Received Growth Hormone Therapy Research Articles

Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer

This cohort and nested case–control study analyzed the impact of growth hormone (GH) treatment on the risk of second neoplasm (SN) in a French cohort of 2852 childhood cancer survivors (CCS) treated before 1986. In total, 126 (64.3%) survivors who received GH had been treated for a brain tumor, 22 (11.2%) for a retinoblastoma, 20 (10.2%) for a lymphoma and 28 (14.3%) for another type of solid tumor; 374 survivors developed a SN, including 40 who had received GH therapy. In multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors, secondary non-brain cancer, or meningioma. Slight non-significant increases in the risk of meningioma (1.6-fold) were observed after an exposure to GH of less than 4 years vs 2.3-fold after a longer exposure.

Design of an educational plan for children receiving growth hormone and their families in safe drug handling

IntroductionGrowth hormone deficiency (GHD) treatment for children requires growth hormone (GH) injections, typically administered daily or weekly until the child reaches adult height. Because therapy continues over many years, compliance with the therapy regimen is indispensable. As hospital pharmacists we are uniquely positioned to play a key role in educating patients in safe drug handling.AimThe aim of this attempt is to increase patient adherence through understanding the treatment burden for children treated with GHD and trying to overcome it, through educational sessions involving them and their family. As hospital pharmacists our goal is to adequately educate children and their families in safe drug handling, taking into consideration that GH is an expensive drug (≈1.500 euros per child per month) which needs to be stored in specific conditions.Service descriptionMost pediatric endocrinologists see patients who are receiving GH therapy 2-4 times per year. On the other hand pharmacists meet with the patients every month, during their visit to the hospital pharmacy, in order to get their monthly treatment.The hospital pharmacy of Panarkadian General Hospital is dispensing, for the time being, GH to 21 children aged 11-17 years old. Plans are made to establish a 10-15 min educational interview during patient venue, in order to ensure/guarantee two key points of their treatment outcome. The first one should be appropriate drug storage. GH needs to be stored at temperatures 3-10⁰C, that sometimes may raise issues during summer vacations and while traveling. The second one should be proper drug administration. Demonstration models of the injection devices can be requested by the pharmaceutical companies in order for the children to get used to handling them on their own. Moreover, proper injection sites for GH should be indicated. Parents are informed via printed material while children are educated through practice using demonstration models. Video presentation was found pleasant, usefull and more effective in the case of children. ConclusionsOptimizing patient management and adherence for children receiving growth hormone (GH) therapy is not the only responsibility of the patient, their family, and of the prescribing doctor but also the pharmacist. There needs to be a multi-disciplinary approach, involving a number of different healthcare professionalsconsisting of doctors, nurses, psychologists at the first period after diagnosis (concerning the necessity and the benefits of treatment) and hospital pharmacists throughout the course of treatment (concerning drug storage and administration). Hospital pharmacists can ensure timely and efficient drug dispensing, educate children and their family in safe drug handling in order to prevent loss of quality of life due to non-adherence to GH regimens and optimize outcomes for patients.

Persistence of Use in Children Receiving Growth Hormone Therapy

Abstract Background: Long-term persistence of use and starting at the earliest possible age are associated with attainment of near-normal adult or final height in children who are treated with growth hormone therapy. However, there are many factors associated with a lack of persistence. Our aim was to study persistence of use in children with growth disorders using the easypod™ connected autoinjector e-device, which automatically records adherence data and can transmit them via an online portal (easypod™ connect). We investigated persistence of use, defined indicators of a long persistence of use, and developed a model to predict and identify children at risk of discontinuing treatment in the following 6 months. Data and Methods: Anonymized data from children transmitting over 10 injections between January 2007 and April 2020 were analyzed. A child was considered to discontinue the use if they had no injection in the last 6 months (before April 2020) or had an injection pause of at least 6 consecutive months. Persistence was estimated by Kaplan-Meier analyses and Weibull accelerated failure time modeling. To predict the individual risk of discontinuing the use in the following 6 months, individual survival probabilities curves were estimated for each patient still using the system, and the survival probabilities were then recalculated such that they were conditional on the fact that a child had already used the device for a certain time. The Harrell’s c-index was used to assess the algorithm performance. Results: Data were available for 17,651 children of whom 11,056 discontinued the use and 6,595 were still persistent in April 2020. Median persistence of use for all patients using the device was 2.1 years. There was a highly significant difference in median persistence of use between the regions: 1.0, 1.5 and 2.8 years in the available countries in the Asia-Pacific, America and Europe regions, respectively. Other indicators that had a significant positive impact on persistence of use were: at least one dose change a year, having auxological measurements recorded in the system (and if ‘Yes’, height standard deviation < -2 at start of use had an additional effect), starting treatment at an early age, adherence ≥85%, customized injection speed setting and being male. For the individual prediction, random survival forests showed the best performance (Harrell’s c-index=0.72). Conclusions: Data from the connected autoinjector e-device showed that the persistence of use was approximately 2 years in children with growth disorders. We were able to define 8 indicators that had a positive impact on persistence of use of which several indicators were related to patient management. Our prediction model can be used to identify children needing support to reach longer persistence of use and subsequently optimal clinical outcomes.

