Prediction of the growth response in children with various growth disorders treated with growth hormone: analyses of data from the Kabi Pharmacia International Growth Study

Analyses to predict the growth response to recombinant human growth hormone (GH) in prepubertal children during the first year of treatment were performed on data from 472 patients with idiopathic GH deficiency (IGHD), 202 children with Turner's syndrome, 327 children with idiopathic short stature (ISS) and 135 children with intrauterine growth retardation (IUGR). In IGHD, 56% of the variability of the response could be predicted from a model based on six variables. These variables could be ranked in order of importance as follows: target height SDS minus height SDS, chronological age, frequency of GH injections, dose of GH, weight-for-height index, and birth weight SDS. When the model for IGHD was applied to Turner's syndrome, ISS and IUGR, there was a high degree of similarity between the predicted and achieved growth response in ISS and IUGR. However, an uneven distribution within the plot of Studentized residuals in ISS and IUGR suggested heterogeneity within these populations. Prediction of growth in Turner's syndrome was greatly exaggerated by the model for IGHD, suggesting a different pathogenesis as the basis of the growth disorder. Specific prediction models were therefore developed for Turner's syndrome, ISS and IUGR. In all three disorders, the dose of GH was found to be the most important predictor, suggesting that, in contrast to IGHD, first-year growth is governed less by the difference between height and the presumed genetically determined target height. Again, in contrast to IGHD, this suggests that catch-up phenomena are not involved. As the predictability of the variation in growth response in Turner's syndrome, ISS and IUGR did not exceed 32% (for ISS), the search for new predictors should continue in these disorders.     

Update on the Kabi International Growth Study, April 1989

International Board, Kahi International Growth Study (Kahi, Stockholm, Sweden). Update on the Kahi International Growth Study, April 1989. Acta Paediatr Scand [Supp] 356: 173, 1989.
The efficacy and safety of recombinant human growth hormone (rhGH) treatment is under prospective evaluation in children with various short stature conditions. Of the 987 children enrolled up to April 1989, 836 (84.7%) had classic growth hormone deficiency (GHD) and 151 (15.3%) non-GHD. There was a predominance of idiopathic growth hormone deficiency (IGHD), with a ratio of IGHD to secondary or organic GHD (OGHD) of 2.2:l. There were more boys than girls in both the IGHD and OGHD groups. Isolated GHD was more common than multiple pituitary hormone deficiency except in some of the groups with OGHD. About half of the OGHD patients had GHD secondary to treatment for CNS tumours. Idiopathic short stature and Turner's syndrome were the most common diagnoses in the non-GHD group. The median age at onset of treatment in IGHD was 8.2 years for boys and 8.6 years for girls. The corresponding figures for OGHD were 14.0 years and 12.2 years, respectively. The height SDS for chronological age at the start of treatment was -3.0 for IGHD and slightly less for children with OGHD. Approximately one-third of the children had already reached puberty at the start of hGH treatment.     

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from –3.5 at baseline to –2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.     

Final height in idiopathic growth hormone deficiency: the KIGS experience. KIGS International Board

Final height was evaluated in 369 patients with idiopathic growth hormone deficiency (IGHD) enrolled in KIGS--the Pharmacia & Upjohn International Growth Database. At the start of growth hormone (GH) therapy, the patients were 9.8 years of age, their mid-parental height SDS was -0.8, and their height SDS was -3.1. Of the 369 patients, 50% had multiple hormone deficiencies, and puberty was induced in 31%. Patients were 18 years of age at completion of GH therapy, and had received GH at a dose of 0.49 IU/kg/week (0.16 mg/kg/week), with a mean of 5.2 injections/week for 8.1 years. Final height SDS was -1.5, final minus initial height SDS was 1.7 and final minus mid-parental height SDS was -0.5. A Swedish subgroup (n = 69) received conventional GH therapy throughout at 0.65 IU/kg/week (0.22 mg/kg/week), with seven injections/week for a mean of 9.4 years. These patients achieved their genetic potential (final minus mid-parental height SDS, 0.03), with a normal final height SDS of -0.3. For the total group, the following variables were associated with final height: mid-parental height SDS (r = 0.62), injection frequency (r = 0.37), duration of GH treatment (r = 0.28), peak stimulated GH concentration (r = -0.25), age (r = -0.19) (all p < 0.001) and height velocity SDS in the first year of treatment (r = 0.20, p = 0.004). In conclusion, genetic potential, expressed as the mid-parental height, is the variable with the greatest identified influence on final height during GH treatment in IGHD. Current GH regimens will lead to a normal height and attainment of mid-parental height. However, higher dose, individualized GH regimens are likely to be necessary for patients with IGHD who are disadvantaged at the time of commencing GH therapy, such as those with short parents, those whose treatment began in late childhood or adolescence and those with less severe GHD.     

