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Background: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited., Objective: To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls., Design/patients: Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group (n = 15) receiving 1 mg/m(2)/day GH or a non-GH-treated control group (n = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated., Results: Infants in the GH group had a median age of 2.3 years [interquartile range (IQR) 1.7-3.0] and in the control group of 1.5 years (IQR 1.2-2.7) (P = 0.17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9.3% (-5.3 to 13.3) vs.-2.9% (-8.1 to 4.9) (P < 0.05) in mental development and +11.2% (-4.9 to 22.5) vs.-18.5% (-27.9 to 1.8) (P < 0.05) in motor development, respectively., Conclusion: One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.

Aarskog syndrome is an X-linked disorder characterized by faciogenital dysplasia and short stature. The present study set out to determine the effect of growth hormone (GH) therapy in patients with Aarskog syndrome enrolled in KIGS--the Pharmacia International Growth Database. Twenty-one patients (20 males) were evaluated. Median age at start of treatment was 8.3 years (10-90th percentiles, 5.1-14.1 years) and median height SDS was -2.8 (10-90th percentiles, -2.1 to -3.7). The median dose of GH was 0.22 mg/kg/week (10-90th percentiles, 0.15-0.30 mg/kg/week) given at a median frequency of six (4-7) times per week. Prepubertal patients were followed longitudinally for 1 year (n = 13) or 3 years (n = 7). After 1 year, the median height SDS had improved from -2.8 to -2.3 in 13 patients. After 3 years, height SDS had improved significantly (p <0.05) to -1.8 (10-90th percentiles, -2.1 to -1.1) in the seven patients. No adverse events were noted. Although final height data for these patients are still awaited, the present results support the use of GH to promote growth in children with Aarskog syndrome.

We assessed bone mineral density (BMD) and body composition in children with Noonan's syndrome (NS) before and during growth hormone (GH) treatment. Sixteen children (12 boys, 4 girls) with NS aged 5.8-14.2 (mean 10.0) years were studied for 2 years. Anthropometry, BMD measurements by radiographic absorptiometry and bioimpedance measurements (Akern-BIA 101/S) were performed at baseline and after 3, 6, 12 and 24 months. Daily GH dosage was 0.05 mg/kg. Trabecular volumetric BMD was normal; cortical BMD was in the lower normal range at baseline and slightly increased over the 2 years. Fat free mass and total body water were below normal at the start and increased significantly over the first 3 months, with a slight increment thereafter. Percentage fat mass decreased over the first 6 months and increased thereafter. These findings are comparable to the data on body composition in short normal children and girls with Turner's syndrome treated with GH.

Unlabelled: The aim of the study was to evaluate the effect of continuous and discontinuous growth hormone treatment in Noonan's syndrome (NS) on linear growth and bone maturation. Thirty-seven children with NS aged between 5.4 and 17.5 y were treated with growth hormone (GH) in a dose of 0.15 IU kg)(-1) per day; 23 of these children were randomly assigned to one of 2 groups in a 3 y partly controlled prospective multicentre study. Group A (n = 8) immediately started GH treatment and after 2 y discontinued GH treatment for 1 y; group B (n = 15) served as a control group during the first year and started GH treatment after 1 y. After the 3 y study period, 17 out of the 23 children continued GH treatment. An additional 14 children (group C) were treated according to the same protocol, but without discontinuation of GH treatment. The effect of GH treatment for up to 3 y was evaluated in terms of gain in height standard deviation score (H-SDS) for calendar age and for bone age. Gain in H-SDS over the first year was significantly higher in the GH treatment group (+0.5) than in the non-treated group (+0.0); mean bone maturation was significantly faster in the GH treatment group (1.2 vs 0.5 y/y). Discontinuation in group A in the third study year resulted in catch-down growth (mean deltaH-SDS -0.2). Over 3 y of GH treatment, mean AH-SDS for calendar age was not significantly different between discontinuous (A: +0.8) and continuous treatment (B: +0.8; C: +1.2). Mean gain in H-SDS for bone age in the 3 groups (+0.2, 0.0. +0.3) was minimal after 3 y of GH treatment., Conclusion: This study confirmed the gain in H-SDS CA in Noonan's syndrome during long-term GH treatment. However, the accelerating effect of GH on bone maturation seemed to compromise the final height prognosis.

