Noonan's Syndrome: Abnormalities of the Growth Hormone/IGF-I Axis and the Response to Treatment with Human Biosynthetic Growth Hormone

ABSTRACT. Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5–12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.     

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children

Schwarze CP, Wollmann HA, Binder G, Ranke MB. Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children. Acta Paediatr 1999; Suppl 428:200-8. Stockholm. ISSN 0803-5326
The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from-1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGEBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS. □ Growth hormone treatment, insulin-like growth factor I, insulin-like growth factor binding protein-3, insulin-like growth factor generation test     

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children

The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from -1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGFBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS.     

Growth hormone treatment in young children with Down's syndrome: effects on growth and psychomotor development.

BACKGROUND: Learning disability and short stature are cardinal signs of Down's syndrome. Insulin-like growth factor I (IGF-I), regulated by growth hormone (GH) from about 6 months of age, may be involved in brain development. AIMS: To study long term effects of GH on linear growth and psychomotor development in young children with Down's syndrome. Study design-Fifteen children with Down's syndrome were treated with GH for three years from the age of 6 to 9 months (mean, 7.4). Linear growth, psychomotor development, skeletal maturation, serum concentrations of IGF-I and its binding proteins (BPs), and cerebrospinal fluid (CSF) concentrations of IGF-II were studied. RESULTS: The mean height of the study group increased from -1.8 to -0.8 SDS (Swedish standard) during treatment, whereas that of a Down's syndrome control group fell from -1.7 to -2.2 SDS. Growth velocity declined after treatment stopped. Head growth did not accelerate during treatment. No significant difference in mental or gross motor development was found. The low concentrations of serum IGF-I and IGFBP-3 became normal during GH treatment. CONCLUSIONS: GH treatment results in normal growth velocity in Down's syndrome but does not affect head circumference or mental or gross motor development. Growth velocity declines after treatment stops.     

Long-term treatment with growth hormone in Noonan's syndrome

Five children (four boys, one girl) with Noonan's syndrome were treated with growth hormone for a mean of 2.9 (range 1.8 to 4.6) years. Treatment was commenced at a mean age of 3.9 (range 2.5 to 6.0) years. After one year of treatment, height velocity SDS increased from a mean of -2.1 (range -4.1 to - 0.3) to a mean of +3.1 (range +2.0 to +3.5). Subsequently, height SDS increased significantly from -3.3(range -4.2 to -2.2)to -2.4(range -3.3 to - 1.6). Although in all patients a marked decrease in height velocity was observed in the following years of treatment, compared to the first year, height SDS continued to improve in comparison to pretreatment (mean height SDS in the third year for four patients was -2.1) (range -3.1 to - 1.4). In the four patients who had completed their second year of treatment, height SDS for bone age had increased from -1.8 (range - 2.8 to - 09) to -1.2 (range - 1.6 to -0.6).     

Long-term treatment with growth hormone in Noonan's syndrome

Five children (four boys, one girl) with Noonan's syndrome were treated with growth hormone for a mean of 2.9 (range 1.8 to 4.6) years. Treatment was commenced at a mean age of 3.9 (range 2.5 to 6.0) years. After one year of treatment, height velocity SDS increased from a mean of -2.1 (range -4.1 to - 0.3) to a mean of +3.1 (range +2.0 to +3.5). Subsequently, height SDS increased significantly from -3.3(range -4.2 to -2.2)to -2.4(range -3.3 to - 1.6). Although in all patients a marked decrease in height velocity was observed in the following years of treatment, compared to the first year, height SDS continued to improve in comparison to pretreatment (mean height SDS in the third year for four patients was -2.1) (range -3.1 to - 1.4). In the four patients who had completed their second year of treatment, height SDS for bone age had increased from -1.8 (range - 2.8 to - 09) to -1.2 (range - 1.6 to -0.6).     

Growth hormone responsiveness: peak stimulated growth hormone levels and other variables in idiopathic short stature (ISS): data from the National Cooperative Growth Study

HYPOTHESIS: In children with idiopathic short stature (ISS), growth hormone (GH) response to a provocative test will be inversely related to the first year response to hGH and be a variable accounting for a degree of responsiveness. BACKGROUND: Because high levels of GH are a characteristic of GH insensitivity, such as in Laron syndrome, it is possible that a high stimulated GH is associated with a lower first year height velocity among children diagnosed as having ISS. METHODS: We examined the relationship between the peak stimulated GH levels in 3 ISS groups; GH >10 -<25, 25-40, and >40 ng/mL and the first year growth response to rhGH therapy. We also looked at 8 other predictor variables (age, sex, height SDS, height age, body mass index (BMI), bone age, dose, and SDS deficit from target parental height. Multiple regression analysis with the first year height as the dependent variable and peak stimulated GH was the primary endpoint. The predictive value of adding each of the other variables was then assessed. RESULTS: Mean change in height velocity was similar among the three groups, with a maximum difference among the groups of 0.6 cm/yr. There was a small but statistically significant correlation (r=-0.12) between the stimulated GH and first year height velocity. CONCLUSIONS: The small correlation between first year growth response and peak GH is not clinically relevant in defining GH resistance. No cut off level by peak GH could be determined to enhance the usefulness of this measure to predict response. Baseline age was the only clinically significant predictor, R-squared, 6.4%. All other variables contributed less than an additional 2% to the R-squared.     