Effect of long-term recombinant growth hormone therapy in children--the National Cooperative Growth Study, USA, 1985-1994

Over a 9-year period (1985-1994) approximately 20,000 children received recombinant human growth hormone (rhGH) while enrolled in the National Cooperative Growth Study (NCGS), an observational, longitudinal study designed to monitor the long term efficacy and safety of rhGH administered to children in North America. Forty-four percent of the patients had idiopathic growth hormone deficiency (IGHD), 13.8% organic GHD (OGHD), 25% idiopathic short stature (ISS), 9.9% Turner's syndrome (TS), and 7.3% miscellaneous disorders. Eighty-five percent of the patients enrolled were Caucasian, and approximately two-thirds of the non-Turner patients were male. For the subset of patients treated for at least 4 years and who were prepubertal throughout this period (IGHD N=308, OGHD N=93, ISS N=169, TS N=82), mean growth rates increased in all patient categories and remained at or above pretreatment growth rates through 4 consecutive years of therapy with rhGH. Growth rates during administration of rhGH were greater in children in whom the pretreatment maximum stimulated GH concentration was < or =3 microg/l. Patients treated with 6 or 7 doses of rhGH each week grew more rapidly than did those receiving thrice weekly dosages, although the ratios of the increment in bone age to the increment in height age after two years of therapy were similar in the two treatment regimens. For patients treated with rhGH for 7 consecutive years, the mean height standard deviation scores increased by 2.5 in IGHD (N=169), 2.0 in OGHD (N=50), 1.9 in ISS (N=69), and 1.3 in TS (N=19), but remained below target heights in all categories. It is concluded that administration of rhGH increases growth rates in patients with IGHD, OGHD, ISS, and TS, and that this stimulatory effect can persist for at least 4 years.     

Final height in Swedish children with idiopathic growth hormone deficiency enrolled in KIGS treated optimally with growth hormone

Aim: To assess final height in children with growth hormone deficiency (GHD) treated with human recombinant growth hormone (GH). Methods: Final height data for 401 Swedish children with idiopathic GHD and treated with GH, included in KIGS (Pfizer International Growth Database) between 1987 and spring 2006, were analysed retrospectively. Data were grouped according to sex, age and severity of GHD. Height at entry into KIGS, at the onset of puberty and near final height were analysed between groups. Results: Groups were heterogeneous for GHD, which ranged from partial to severe. For all groups, mean final height corrected for mid‐parental height was within the normal Swedish height range. In patients with severe GHD, mean final height was almost identical to mean normal Swedish height. About 16% of patients showed disproportionality (short legs) at final height and were significantly shorter than other patients. The parents of these children also demonstrated short stature. Conclusion: Children with idiopathic GHD receiving GH replacement therapy can achieve a final height that as a group is within the normal range and all achieve a height within their genetic potential.     

An Overview of the Diagnoses in the Kabi Pharmacia International Growth Study

This paper provides an overview of the diagnoses of patients entered in the Kabi Pharmacia International Growth Study (KIGS). By May 1991, data from a total of 5377 children treated with growth hormone (GH) were included in the main database. Of these children, 2691 were classified as having idiopathic GH deficiency (GHD), 866 as having GHD of known origin, and 1820 as having other causes of short stature. The majority of patients with idiopathic GHD have no history of perinatal trauma. In the patients with GHD of known origin, 137 were congenital cases and 729 acquired GHD. The largest number of congenital cases (114) belonged to the group of central malformations (e.g. septo-optic dysplasia and empty sella syndrome). Of the cases with acquired GHD, 73% were associated with tumours or leukaemia. Other causes of short stature include 12 groups of diagnoses, with more than 150 cases in four of them (idiopathic short stature, 635; defined syndromes with chromosomal aberrations, 337, of which 304 were Turner's syndrome; defined syndromes without chromosomal aberrations, 157; intrauterine growth retardation without stigmata, 366). Analysis of the KIGS data allows modern GH therapy for GHD to be compared with older treatment modalities. The study offers the advantage of larger numbers of cases than can be achieved in individual trials and allows assessment of the use of GH therapy for GHD of comparatively uncommon causes.     

