Recombinant Human Growth Hormone Treatment Research Articles

Improvement of Bone Metabolism in Prepubertal Girls with Turner Syndrome Following Long-term Pegylated Growth Hormone Treatment.

The study aims to assess the improvement in bone metabolism in prepubertal girls with Turner Syndrome (TS) after long-term polyethylene glycol recombinant human Growth Hormone (PEG-rhGH) treatment. A 12-month longitudinal prospective study was conducted with 28 prepubertal girls diagnosed with TS. Participants were divided into two groups: 18 received PEG-rhGH therapy (0.1-0.25 mg/kg/week) and 10 did not. Anthropometric measurements, bone turnover markers (BTMs), and serum levels of IGF-1, calcium, and phosphate were collected at baseline and after 12 months. BTMs included bone alkaline phosphatase (BAP), Type I collagen propeptide (CICP), Type I collagen telopeptide (CTX), and fibroblast growth factor 23 (FGF23). After 12 months of PEG-rhGH therapy, the treatment group showed significant increases in growth velocity (GV) and height standard deviation scores (HtSDS). Serum IGF-1 levels increased rapidly within one month and remained elevated. BTMs indicated enhanced bone formation, significantly increasing BAP and CICP, while CTX levels remained low. FGF23 levels initially rose slightly but declined below baseline by 12 months. Elevated blood phosphate levels were observed. PEG-rhGH therapy in children with TS significantly improves linear growth and enhances bone formation markers, benefiting bone metabolism.

6877 Withdrawing Growth Hormone Treatment at Mid-Puberty in Idiopathic Isolated Growth Hormone Deficiency: Baseline Characteristics in Patient-Preference Design Study

Abstract Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg: None. P. voorhoeve: None. A.C. Hokken-Koelega: None. D.C. van der Kaay: None. Background: The majority of children diagnosed with idiopathic isolated growth hormone deficiency (IIGHD) show a normal growth hormone (GH) secretion (assessed by GH stimulation tests) when retested at near adult height (NAH). It appears plausible that, if normal stimulated GH secretion is observed in mid-puberty, continuing recombinant human GH (rhGH) treatment may only have a minor effect on NAH. The effect on NAH has never been investigated in a prospective study. Aim: To evaluate patient preference in the choice to (dis-)continue GH treatment from mid-puberty, and to study whether patients who discontinued treatment differed in baseline characteristics from those who continued treatment. Methods: The study population consisted of adolescents who were diagnosed in childhood with IIGHD (GH peak at diagnosis between 1.7 ug/L and 10 ug/L) and who had started rhGH therapy between 2005-2018. According to the national treatment protocol, GH secretion was retested in mid-puberty (males: Tanner stage G3/4, testicular volume >12 ml and bone age (BA) 13-16 years; females: Tanner stage B3/4 and BA 11-14 years). In this multicentre prospective patient-preference design study, adolescents who tested GH sufficient at mid-puberty (GH peak >6.7 ug/L) had the choice to discontinue or continue rhGH treatment until NAH (height velocity <2cm/year). Results: In total 127 patients (95 male, 75%) participated in this study. Forty-four patients (35%) chose to continue GH treatment until NAH (group 1), and 83 patients (65%) chose to discontinue GH treatment (group 2). Mean height at inclusion (group 1: -0.76±0.69 SDS vs group 2: -0.47±0.85 SDS; P=0.055), target height SDS (group 1: -0.73±0.54 SDS and -0.58±0.53 SDS, P=0.15) and age at inclusion (group 1: 14.0±1.1y and 13.9±1.1y, P=0.69) did not significantly differ between groups. Males and females did not differ in these characteristics. Currently, 109 patients (86%) have reached NAH. Conclusions: The majority of patients (65%) preferred to discontinue rhGH treatment after sufficient GH retesting in mid-puberty. An anticipated difference in baseline data between the groups (adolescents who choose to discontinue treatment may be taller and older) could not be confirmed. Data are being collected until all patients reach near adult height. Presentation: 6/3/2024

9262 Withdrawing Growth Hormone Treatment at Mid-Puberty in Idiopathic Isolated Growth Hormone Deficiency: Baseline Characteristics in Patient-Preference Design Study

