is evidence of growth delay. Supplementation with salt, water and bicarbonate is usually necessary in children with structural renal anomalies. Prevention of renal osteodystrophy by the use of phosphate binders and activated vitamin D may help growth but this is not proven (2). Ensuring adequate dialysis is another important factor (6). Post transplant the prescription of alternate day prednisolone as immunosuppression has been shown to allow better catch-up growth than the same dose given daily without compromising transplant function (15). Ten years ago the first trials of the use of recombinant human GH in children with conservatively managed CRF, on dialysis and post transplant were published (16,17), and since then there have been many studies showing its benefit in the short-term, at least up to 5 years of therapy (18-21), although the effect on final height remains unknown (22-25). Rationale for the use of GH Work in the 1980s demonstrated a positive response to GH in uraemic rats (26). This led to trials of the use of GH in growth retarded children with CRF. The rationale for its use is that there is resistance to GH in CRF, as circulating GH levels are normal or high and bioavailability of IGF-1 is low. Post transplant, steroid therapy may interfere with GH secretion and IGF-1 action (7,8). Who is offered GH? Currently, most centres would offer GH to children whose Ht SDS is more than 2SD below the mean, with a height velocity SDS of less than the 25th centile after all other causes of poor growth have been treated. Dose of GH Most reports have used a dose of GH of 1.4mg/m2/day (50mcg/kg/day). A trial comparing 0.67 and 1.33mg/m2/day suggested an improvement in height velocity over 1 year with the bigger dose (27). One trial compared 2.66 to 1.33/m2/day in adolescents, but found no added benefit with the larger dose (28). Frequency of reported use of GH The use of GH in Europe is increasing. In 1990 only one third of Paediatric Nephrology centres were using GH. By 1991 the proportion had increased to almost two thirds (29). However, only 15% of the centres reporting to NAPRTCS were using GH in children whose height was below the 3rd centile (15). Reasons for not prescribing GH were not given, but may be related to cost as well as to unanswered questions that remain regarding its use.
Results of GH therapy Since the first studies in the late 1980s there have been many reports demonstrating the effectiveness of GH in the short term in children with CRF, on dialysis and post transplant (16-24). However, unanswered questions are as follows: Is GH more effective than intensive feeding in the first 2 years of life? A 2 year placebo controlled trial of GH treatment in 24 children under 2 years of age with a mean GFR of 26 ml/min/1.73m2 demonstrated significantly better growth in the GH treated group (30). However, equally good growth has been shown with an intensive enteral feeding regimen in infants with more severe CRF (2). Is GH effective during puberty? The Dutch group treated 18 adolescent transplant recipients with GH. The height increase was 15.1 (5.1) cm over 2 years in comparison to 5.8 (3.4) cm in retrospective controls (28). However the patients were treated with daily steroids whereas catch-up growth is better in adolescents who are taking alternate day steroids (14). It is also clear that the growth spurt continues for longer than normal in some patients with renal transplants taking prednisolone as immunosuppression (23). Does GH continue to be effective over years of treatment? There are now published studies to show improvement in Ht SDS with GH treatment for 5 years: in CRF (20 patients, -2.6 to -0.7) (19); in children on dialysis (8 patients, -4.2 to -2.9) (21) and post transplant (6 patients, -3.6 to -1.9) (22). After the first year of treatment, growth velocity begins to decline, although it remains above pre-treatment levels. This has led to the conclusion that the effect is significant as it might be expected that the Ht SDS if the children had not been treated would have continued to decline. However, none of these are controlled studies and not all papers show an inevitable decline in Ht SDS in children with CRF and post transplant. When should GH be stopped? There is little point in continuing GH if the response is poor. However, when to stop GH in the child who has demonstrated a response is less clear. A pause in GH therapy after attainment of target height (defined as the 50th percentile for mid-parental height) led to