Growth Hormone Treatment for Short Stature in the USA, Germany and France: 15 Years of Surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS)

2018 ◽  
Vol 90 (3) ◽  
pp. 169-180 ◽  
Author(s):  
Roland Pfäffle ◽  
Christof Land ◽  
Eckhard Schönau ◽  
Paul-Martin Holterhus ◽  
Judith L. Ross ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Standard Deviation Score ◽  
Measurement Data ◽  
International Study ◽  
Hormone Treatment ◽  
Height Velocity ◽  
Growth Disorders ◽  
Gh Treatment ◽  
The Usa

Background/Aims: To describe characteristics, auxological outcomes and safety in paediatric patients with growth disorders treated with growth hormone (GH), for cohorts from the USA, Germany and France enrolled in GeNeSIS, a post-authorisation surveillance programme. Methods: Diagnosis and biochemical measurement data were based on reporting from, and GH treatment was initiated at the discretion of, treating physicians. Auxological outcomes during the first 4 years of GH treatment and at near-adult height (NAH) were analysed. Serious and treatment-emergent adverse events were described. Results: Children in the USA (n = 9,810), Germany (n = 2,682) and France (n = 1,667) received GH (dose varied between countries), most commonly for GH deficiency. Across diagnostic groups and countries, mean height velocity standard deviation score (SDS) was > 0 and height SDS increased from baseline during the first 4 years of treatment, with greatest improvements during year 1. Most children achieved NAH within the normal range (height SDS >−2). No new or unexpected safety concerns were noted. Conclusion: GH treatment improved growth indices to a similar extent for patients in all three countries despite variations in GH doses. Data from these three countries, which together contributed > 60% of patients to GeNeSIS, indicated no new safety signals and the benefit-risk profile of GH remains unchanged.

scholarly journals Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study

2017 ◽  
Vol 102 (9) ◽  
pp. 3195-3205 ◽  
Author(s):  
Charmian A Quigley ◽  
Christopher J Child ◽  
Alan G Zimmermann ◽  
Ron G Rosenfeld ◽  
Leslie L Robison ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Turner Syndrome ◽  
International Study ◽  
Hormone Treatment ◽  
Idiopathic Short Stature ◽  
Growth Disorders ◽  
Gh Treatment ◽  
Increased Risk ◽  
History Of

Abstract Context Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood. Objective To assess mortality in children receiving GH. Design Prospective, multinational, observational study. Setting Eight hundred twenty-seven study sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment during childhood. Main Outcome Measure Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population. Results Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non–GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65). Conclusions No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non–GH-deficient medical conditions.

scholarly journals Growth Hormone Improves Short-Term Growth in Patients with Temple Syndrome

2018 ◽  
Vol 90 (6) ◽  
pp. 407-413 ◽  
Author(s):  
Diana S. Brightman ◽  
Oluwakemi Lokulo-Sodipe ◽  
Beverly A. Searle ◽  
Deborah J.G. Mackay ◽  
Justin H. Davies ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Growth Hormone Treatment ◽  
Standard Deviation Score ◽  
Uniparental Disomy ◽  
Hormone Treatment ◽  
Height Velocity ◽  
Short Term ◽  
Temple Syndrome ◽  
Hands And Feet

Background/Aims: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome. Methods: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone. Results: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year. Conclusions: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.

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

2019 ◽  
Vol 91 (4) ◽  
pp. 241-251 ◽  
Author(s):  
Christopher J. Child ◽  
Charmian A. Quigley ◽  
Gordon B. Cutler, Jr ◽  
Wayne V. Moore ◽  
Kupper A. Wintergerst ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
International Study ◽  
Study Data ◽  
Idiopathic Short Stature ◽  
Gh Treatment ◽  
Safety Issues ◽  
Safety Outcomes ◽  
Height Gain ◽  
Over Time

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.

Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results

2017 ◽  
Vol 88 (3-4) ◽  
pp. 258-264 ◽  
Author(s):  
Dina A. Schott ◽  
Willem J.M. Gerver ◽  
Constance T.R.M. Stumpel
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Standard Deviation Score ◽  
Height Velocity ◽  
Kabuki Syndrome ◽  
Body Proportions ◽  
Leg Length ◽  
Gh Treatment ◽  
Igf I ◽  
Rhgh Treatment

Background/Aims: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. Methods: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured. Results: This study showed an increase in height standard deviation score (SDS) for the whole group from –2.40 to –1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was –0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects’ body proportions remained normal. Conclusions: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.

scholarly journals Urinary Growth Hormone Excretion as Measured by a Sensitive Immunochemiluminometric Assay