Abstract Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg: None. P. voorhoeve: None. A.C. Hokken-Koelega: None. D.C. van der Kaay: None. Background: The majority of children diagnosed with idiopathic isolated growth hormone deficiency (IIGHD) show a normal growth hormone (GH) secretion (assessed by GH stimulation tests) when retested at near adult height (NAH). It appears plausible that, if normal stimulated GH secretion is observed in mid-puberty, continuing recombinant human GH (rhGH) treatment may only have a minor effect on NAH. The effect on NAH has never been investigated in a prospective study. Aim: To evaluate patient preference in the choice to (dis-)continue GH treatment from mid-puberty, and to study whether patients who discontinued treatment differed in baseline characteristics from those who continued treatment. Methods: The study population consisted of adolescents who were diagnosed in childhood with IIGHD (GH peak at diagnosis between 1.7 ug/L and 10 ug/L) and who had started rhGH therapy between 2005-2018. According to the national treatment protocol, GH secretion was retested in mid-puberty (males: Tanner stage G3/4, testicular volume >12 ml and bone age (BA) 13-16 years; females: Tanner stage B3/4 and BA 11-14 years). In this multicentre prospective patient-preference design study, adolescents who tested GH sufficient at mid-puberty (GH peak >6.7 ug/L) had the choice to discontinue or continue rhGH treatment until NAH (height velocity <2cm/year). Results: In total 127 patients (95 male, 75%) participated in this study. Forty-four patients (35%) chose to continue GH treatment until NAH (group 1), and 83 patients (65%) chose to discontinue GH treatment (group 2). Mean height at inclusion (group 1: -0.76±0.69 SDS vs group 2: -0.47±0.85 SDS; P=0.055), target height SDS (group 1: -0.73±0.54 SDS and -0.58±0.53 SDS, P=0.15) and age at inclusion (group 1: 14.0±1.1y and 13.9±1.1y, P=0.69) did not significantly differ between groups. Males and females did not differ in these characteristics. Currently, 109 patients (86%) have reached NAH. Conclusions: The majority of patients (65%) preferred to discontinue rhGH treatment after sufficient GH retesting in mid-puberty. An anticipated difference in baseline data between the groups (adolescents who choose to discontinue treatment may be taller and older) could not be confirmed. Data are being collected until all patients reach near adult height. Presentation: 6/3/2024

6778 Visual Presentations for Adherence Risk Management In Patients Receiving Recombinant Human Growth Hormone Therapy

Abstract Disclosure: P. van Dommelen: Consulting Fee; Self; PvD has a consultancy agreement with Merck KGaA, Darmstadt, Germany. F. Michelis: Employee; Self; FL is an employee of Ares Trading SA, an affiliate of Merck KGaA. L. Arnaud: Employee; Self; LA is an employee of Ares Trading SA, an affiliate of Merck KGaA. S. Loche: Advisory Board Member; Self; SL has received advisory board fees from Merck KGaA, Darmstadt, Germany. Consulting Fee; Self; SL has received consultancy fees from Merck KGaA, Darmstadt, Germany. Speaker; Self; SL has received lecture fees from Merck KGaA, Darmstadt, Germany. E. Koledova: Employee; Self; EK is an employee of Merck KGaA,Darmstadt, Germany. Stock Owner; Self; EK holds shares in Merck KGaA, Darmstadt, Germany. Background: A data-driven clinical decision support system based on visual presentations for adherence risk management can support patients receiving recombinant human growth hormone (r-hGH) treatment. Our focus is on examining adherence patterns during the first 6 weeks of treatment, with a particular emphasis on the days of the week, the variability in injection timings and the summer holiday. Our aim is to assess whether these early patterns can serve as indicators for predicting adherence in the subsequent 7-12 weeks of treatment. Data and Methods: Adherence data between March-November 2023 were extracted from the newly launched third generation of easypod™ device (EP3) and GrowZen Connect Next ecosystem. EP3 is the only connected device that delivers r-hGH and monitors real-time adherence to therapy. EP3 was perceived by health care professionals as more intuitive, comfortable, user-friendly, simpler, and easier to use than previous EP2. Patients with age 2-18 years at treatment start, a 7-day regimen and complete adherence data available between 1-12 weeks of treatment were selected. Data about sex, age at start treatment, as well as adherence, classified as high (≥95%) versus low/medium <95%), standard deviation (SD) of adherence (%), log (to adjust for skewness) of the interquartile range (IQR) of the timing of injection throughout the day, median timing of the injection after midnight, and ≥50% versus <50% of the injections fall in the summer period (July-August) aggregated by day over the first 6 weeks of treatment were included in a generalized linear mixed model with adherence between 7-12 weeks as outcome. Results: In total, data for 232 patients (124 boys and 108 girls, median (Q25-Q75) age at treatment start was 10.5 (7.6-12.3)) were available. The model showed no difference in effect of adherence rates during Monday-Thursday. We, therefore, aggregated the data by weekday (Monday-Thursday) versus weekend day (Friday-Sunday, Friday was included due to the common practice of administering injections during the evening). Adherence, SD of adherence, IQR of timing of injections, and injections falling in summer were significant (p<0.05) predictors of adherence during a weekday and weekend between 7-12 weeks. Areas under the curves were both 0.96 during the weekday and weekend. Conclusions: Our research shows that adherence and timing of injections, as well as taking into account the summer holidays, can predict future adherence accurately. Visual presentations showing aggregated adherence rates and variation of timing of injections by days of the week, as well as highlighting the summer periods may improve adherence risk management and timely support. Presentation: 6/3/2024

