Gain In Height SD Score Research Articles

Timing of Puberty, Pubertal Growth, and Adult Height in Short Children Born Small for Gestational Age Treated With Growth Hormone.

Growth hormone (GH) is used to treat short children born small for gestational age (SGA); however, the effects of treatment on pubertal timing and adult height are rarely studied. To evaluate adult height and peak height velocity in short GH-treated SGA children. Prospective longitudinal multicenter study. Participants were short children born SGA treated with GH therapy (n = 102). Adult height was reported in 47 children. A reference cohort of Danish children was used. Main outcome measures were adult height, peak height velocity, age at peak height, and pubertal onset. Pubertal onset was converted to SD score (SDS) using Danish reference data. Gain in height SDS from start of treatment until adult height was significant in both girls (0.94 [0.75; 1.53] SDS, P = .02) and boys (1.57 [1.13; 2.15] SDS, P < .001). No difference in adult height between GH dosage groups was observed. Peak height velocity was lower than a reference cohort for girls (6.5 [5.9; 7.6] cm/year vs 7.9 [7.4; 8.5] cm/year, P < .001) and boys (9.5 [8.4; 10.7] cm/year vs 10.1 [9.7; 10.7] cm/year, P = .002), but no difference in age at peak height velocity was seen. Puberty onset was earlier in SGA boys than a reference cohort (1.06 [-0.03; 1.96] SDS vs 0 SDS, P = .002) but not in girls (0.38 [-0.19; 1.05] SDS vs 0 SDS, P = .18). GH treatment improved adult height. Peak height velocity was reduced, but age at peak height velocity did not differ compared with the reference cohort. SGA boys had an earlier pubertal onset compared with the reference cohort.

Height Gain and Safety Outcomes in Growth Hormone-Treated Children with Idiopathic Short Stature: Experience from a Prospective Observational Study

Background/Objectives: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. Methods: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. Results: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and –1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD – most were common childhood conditions or previously reported in GH-treated patients. Conclusions: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.

Genetic predictors of long-term response to growth hormone (GH) therapy in children with GH deficiency and Turner syndrome: the influence of a SOCS2 polymorphism.

There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P= .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.

IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children.

GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (heightSDS) was 1.3 (range 0-3), compared with 0.2 in the untreated group. The objective of the study was to analyze the relationship between IGF-1SDS, IGF binding protein-3 SDS (IGFBP3SDS), and their ratioSDS with a gain in the heightSDS until AH in non-GH-deficient short children. This was a randomized, controlled, multicenter clinical trial. The intervention included GH treatment: 33 or 67 μg/kg · d plus untreated controls. One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). Increments from baseline to on-treatment study mean IGF-1SDS (ΔIGF-1SDS), IGFBP3SDS, and IGF-1 to IGFBP3 ratioSDS were assessed in relationship to the gain in heightSDS. Sixty-two percent of the variance in the gain in heightSDS in children on GH treatment could be explained by four variables: ΔIGF-1SDS (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1SDS was at baseline, the higher was its increment during treatment. For both the AllPP- and the ISSPP-treated groups, the attained IGF-1SDS study level did not correlate with height gain. In short non-GH-deficient children, the GH dose-related increment in IGF-1SDS from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1SDS, IGFBP3SDS, and their ratioSDS were compared concurrently.

Three-Year Efficacy and Safety of LB03002, a Once-Weekly Sustained-Release Growth Hormone (GH) Preparation, in Prepubertal Children with GH Deficiency (GHD)

GH treatment currently requires daily sc injections, resulting in suboptimal compliance. A GH regimen with fewer injections may offer patients and caregivers a less arduous option. LB03002 is a novel sustained-release GH formulation for once-weekly dosing. GH-deficient, GH-naive prepubertal children were randomized to four groups who received 0.2 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); 0.5 mg/kg/wk LB03002 for 36 months (n=13); 0.7 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); or daily GH 0.03 mg/kg/d for 24 months, switched to 0.5 mg/kg/wk LB03002 for 12 months (n = 12). Height velocity increased in all groups; the increase was less for the 0.2 mg/kg/wk LB03002 group at 12 (P = 0.008) and 24 months (P = 0.030), with no statistically significant differences at any time for the 0.5 mg/kg/wk and 0.7 mg/kg/wk LB03002 groups, vs. daily GH. Height sd score gain at 12 months was significantly (P = 0.023) less for the 0.2 mg/kg/wk group (1.05 ± 0.38) than daily GH (1.47 ± 0.29), but with no statistically significant difference for the 0.5 mg/kg/wk (1.37 ± 0.39) and 0.7 mg/kg/wk (1.50 ± 0.44) LB03002 groups vs. daily GH. There were no significant differences in height sd score gain between any groups at 24 and 36 months. Bone maturation did not differ for any LB03002 dose compared with daily GH. Serum IGF-I concentrations increased as expected, with no long-term differences between groups. Mean fasting glucose and glycosylated hemoglobin concentrations did not exceed normal ranges for any treatment group at any time. LB03002 at doses of 0.5 mg/kg/wk and 0.7 mg/kg/wk was shown to be effective and safe with once-weekly dosing in GH-deficient children, and 0.5 mg/kg/wk LB03002 was chosen as the optimal dose for long-term assessment.