1993 ◽  
Vol 30 (2) ◽  
pp. 180-185 ◽  
Author(s):  
G Turner ◽  
R C Brown ◽  
I Weeks ◽  
G E Butler ◽  
F N Creagh ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Individual Variability ◽  
Height Velocity ◽  
Growth Disorders ◽  
Serum Growth Hormone ◽  
Renal Handling ◽  
Gh Secretion ◽  
Normal Stature ◽  
Optimum Sampling

A sensitive immunochemiluminometric assay with a detection limit of 1 · 1μU/L was developed for the measurement of urinary growth hormone (UGH). The assay was shown to be specific and precise. There was a good correlation between serum growth hormone (GH) and UGH concentrations in 20 patients with acromegaly and six volunteers following an intravenous injection of recombinant GH. We concluded therefore that UGH measurements appear to provide a satisfactory index of GH secretion. The use of the assay in the investigation of growth disorders was assessed. We studied 11 pre-pubertal children, six of normal stature, and five of short stature, over a 6-month period. Sequential fortnightly measurements of UGH were carried out and height velocity was determined. The children of short stature grew at a slower rate and excreted less GH than the children of normal stature. However, we observed considerable within-individual variability in GH excretion in both groups (CV 22–98%). We therefore recommend that sequential UGH analyses should be carried out and the results interpreted in conjunction with growth measurements. However, further investigations into the renal handling of GH are needed to establish optimum sampling regimes.

scholarly journals ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment

2016 ◽  
Vol 102 (5) ◽  
pp. 1458-1467 ◽  
Author(s):  
Manouk van der Steen ◽  
Rolph Pfundt ◽  
Stephan J.W.H. Maas ◽  
Willie M. Bakker-van Waarde ◽  
Roelof J. Odink ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Bone Age ◽  
Hormone Treatment ◽  
Gh Treatment ◽  
Midface Hypoplasia ◽  
Short Children ◽  
Hormone Analog

Abstract Background: Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. Objective: To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. Methods: BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age. Results: Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. Conclusion: This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.

scholarly journals First report on growth hormone treatment response in a patient with spondylodysplastic type of Ehlers-Danlos syndrome with normal growth hormone secretion

2021 ◽  
Vol 50 (1) ◽  
pp. 47-56
Author(s):  
Katarina Božić ◽  
Tatjana Milenković ◽  
Srđan Pašić ◽  
Katarina Mitrović ◽  
Slađana Todorović ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Case Report ◽  
Short Stature ◽  
Treatment Response ◽  
Growth Hormone Treatment ◽  
Hormone Treatment ◽  
Gh Treatment ◽  
Ehlers Danlos Syndrome ◽  
Gh Secretion ◽  
First Case

Introduction/Aim: Spondylodysplastic Ehlers-Danlos Syndrome (sdEDS) is a rare genetic disorder of collagen synthesis, caused by a mutation in the B4GALT7, B3GALT6, or SLC39A13 gene. Features of this very rare disorder are short stature, hypotonia, hyperflexible joints, soft, thin, and overly stretchable skin, sparse hair and eyebrows, elderly face, wide forehead and prolonged wound healing. Molecular genetic analysis is needed for definite confirmation of the diagnosis. So far, only three case reports describing growth hormone treatment response in patients with sdEDS have been published. All of these patients had growth hormone (GH) deficiency. We present the first case report regarding growth hormone treatment response in a patient with sdEDS and normal GH secretion (without GH deficiency). Case report: Patient was a girl with short stature and normal GH secretion. Having in mind that the girl was born small for the gestational age, due to her short stature, she started using HR, before the diagnosis of sdEDS was made. Based on the lack of improvement in growth velocity as well as the girl's phenotype, genetic analyses were performed and the diagnosis of sdEDS due to biallelic mutations of the B4GALT7 gene was established. After the diagnosis of sdEDS was made and due to suboptimal response in growth velocity to the GH treatment, the GH therapy was stopped at the age of 11 years. Conclusion: This is a first case report regarding GH treatment in a child with sdEDS and normal GH secretion, demonstrating a very limited therapeutic effect of GH on linear growth in the presented patient.

Growth hormone treatment and bone mineral density in pediatric patients with Prader–Willi syndrome

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Yuji Oto ◽  
Nobuyuki Murakami ◽  
Takeshi Inoue ◽  
Keiko Matsubara ◽  
Sohei Saima ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Growth Hormone ◽  
Bone Mineral ◽  
Pediatric Patients ◽  
Standard Deviation Score ◽  
Hormone Treatment ◽  
Prader Willi Syndrome ◽  
Mineral Density ◽  
Gh Treatment ◽  
Total Body