7548 Final adult height in children with idiopathic growth hormone deficiency after growth hormone treatment

Abstract Disclosure: H. Lee: None. S. An: None. M. Cho: None. H. Nam: None. Objective: The aim of this study was to assess the final adult height (FAH) achieved through recombinant human growth hormone (GH) treatment and the factors influencing FAH. Methods: We retrospectively reviewed the charts of all patients diagnosed with IGHD who were prepubertal when they began GH treatment since August 2007. FAH was determined in 41 patients (28 males and 13 females) by July 2023. Results: 41 patients started treatment at an average age of 9.1 years and continued for 6.5 years. The mean initial height was -2.6 standard deviation scores (SDS) and the mean FAH was -0.6 SDS. GH treatment was initiated at a significantly younger age in females than in males (7.2±1.9 vs 10.0±3.2; p=0.01). The mean FAH was 169.9±4.5cm for males and 156.1±3.2cm for females. Differences between initial height and final height SDS were not significant between males and females. The mean of FAH SDS was higher compared to their mid-parental height -1.0 SDS (p=0.017). In multiple regression analysis, FAH showed a positive correlation with initial height, duration of treatment, and growth rate in the first year of treatment, and a negative correlation with BMI SDS at the start of GH (r2=0.59; p=0.000). FAH SDS was positively related to initial height SDS and growth rate in the first year of treatment. (r2=0.3; p=0.001) Conclusions: The mean FAH SDS after GH treatment was significantly higher than the mean MPH SDS in IGHD patients. Moreover, the good response of GH treatment was associated with longer treatment duration, greater height at the start of treatment, better treatment response at 1 year, and lower initial BMI SDS. Presentation: 6/3/2024

Factors affecting growth hormone treatment in short stature children born small for gestational age in China: a single-centre, real-world study.

The study aimed to evaluate the factors influencing recombinant human growth hormone (rhGH) treatment in Chinese children with short stature born small for gestational age (SGA). A single-centre, real-world retrospective study was conducted in short stature children born SGA in China. Outcomes were observed at 6, 12, 18, 24, 30, and 36 months. Outcome measures included height standard deviation score (HTSDS), height, growth velocity (GV), and change of HTSDS (ΔHTSDS). The study used the generalized estimating equation (GEE) to identify potential influencing factors, such as rhGH treatment duration, age at rhGH initiation, sex, 11p15 hypomethylation, GH secretion, and birth weight. A subgroup analysis was conducted to investigate the impact of 11p15 hypomethylation related to SGA or impaired GH secretion. Of all 101 SGA patients included in the screening, 41 were eligible for inclusion in the study. The mean age at rhGH initiation was 5.6 ± 2.4 years. The results of the GEE analysis showed a significant association between time after rhGH initiation and HTSDS, height, GV, and ΔHTSDS. GV increased after treatment, with the highest increase observed in the first six months. Additionally, the study found negative correlations between 11p15 hypomethylation and GV, as well as between birth weight and both GV and ΔHTSDS. The study found a positive correlation between impairment in GH secretion and both GV and ΔHTSDS. No statistically significant difference was observed in the comparison of GV or ΔHTSDS between the initiation age of GH treatment and 11p15 hypomethylation. After 24 and 30 months of rhGH treatment, patients with impaired GH secretion had significantly higher ΔHTSDS scores. In short stature Chinese children born SGA, those without SGA-related 11p15 hypomethylation or with impaired GH secretion showed better response to rhGH treatment. These findings highlight the importance of pre-treatment evaluation, including genetic and endocrine assessments.

Over Three Decades of Growth Hormone Treatment in Children With Chronic Kidney Disease-Associated Growth Failure Before and After Kidney Transplantation.

Growth retardation and short final height is a common complication of chronic kidney disease (CKD) beginning in childhood, with profound deleterious effects on quality of life, mental health, and social achievement. Despite optimal treatments of causative factors for growth retardation in children with CKD, more than 50% of patients reach end-stage renal failure with a height >2 SD below the mean, and most do not demonstrate "catch-up" growth after receiving a kidney transplant. Four decades ago, recombinant human growth hormone (rhGH) treatment was introduced after studies showed increased growth velocity and improved height SDS in uremic subjects. Since then, an abundance of published data showed significant improvements in health-related quality of life, and most studies revealed no significant adverse effects. Clinical practice guidelines recommended rhGH treatment in CKD Stages 3-5D and after transplantation. Despite these guidelines, this therapy remained underutilized. Most commonly cited barriers to the implementation of rhGH treatment were the need for daily injections, financial challenges, physicians' unfamiliarity with guidelines, and fear of adverse events. rhGH has been shown to improve growth and final height in short children with CKD, with minimal adverse effects. Despite data of its successful use generated over 3 decades, this treatment is underutilized. More judicious utilization of the treatment should emphasize educating patients, their care givers, and members of the multidisciplinary treating team. Additional studies are needed to assess the longer-term rhGH treatment in larger cohorts of patients, leading to additional supportive data and clearer recommendations.