maintenance of Ht SDS in 27% and reduction in height velocity in the other 73% that necessitated reinstitution of GH (31). However in another study, there was no difference between the change in Ht SDS before and after GH (23). Most centres stop GH at the time of transplantation, and this does not adversely effect the rate of growth post transplant (33) What is the effect on final height? As yet there are little data available on final height, and what there are either uncontrolled studies or use retrospective controls. Of the 13 patients in the Great Ormond Street study who reached final height, as much of the improvement in Ht SDS was after stopping GH as when on GH (23). The Belgian group looked at final height attainment of 17 patients who had been treated with GH for a median of 2.9 years in the boys and 3.4 years in the girls. They found that there was a significant improvement in Ht SDS, from -3.0 on starting to -2.1 on stopping GH and to -1.9 at final height. When they compared them to a historical control group, who showed no change from -3.3 at transplant to -3.2 at final height, the boys, but not the girls, grew significantly better (22). The Australian and New Zealand Paediatric Nephrology Association reported 39 patients who reached adult height. The mean Ht SDS before commencement of GH was -2.7, and at final height was -2.3 (mean final height 161.8cm for males and 149.5cm for females) (presented at the Asian society for Paediatric Nephrology, 2000). The German group compared the final height of 38 children treated with GH for a median of 5.3 (range 2.8-8.8) years to 50 untreated retrospective controls who had less severe growth retardation. The treated children had sustained catch-up growth (mean Ht SDS from -3.1(1.2) to -1.6(1.2)) whereas the control children had progressive growth failure (final ht SDS -2.1(1.2)). The mean final height was 165.2 (8.2)cm in the boys and 152.2 (9.8) cm in the girls in the treated group, compared to 162.1 (9.0) cm and 151.9 (6.7) cm respectively in the controls (24). Factors affecting response to GH GH has the most beneficial effect in the youngest, most growth retarded patients. Children with less severe CRF do better than those on dialysis. Post transplant, those with the best renal function, on low doses of steroids have the greatest response to GH (34). Failure to respond to GH Causes of failure to respond to GH are continuing poor nutrition and metabolic control, inadequate dialysis and poor renal function and high steroid dose post transplant (34). Poor compliance is another possible cause (35). Side effects There are few reported side effects of GH in CRF, although avascular necrosis of the femoral head and slipped femoral epiphysis have been reported, particularly if there renal osteodystrophy. Intracranial hypertension has been reported post transplant. Concerns about an increase in the rate of decline in renal function have proven unfounded (36,37). Children with CRF are insulin resistant and this is worsened by the use of prednisolone post transplant. However, carbohydrate intolerance has not been a problem. There is a slight increase in the risk of transplant rejection in patients who have had previous rejection episodes, but no increase in graft loss (38). Several cases of renal cell carcinoma have been identified in post-transplant patients who have received GH. The causality is not known but is unlikely. Cochrane review The Cochrane renal group will publish their latest review of the benefits and side effects of GH during 2001. The group identified 10 randomised controlled trials involving 481 children. Although there was a significant increase in height SDS and growth velocity at 1 year, resulting in an increase in height of on average 4 cm, there was no demonstrable benefit from longer courses of treatment. Results were better at a dose of 1.33 than 0.67mg/m2/day. The frequency of side effects did not differ from the control group (38). Recommendations GH can be offered to children of all ages who have a height SDS more than 2SD below the mean and a height velocity SDS less than the 25th centile, but only after adequate nutrition has been established, metabolic abnormalities have been corrected, dialysis adequacy ensured and prednisolone therapy reduced to a minimum. The recommended dose is 1.4mg/m2/day (50mcg/kg/day). Parental heights should be measured. Preliminary investigations should include fasting plasma glucose and insulin levels, thyroid function and bone age. Glucose and