Comparison of the growth-promoting effects of insulin-like growth factor I and growth hormone in the early years of life

Aims: Four infants with isolated growth hormone deficiency (IGHD) and five with Laron syndrome (LS) were studied. Birth length ranged from -2.5 to -4.5 SDS in both groups. Results: Untreated IGHD children decreased in length from -2.5 to -5.2 SDS at 1 y and to -5.7 SDS at 2 y. Human growth hormone (hGH) treatment (0.07 U/kg/d) increased height by 1.2-2.4 SDS in 3 y. Untreated children with LS decreased in length from -3.5 to -6.5 SDS. Insulin-like growth factor (IGF)-I treatment (150-200 μg/kg/d) in 3 LS patients increased height by 0.5-1.5 SDS in 3 y. All untreated infants had borderline or below normal head circumferences. Both treatments induced a rapid catch-up in head size. In the two untreated LS patients, head circumference remained subnormal. Conclusions: Despite similar birth length, infants with IGHD responded better to hGH in terms of linear growth than did infants with LS to IGF-I, whereas the response in brain growth was similar.     

Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5 SDS ± 0.8 SD vs -0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9 SDS to + 6.0 SDS in the treated group ( p < 0:001) and decreased from -0.1 SDS to -1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat-free mass increased ( p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.     

The efficacy of grwoth hormone in different types of growth failure

One hundred and one children with GH deficiency, prenatal growth disorders, growth-retarding diseases, or normal variant short stature received GH for at least one year. Responders were observed in all groups. In the whole series of 72 prepubertal children the increments in height velocity showed negative correlations with the highest serum GH levels obtained in provocation tests.In the prepubertal children with normal growth potential the velocity SDSs during the first year of therapy showed positive correlations with initial ages and BAs, and negative correlations with height SDSs. In the 5 children with cartilage-hair hypoplasia the mean velocity increased from -1.9 to -0.6 SD. In the 8 children with Mulibrey nanism the mean velocity increased from -2.0 to 0.8 SD. The 4 children with various chromosome anomalies also showed an acceleration.The therapy brought about a significant increase in predicted final height only in the groups with normal growth potential. Final heights were known for 16 patients. Their heights were fairly accurately predicted by the RWT method, but the IPH method gave overpredictions. Both predictions showed strong correlations with the final heights.Additional low-dose androgen therapy in 10 boys, started at ages 9.5 to 18.9 years and after 1.4 to 4.7 years of GH therapy, accelerated growth without substantially affecting predicted height. The acceleration was mostly of the growth of sitting height.Abbreviations BA bone age - CHH cartilage-hair hypoplasia - GHD GH deficiency, GH deficient - iGHD isolated GHD - IPH index of potential height (height SDS for adjusted BA) adult height prediction method [23] - Maximal GH highest plasma GH level during an insulin or insulin-arginine test - MPHD multiple pituitary hormone deficiency - RWT the adult height prediction method of Roche, Wainer and Thissen [39] - SDS height standard deviation score - SDS SDS corrected for parental height     

A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group

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.     

Foot length before and during insulin-like growth factor-I treatment of children with laron syndrome compared to human growth hormone treatment of children with isolated growth hormone deficiency

OBJECTIVE: To compare foot length deficits between patients with Laron syndrome (LS) (primary growth hormone [GH] insensitivity) and congenital isolated GH deficiency (IGHD) and their response to replacement therapy with insulin-like growth factor-I (IGF-I) and hGH, respectively. DESIGN: Data for the study were collected from the records of nine children with LS (3 M, 6 F) 7.8 +/- 4.8 years old (mean +/- SD), and nine children with IGHD (3 M, 6 F), 3.8 +/- 3.3 years old. Fifteen non-treated adult patients with LS were also included in the study. METHODS: Measurements of foot length were recorded without treatment and monitored during 9 years of treatment in the children and in the untreated adult patients. For statistical analysis the non-parametric Mann-Whitney U test was used. RESULTS: With almost similar basal values in growth deficit and pre-treatment growth velocities, the achievements towards norms after 9 years of treatment were greater in the patients with IGHD than in the patients with LS: foot length reached -1.4 +/- 0.8 vs. -3.3 +/- 1.0 SDS (mean +/- SD), and body height -2.2 +/- 1.0 vs. -3.9 +/- 0.5 SDS. The difference between the two groups could be due to the initiation of replacement therapy in the patients with IGHD at a younger age. Adult foot size of untreated patients with LS is small but less retarded than the height deficit. CONCLUSIONS: Both IGF-I and hGH are potent growth stimulating hormones of linear growth and acrae as exemplified by foot growth.     