The growzen™ buddy smartphone app to improve adherence in patients receiving recombinant human growth hormone therapy: a retrospective observational study in Argentina.

This study in Argentina evaluated the impact of the growzen™ buddy smartphone app on adherence to recombinant human growth hormone (r-hGH) treatment. The adherence data, invitation dates with a link to the app, app activation dates, and height measurements entered were extracted from the growzen™ digital health ecosystem. Patients with 12 months of adherence data, aged ≥2 years at treatment start, and aged <19 years were selected both before and after app implementation. Mean adherence was classified as optimal (≥85%) versus suboptimal (<85%). Adherence before and after implementation and the pre-post effect on adherence were assessed. Data for 830 patients were available. Prior to app implementation, the proportion of patients with optimal adherence was 68% (n = 348/515). Following the app implementation, out of 315 patients, 302 (96%) received an invitation with a link to the app, 225 (71%) activated their account, and 127 (40%) entered height data in the first year. There was a significant early increase in the proportion of patients with optimal adherence following implementation: 82% (n = 258/315), p < 0.001. After implementation, the proportion of patients with optimal adherence included 80% (n = 78/98) of those with an active account who did not enter height measurements and 89% (n = 113/127) of those who did. There was a significant and positive pre-post app effect on adherence (p < 0.01) in patients with an active account. Our results show that using the growzen™ buddy app has a rapid and positive impact on adherence to r-hGH treatment, and patients who were more engaged with the app demonstrated better adherence.

Changes in body proportions and body fat content in GH-deficient and non-GH-deficient children during the first year of growth hormone treatment.

Introduction: The growth hormone/insulin-like growth factor-1 axis (GH/IGF-1) is crucial for longitudinal bone growth and exerts several metabolic effects. It is debatable whether and how the recombinant human growth hormone (rhGH) treatment affects the trunk-limb proportions. Aim of the study: We aim to evaluate the changes in body proportions and body fat content in short children with growth hormone deficiency (GHD), children born small for gestational age (SGA), and girls with Turner syndrome (TS) during the first year of rhGH therapy. Material and methods: The data of 70 children with GHD, 40 children born SGA, and 36 girls with TS from 1998 to 2019 were analyzed. The following parameters were measured: height, body weight, sitting height, and two skinfolds on the arm above the triceps brachii and below the scapula at the beginning of rhGH therapy and after the first year of treatment. Sitting height and lower limb length were presented as percentages (%) of body height. Fat mass percentage (%FAT) was calculated using the Slaughter formula. Results: At the beginning of rhGH, TS girls had the greatest height deficit (-2.7 SDS), the highest sitting height (%), and the lowest lower limb length (%) compared to children with GHD and children born SGA. Moreover, TS girls had higher body weight SDS, BMI SDS compared to SGA children (p < 0.001), and higher %FAT compared to both GHD and SGA children (p < 0.001 for both). After the first year of rhGH therapy, a significant increase in lower limb share (%) and a decrease in %FAT were observed in all the study groups. TS girls still had significantly higher sitting height (%), shorter lower limbs (%), and higher %FAT, body weight SDS, and BMI SDS compared to children with GHD and children born SGA (p < 0.05 for all variables). Conclusions: Our results show that rhGH treatment could increase lower limb length in relation to height and reduce fat mass in treated children. Girls with TS had the largest baseline body disproportions and the highest body fat content. Despite a satisfactory reduction in height deficit, after the first year of rhGH therapy, these girls had still higher body weight SDS, BMI SDS, %FAT, the highest sitting height (%), and the lowest lower limb length (%) compared to children with GHD and born SGA.

Heightism, growth hormone treatment, and social functioning: a holistic approach to a persistent clinical challenge.

Use of recombinant human growth hormone (rhGH) treatment to increase height in children with non-growth hormone deficient short stature is becoming more common. Yet, the evidence to support the notion that augmenting height directly leads to increased well being, specifically psychosocial well being, is inconsistent, with high-quality evidence lacking. Review of recent studies demonstrates that the association between height augmentation and psychosocial well being is complex. The direct contribution of height to well being may be less than the current model of clinical care of short stature assumes. Rather, the new studies provide evidence to support a role for psychosocial factors, including height-related beliefs, social support, and coping skills, in promoting psychosocial well being, specifically quality of life and self-esteem. Clinical care of short stature would benefit from incorporating a holistic model of care that considers psychosocial interventions in addition to, or instead of, rhGH treatment.

Optimal final adult height achieved by low-dose recombinant human growth hormone therapy.