insulin levels should be repeated 6 monthly along with a full auxological assessment. GH should be stopped if there is no improvement in growth, if there are side effects, or if the child receives a renal transplant. It should not be restarted before 1 year in order to ascertain if post transplant catch-up growth will occur. Consideration may be given to stopping GH when the growth velocity has fallen to the pre GH value or when the target height is achieved. Any potential side effects must be reported via the CSM yellow card system and to KIGS. 5. Efficacy of GH treatment in children with Prader-Willi syndrome Introduction Experience with GH treatment by UK paediatric endocrinologists in children with this condition is limited, a product licence only having been recently granted based largely on evidence from European controlled trials. Prader-Willi syndrome (PWS) is caused by a deletion of part of the long arm of the paternally derived chromosome 15, or inheritance of a double copy of maternal 15 (uniparental disomy). The clinical effects include short stature, muscular hypotonia, mild to moderate mental retardation, escalating obesity caused by uncontrolled hyperphagia, and hypogonadism. The treatment goals for this condition are somewhat different from all the above groups in that growth is not the only target for improvement. Obesity Children with PWS become overweight by age 4 (1) and obesity escalates on account of the disordered satiety. Rigorous dietary control has a major part to play in the management of this problem. Percentage body fat ranges between 40-50% compared with 11-25% in age and sex matched normal children and young adults (2,3). Lean body mass is reduced (63-83%) compared with controls (81-93%) (4). PWS patients expend 50% less energy than controls (5). Massive obesity is associated with a poor prognosis on account of type 2 diabetes, hyperlipidaemia, atherosclerosis and cardiopulmonary disease due to respiratory embarassment (6). Growth Failure to thrive occurs in infancy on account of poor feeding resulting from the hypotonia, thereafter growth follows a slow but steady pattern although the pubertal growth spurt is absent (7). The mean adult height for men is 155-162cm and women 148-150cm (6,7). GH secretory status Reduced spontaneous GH secretion with subnormal GH response to stimulation and low IGF-1 levels to a level fulfilling the criteria for GHD have been found in 40-100% patients studied (depending on the pharmacological agent used), irrespective of whether obesity is present (9-12). This is ascribed to a reduction in hypothalamic GHRH neurones. Effect of GH on height Published studies indicate a short-term increase in height velocity and height SDS over 36 months As yet none has continued to final adult height. Three placebo controlled studies have been reported. Response to treatment is midway between classical GHD and ISS children with reports of increases in height SDS of 0.5 and 1.2 in the first year (10,12,13). Metabolic effects of GH GH treatment has been shown to reduce fat mass and increase muscle mass in the presence of a controlled diet (10,12,14,15). Improved motor performance has also been documented along with more subjective benefits such as greater physical energy, psychomotor functioning and endurance (12,15,16). Claims have also been made about improved respiratory function with GH treatment (12). These observations require further careful evaluation. Side effects Observations of side effects in PWS children are generally similar to those of classical GHD patients, however, although no overt cases of diabetes mellitus have been reported, glucose levels remain unchanged or only increased within reference ranges along with some elevation in insulin levels (12,17). Carbohydrate metabolism needs to be carefully monitored in these patients. Scoliosis has been reported, but worsening is not specifically associated with GH treatment (10,12). Conclusions Limited clinical experience with this group of patients necessitates ongoing and careful surveillance when GH treatment is initiated. Outcome measures require careful documentation and it is recommended that all patients on GH treatment are registered through a national database and KIGS. REFERENCES a. Hilken J. UK audit of childhood growth hormone prescription, 1998. Archives of Disease in Childhood 2001;84:387-389. Growth hormone deficiency 1. Juul A, Bernasconi S, Chatelain P, et al. Diagnosis of growth hormone (GH) deficiency and the use of GH in children with growth disorders. Hormone Research 1999;51:284-299. 