The role of insulin like growth factor (IGF) — 1 and IGF — binding protein-3 in diagnosis of Growth Hormone Deficiency in short stature children

Objective  The purpose of this study was to evaluate the role of IGF-1 and IGFBP-3 in diagnosis of short stature children and adolescents in whom Growth Hormone Deficiency (GHD) was found. Methods  In this cross sectional study the referred short stature children and adolescents to Namazi Hospital in Shiraz- Iran, in 2003–2005 were studied. The inclusion criteria were proved short stature based on the physical examination, weight, height, standard deviation score (SDS) of height < −2, with considering stage of puberty and predicted height in children without any genetic or chronic disorders. The exclusion criteria were any positive physical or laboratory data suggesting hypothyroidism, rickets or liver disorders. For all patients a provocative growth hormone test was performed with propranolol and L-dopa and serum IGF-1 and IGFBP-3 were measured. GHD defined as peak(cutoff) serum GH level under 10 ìg/L and low IGF-1 and IGFBP-3 considered as cutoff serum level under −2 standard deviation. Results  Eighty one short stature patients (39 boys and 42 girls) with mean age of 10.6 ± 3.5 years completed the study. Seventeen patients with GHD were found and in 18 patients IGF-1 level were low. Only in 6 patients both GH and IGF-1 were low and 2 of them had low IGFBP-3. There were no correlations between the levels of GH,IGF-1 and IGFBP-3 in children with short stature due to GHD. The sensitivity and specifity of IGF-1 and IGFBP-3 in assessment of GHD were 35% and 81% for IGF-1 and 12% and 94% for IGFBP-3, respectively. Conclusion  No correlations were found between GH level and serum levels of IGF-1 and IGFBP-3 in short patients and the sensitivity of those tests in assessment of GHD were poor.     

Acid-base homeostasis in children with growth hormone deficiency

BACKGROUND: Although the primary use of growth hormone (GH) is to promote linear growth, it is also known to affect many metabolic processes and to influence renal function. In laboratory animals, growth hormone deficiency (GHD) causes a mild metabolic acidosis that is corrected by GH treatment. We observed a patient with GHD who initially presented with acidosis of unclear etiology and corrected the acidosis with GH treatment. OBJECTIVES: To determine: 1) whether children with GHD have lower mean serum bicarbonate concentrations than do children with short stature because of other causes; and 2) whether the presence of a low serum bicarbonate concentration increases the probability of GHD among children with short stature. METHODS: We collected data from the medical records of 143 children with short stature who had serum electrolyte concentrations measured as part of their initial evaluations, 66 with GHD and 77 with short stature as a result of other causes. We compared mean serum bicarbonate concentrations and bicarbonate standard deviation scores (SDS) between these two groups and determined the probability of GHD for patients according to bicarbonate SDS. RESULTS: The mean serum bicarbonate concentration was significantly lower in patients with GHD (mean standard deviation [SD]; 23.9 [0.4] mEq/L vs 25.2 [0.3] mEq/L) as was the bicarbonate SDS (-0.12 [0.14] SD vs 0.38 [0.10] SD). Twelve (75%) of 16 patients with bicarbonate SDS 1 SD. Patients with bicarbonate SDS between -1 SD and 1 SD had an intermediate probability of GHD, 46/102 (45%), similar to the overall prevalence of GHD in the study population (46%). Mean bicarbonate concentrations and bicarbonate SDS increased significantly in 9 patients who had repeat electrolyte measurements during treatment with GH (mean bicarbonate; 21.7 [1.1] mEq/L vs 26.9 [0.59] mEq/L, mean bicarbonate SDS; -1.24 [0.43] SD vs 0.55 [0.27] SD). CONCLUSIONS: Serum bicarbonate concentrations are lower in patients with GHD than in patients with short stature as a result of other causes. In addition, serum bicarbonate concentrations rise with GH treatment in patients with GHD. The probability of GHD is increased for patients with bicarbonate SDS 1 SD. These findings indicate a role for GH in maintaining normal acid-base homeostasis and suggest that GHD should be considered in children whose growth failure is attributed to other causes of acidosis.     