The role of GH insufficiency in the pathogenesis of short stature in Noonan syndrome is unclear. Cross-sectional study. Seventeen patients with Noonan syndrome (13 boys, 4 girls; aged 4.8-13.3 (mean 9.2) years) and short stature before start of GH treatment. Spontaneous 12-h overnight GH secretion by continuous sampling analysed using Pulsar, plasma IGF-I and IGFBP-3 levels, and 24-h urinary GH excretion were measured at start of GH treatment. A glucagon stimulation test was performed. Height and height velocity were monitored before and after 1 year of GH treatment. IGF-I and IGFBP-3 were remeasured after 1 year of GH treatment. Nine of the 17 children had a mean overnight GH concentration below the lower limit of the normal range. In six of the 17 patients, overnight GH profiles showed high trough GH concentrations. Glucagon stimulation tests were normal in 16 of the 17 patients. Mean IGF-I level was below normal (-0.4 SD). None of the parameters regarding GH secretion obtained from the overnight profile or provocative test was related to height or height velocity, nor to first year response to GH treatment. IGF-I and IGFBP-3 did not correlate with any of the GH secretion data. IGF-I and IGFBP-3 were related to height and height velocity at the start of GH treatment (r = 0.53 (P < 0.01) and r = 0.61 (P < 0.03) respectively). Rises in IGF-I and IGFBP-3 under GH treatment were related to the increment in height velocity (r = 0.70 (P < 0.01) and r = 0.71 (P < 0.02) respectively). Abnormalities in GH secretion are frequent in patients with Noonan syndrome and short stature. These abnormalities were not related to auxology at start of or response to GH treatment. Clinically GH insufficiency is not important in Noonan syndrome and monitoring spontaneous GH secretion is not necessary before the start of GH treatment.

Objective: To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan's syndrome (NS)., Methods: Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart., Results: At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment., Conclusion: Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS., (Copyright 2002 S. Karger AG, Basel)

We studied the growth-promoting effect of treatment with recombinant human growth hormone in 23 pre-pubertal children with Noonan syndrome, aged between 5.4 and 14.3 y, and all with a height < 1.4 SD for Tanner standards. The growth response and skeletal maturation after 1 y of recombinant human growth hormone treatment (0.15 U/kg/day given by daily injection) in the Noonan syndrome patients was compared with the auxological changes observed in a group of 17 girls with Turner syndrome with a comparable age and height deficit who were treated with recombinant human growth hormone in a similar way. During 1 y of treatment, the mean +/- SD height velocity increased by 4.0 +/- 1.6 cm/y in the Noonan syndrome group and by 3.6 +/- 1.3 cm/y in the Turner syndrome group. Height SDS for chronological age in the Noonan syndrome group increased by 0.53 +/- 0.46 (p < 0.001). In the Noonan syndrome patients the changes in height velocity were positively related to birthweight (r = 0.48, p < 0.05). The changes in height velocity or height SDS were not related to the age, height deficit or a delay in bone age maturation at start of treatment. In neither the patients with Noonan syndrome nor Turner syndrome was an acceleration of bone maturation found. We conclude that treatment with recombinant human growth hormone in pre-pubertal NS patients induces an increase in height velocity and height SDS comparable to that observed in Turner syndrome girls.

Height and weight growth before and during treatment with human growth hormone (hGH) was studied in 46 Dutch patients treated for craniopharyngioma. Weight was expressed as body mass index (BMI, weight/height). At the time of tumor treatment mean +/- SD height standard deviation score (SDS) was -1.22 +/- 1.38 and BMI SDS was 0.56 +/- 1.32. The initial height SDS was inversely related to age (r = -0.38; p < 0.02). Before hGH treatment height SDS decreased to - 1.57 +/- 1.08 (p < 0.05) and BMI SDS increased to 1.54 +/- 1.58 (p < 0.005) during the first year after tumor treatment. Changes in height SDS correlated positively with basal prolactin (PRL) levels (r = 0.46; p < 0.05). Neither tumor localization nor treatment mode was related to changes in height SDS and BMI SDS. Forty patients were treated with hGH, started a median interval of 2.0 years after tumor treatment. At the time of the start of hGH treatment height SDS in these patients was -1.70 +/- 1.13, and BMI SDS was 1.44 +/- 1.79. During treatment with hGH, height SDS increased to -1.05 +/- 1.10 (p < 0.001) in the first, and to -0.80 +/- 1.04 (p < 0.001) in the second year. BMI SDS did not change during hGH therapy. In conclusion, there is a large variation in height SDS and BMI SDS at the time of initial presentation as well as during spontaneous growth after tumor treatment. Spontaneous growth is related to serum PRL concentrations. Treatment with hGH significantly increased height SDS during the first 2 years, whereas BMI SDS did not change.