2. Tillman V, Buckler JMH, Kibirige MS et al. Biochemical tests in the diagnosis of childhood growth hormone deficiency.. J Clin Endocrinol Metab 1997;82:531-535. 3. Saggese G, Ranke MB, Saenger P, et al. Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Hormone Research 1998;50:320-340. 4. Hindmarsh PC, Smith PJ, Brook CGD, Matthews DR. The relationship between growth velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol 1987;27:581-591. 5. Cutfield W, Lindberg A, Albertsson Wikland K et al. Final height in idiopathic growth hormone deficiency: the KIGS experience. Acta Paediatrica 1999; 88 Supplement 428:72-75. 6. Busschbach JJ, Rikken B, Grobbee DE, De Charro FT, Wit JM. Quality of life in short adults. Hormone Research 1998;49:32-38. 7. DeVile CJ, Grant DB, Hayward RD, Stanhope R. Growth and endocrine sequelae of craniopharyngioma. Arch Dis Child 1996;75:108-114. 8. de Muinck Keizer-Schrama SM, Rikken B, Wynne HJ, et al. Dose-response study of biosynthetic human growth hormone (GH) in GH-deficient children: effects on auxological and biochemical parameters. Dutch Growth Hormone Working Group. Journal of Clinical Endocrinology & Metabolism 1992;74:898-905. 9. Albertsson Wikland K, Alm F, Aronsson S, et al. Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results from an ongoing randomized trial with different dose regimens. Acta Paediatrica 1999;Supplement. 88:80-84. 10. Ranke MB. New paradigms for growth hormone treatment in the 21st century: prediction models. J Ped Endocr Metab 200;13:1365-1369. 11. Tillman V, Patel L, Gill MS et al. Monitoring of serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth. Clinical Endocrinology 2000;53:329-336. 12. Cutfield W, Lindberg A, Chatelain P, et al. Final height following growth hormone treatment of idiopathic growth hormone deficiency in KIGS. . In Growth hormone therapy and KIGS: 10 year’s experience. Ed MB Ranke, P Wilton. Barth, Heidelberg and Leipzig 1999;93-109. 13. Tanaka T. Puberty and growth in children with growth hormone deficiency. In Growth hormone therapy and KIGS: 10 year’s experience. Ed MB Ranke, P Wilton. Barth, Heidelberg and Leipzig 1999;81-91. 14. Mericq MV, Eggers M, Avila A, Cutler GB, Jr., Cassorla F. Near final height in pubertal growth hormone (GH)-deficient patients treated with GH alone or in combination with luteinizing hormone-releasing hormone analog: results of a prospective, randomized trial. Journal of Clinical Endocrinology & Metabolism 2000;85:569-573. 15. Wilton P. Adverse events during GH treatment: 10 year’s experience in KIGS’ a pharmacoepidemiological survey. . In Growth hormone therapy and KIGS: 10 year’s experience. Ed MB Ranke, P Wilton. Barth, Heidelberg and Leipzig 1999;349-364. 16. Consensus guidelines for the diagnosis and treatment of GH deficiency in childhood and adolescence: Summary statement of the GH Research Society on child and adolescent GH deficiency. J Clin Endocrinol Metab 2000;85:3990-3993. 17.Ranke MB, Monson JP. Continuing the treatment of growth hormone deficiency during the transition from childhood into adulthood. In Growth hormone therapy and KIGS: 10 year’s experience. Ed MB Ranke, P Wilton. Barth, Heidelberg and Leipzig 1999;111-124. Turner Syndrome 1.Nielsen J, Wohlert M. Chromosome abnormalities found among 34910 newborn children: results from a 13 year incidence study in Arhus, Denmark. Hum Genet 1991; 87(1): 81-3 2.Rochiccioli P, David M, Malpuech G, Colle M, Limal JM, Battin J et al. Study of final height in Turner’s syndrome: ethnic and genetic influences. Acta Paediatr 1994; 83: 305-8 3.Ranke MB, Stubbe P, Majewski F, Bierich JR. Spontaneous growth in Turner’s Syndrome. Acta Paediatr Scand [Suppl] 1988; 343: 22-30 4.Davenport ML, Punyasavatsut N, Gunther D, Savendahl L & Stewart, PW. Turner syndrome: a pattern of early growth failure. Acta Paediatr Suppl 1999; 433: 118-21 5.Rosenfeld RG and the Genentech National Cooperative Study Group. Growth hormone therapy in Turner’s syndrome: an update on final height. Acta Paediatr Suppl 1992;383:3-6 6.Plotnick L, Attie KM, Blethen SL, Sy JP. Growth Hormone Treatment of Girls With Turner Syndrome: The National Cooperative Growth Study Experience. Pediatrics 1998; 102(2): 479-81 7.Takano K, Shizume K, Hibi I, Ogawa M, Okado Y, Suwa S, Tanaka T, Hizuka N and the Committee for the Treatment of Turner Syndrome. Long-Term effects of growth hormone treatment on height in Turner syndrome: results of a 6-year multicentre study