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     

Diagnosis of idiopathic growth hormone deficiency: contributions of data on the acid-labile subunit, insulin-like growth factor (IGF)-I and-II, and IGF binding protein-3

The diagnosis of non-organic growth hormone (GH) deficiency (GHD) remains difficult. OBJECTIVE: To evaluate the value of measuring plasma insulin-like growth factor (IGF)-I and -II, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) as criteria for diagnosing GHD. PATIENTS: 120 prepubertal patients having at least one of the main auxological criteria defined by the GH Research Society for initiating GH exploration were classified as (1) certain GHD (n = 40), (2) transient GHD (n = 18), (3) idiopathic short stature (n = 27), or (4) extreme short stature (n = 35). RESULTS: All the patients with certain GHD had low (< or = -2 z-score) plasma concentrations of IGF-I and ALS, but only 35.1% had low IGF-II, and 48.6% had low IGFBP-3. All the patients but three (83.3%) with transient GHD had low IGF-I, but only 44.4% had low ALS, and only one had low IGF-II or IGFBP-3. The data for patients with idiopathic and extreme short stature and normal GH peak were similar to each other and to those for patients with transient GHD, except that IGF-I was less frequently low (49.2%, p <0.05). CONCLUSIONS: All the patients with certain GHD had both IGF-I and ALS z-scores < or = -2, unlike those with transient GHD, and idiopathic or extreme short stature. Almost all the patients with short stature and normal GH peak had normal serum IGF-II and IGFBP-3 concentrations.     

Effect of Growth Hormone Treatment on Quality of Life in Japanese Children with Growth Hormone Deficiency: An Analysis from a Prospective Observational Study

The aim of this study was to assess changes in quality of life (QoL) in Japanese children with GH deficiency (GHD) after 12 mo of GH treatment or with idiopathic short stature (ISS) after 12 mo without treatment. Children with GHD were treated with GH after enrollment. Outcome measures included the parent-rated Child Behavior Checklist (CBCL), the Youth Self-Report Form (YSR), and height standard deviation scores (SDS). Total CBCL scores significantly decreased in children with GHD (n = 152, mean change (standard deviation [SD]) = –3.42 [11.21]) and ISS (n = 129, mean change = –4.82 [10.09]) after 12 mo (p < 0.001). Total YSR scores (mean change = –9.21 [14.07]) and height SDS (mean change = 0.35 [0.38]) significantly decreased in children with GHD (p < 0.001), but were unchanged in children with ISS. The change in total YSR score was significantly correlated with the change in height SDS in children with GHD (r = –0.516, p = 0.003). Our findings demonstrate that GH treatment can improve QoL in Japanese children with GHD. The correlation between the changes in total YSR score and height SDS demonstrated that increased height resulted in improved QoL.     

Growth response, pubertal growth and final height in Greek children with growth hormone (GH) deficiency on long-term GH therapy and factors affecting outcome