Background and Objective: Growth hormone treatment in children with idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with idiopathic short stature., Design: We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n = 21) were compared to those of an untreated control group with ISS (ISS controls, n = 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n = 7)., Results: In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from -3.8 +/- 0.7 to -2.3 +/- 0.9 (mean +/- standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from -3.9 +/- 0.6 to -1.8 +/- 0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated in the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was -2.6 +/- 1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome., Conclusion: rhGH treatment in this group of children with idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.

In 1987 a multicentre trial of recombinant human growth hormone (GH) was started in girls with Turner syndrome. Fifty-four patients were randomly assigned to receive GH, 8 IU/m2 3 times/week (group 1), or 4 IU/m2 6 times/week (group 2). In addition, the 35 patients older than 12 years received ethinyloestradiol, 100 ng/kg body weight/day, and after 2 years GH therapy was increased to 6 IU/m2 6 times/week. Recombinant human GH treatment was stopped when the height increment during the previous 6 months of treatment was less than 0.5 cm. Treatment has so far been stopped in 48 patients: treatment was stopped early in 2 patients due to lack of motivation, 1 patient died suddenly and the treatment protocol was completed in 45 patients. The last height measurement obtained, which was considered as (near) final height, was 152.3 +/- 5.3 cm (mean +/- SD) in these patients, which is higher (p < 0.001) than the adult height of 147.0 +/- 6.3 cm reported in 63 untreated adult Dutch patients with Turner syndrome. No differences in outcome were found between the two dose regimens.

A combination of humoral immunodeficiency and isolated growth hormone deficiency was observed in a girl with Mulibrey nanism. The humoral immunodeficiency consisted of subnormal concentration of serum IgG, in particular IgG2 and IgG4, and low concentration of serum IgM. Serum IgA and IgD were elevated, IgE was absent. Antibody response in vivo was very low or absent and opsonization in vitro was defective. Total B-cell number was low. In addition, the serum kappa/lambda light chain ratios within the immunoglobulin classes G, A, and M were abnormal. The defective antibody response may be linked to the abnormal kappa/lambda light chain ratios. Endocrine functions were normal except for isolated growth hormone deficiency. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions.

A cephalometric study was performed in 19 patients with Turner's syndrome, aged 8.7-16.5 years. A lateral roentgen-encephalogram was taken before and after two years of treatment with biosynthetic growth hormone in a dose of 24 IU/m2/week. During two years of growth hormone treatment, the mandibular length increased mainly due to vertical growth. The initially posteriorly rotated mandible showed an anterior rotation, although the normal position was not reached. The other linear measurements and angles did not change during treatment. No indications were found for an increase in the disproportionate growth or for excessive chin growth as a sign of acromegaly during growth hormone treatment. In conclusion, growth hormone treatment in patients with Turner's syndrome resulted in an increase in mandibular length, mainly due to vertical growth of the ramus and in the anterior rotation of the mandible.

Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (A1 and B1, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/m2/week, with an increase in height velocity, though in the older girls, the response was comparatively poor. Therefore, the dose regimens in groups B1 and B2 were increased to 36 IU/m2/week given as six injections in both groups. This change resulted in an increase in height velocity only in group B1. During the first 2 years only, the height velocity was greater in group A2 than group A1. The conclusion is that a regimen of six injections/week is more effective than one of three injections/week in terms of initial height gain and change in predicted adult height. In girls with Turner syndrome aged over 16 years, GH therapy has no significant effect.

Sixteen girls with Turner syndrome (TS) were treated for 4 years with biosynthetic growth hormone (GH). The dosage was 4 IU/m2 body surface s.c. per day over the first 3 years. In the 4th year the dosage was increased to 6 IU/m2 per day in the 6 girls with a poor height increment and in 1 girl oxandrolone was added. Ethinyl oestradiol was added after the age of 13. Mean (SD) growth velocities were 3.4 (0.9), 7.2 (1.7), 5.3 (1.3), 4.3 (2.0) and 3.6 (1.5) cm/year before and in the 1st, 2nd, 3rd and 4th year of treatment. Skeletal maturation advanced faster than usual in Turner patients especially in the younger children. Although the mean height prediction increased by 5.6 cm and 11 of the 16 girls have now exceeded their predicted height, the height of the 4 girls who stopped GH treatment exceeded the predicted adult height by only 0 to 3.4 cm.