Calcium-phosphate metabolism and bone markers in two patients with Noonan's syndrome treated with growth hormone

AIM: To evaluate the possible effects of recombinant growth hormone (rhGH) therapy on mineral homeostasis and bone turnover, the authors studied calcium-phosphate metabolism parameters, including some bone markers, in 2 prepubertal subjects with Noonan's syndrome (NS). METHODS: Two prepubertal males suffering from NS, short stature (-3.9 and -5.4 SDS respectively) and low growth velocity (3.9 and 3.3 cm/year), were treated with rhGH (0.85 U/kg/week) for 1 year. Serum levels of total calcium (Ca), inorganic phosphate (P), magnesium (Mg), parathyroid hormone (PTH), calcitonin (CT), 25OH vitamin D, 1.25(OH)(2)D, osteocalcin (BGP), type I procollagen carboxy-terminal propeptide (PICP) and its telopeptide (ICTP) were measured. RESULTS: The baseline values were in the normal range; during the treatment no remarkable difference in the values of every one parameters was detected in the 2 patients studied. In one of them, who responded to GH treatment with significantly improved growth velocity, serum levels of the BGP increased during the first semester, and then progressively declined; conversely, serum levels of the ICTP remained stable during the first 6 months of GH-therapy, whereas increased in the following 6 months. CONCLUSION: The results suggest that in Noonan's syndrome patients responding to GH-therapy, a stimulation of bone turnover, with ensuing increase of height velocity, takes place, at least during the first year of GH-therapy. The authors underline the necessity of confirming their results on a larger group of patients with Noonan's syndrome.     

Short stature in Noonan syndrome: response to growth hormone therapy.

BACKGROUND: Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. AIMS: To assess the short and long term response to GH therapy in patients with Noonan syndrome. METHODS: Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this post-marketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. RESULTS: Data on 66 patients (54 males) were available for study. At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from -2.9 pretreatment to -2.6 after one year and -2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range -1.1 to 6.5 cm). CONCLUSIONS: GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of effect; initial indications are that final height is not improved substantially in most patients.     

Predictors of first-year growth response to a fixed-dose growth hormone treatment in children born small for gestational age: results of an open-label, multicenter trial in the United States

BACKGROUND: Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM: To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS: 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS: Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION: GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.     

Growth response to growth hormone therapy following cranial irradiation

The growth response to growth hormone (GH) therapy has been studied in 12 children who received irradiation to the cranium alone either for brain gliomas, distant from the hypothalamic-pituitary axis, or as prophylaxis against CNS leukaemia. Seven children have completed GH treatment (mean duration 4 years) and five are presently on GH (mean duration 1.2 years). This response has been compared to that seen in 14 children with isolated idiopathic GH deficiency (IGHD), following GH therapy. Before treatment, the cranially irradiated patients (C-PRGHD) had higher standard deviation scores (SDS) for standing height, sitting height and leg length, and less bone age (BA) retardation, but started treatment at a similar age, and with a similar pre-treatment growth velocity and GH peak to standard provocative tests, compared to IGHD patients. GH produced a significant and similar increase in growth velocity (cm/year and SDS for BA) over the first 2 years' treatment in both groups. However C-PRGHD patients entered puberty and thus completed growth earlier than the IGHD group. As a result, cranially-irradiated children showed no change in height SDS with GH therapy, compared to catch-up growth in IGHD. Nevertheless, GH has enabled C-PRGHD patients to maintain their centile position and to achieve a more acceptable final height.Abbreviations GH growth hormone - IGHD idiopathic growth hormone deficiency - C-PRGHD post cranial-irradiation growth hormone deficiency - SDS standard deviation score - BA bone age - ALL acute lymphatic leukaemia - TSH thyroid stimulating hormone - CA chronological age - HA height age     