The growth data of 156 children (100 boys, 56 girls) with growth hormone deficiency (GHD), treated with human growth hormone (GH) for 5.7+/-3.7 years, from 1970-1997, were retrospectively analyzed to assess the efficacy of GH treatment and the factors involved. 62.2% of the studied population had idiopathic GHD (IGHD) and 35.2% had organic GHD (OGHD). At initiation of treatment, chronological age (CA) was 10.1+/-4.0 years in children with IGHD and 9.7+/-4.0 years in those with OGHD, while bone age (BA) was 7.0+/-3.7 and 7.7+/-3.2 years, respectively. The SDS of the growth velocity during the first year of therapy (GV1) was negatively related to CA at start of therapy (r = -0.53, p = 0.01). 109 children have reached final height (FH): 67 boys (FH = 165.3+/-6.3 cm) and 42 girls (FH = 153.9+/-5.4 cm). FH SDS was not significantly different from target height (TH) SDS. In the total group, FH SDS was positively related to height SDS for CA and BA at start of therapy (p = 0.01, p = 0.001, respectively), to TH SDS (r = 0.40, p = 0.001), and to GV1 (r = 0.33, p = 0.001). TH SDS was not different between the IGHD and OGHD groups (-1.02+/-0.8 vs. -0.94+/-6.9). The height gain at puberty did not differ between the groups with induced or spontaneous puberty in boys (23.7+/-8.6 vs. 25.4+/-6.9, not significant), while in girls it was higher in the group with spontaneous puberty (12.7+/-7.3 vs. 20.0+/-9.0, p = 0.008). The age and height at start of puberty was higher in girls and boys with induced puberty. In the total group, the FH SDS of children with induced puberty was higher in comparison with those with spontaneous puberty (-1.0+/-0.8 vs. -1.7+/-0.9, p = 0.001) and it was positively related to the height at start of puberty. When the two sexes were analyzed separately, the difference reached significance only in boys. In conclusion, children with GHD on GH treatment achieved a final height which was comparable to their genetic potential. The FH of children with OGHD was not different from those with IGHD. The age and height at start of puberty were the most significant determining factors for FH. Hence, a better FH might be expected by delaying or arresting puberty.     

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     

Profile of growth hormone deficiency in Bombay

Of the 430 children referred for the evaluation of short stature 100 (23%) were confirmed to have growth hormone deficiency. The male to female ratio was 1.94: 1. Less than 10% belonged to the lower socio-economic group. Most of the cases (73%) presented between the ages of 6–15 years though growth failure was usually recognised earlier. Minimum of two stimulation tests were performed in each case. Seventy five GH deficient children had idiopathic GHD (IGHD) and 31% of these were familial. Fourteen had organic causes and 11 had GH resistance. Of 75 with IGHD, 18 had abnormal deliveries, breech or birth asphyxia. Multitropic pituitary hormone deficiency (MPHD) was found in 9/75 cases of idiopathic GHD and in three of the organic group. The height age was much more retarded than chronologic age in the GH resistant group (p<0.05) and the HA/BA ratio was also lowest in this group (p<0.001). Growth velocity was less than 4 cm/year in all the GHD children but was lowest in those with MPHD. The interesting feature of this study is the marked predominance of the familial cases 31% and a high incidence of growth hormone resistant cases (11%).     

Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect

OBJECTIVES: To investigate in an open-label randomized study, the effect of two doses of growth hormone (GH) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature (mean baseline height standard deviation score [SDS] -3.2). STUDY DESIGN: Patients were treated with GH at 0.24 mg/kg/week, 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter (0.24-->0.37), or 0.37 mg/kg/week. Final height was evaluated in 50 patients at study completion (mean treatment duration, 6.5 years). RESULTS: Patients who received 0.37 mg/kg/week (n = 72) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week (n = 70) (treatment difference = 0.8 cm/year; P = .003) or 0.24-->0.37 mg/kg/week (n = 67) (treatment difference = 0.9 cm/year; P = .001). For the 50 patients for whom final height measurements were available, mean height SDS increased by 1.55, 1.52, and 1.85 SDS, respectively, for the three dose groups. For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, the mean treatment difference (adjusted for differences in baseline predicted height SDS) was 0.57 SDS (3.6 cm; P = .025). Mean overall height gains (final height minus baseline predicted height) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, respectively, without dose effects on safety parameters. Final height measurements were within the normal adult height range for 94% of patients randomized to 0.37 mg/kg/week who continued to final height. CONCLUSION: GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature.     