Abstract Objectives Previous reports indicate that growth hormone (GH) treatment for Prader–Willi syndrome (PWS) improves bone mineral density (BMD) only when initiated at a young age and not when initiated in adulthood. However, there are no data on BMD during long-term GH treatment of Japanese children and adolescents with PWS. Thus, this study aimed to investigate BMD changes among patients with PWS, who were undergoing GH treatment from childhood to adolescence. Methods Sixty-seven pediatric patients with PWS who had GH treatment initiated during childhood between January 2003 and June 2020 were evaluated. To avoid underestimation, we used total body BMD, which was evaluated using dual-X-ray absorptiometry adjusted for the BMD z-score using patient height, sex, and age. Results In both sexes, age was negatively correlated with the BMD-standard deviation score (SDS) (male: r=−0.156 [p=0.042]; female: r=−0.197 [p=0.043]), which started to decrease in childhood. Conclusions The BMD-SDS of patients with PWS decreases gradually despite GH treatment. As there are no clear recommendations about monitoring of bone health in patients with PWS, further studies are needed to improve the guidelines for screening of BMD and treatment of patients with PWS.

scholarly journals Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study

2018 ◽  
Vol 90 (1) ◽  
pp. 54-63 ◽  
Author(s):  
Jin Soon Hwang ◽  
Hae Sang Lee ◽  
Kee-Hyoung Lee ◽  
Han-Wook Yoo ◽  
Dae-Yeol Lee ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Sustained Release ◽  
Short Stature ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Recombinant Human Growth Hormone ◽  
Standard Deviation Score ◽  
Idiopathic Short Stature ◽  
Height Velocity ◽  
Prepubertal Children

Background/Aims: To determine the optimal dose of LB03002, a sustained-release, once-weekly formulation of recombinant human growth hormone (rhGH), and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature (ISS). Methods: This multicenter, randomized, open-label, phase II study included GH-naïve, prepubertal children with ISS, randomized to receive daily rhGH 0.37 mg/kg/week (control, n = 16), LB03002 0.5 mg/kg/week (n = 14), or LB03002 0.7 mg/kg/week (n = 16). The primary endpoint was height velocity (HV) change at week 26. Results: At week 26, the least square (LS) means for HV change (cm/year) with control, LB03002 0.5 mg/kg/week, and LB03002 0.7 mg/kg/week were 5.08, 3.65, and 4.38, and the LS means for the change in height standard deviation score were 0.65, 0.49, and 0.58, respectively. The lower bound of the 90% confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change (–1.72) satisfied the noninferiority margin (–1.75). Adverse events were generally mild and short-lived. Conclusion: A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments. LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH.

scholarly journals Racial/Ethnic Disparities in US Pediatric Growth Hormone Treatment

2018 ◽  
Vol 90 (2) ◽  
pp. 102-108 ◽  
Author(s):  
Adda Grimberg ◽  
Anders Lindberg ◽  
Michael Wajnrajch ◽  
Andrew J. Cucchiara ◽  
Cecilia Camacho-Hübner
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Census Data ◽  
Treatment Initiation ◽  
Ethnic Disparities ◽  
Hormone Treatment ◽  
Gh Treatment ◽  
Male Predominance ◽  
Relative Risks ◽  
Racial Ethnic

Background/Aims: To compare racial/ethnic proportions of subjects receiving growth hormone (GH) treatment to the expected proportions, and secondarily, to assess racial/ethnic differences in subject characteristics at GH treatment initiation. Methods: Race/ethnicity-based expected frequencies of height <–2.25 SD were determined by applying relative risks for short stature, calculated from a regional population of 189,280 pediatric primary care patients, to US census data, and compared to racial/ethnic proportions of US subjects enrolled in the Pfizer International Growth Study (KIGS) using the χ2 test. Characteristics of white and black subjects at GH treatment initiation were presented as medians and compared by the Wilcoxon rank sum test (significant p < 0.01). Results: White subjects exceeded the expected frequency (63%) for all indications (83%) and each separately, ranging from 73% for congenital GH deficiency (GHD) to 85% for idiopathic short stature (p < 0.001). Compared to white subjects, black subjects treated for idiopathic GHD had greater height deficits relative both to the population (–2.97 vs. –2.56 SD) and to their mid-parental heights (–2.47 vs. –1.89 SD), lower stimulated GH peak levels (4.9 vs. 6.0 ng/mL), and lower birth weights (–0.86 vs. –0.48 SD). Black subjects with congenital GHD had lower stimulated GH peaks (2.1 vs. 3.2 ng/mL) and started GH treatment at younger ages (2.9 vs. 4.8 years), while those with acquired GHD had lower birth weights (–1.12 vs. –0.08 SD). Male predominance did not differ by race for any or all indications. Conclusion: Overrepresentation of white children among those receiving GH treatment in the US KIGS registry reflects racial/ethnic treatment biases, not just differences in growth rates.

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