in Japan. Horm Res 1995; 43:141-143 8.Sas TCJ, de Muinck Keizer-Schrama SMPF, Stijnen T, Jansen M, Otten BJ et al. Normalization of Height in Girls with Turner Syndrome after Long-Term Growth Hormone Treatment: Results of a Randomized Dose-Response Trial. J Clin Endocr Metab 1999; 84(12): 4607-12 9.Nilsson KO, Albertsson-Wikland K, Alm J, Aronson S et al. Improved final height in girls with Turner’s syndrome Treated with Growth Hormone and Oxandrolone. J Clin Endocr Metab 1996; 81(2): 635-40 10.Rosenfeld RG, Attie KM, Frane J, Brasel JA, Burstein S, Cara JF et al. Growth hormone therapy of Turner’s syndrome: Beneficial effect on adult height. J Pediatr 1998; 132(2): 319-24 11.Rochiccioli P & Chaussain JL. Final height in patients with Turner Syndrome treated with growth hormone (n=117). In: Albertsson-Wikland K & Ranke M (Eds.) Turner syndrome in a life-span perspective. Amsterdam: Elsevier Science BV 1995: 123-8 12.Heinrichs C, De Schepper J, Thomas M, Massa G, Craen M, Malvaux P et al. Final height in 46 girls with Turner syndrome treated with growth hormone in Belgium: evaluation of height recovery and predictive factors. In: Albertsson-Wikland K & Ranke MB (Eds.) Turner syndrome in a life-span perspective. Amsterdam: Elsevier Science BV 1995: 137-47 13.Carel J-C, Mathivon L, Gendrel C, Ducret J-P, Chaussain J-L. Near Normalization of Final Height with Adapted Doses of Growth Hormone in Turner’s Syndrome J Clin Endocr Metab 1998; 83(5): 1462-66 14.Massa G, Otten BJ, de Muinck Keizer-Schrama SM, Delemarre-van de Waal HA, Jansen M, Vulsma T, Oostdijk W, Waelkens JJ, Wit JM et al. Treatment with Two Growth Hormone Regimens in Girls with Turner Syndrome: Final Height Results. Hormone Research 1995; 43(4):144-6 15.Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985; 60: 932-5 16.Ranke MB, Pfluger H, Rosendahl W, Stubbe P, Enders H, Bierich JR, Majewski F. Turner syndrome: spontaneous growth in 150 cases and review of the literature. Eur J Peds 1983; 141(2): 81-8 17.Donaldson MDC. Unresolved problems in the treatment of short stature for Turner Syndrome. International Growth Monitor 1998; 8(1): 2-9 18.Guyda HJ Four Decades of Growth Hormone Therapy for Short Children: What Have We Achieved? J Clin Endocr Metab 1999; 84(12): 4307-16 19.Van den Broeck J, Massa GG, Attanasio A, Matranga A, Chaussain J-L, Price DA, Aardkog D, Wit J-M and the European Study Group. Final height after long-term growth hormone treatment in Turner syndrome. J Pediatr 1995; 127(5): 729-35. 20.Taback SP, Collu R, Deal CL, Guyda HJ, Salisbury S, Dean HJ, Van Vliet G. Does growth hormone supplementation affect adult height in Turner’s syndrome? Lancet 1996; 348: 25-7 21.Chu C, Paterson WF, Kelnar CJH, Smail PJ, Greene SA, Donaldson MDC. Variable effect of growth hormone on growth and final adult height in Scottish patients with Turner’s syndrome. Acta Paediatr 1997; 86: 160-4 22.Haeusler G, Schmitt K, Blumel P, Plöchl E, Waldhör T, Frisch H. Growth hormone in combination with anabolic steroids in patients with Turner syndrome: effect on bone maturation and final height. Acta Paediatr 1996; 85:1408-14 23.Betts PR, Butler GE, Donaldson MDC, Dunger DB, Johnston DI, Kelnar CJH, Kirk J, Price DA, Wilton P, the UK KIGS Executive Group on behalf of the participating centres. A decade of growth hormone treatment in girls with Turner syndrome in the UK. Arch Dis Child 1999; 80: 221-25 24.Sas ThCJ, De Muinck Keizer-Schrama SMPF, Stijnen Th, van Teunenbroek A, Hokken-Koelega ACS, Waelkens JJJ, Massa GG, Vulmsa Th, Gerver WJ, Reeser HM, Delemarre-van de Waal HE, Jansen M, Drop SLS, & the Dutch Advisory Group on Growth Hormone. Final height in girls with Turner’s syndrome treated with once or twice daily growth hormone injections. Arch Dis Child 1999; 80: 36-41 25.Dacou-Voutetakis C, Karavanaki-Karanassiou K, Petrou V, Georgopoulos N, Maniati-Christidi M, Mavrou A. The Growth Pattern and Final Height of Girls with Turner Syndrome With and Without Human Growth Hormone Treatment. Pediatrics 1998; 101(4): 663-8 26.Ranke MB, Lindberg A, Chatelain P, Cutfield W, Albertsson-Wikland K, Wilton P & Price DA on behalf of the KIGS International Board. Turner Syndrome: Demography, Auxology and Growth During Growth Hormone Therapy in KIGS. In: Ranke MB & Wilton P (Eds.) Growth Hormone Therapy in KIGS – 10 Years’ Experience. Heidelberg: Barth 1999: 245-58 27.Johnston DI, Betts P, Dunger D et al A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndreome: near final height analysis. Arch Dis Child 2001;84:76-81 28.Price DA & Albertsson-Wikland K on behalf of the International Board of the Kabi Pharmacia International Growth Study. Demography, auxology and response to recombinant human growth hormone treatment in girls with Turner’s syndrome in the Kabi Pharmacia International Growth Study. Acta Paediatr Suppl 1993; 391: 69-74 29.Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J and the Genentech, Inc Collaborative Study Group. Growth Hormone Therapy of Turner Syndrome: The Impact of Age of Estrogen Replacement on Final Height. J Clin Endocr Metab 2000; 85(7): 2439-45 Unlicensed indications 1. DeZegher F, du Caju MVL, Heinrichs C et al. Early, discontinuous, high dose growth hormone treatment to normalise height and weight of short children born small for gestational age: results over 6 years. J Clin Endocrinol Metab 1999;84:1558-1561. 2. Cutfield WS, Wilton P, Bennmarker H et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet 2000;355:610-613. 3. Hindmarsh PC, Smith PJ, Brook CGD, Mathews DR. The relationship between growth velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol 1987;27:581-91. 4. Hindmarsh PC, Smith PJ, Pringle PJ, Brook CGD. The relationship between the response to growth hormone therapy and pretreatment growth hormone secretory status. Clin Endocrinol 1988;28:559-563. 5. Downie AB, Mulligan J, McCaughey ES et al. Psychological response to growth hormone treatment in short normal children. Arch Dis Child 1996;75:32–35) 6. Downie AB, Mulligan J, Stratford RJ et al. Are short normal children at a disadvantage? The Wessex Growth Study. Brit Med J 1997;314:97–100 7. McCaughey ES, Mulligan J, Voss LD, Betts PR. Growth and metabolic consequences of growth hormone therapy in prepubertal short normal children. Arch Dis Child 1994;71:201-206. 8. Guyda HJ. Four decades of growth hormone therapy for short children: what have we achieved? J Clin Endocrinol Metab 1999;84:4307-4316. 9. Hintz RL, Attie KM, Baptista J, Roche A. Effect of growth hormone tretament on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502-507. 10. Hokken-Koelega CS - What is the role of growth hormone therapy in children born small for gestational age. In "Challenges in Growth Hormone Therapy" Ed. Monson JP, Blackwell Science, 1999. 11. DeZegher F, Albertsson-Wikland K, Wilton et al. Growth hormone treatment of children born small for gestational age: meta-analysis of four independent, randomized controlled, multicentre studies. Acta Paediatr 1996:417(suppl):27-31. 12. Ranke MB, Linberg A – Growth hormone treatment of short children born small for gestational age or with Russell-Silver syndrome. results from KIGS (Kabi International Growth Study) including the first report on final height. Acta Paediatrica 1996;417 (suppl):18–26) 13. Coutant R, Carel JC, Letrat M, et al – Short stature associated with intrauterine growth retardation final height of untreated and growth hormone treated children. J Clin Endocrinol Metab 1998;83:1070-1074. 14. Cotterill AM, McKenna WJ, Brady AF et al. The short-term effects of growth hormone therapy on height velocity and cardiac ventricular wall thickness in children with Noonan’s syndrome. J Clin Endocrinol Metab 1996;81:2291-2297. 15. Romano AA, Blethen SL, Dana K, Nato RA . Growth hormone treatment in Noonan’s Syndrome; the National Co-operative Growth Study experience. J Pediatr 1996;128: Suppl 18–21. 16. Kirk JMW, Betts PR, Butler GE et al. Short Stature in Noonan syndrome: response to growth hormone therapy. Arch Dis Child 2001;84;440-443. 17. Bridges NA. Does GH therapy influence final height in skeletal dysplasia syndromes? In "Challenges in Growth Hormone Therapy" Ed. Monson JP, Blackwell Sciences, 1999. 18. Lawson Wilkins Pediatric Endocrine Society. Guidelines for the use of growth hormone in children with short stature. A report of the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. J Pediatr 1995;127:857-867. Chronic Renal Failure 1. Lewis MA, Shaw J, on behalf of the British Association for Paediatric Nephrology. Demography of end-stage renal failure in the UK-the first report of the BAPN national registry. Pediatr Nephrol 1998;7:P365 2. Kari JA, Gonzalez C, Ledermann SE, Shaw V, Rees L. Outcome and growth of infants with severe CRF. Kidney Int 2000;57:1681-1687 3. Schaefer F, Wingen A-M, Hennicke M,Rigden SPA, Mehls O, European study group for nutritional treatment of CRF in childhood. Growth charts for pre-pubertal children with CRF due to congenital renal disorders. Pediatr Nephrol 1996;10:288-294 