Study Objective: To determine the influence of the injection frequency and the initial bone age on the efficacy of treatment with biosynthetic growth hormone in Turner's syndrome., Design: Randomized study., Setting: Referral-based pediatric endocrinology departments of seven university medical centers., Patients: Fifty-two patients with Turner's syndrome confirmed with chromosomal analysis., Treatment: Somatotropin recombinant DNA (24 IU/m2 of body surface area) subcutaneously administered in three or six injections per week for 2 years. Patients who were older than 12 years at the beginning of the study received low doses of estrogen., Results: The following statistically significant findings supported the use of six injections per week compared with three injections per week: the mean (+/- SD) increment in height during 2 years was 11.3 cm (3.8 cm) with six injections vs 8.6 cm (3.4 cm) with three injections; the increment in height standard deviation score was 0.9 cm (0.5 cm) vs 0.6 cm (0.3 cm); the growth velocity was 6.6 cm/y (2.0 cm/y) vs 5.2 cm/y (1.7 cm/y) in year 1 and 4.7 cm/y (2.0 cm/y) vs 3.4 cm/y (1.7 cm/y) in year 2; and the increment in height standard deviation score for bone age was 0.8 cm (0.5 cm) vs 0.4 cm (0.6 cm). For patients whose initial bone age was more than 13 years, growth velocity increased by 1 to 2 cm in year 1; in year 2 no increment was observed. We did not observe adverse effects., Conclusions: Biosynthetic growth hormone in a higher-frequency regimen in Turner's syndrome is more efficient in terms of increment in height, growth velocity, and height standard deviation score for bone age than treatment in a lower-frequency regimen. In patients with an initial bone age of more than 13 years, the response was poor. Longer follow-up is necessary to assess the effect on final height.

Methionyl growth hormone (somatrem) in a daily dosage of 4 IU/m2 body surface area was administered to 16 girls with Turner syndrome. Low dose ethinyl estradiol (0.1 microgram/kg body weight) was added in girls aged 13 years or more. Mean (SD) height velocity increased from 3.4 (0.9) to 7.2 (1.7) and 5.3 (1.3) cm/year in the first and second year, respectively. Bone age advanced 1.8 years over 2 years and predicted adult height was increased. Apart from the occurrence of anti-GH antibodies there were no side effects. In conclusion, somatrem is an efficacious and safe therapy for short stature in Turner syndrome over a period of 2 years. Longer follow-up is needed before conclusions about its effect on final height can be drawn.

Sixteen girls with Turner's syndrome aged 7.9-15.2 years (bone ages 7.0-11.8 years) were given methionyl growth hormone (somatrem) 4 IU/m2 body surface daily, corresponding to 0.9 IU/kg/week. During one year of treatment their mean (SD) height velocity increased from 3.4 (0.9) to 7.2 (1.7) cm/year and height prediction from 148.2 (4.4) to 150.0 (4.4) cm. All the girls except one had a height velocity increment of more than 2 cm/year and these velocities are above the age references for girls with Turner's syndrome. The girl with a low growth response had antibodies against growth hormone with high binding capacity (3.7 U/l). The height velocity increment was inversely correlated with age and bone age, but this might be partly due to the somewhat higher dosage/m2 body surface and kg body weight that the younger patients were given because of the rounding off of the dose. The better results of our study compared with those of other workers who used similar dosages but did not give the drug as often suggest that giving it daily might have increased the growth response as it does in children deficient in growth hormone.

In a double-blind study 12 prepubertal children with idiopathic growth hormone (GH) deficiency were treated with growth hormone releasing factor (GRF) 1-44 in a dosage of 7.5 or 15 micrograms/kg body weight, administered once a day subcutaneously. With 7.5 micrograms/kg the average growth velocity increased from 2.5 to 4.6 cm/year, an insufficient response. With the higher dosage the average growth velocity increased from 2.7 to 7.0 cm/year, a similar increase as observed with GH therapy in subsequent periods. In 3 of the 6 children treated with the higher dose appropriate catch-up growth was observed. The growth response of the lower leg length was not always consistent with the statural growth response.

Thirty short and slowly growing children with normal plasma growth hormone (GH) responses to standard provocation tests were randomly assigned to either a group (n = 20) undergoing treatment with methionyl GH (somatrem), 2 IU per m2 body surface s.c. daily, or a control group (n = 10). Twelve out of 18 children who completed the first year of treatment showed a height velocity increment of more than 2 cm/year. The mean (SD) growth velocity of the treatment group increased by 3.0 (1.9) cm/year over the first year, compared with -0.2 (0.7) cm/year in the control group. Neither parameters of endogenous GH secretion nor plasma IGF-I levels showed a significant correlation with the growth response. Of the auxological variables studied, pre-treatment growth velocity (r = -0.8) and the short-term height velocity increment (r = 0.7-0.9) showed significant correlations with the growth response in the first year of treatment. Somatrem therapy was without side effects, except in one child who developed anti-GH antibodies in combination with a poor growth response.