Screening for growth hormone deficiency using urinary growth hormone measurement

The diagnostic approach in growth hormone deficiency (GHD) is complicated. Two or more provocative tests are essential for definitive diagnosis of GHD. However, such testing cannot be carried out routinely on all subjects with short stature because of the need for hospitalization and blood sampling. A simple screening method for GHD would be of great value. Human growth hormone (hGH) levels were measured in the early morning urine of 192 children aged 7–15 years with height 2.0 s.d. below the mean for their ages. Sixty-eight subjects were selected because they showed a urinary hGH level < 10 ng/g creatinine. They were further examined in terms of bone age and plasma insulin-like growth factor (IGF-I) levels. In 30 subjects, the ratio of bone age: chronological age was < 0.8 and/or plasma IGF-I level was < 0.7 U/mL. Finally 24 of these subjects were examined with provocative tests and other endocrinological tests. Eleven subjects proved to have poor growth hormone secretion and one subject was diagnosed as having Turner syndrome. In conclusion, 11 patients with GHD were diagnosed from 192 children with short stature using urinary hGH measurement as the first screening method. These findings suggests that urinary hGH measurement could be a useful and simple method for detecting GHD.     

Prediction of growth response in prepubertal children treated with growth hormone for idiopathic growth hormone deficiency

Several multiple regression models have been developed to predict the first-year growth response to human growth hormone (hGH) in children with growth hormone deficiency (GHD). It was the aim of this study to analyse the significance of various growth parameters for a height prediction model. Data from 148 prepubertal children with idiopathic GHD were evaluated. The prediction model was developed by means of univariate and stepwise linear regression analysis and an “all possible” regression approach using Mallow's C(p) statistics. Six out of eight selected variables had a significant influence on the first-year growth rate. The most important parameter was the difference between target height SDS and height SDS at the start of therapy (THSDS - HSDSC0), accounting for 23.95% and 25.74% of the variability. No other single variable or combination of variables was more informative than the variable THSDS - HSDSC0 alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS - HSDSC0) + 6.8 cm/y ± 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSC0. This equation was validated in a small group of 18 GHD patients demonstrating a predicted vs. observed first-year growth rate of 9.4 ± 1.1 vs. 9.5 ± 2.6 cm/y. We conclude that the difference between THSDS and height SDS at the start of therapy is an important predictor of the first-year growth response in children treated with hGH for idiopathic GHD. Unlike in previous studies, additional parameters did not increase predictability.     

Growth hormone treatment in short children with beta-thalassemia major

The effect of one year recombinant human growth hormone (rhGH) treatment on growth rate and bone age was studied in ten short prepubertal children with beta-thalassemia major (age range 7.10-12.03 yr) with normal GH response to provocative stimuli. rhGH was given subcutaneously every day in a dose of 28 IU/m2/week. In the 10 children who completed 12 months of treatment the growth velocity increased from 4.22+/-0.81 cm/yr (-1.38+/-0.80 SDS for CA) to 7.61+/-1.16 cm/yr (+2.27+/-1.64 SDS for CA). IGF-I was low before treatment, 138.3 +/-38.9 ng/ml, and rose significantly to 232.2+/-122.1, 243.2+/-98.4 and 227.5+/-86.2 at 3, 6 and 12 months post-treatment, respectively (p<0.01). Bone maturation was accelerated in proportion to the increase in chronological age. The mean pre-treatment bone age in the ten children was 8.20+/-1.97 and increased to 9.55+/-1.80 yr after one year of treatment. Our data demonstrate that GH treatment of thalassemic children with normal GH reserve and low serum IGF-I concentrations with supraphysiological doses of rhGH for one year can cause a significant increase in serum IGF-I levels and growth velocity, but it remains to be elucidated whether long-term administration will affect the final height.     

Prediction of the growth response of short prepubertal children treated with growth hormone

The aim of this study was to identify predictors of the growth response to growth hormone (GH) during the first 2 years of GH treatment, using auxological data and the maximum GH response (GH_max) to provocation tests. The patients were 169 prepubertal short children (27F, 142M), with Gmax values ranging from 0 to 65 mU/1. Their mean age (± SD)was8.3 ± 2.4 years (range 3-13 years), mean height SDS –3.0 ± 0.7 (range –1.5 to –6.0SDS) and mean pretreatment height velocity was normal (± 0.0 SDS) (range -1.6 to + 0.9 SDS). The increase in height SDS during the first 2 years of GH treatment (0.1 U/kg/day) varied from 0.10 to 3.75 SDS, with younger children having a better growth response. Individual growth responses correlated (p < 0.001) with GH_max (r =–0.37), age (r= -0.35), 1-year pretreatment delta SDS (r = -0.25), mid-parental height SDS (r = 0.34), height SDS at start of treatment (r =–0.22) and difference between height SDS of an individual child at the onset of GH treatment and mid-parental height expressed in SDS (diff SDS) (r = –0.43). In a multiple stepwise linear regression model, diff SDS and log GH_max were found to be the strongest predictors of the magnitude of the growth response. In the short children in this study who exhibited a broad range of GH_max values, 33% of the growth response during the first 2 years of treatment could be predicted.