Thailand has been administering the recombinant human growth hormone (rhGH) treatment for >20 years. Due to limited resources being available, efforts have been directed toward utilizing rhGH at the lowest feasible dose. However, there is currently a lack of evidence in terms of the efficacy and outcomes. To evaluate the auxological outcomes of growth hormone (GH) treatment and the GH secretion ability after reaching final adult height (FAH) and discontinuing rhGH. Data of 40 patients were retrospectively reviewed. The clinical characteristics, auxological data, and results of biochemical and endocrine investigations before and during rhGH treatment were evaluated. In addition, GH retesting was performed in 24 patients using the insulin tolerance test. Twenty patients (50%) had complete growth hormone deficiency (GHD), defined as peak stimulated GH level <5 ng/mL, and the remaining patients had partial GHD. Most patients were male (n = 25, 62.5%). The mean age at which rhGH was initiated was 8.9 years. Patients with partial GHD received a higher dose of rhGH than those with complete GHD (30.9 µg/kg/d vs. 26.2 µg/kg/d, P = 0.02). Patients with complete and partial GHD reached FAH at height standard deviation scores (SDSs) of -0.65 and -1.47, respectively. The factors associated with obtaining a good clinical response in terms of height gain included peak-stimulated GH level, age of puberty, and age of discontinuing rhGH. After completing the rhGH treatment, 13 of the 24 patients showed normal GH secretion. Patients with multiple pituitary hormone deficiency (MPHD) were likely to have persistent GHD through adulthood (n = 8, 88.9%). This study has demonstrated that the use of low-dose rhGH could result in healthy populations achieving optimal FAHs. Patients with MPHD might not require retesting as they were likely to have persistent GHD. The results obtained in this research highlight the benefits of the treatment. This treatment can be applied in resource-limited countries.

Long-term risk of neoplastic events after childhood growth hormone treatment: a population-based cohort study in Sweden.

Increased risk of neoplastic events after recombinant human growth hormone (rhGH) treatment in childhood has been an ongoing concern but long-term safety data are limited. A nationwide population-based cohort study in Sweden of patients treated with rhGH during childhood between 1985-2010, due to isolated growth hormone deficiency (GHD), small for gestational age (SGA) and idiopathic short stature (ISS). The comparison group consisted of 15 age-, sex-, and region-matched controls per patient, randomly selected from the general population. Data on neoplastic events and covariates, such as gestational age, birth weight, birth length, socioeconomic status, and height at study start, were collected through linkage with population-based registers. The cohort was followed for neoplastic events until the end of 2020. 53,444 individuals (3,408 patients; 50,036 controls) were followed for up to 35 years, with a median follow-up of 19.8 years and a total of 1,050,977 person-years. Patients showed a moderately increased hazard ratio (HR) for neoplastic events overall compared to controls (HR 1.28, 95% CI: 1.12-1.46), but only significant for males (HR 1.39, 95% CI: 1.17-1.66) and not females (HR 1.15, 95% CI: 0.94-1.41). Longer treatment duration was associated with an increased HR, but no association was found between neoplastic events and mean or cumulative dose. No increased risk of malignant neoplasms was observed for the patients compared to matched controls (HR 0.91 95% CI: 0.66-1.26). No association was found between rhGH treatment during childhood for GHD, SGA, or ISS and malignant neoplastic events in early to mid-adulthood. A moderate increase in overall neoplastic events was observed due to an increased number of events in male patients.

Molecular diagnosis is an important indicator for response to growth hormone therapy in children with short stature

BackgroundSignificant differences have been observed in the efficacy of recombinant human growth hormone (rhGH) treatment for short children. The present study aimed to identify the genetic etiology of short stature and to assess the role of molecular diagnosis in predicting responses to rhGH treatment. MethodsA total of 407 short children were included in the present study, 226 of whom received rhGH treatment. Whole-exome sequencing (WES) was conducted on short children to identify the underlying genetic etiology. Correlations between molecular diagnosis and the efficacy of rhGH treatment were examined. ResultsPathogenic or likely pathogenic mutations were identified in 86 of the 407 patients (21.1%), including 36 (41.9%) novel variants. Among the multiple pathways affecting short stature, genes involved in fundamental cellular processes (38.7%) play a larger role, especially the RAS-MAPK pathway. In general, patients without pathogenic mutations responded better to rhGH than those with mutations. Furthermore, patients with hormone signaling pathway mutations had a better response to rhGH, while those with paracrine factor mutations had a worse response to rhGH. ConclusionsThis study highlights the utility of WES in identifying genetic etiology in children with short stature. Identifying likely causal mutations is an important factor in predicting rhGH response.

Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader–Willi syndrome: a one-year retrospective cohort study

BackgroundRecombinant human growth hormone (rhGH) therapy is beneficial for children with Prader–Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS.MethodsA total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected.ResultsThe mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea–hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs.ConclusionTreatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

Effect of recombinant human growth hormone on serum Klotho and fibroblast growth factor 23 in children with idiopathic short stature

To investigate the changes in the serum levels of Klotho, fibroblast growth factor 23 (FGF23), and insulin-like growth factor-1 (IGF-1) in children with idiopathic short stature (ISS) before and after recombinant human growth hormone (rhGH) treatment, as well as the correlation of Klotho and FGF23 with the growth hormone (GH)/IGF-1 growth axis in these children. A prospective study was conducted on 33 children who were diagnosed with ISS in the Department of Pediatrics, Hebei Provincial People's Hospital, from March 10, 2021 to December 1, 2022 (ISS group). Twenty-nine healthy children, matched for age and sex, who attended the Department of Child Healthcare during the same period, were enrolled as the healthy control group. The children in the ISS group were treated with rhGH, and the serum levels of Klotho, FGF23, and IGF-1 were measured before treatment and after 3, 6, and 9 months of treatment. A correlation analysis was conducted on these indexes. There were no significant differences in the serum levels of IGF-1, Klotho, and FGF23 between the ISS and healthy control groups (P>0.05). The serum levels of Klotho, FGF23, and IGF-1 increased significantly in the ISS group after 3, 6, and 9 months of rhGH treatment (P<0.05). In the ISS group, Klotho and FGF23 levels were positively correlated with the phosphate level before treatment (P<0.05). Before treatment and after 3, 6, and 9 months of rhGH treatment, the Klotho level was positively correlated with the IGF-1 level (P<0.05), the FGF23 level was positively correlated with the IGF-1 level (P<0.05), and the Klotho level was positively correlated with the FGF23 level (P<0.05), while Klotho and FGF23 levels were not correlated with the height standard deviation of point (P>0.05). The rhGH treatment can upregulate the levels of Klotho, FGF23, and IGF-1 and realize the catch-up growth in children with ISS. Klotho and FGF23 may not directly promote the linear growth of children with ISS, but may have indirect effects through the pathways such as IGF-1 and phosphate metabolism. The consistent changes in Klotho, FGF23 and IGF-1 levels show that there is a synergistic relationship among them in regulating the linear growth of ISS children.

THU162 Impact On Visual Function And Optic Nerve Morphology In Early Stages Of Growth Hormone Treatment

Abstract Disclosure: D.G. Braslavsky: None. A.C. Keselman: None. M.G. Ballerini: None. S. Rosenbrock: None. N. Cappa: None. G. Negrete: None. G. Dech: None. M.G. Ropelato: None. S. Gamio: None. I. Bergada: None. Background Current safety of recombinant human growth hormone (rhGH) treatment arises mainly from postmarketing surveillance. Headache is a relatively frequent symptom in children under rhGH. Secondary intracranial hypertension (SIH), is an adverse effect (AE), usually occurring within the first 12 weeks of treatment associated to headaches. Permanent visual defects are the most feared complication. Scarce information exists regarding incidence and natural history of visual impairment under rhGH. Aim To evaluate visual impairment and/or optic nerve affection in children throughout early rhGH treatment. Materials and Methods Prospective interventional study conducted from February 2018 to January 2020. Children ≥4 yr who received rhGH treatment for growth hormone deficiency (GHD), 0.16-0.25 mg/kg/w; Turner syndrome (TS), small for gestational age (SGA), 0.33 mg/kg/w and Prader Willy Syndrome (PWS) 1 mg/m2/d. Patients were assessed at basal, 1, 3, and 6 months of treatment. Each visit included clinical variables (adherence, auxology, AE, presence of headache), serum IGF1, IGFBP3, glucose, insulin, aldosterone, plasma renin activity, electrolytes and ophthalmologic evaluation [fundoscopy, optical coherence tomography (OCT), retinal nerve fiber layer (RNFL), ganglionic eye complex, ocular ultrasound, intraocular pressure (IOP), autorefractometry, biomicroscopy]. Results Sixty patients were enrolled, 12 GHD, 11 ST, 31 SGA, 3 PWS, 3 TBI (23 females), with a median age of 8.08 yrs (ranged 4.24-15). Median height was -2.25 ± 1.05 SDS. Baseline ophthalmologic evaluation was normal. Abnormal ophthalmological findings were observed in 15/60 (25%). Twelve patients showed changes in OCT, spontaneous recovery occurred in 8, whereas persistence or worsening of RNFL thickening lead to an MRI assessment and lumbar puncture (LP) in 4 patients (1 GHD, 2 SGA, 1 ST); only one referred headache. LP revealed opening pressure of 19, 21, 22 and 30 mmHg, respectively, the latter assumed as SIH at the 1st month of treatment. In these four patients, during the findings of ocular abnormalities, they presented a mean IGF1 1.12 ± 1.04 SDS and IGFBP3 -0.02 ± 2.34 SDS. ΔBMI -0.45 ± 0.71 SDS. Prevalence of SIH was 1.6%. All four patients received acetazolamide; median time for RNFL improvement took 4 months (range 4-8). One patient developed post-dural puncture headache. Three had elevated IOP. Along the protocol 19/60 referred headache (26 events). Three of these patients with headaches had abnormal ophthalmological findings (2 mild changes in OCT; 1 elevated IOP). Conclusion We have demonstrated a marked prevalence of abnormal ophthalmological findings upon early rhGH treatment. These observations occurred in the absence of suggestive clinical symptoms, and conversely, headache did not predict SIH. The prevalence of SIH due to rhGH is higher than previously reported. Presentation: Thursday, June 15, 2023