4. Schaefer F, Seidel C, Binding A, Gasser T, Largo RH, Prader A, Scharer K. Pubertal growth in CRF. Pediatr Res1990;20:5-10 5. Hokken-Koelega ACS, van Zaal MAE, van Bergen W, de Ridder MAJ, Stijnen T, Wolff ED, de Jong RCJW, Donckerwolcke RA, de Muinck Keizer-Schrama SMPF, Drop SLS. Final height and its predictive factors after renal transplantation in childhood. Pediatr Res 1994;36:323-328 6. Holtta T, Ronnholm K, Jalanko H, Holmberg C. Clinical outcome of pediatric patients on peritoneal dialysis under adequacy control. Pediatr Nephrol 2000;14:889-898 7. Rees L, Greene SA, Adlard P, Jones J, Haycock GB, Rigden SPA, Preece M, Chantler C.Growth and endocrine function after renal transplantation. Arch Dis Child 1988;63:1326-1332 8. Schaefer F, Velduis JD, Stanhope R and the Co-operative study group of pubertal development in CRF. Alterations in GH secretion and clearance in peripubertal boys with CRF and after renal transplantation. J Clin Endocrinol Metab 1994;78:1298-1306 9. Fivush BA, Jabs K, Neu AM, Sullivan EK, Feld L, Kohaut E, Fine R. Chronic renal insufficiency in children and adolescents: the 1996 annual report of NAPRTCS. Pediatr Nephrol 1998;12:328-337 10. Rees L, Rigden SPA, Ward GM. Chronic renal failure and growth. Arch Dis Child 1989;64:573-577 11. Warady BA, Hebert D, Sullivan EK, Alexander SR, Tejani A. Renal transplantation, chronic dialysis, and chronic renal insufficiency in children and adolescents. The 1995 Annual report of the North American Pediatric Renal transplant Cooperative study. Pediatr Nephrol 1997;11:49-65 12. Feld LG, Stablein D, Fivush B, Harmon W, Tejani A. Renal transplantation in children from 1987-1996: The 1996 annual report of the NAPRTCS. Pediatr Transplantation 1997;1:146-162 13. Kari JA, Romagnoli J, Duffy P, Fernando O, Rees L, Trompeter RS. Renal transplantation in children under 5 years of age. Pediatr Nephrol 1999;13:730-737 14. Maxwell H, Haffner D, Rees L. Catch-up growth occurs after renal transplantation in children of pubertal age. J Pediatr 1998;133:435-440 15. Jabs K, Sullivan EK, Avner ED, Harmon WE. Alternate day steroid dosing improves growth without adversely affecting graft survival or long-term graft function. A report of NAPRTCS. Transplantation 1996;61:31-36 16. Rees L, Rigden SPA, Ward G, Preece MA. Treatment of short stature in renal disease with recombinant human growth hormone. Arch Dis Child 1990;65:856-861 17. Koch VH, Lippe BM, Nelson PA. Accelerated growth after rhGH treatment of children with CRF. J Pediatr 1989;115;365-371 18. Maxwell H, Rees L, on behalf of the British Association for Paediatric Nephrology. Randomised, controlled trial of the use of recombinant human growth hormone in prepubertal and pubertal renal transplant recipients. Arch Dis Child 1998;79:481-488 19. Fine RN, Kohaut E, Brown D, Kuntze J, Attie KM. Long-term treatment of growth retarded children with chronic renal insufficiency, with recombinant human growth hormone. Kidney Int 1996;49:781-785 20. Yadin O, Fine RN. Long-term use of recombinant human growth hormone in children with chronic renal insufficiency. Kidney Int 1997;51:suppl. 58, S114-S117 21. Berard E, Crosnier H, Six-Beneton A, Chevallier T, Cochat P, Broyer M. Recombinant human growth hormone treatment of children on hemodialysis. Pediatr Nephrol 1998;12:304-310 22. Janssen F, Van Damme-Lombaerts R, Van Dyck M, Hall M, Schurmans T, Herman J, Hooghe L, Van Damme B. Impact of growth hormone treatment on a Belgian population of short children with renal allografts. Pediatr Transplantation 1997;1:190-196 23. Rees L, Ward G, Rigden SPA Growth over ten years following a one year trial of growth hormone therapy. Pediatr Nephrol 2000; 14:309-315 24. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O. Effect of growth hormone treatment on the adult height of children with chronic renal failure. N Engl J Med 2000;343:923-930 25. Rodriguez-Soriano J, Vallo A, Quintela MJ, Malaga S, Loris C. Predictors of final adult height after renal transplantationduring childhood: A single centre study. Nephron 2000;86:266-273 26. Mehls O, Ritz E, Hunziger E-B, Eggli P, Heinrich U, Zapf J. Improvement of growth and food utilisation by human recombinant growth hormone in uremia. Kidney Int 1988;33:45-52 27. Hokken-Koelega ACS, Stijnen T, De Jong MC, Donckerwolcke RA, de Muink Keizer-Schrama SMP, Blum WF, et al. Double blind trial comparing the effects of 2 doses of rhGH in prepubertal patients with chronic renal insufficiency. J Clin Endocrinol Metab 1994;79:1185-1190 