Impact of Growth Hormone Therapy on Adult Height of Children Born Small for Gestational Age

Use of growth hormone (GH) therapy to promote growth in short children born small for gestational age (SGA) was recently approved in the United States and Europe, but there is still disagreement about the magnitude of effectiveness of GH. To determine the impact of GH therapy on adult height in short SGA children by a meta-analysis of randomized, controlled trials (RCTs). We performed a systematic review of controlled studies using as data sources the Cochrane Central Register of Controlled Trials, Medline, and the bibliographic references from all retrieved articles describing RCTs up to November 2008. A meta-analysis of all RCT studies conducted up to the achievement of adult height was performed. Inclusion criteria were birth weight and/or length below -2 SD score (SDS), initial height less than -2 SDS, and GH dose range of 33 to 67 microg/kg per day. Adult height SDS and overall height gain SDS were the primary outcome measures. Four RCTs (391 children) met the inclusion criteria. The adult height of the GH-treated group significantly exceeded controls by 0.9 SDS. Mean height gain was 1.5 SDS in treated versus 0.25 SDS in untreated SGA subjects. No significant difference in adult height was observed between the 2 GH dose regimens. GH therapy seems to be an effective approach to partially reduce the adult height deficit in short SGA children. However, the response to therapy is highly variable, and additional studies are needed to identify the responders.

Improvement in Growth after Two Years of Growth Hormone Therapy in Very Young Children Born Small for Gestational Age and without Spontaneous Catch-Up Growth: Results of a Multicenter, Controlled, Randomized, Open Clinical Trial

GH treatment is effective in children born small for gestational age (SGA); however, its effectiveness and safety in very young SGA children is unknown. The aim was to analyze the outcome of very young SGA children treated with GH and followed for 2 yr. The results after 24 months of treatment, compared with a control group without treatment during 12 months followed by 12 months of treatment, are shown. We performed a multicenter, controlled, randomized, open trial. The pediatric endocrinology departments of 14 public hospitals in Spain participated in the study. Seventy-six children, aged 2-5 yr born SGA and without catch-up growth, were studied. Children received GH at 0.06 mg/kg.d for 2 yr (group I) or were followed for 12 months with no treatment and then treated for 12 months (group II). Age, general health status, pubertal stage, bone age, height, weight, biochemical and hormonal analyses, and adverse side effects were determined at biannual check-ups. The mean height sd score gain for chronological age in children treated for 24 months (group I) was 2.10, whereas in those treated only during the last 12 months (group II) was 1.43. In both groups, children under 4 yr of age had the greatest gain in growth velocity. No significant acceleration of bone age or side effects related to treatment was seen. Very young SGA children without spontaneous catch-up growth could benefit from GH treatment because growth was accelerated and no negative side effects were observed.

SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity.

SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1-18.3), mean height sd score (SDS) (sd in parentheses) was -2.85 (1.04), and mean sitting height/height ratio SDS was +3.06 (1.09). Mean birth length SDS was -0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3-11.3) was insignificant with a mean change in height SDS of -0.10 (0.52). Mean height SDS of affected parents was -2.70 (0.85) vs. -0.91 (1.10) in unaffected parents. Height loss due to LWD was estimated calculating delta height defined by actual height SDS minus target height SDS of the unaffected parent(s). In the children, mean delta height SDS was -2.16 (1.06), the loss being greater in girls at -2.30 (1.02) than in boys at -1.72 (1.09) (P = 0.32). In patients with SHOX deletions, it was -2.14 (1.15) vs. -1.67 (0.73) for the SHOX point mutation group (P = 0.38). Mean delta height SDS was -2.26 (0.68) for the girls with early menarche (<12 yr) vs. -2.08 (0.91) for the other postmenarcheal girls (P = 0.72). Height loss in patients with radiologically severe wrist deformities in comparison with those having milder radiological signs was -2.81 (1.01) vs. -1.70 (1.04) (P = 0.03). GH treatment in five children during a median duration of 3.4 yr (range, 1.5-9.8 yr) with a median dosage of 0.23 mg/kg.wk (range, 0.14-0.25) resulted in a mean height SDS gain of +0.82 (0.34). In conclusion, SHOX defects were the main cause of LWD. Growth failure occurred during the first years of life with a mean height loss of 2.16 SDS whereas pubertal growth may only be mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. No statistically significant effects of type of mutation, age of menarche, or sex on height were observed. The effect of GH therapy varied between individuals and needs to be examined in controlled studies.

Final Height Gain by GH Therapy in Children with Idiopathic Short Stature Is Dose Dependent

Recombinant human GH therapy to children with idiopathic short stature (ISS) increases growth velocity, but its effect on final height (FH) is still uncertain. The aim of this study was to investigate the effect of recombinant human GH on FH of patients with ISS who were treated according to two protocols in comparison to untreated historical controls. In study 1 (n = 24), all patients were treated with 14 IU (4.6 mg)/m2 body surface·wk in the first year; thereafter the dosage was doubled if the growth response was insufficient. In study 2 (n = 34), patients were randomized into three arms: 18 IU (6 mg)/m2·wk; 27 IU (9 mg)/m2·wk; and 18 IU/m2·wk in the first year, followed by 27 IU/m2·wk thereafter. Observed or estimated FH was available for 53 patients. Thirty-four untreated controls from the same centers were available for comparison. Mean FH sd score in GH-treated children was −2.1, vs. −2.4 in controls (−2.4) (NS), but height sd score gain (1.3 vs. 0.7) and the difference between FH and predicted adult height (4.0 vs. 0.8 cm) were significantly greater. The growth response on an initial dosage of 27 IU/m2·wk (6.9 cm) was significantly better than on other regimens (2.8 cm). We conclude that a GH dosage of 27 IU (9 mg)/m2·wk to prepubertal children with ISS leads to a mean FH gain of approximately 7 cm, whereas regimens starting on lower dosages are less efficacious.

Final Height Gain by GH Therapy in Children with Idiopathic Short Stature Is Dose Dependent

Recombinant human GH therapy to children with idiopathic short stature (ISS) increases growth velocity, but its effect on final height (FH) is still uncertain. The aim of this study was to investigate the effect of recombinant human GH on FH of patients with ISS who were treated according to two protocols in comparison to untreated historical controls. In study 1 (n = 24), all patients were treated with 14 IU (4.6 mg)/m(2) body surface x wk in the first year; thereafter the dosage was doubled if the growth response was insufficient. In study 2 (n = 34), patients were randomized into three arms: 18 IU (6 mg)/m(2) x wk; 27 IU (9 mg)/m(2) x wk; and 18 IU/m(2) x wk in the first year, followed by 27 IU/m(2) x wk thereafter. Observed or estimated FH was available for 53 patients. Thirty-four untreated controls from the same centers were available for comparison. Mean FH SD score in GH-treated children was -2.1, vs. -2.4 in controls (-2.4) (NS), but height SD score gain (1.3 vs. 0.7) and the difference between FH and predicted adult height (4.0 vs. 0.8 cm) were significantly greater. The growth response on an initial dosage of 27 IU/m(2) x wk (6.9 cm) was significantly better than on other regimens (2.8 cm). We conclude that a GH dosage of 27 IU (9 mg)/m(2) x wk to prepubertal children with ISS leads to a mean FH gain of approximately 7 cm, whereas regimens starting on lower dosages are less efficacious.

Effect of growth hormone treatment in children with craniopharyngioma with reference to the KIGS (Kabi International Growth Study) database.