THU163 Traffic Light Alerting System For Adherence Risk Management To Improve Catch-Up Growth In Patients Receiving Recombinant Human Growth Hormone Therapy

Abstract Disclosure: S. Loche: Advisory Board Member; Self; SL has received advisory board fees from the healthcare business of Merck KGaA, Darmstadt, Germany. Consulting Fee; Self; SL has received consultancy fees from the healthcare business of Merck KGaA, Darmstadt, Germany. Speaker; Self; SL has received lecture fees from the healthcare business of Merck KGaA, Darmstadt, Germany. P. van Dommelen: Consulting Fee; Self; PvD has a consultancy agreement with the healthcare business of Merck KGaA, Darmstadt, Germany. E. Koledova: Employee; Self; EK is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. Stock Owner; Self; EK holds shares in the healthcare business of Merck KGaA, Darmstadt, Germany. Background: In our previous study, a data-driven clinical decision support system based on “traffic light” visualizations for adherence risk management in patients receiving recombinant human growth hormone (r-hGH) treatment was developed.1 Two “traffic lights” were most promising: mean adherence and standard deviation (SD) of hours to next injection (administering injections at around the same time each day). We aimed to study the effect of these two adherence-based traffic lights on catch-up growth in the first year of treatment in patients with growth hormone deficiency (GHD) and those born small for gestational age (SGA). Data and Methods: Height and adherence data were extracted from the easypod™ connect ecosystem and taken from the easypod™ connect observational study.2 Patients with: height standard deviation scores (HSDS) of ≤-2 at treatment start; age 2-15 years at treatment start; and ≥1 measurement and adherence data available in the first year of treatment, were selected. Mean adherence was classified as high (≥85%), intermediate (&amp;gt;56%-&amp;lt;85%), or low (≤56%); high (≥15.9 [P95]), intermediate (≥10.1 [P85]), or low (&amp;lt;10.1) were used for SD of hours to next injection. Linear regression analysis was performed with ΔHSDS between treatment start and first year of treatment as dependent variables and the adherence-based values as independent variables, all adjusted for age and HSDS at treatment start. Results: In total, data for 1,045 patients (776 and 269 with GHD and those born SGA, respectively) were available. Only some of the adherence-based categories had a significant and independent effect on ΔHSDS (P=0.004). Adjusted for age and HSDS at treatment start, patients with high/intermediate mean adherence had, on average, a +0.15 SD higher ΔHSDS (P=0.004), while this was +0.09 SD for patients with a low SD of hours to the next injection (P=0.003). Therefore, patients with both high/intermediate mean adherence and a low SD of hours to the next injection had, on average, a +0.24 SD higher ΔHSDS compared with patients with both low mean adherence and a high SD of hours to the next injection. Conclusions: Our research shows that good adherence and administering injections around the same time each day play an essential role in optimizing catch-up growth. Adherence-based traffic lights can alert clinicians to have discussions with patients/caregivers to mitigate the risk of sub-optimal adherence and, consequently, improve catch-up growth.

Evaluation of Clinical Characteristics and Growth Hormone Response in a Rare Skeletal Dysplasia: Pycnodysostosis.