Causes of short stature in children in relation to their midparental height

Introduction: It is considered that the evaluation of a child's height strongly depends on the evaluation of his/her midparental height. Aim of study: Analysis of causes of short stature in children in relation to midparental height. Material and methods: The study included 452 children with short stature, aged 3-18 yrs. The group of children included 178 girls and 274 boys. The children's measurements were standardized using the arithmetic mean and standard deviation for the Institute of Mother and Child norms. Midparental height was evaluated according to standards for 18-year-olds. The average height deficit was -2.5 SDS±0.65. The average midparental height was 166.07 cm±4,63 and in SDS it was -0.93±0,74. Results: Growth hormone deficiency (GHD) or multihormonal pituitary deficiency was found in 34.3% of the patients (50 girls and 105 boys). In 22 girls (12.48) the Turner syndrome (TS) was diagnosed. Other causes of short stature were observed in 37 children. No hormonal disorders were found in the remaining group (275 children). 7% of those children were characterized by significant height deficit (-3 SDS). The difference between midparental height of GHD children and healthy children was not statistically significant. Body height of 20% of GHD children was consistent with their midparental height. The midparental height of girls with TS was significantly higher than the midparental height of the other children. The body height of 50% of girls with TS differed from their midparental height. The body height of 40% of healthy short children was consistent with their midparental height. Conclusions: 1. Children with short stature are a very heterogenous group of patients. 2. Comprehensive evaluation of physical development in children should not be restricted to the widely used criterion of midparental height.     

The GHRH test in Turner's syndrome

GHRH test was performed in 11 girls suffering from Turner's syndrome ranging in age from 5.6-13.5 years. GH peak resulted lower than 10 ng/ml in three subjects, who had also shown reduced GH values after two conventional pharmacological stimuli (L-dopa- and insulin-induced hypoglycemia) and a value of mean GH concentration over 24 hours lower than 3 ng/ml. Both GH peak and area under the curve were not correlated with height, height velocity, bone age/chronological age ratio, GH peak after conventional pharmacological stimuli and mean GH value of spontaneous secretion. The comparison with the results of GHRH test in other kinds of short stature evidenced in girls with Turner's syndrome the presence of GH values (peak and area under the curve) higher than those in subjects with "classical" GH deficiency, lower than those in "short normal stature" and similar to those in subjects with "non classical" GH deficiency. In conclusion, our data suggest, even if within a certain variability of the responses, a possible involvement of GH deficiency to the pathogenesis of short stature in Turner's syndrome, suggesting the existence of a prevalent hypothalamic nature of GH deficiency.     

Growth hormone therapy

Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3–4 cm/year before therapy to 10–12 cm/year during the first two years of therapy and is maintained at 7–8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.     

Evaluation of insulin-like growth factor (IGF)-I and IGF binding protein-3 generation test in short stature

BACKGROUND: Differentiation between growth hormone deficiency (GHD) and idiopathic short stature (ISS) based on GH tests and basal IGF-I and IGFBP-3 levels may be difficult. The aim of this study was to evaluate the role of pharmacological GH tests, IGF-I and IGFBP-3 generation test and height velocity off-treatment in the evaluation of GHD and ISS. METHODS: Thirty-three (17 M, 16 F) prepubertal short (height SDS < -2) children were divided into two groups: Group 1 (n = 19) with peak GH level <10 tg/l (GHD) and Group 2 (n = 14) GH > or =10 microg/l in two sex steroid primed pharmacological GH tests. Having excluded other diagnoses, Group 2 was regarded as having ISS. The generation test was performed concomitantly (0.1 IU/kg GH s.c. for 4 days) with IGF-I and IGFBP-3 measured on the 4th day in both groups. The patients were followed for a year for height velocity (HV). RESULTS: Group 1 and 2 had comparable height SDS (-2.3 +/- 0.4 and -2.3 +/- 0.3) at comparable ages (7.8 +/- 2.8 and 7.0 +/- 2.7 yr). Although the deltaIGF-I response was low (<2.0 nmol/l 115 ng/ ml]) in seven (37%) children in the GHD group, all GHD patients with low height velocity had adequate (> or =14 nmol/I [400 ng/ml]) deltaIGFBP-3 response. deltaIGFBP-3 in the generation test showed a negative correlation with HV (p = 0.021, r = -0.570) and also with basal IGFBP-3 (p <0.001, r = -0.743) in the GHD group. In the ISS group, deltaIGF-I and deltaIGFBP-3 responses were low in 31% and 7%, respectively, and the correlation between basal IGF-I, IGFBP-3 and HV and between delta values in the generation test were significantly positive, pointing to a difference in the growth response of these children. CONCLUSION: In the GHD group, based on pharmacological tests, an adequate deltaIGFBP-3 response in the generation test predicts poor height velocity at follow up and thus strengthens the diagnosis of true GHD.