In children with craniopharyngioma, poor growth commonly precedes diagnosis, but is observed less frequently than neurological or visual symptoms. A deficiency of growth hormone (GH) is common before, and almost universal after, treatment of the tumour, and is usually treated with GH. However, a minority of these children with GH deficiency (GHD) grow well without GH replacement therapy but exhibit other metabolic effects of GHD that are correctable by GH treatment. This article provides a review of studies in 422 children with craniopharyngioma whose details have been entered into the database of KIGS, the Kabi International Growth Study. The response to GH during the first year of therapy was similar to that seen in children with idiopathic GHD (IGHD). Leg length was relatively greater than sitting height and this disproportion was maintained during treatment. Adiposity increased in some children receiving GH treatment. At the end of GH treatment in 82 patients, there was a median gain in height SD score of 1.51, with evidence of residual growth potential still remaining in the majority. Tumour recurrence occurred in 13.5% of the total group of patients with craniopharyngioma within KIGS, at a median of 3.9 years from diagnosis and 2.3 years from the start of GH therapy. Tumour recurrence was not associated with an impairment in height achieved, but there was a tendency towards greater adiposity in patients in whom recurrence occurred. Adverse events during GH treatment were more frequent in children with craniopharyngioma than in those with IGHD, and headache was commonly reported. The results of these studies suggest that GH treatment is recommended for the treatment of children with craniopharyngioma on the grounds of improved growth velocity, adult height and other GH-dependent metabolic functions, and of the good safety profile of GH in these patients.

Outcome of a four-year randomized study of daily versus three times weekly somatropin treatment in prepubertal naive growth hormone-deficient children. Genentech Study Group.

A comparison was made of the growth responses of prepubertal naive GH-deficient children who were randomly assigned to receive 0.3 mg/kg.week recombinant human GH administered either daily (QD) or three times weekly (TIW) over 4 yr. The effects of the two regimens on annual growth velocity, change in height SD score, bone maturation, and age at onset of puberty are presented as the mean +/- SD. During each of the 4 yr, the annual growth velocity was significantly greater in the QD vs. TIW group. At 48 months, the mean total gain in height was 9.7 cm greater in the QD group (38.4 +/- 5.5) than that in the TIW group 28.7 +/- 3.2; P = 0.0002). The mean height SD score at the end of each year was significantly greater in the QD group. After 4 yr, the total gain in height SD score was 3.2 +/- 1.2 in the QD group compared to 1.5 +/- 0.5 in the TIW group (P = 0.0003). The height SD score at 4 yr was 0.2 in the QD group (pretreatment, -2.9) compared to -1.4 in the TIW group (pretreatment, -2.9). After 4 yr of rhGH treatment, the increment in bone age was similar in the QD (4.9 +/- 1.0 yr) and TIW (4.8 +/- 1.1 yr) groups. The change in height age minus the change in bone age was more favorable in the QD (1.2 +/- 0.8 yr) than in the TIW (0.0 +/- 0.9 yr) group (P = 0.003). The mean age at onset of puberty in boys was the same in the QD (13.2 yr) and TIW (13.0 yr) groups (P = 0.71), and the mean bone age at the start of puberty was also similar (11.5 in QD and 11.3 in TIW groups; P = 0.66). The advantages of QD rhGH treatment in prepubertal GH-deficient children after 4 yr were additional gains of 1.7 height SD score and 9.7 cm in height over those treated with the TIW regimen (P = 0.0002).

Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature.

Isolated idiopathic growth hormone deficiency (GHD) and idiopathic short stature (ISS) can be difficult to distinguish, but the therapeutical consequences are different. In this report the data on final height of untreated and treated children with GHD and ISS are reviewed. Untreated GH-deficient individuals who underwent spontaneous puberty (22 male, 14 female patients) reached a mean final height of 4.7 SD (range 3.9 to 6.0) below the population's mean. If puberty was induced (19 male patients), mean final height SD score (SDS) was -3.1. Traditional regimens of GH administration (2-4 injections/wk) in 236 children (184 boys, 52 girls) with GHD and spontaneous puberty resulted in a final height SDS of -2.8 (range -1.5 to -4.7). In 190 children in whom puberty was induced (139 boys, 51 girls) mean final height was -1.6 (range - -1.1 to -2.4). The mean gain in final height SDS is therefore estimated at 1.5-2.0 in average cases, and 3.5 in extreme cases. Preliminary data suggest that on present regimens mean final height may approach target height. In untreated boys with ISS the mean final height was 2-5 cm lower than that predicted before puberty, whereas in girls it was almost equal to the prediction. After GH treatment the mean final height was 0.4-3.0 cm higher than the predicted adult height, which results in an average net gain in final height SDS of approximately 0.5-0.8 (3-5 cm).