A High Proportion of Novel ACAN Mutations and Their Prevalence in a Large Cohort of Chinese Short Stature Children.

ContextAggrecan, encoded by the ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated.ObjectiveWe sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone therapies.Patients and MethodsOver 1000 unrelated short stature patients ascertained across China were genetically evaluated by next-generation sequencing–based test.ResultWe identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort; it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, 5 of 11 ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SD score improvement.ConclusionOur data suggest that ACAN mutation is 1 of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

The use of growth hormone therapy in adults with Prader-Willi syndrome: A systematic review.

Despite clear benefits in the management of children with Prader-Willi syndrome (PWS), the role of growth hormone (GH) in adults is unclear. The aim of this study was to conduct a systematic review to evaluate the effects of GH on body composition, bone health and cardiovascular health in adults with PWS. A systematic computerized literature search of the PubMed database was conducted by two independent reviewers. Inclusion criteria were individuals over the age of 16years with a genetic diagnosis of PWS who had received GH therapy, together with assessment of body composition, bone health or cardiovascular health. Twenty full-text papers met the inclusion criteria, encompassing 364 unique patients. No differences in body mass index (BMI) were noted, although 2 studies reported increased BMI after GH cessation. Data demonstrated statistically significant increases in lean body mass and reductions in percentage fat mass. Studies reported inconsistent effects of GH on cholesterol and echocardiography parameters. No studies reported differences in bone mineral density, although one reported improved bone geometry. Minor adverse events including pretibial oedema, headache and transient impaired glucose tolerance were reported in 7 studies. These data suggest that GH is safe and well tolerated in adults with PWS, with evidence of improvement in body composition. Further longitudinal studies are still required to investigate the effects of GH on bone and cardiovascular health. Where GH is used in adults with PWS, this should be managed by a specialist multidisciplinary team with regular monitoring initiated.

Is Normal Growth and Development Achieved By Current Management Approaches to Thalassemia Major in the New Era?