Introduction Pycnodysostosis is a rare osteosclerotic skeletal dysplasia; its clinical features include short stature, characteristic facial features, increased bone fragility, and acro-osteolysis of the distal phalanx. Lack of clear guidelines for treatment and follow-up in rare diseases such as pycnodysostosis with growth hormone (GH) deficiency poses a difficulty for the clinician. This study aims to identify clinical, radiological, and endocrine findings of patients with pycnodysostosis focusing on the first year of recombinant human growth hormone (rhGH) treatment response. The eminence of this study is that it presents clinical experience with rhGH, providing an approach for future similar cases. Methods Three girls and two boys from three different families diagnosed with pycnodysostosis via clinical, radiological, and genetic evaluation followed up in the pediatric endocrinology clinic between 2022 and 2023 were enrolled in this study. Clinical findings, anthropometric measurements (weight, height, body mass index [BMI]), and laboratory, radiological, and genetic examinations were evaluated retrospectively. Participants were evaluated for GH deficiency using L-DOPA and clonidine tests if growth rate was below -2 standard deviation score (SDS) for gender and age after one-year follow-up. Results Complaints on admission were short stature (80%) and recurrent bone fractures (20%). Characteristic facial features and brachydactyly were seen in all the patients. Median height SDS on admission was -3.0 (range: -1.9 to -3.8). Median height SDS on last clinic visit was -3.2 (range: -1.7 to -4.2) at a median age of 8 years (range: 3.5-14 years). BMI was normal in four patients, while one was overweight. Bone mineral densitometry z-score was high, and two patients had bone fractures following minor trauma, while one had recurrent fractures. Two siblings (first and second cases) and the third case were diagnosed with GH deficiency, and anterior pituitary hormones were normal otherwise. One had partial empty sella in hypophyseal magnetic resonance imaging. rhGH (33 mcg/kg/day, subcutaneously) was started. Growth rate of the first, second, and third cases increased from 3.3, 3.1, 3.9 to 5, 4.3, 7.2 cm/year, respectively. Prior to rhGH, two had adenoid hypertrophy which was stable following rhGH. Growth rate follow-up of the fourth case continues, while the fifth case, the only participant who has reached adult height, has normal height according to age and gender normative. Conclusion Although rare, pycnodysostosis should not be overlooked in a patient with characteristic facial features, disproportionate short stature, and recurrent fractures. GH deficiency should be evaluated early if growth rate is declining. rhGH may restore growth rate and the possibility of catch-up in growth in patients with pycnodysostosis and GH deficiency. Hence, after first year of rhGH, growth rate of patients with pycnodysostosis is lower when compared to other etiologies of GH deficiency.

Noonan syndrome: rhGH treatment and PTPN11 mutation.

To analyze the clinical data and genetic characteristics of Noonan syndrome, both the effect and side effects of recombinant human growth hormone (rhGH) treatment. We collected clinical data from 8 children with Noonan syndrome diagnosed from November 2017 to June 2021. The diagnosis was clarified by exome second-generation sequencing and parental PCR-NGS validation and interpretation of the preceding evidence, and growth hormone therapy was administered. Of the cases, four males and four females were seen for slow height growth and the median age at diagnosis was 8 years 7 months (1 year 7 months to 12 years 6 months). Here, 7 children were treated with rhGH. Compared to the pre-treatment period, the growth rate increased after rhGH treatment [3.7 ± 0.5 cm/year before treatment and 8.0 ± 1.0 cm/year after treatment, p < 0.01], with the maximum growth rate between 3 and 6 months of treatment and decreasing with the duration of treatment thereafter. The growth hormone treatment was discontinued and the orthopedic consultation was ordered with regular follow-up, which was considered to be related to the PTPN11 mutation. Noonan syndrome is characterized by slow growth, short stature, mental retardation, peculiar facial features, structural heart abnormalities and abnormal bone metabolism. and osteochondroma was found after case 2 rhGH treatment. Genetic examination is mostly caused by PTPN11 mutation. It is recommended to pay attention to bone metabolism abnormalities before growth hormone treatment, especially in children with PTPN11 mutations.

Response to growth hormone therapy in ring chromosome 15: Review and evidence from a new case on possible beneficial effect in neurodevelopment

Type 1 Insulin-like Growth Factor Receptor(IGF1R) plays a fundamental role in normal growth and development. Its disruption is usually characterized by severe intrauterine and postnatal growth retardation, microcephaly and neurodevelopmental delay.The efficacy of recombinant human growth hormone treatment remains a challenge for children with IGF1 resistance and pathogenic mutations of IGF1R, with limited data in patients carrying the most severe form of IGF1R defect, the ring chromosome 15. Subject and methodWe tested a high dose of rhGH in a new patient with ring chromosome 15, as confirmed by karyotype and CGH array. We performed a systematic review, and all published r(15) syndrome cases treated by growth hormone(GH) up to April 2023 were searched, and their response to GH therapy was recorded and summarized. ResultsTwelve patients with ring chromosome 15 received GH therapy according to a literature review. We expand the spectrum by the 13th case treated by GH, and we report an impressive improvement in intellectual performance and progressive catch-up growth after 5 and 20 months of follow-up. By introducing our new case in the analysis, the sex ratio was 3:10, and GH therapy was started at the age of 5.5 (3/9.4) (years) for an age of diagnosis of 4.75 (1.3/9.5) (years). The height before GH therapy was −5.1(−5.9/−4.1) SDS. The median duration of treatment was 1.7(0.9/2) (years), with a median height gain of 1(0.3/1.8) SDS and an improvement in growth velocity of 4.1(2.8/5.3) (cm/year). ConclusionGH seems to be effective for r(15) syndrome patients with short stature.