28. Hokken-Koelega ACS, Stijnen T, de Ridder MAJ, de, Wolff ED, de Jong MCJW, Donckerwolcke RA, Groothoff JW, Blum WF, Drop SLS. Growth hormone treatment in growth-retarded adolescents after renal transplant. Lancet 1994;343:1313-1317 29. Mehls O, Rigden S, Ehrich JH, Berthoux F, Jones EHP, Valderrabano, on behalf of the EDTA-ERA registry. Report on management of renal failure in Europe, XXV, 1994. The child-adult interface. Nephrol Dial Transplant 1996;11:suppl 1, 22-36 30. Fine RN, Attie KM, Kuntze J, Brown DF, Kohaut EC for the Genentech Collaborative study group. rhGH in infants and young children with chronic renal insufficiency. Pediatr Nephrol 1995;9:451-457 31. Tonshoff B, Mehls O. Factors affecting growth and strategies for treatment in children after renal transplantation. Pediatr Transplantation 1997;1:176-182 32. Fine RN, Brown DF, Kuntze J, Wooster P, Kohaut EC. Growth after discontinuation of rhGH in children with chronic renal insufficiency. J Pediatr 1996;129:883-891 33. Fine RN, Sullivan EK, Kuntze J, Blethen S, Kohaut EC. The impact of rhGH treatment during chronic renal insufficiency on renal transplant recipients. J Pediatr 2000;136:376-382 34. Rees L, Maxwell H. Causes of failure to respond to growth hormone in children with renal disease. Pediatr Nephrol, 1996;10:337-340 35. Rees L, on behalf of the British Association for Paediatric Nephrology. Compliance with growth hormone therapy in chronic renal failure and post-transplant. Pediatr Nephrol, 1997;11:752-754 36. Maxwell H, Nair D, Dalton RN, Rigden SPA, Rees L. Differential effects of recombinant human growth hormone on glomerular filtration rate and renal plasma flow in chronic renal failure. Pediatr Nephrol 1995;9:458-464 37. Maxwell H, Dalton RN, Nair D, Turner C, Saunders AJS, Rigden SPA, Rees L. Effect of recombinant human growth hormone on renal function in children with renal transplants. J Pediatr 1996;128:177-183 38. Vimalachandra D, Craig J, Cowell CT, Knight J. Growth hormone treatment in children with chronic renal failure; a meta-analysis of randomised controlled trials. J Pediatr; in press Prader-Willi syndrome 1. Laurance BM. Prader-Willi syndrome. Ped Res Commun 1993;7:77-91. 2. Davies PSW, Joughlin c. Using stable isotopes to assess reduced physical activity of individuals with Prader-Willi syndrome. Am J Ment Retard 1993;3:349-353. 3. Lee PD, Hwu K, Brown BT et al. Body composition studies in Prader-Willi syndrome: effects of growth hormone therapy. Basic Life Science 1993;60201-205. 4. Eiholzer U, Blum WF, Molinari L. Body fat determined by skinfold measurements is elevated despite underweight in infants with Prader-Labhart_Willi syndrome. J Pediatr 1999;134:222-225. 5. Schoeller DA, Levitsky LL, Bandibi LG et al. Energy expenditure and body composition in Prader-Willi syndrome. Metabolism 1988;37:115-20. 6. Cassidy SB. Prader-Willi syndrome. J Med Genet 1997;34:917-923. 7. Butler MG, Meaney FJ. Standards for selected anthropometric measurements in Prader-Willi syndrome. Pediatrics 1991;88:853-860 8. Wollmann HA, Schultz U, Grauer ML, Ranke MB. Reference values for height and weight in Prader-Willi syndrome based on 315 patients. Eur J Pediatr. 1998;157:634-642 9. Angulo M, Castro-Magana, Mazur B, Canas JA, Vitollo PM, Sarrantonio M. Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi syndrome. J Ped Endocrinol Metab 1996; 9: 393-400. 10. Lindgren AC, Hagenas L, Miller J, Blichfeld S, Rosenborg M, Brismar T, Ritzen EM. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably. Acta Paediatr 1998; 87; 28-3 1. 11. Thacker MJ, Hainline B, St. Denis-Feezle L, Johnson NB, Pescowitz OH.Growth failure in Prader-Willi syndrome is secondary to growth hormone deficiency. Horm Res 1998;49: 216-20.
13. Hauffa BP. One year results of growth hormone treatment of short stature in Prader-Willi syndrome a preliminary report. Acta Paediatrica Suppl. 1998;423:63-65. 14. Davies PSW, Evans S, Broomhead S, Clough H, Day JME, Laidlaw A, Bames ND. Effect of growth hormone on height, weight, and body composition in Prader-Willi syndrome. Arch Dis Child 1998; 78: 474-6. 15. Eiholzer U, Gisin R, Weimnann C, Kriemler S, Steinert H, Torresani T, Zachman-n M, Prader A. Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance. Eur J Pediatr 1998; 157: 368-77.
17. Lindgren AC, Hagenas L, Ritzen EM. Growth hormone treatment of children with Prader-Willi syndrome: effects on glucose and insulin homeostasis. Horm Res 1999;51:115-117.
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