Introduction: Growth retardation (GR) and pubertal disturbances are the earliest consequences of iron toxicity resulting from the pituitary iron deposition in children and adolescents with thalassemia major (TM). It is suggested that adequate transfusion regimens together with appropriate management of iron chelation with timely initiation and dose tailoring by close monitoring using surrogate markers of the iron load may achieve a normal pattern of complication-free survival in TM. Objectives: The purpose of this study was to evaluate the fact that the current approach to the management of the disease has provided a normal growth progression and sexual development in patients (pts) with TM. Methods: We recruited male (M) and female (F) TM pts born after 2000 and followed-up (FU) in Ege University Thalassemia Center. The pts. with an acute or chronic illness that may interfere with growth and development or stem cell transplantation recipients were excluded. The Committee of Clinical Investigation at Ege University Hospital (19.02.2020, 20-2.1T/2) approved this study. Height (H) and weight (W) assessments were performed by using the Harpenden stadiometer and puberty was evaluated by Tanner staging at 3 monthly intervals. H-standard deviation scores (h-SDS) were calculated. Target-H based on mid-parental-H for M & F pts was estimated. All pts. were evaluated annually for bone mineral density (BMD) using dual-energy X-ray absorptiometry (Hologic QDR-4500W, USA) after 8 years (y) of age. The mean SDS of the lumbar spine (L1-4) BMD between -1 and -2.5 was defined as osteopenia and <-2.5 as osteoporosis. Growth hormone (GH) secretion was evaluated by L-dopa and insulin tests in pts. with standing-H below the -2 SD. Pts whose GH response to both stimulation tests were less than 5 ng/ml with the monoclonal assay were considered as GH deficient. Transfused pRBC units (U) and average pre-transfusion hemoglobin (Hb) per year were recorded. Serum ferritin (SF) was monitored at monthly intervals. Myocardial (T2*) and liver (R2) iron were assessed by a 1.5 Tesla magnetic resonance imaging (MRI) machine (Siemens, Symphony Vision 16034 scanner) after 8 y. Annual median SF, prescribed chelator(s), mean chelator doses were recorded by reviewing pts' records. Transfusional iron intake (TII) was estimated as the total amount of pure RBCs (each U, 250 ml with 57% Hct) transfused in a y (ml) x 1.08. Daily TII was expressed as annual TII (mg)/ mean kg b.w./days of the y. Results: We recruited 30 TM (28 β/β, 1 β/δβ, and 1 non-deletional HbH) pts (13 F and 17 M). Demographics for the population are summarized in Table1. All pts maintained annual mean pre-transfusion Hb> 9 g/dl. Twenty-two of 24 pts maintained Deferasirox (DFX) chelation during 9 ± 3.6 y (median 9, range 2-13 y) and achieved optimum SF levels at all times (Figure a). The dose tailoring of DFX found parallel to the changes in TII during FU (Figure b). Liver iron concentration (LIC) and myocardial T2* (mT2*) in 22 pts on DFX chelation were between 0.9-5.4 (2.1 ± 1.3 SD) mg Fe/g d.w. and 19.4-43.5 (28 ± 6.7 SD) ms, respectively, in all assessments. The only pt with mT2* of 19.4 ms revealed mT2* of >20 ms on FU scans. The puberty initiated at 12.8 ± 1.1 y in M (n=12) & 11.2 ± 1.3 y in F (n=12) and progressed without hormone replacement in all, regardless of the chelator. Overall, growth reduced compared to the non-thalassemic population after 8 y with clear evidence of growth catch-up by the introduction of puberty. h-SDS detected <-2 in 6 pts in whom one had a familial GR and 5 found GH deficient and received GH therapy. All pts but one developed h-SDS< -2 at 10-12 y-old when they had S1/2 puberty. The pt no 4 who was entirely unresponsive to GH stimulation tests, developed GR at 1 y-old. He remained unresponsive to GH therapy (Table 2). The 14 (%58) and 5 (21%) of 24 pts demonstrated osteopenia and osteoporosis, respectively. Improvement in BMD-SDS was observed following pubertal spurt. Conclusions: Puberty was the main determinant of growth and bone maturation in TM. Despite, puberty has achieved within physiological limits in M & F pts, a slight delay was observed compared to the non-thalassemic population. The relative delay in pubertal spurt may lead to overdiagnosis of growth and bone-maturation failure and unnecessary intervention in adolescent TM pts. This hypothesis as well as the appropriateness of current management guidelines remains to be elucidated. Disclosures No relevant conflicts of interest to declare.

Look Beyond Gluten in Short Stature with Celiac Disease - A Prospective, Interventional Study.

Short stature (SS) is a common manifestation of celiac disease (CD). After starting gluten free diet (GFD), children usually have catch-up growth (improvement in height SDS of >1 SD). However, few children in remission, even on GFD, lack catch up growth. This study was planned to assess the growth hormone (GH) axis and the prevalence of anti-pituitary antibodies in such patients. It was a single-centre, prospective study. Patients with CD in remission for the last 1 y, having SS and lacking catch-up growth, were included after excluding other common causes of SS. GH dynamics were studied using stimulation tests: Insulin tolerance test, clonidine stimulation test, and glucagon stimulation test. GH deficiency (GHD) was defined as non-stimulable response to 2 GH stimulation tests. Anti-pituitary antibodies were analysed in these patients using rat pituitary extract as antigen. Ten patients (8 girls), with a mean age of 10 ± 2.8 y, in serological remission for CD and lacking catch-up growth, were enrolled. All had a height SDS of < -2. Fifteen age matched children with CD and adequate catch up growth served as controls. GHD was seen in 7 patients (70%), out of whom 2 received GH therapy and had an improvement in the height SDS from -2.7 to -1.4 and from -2.1 to 2.4 (over 1 y), respectively. Anti-pituitary antibodies were seen in significant titres in 55.5% of the cases and 40% of the controls. Children with CD in remission but lacking catch-up growth should be evaluated for GHD.

Use of the Growth Hormone Stimulation Test Result in the Management of Patients With a Short Stature.

IntroductionA proportionate short stature (SS) assessment involves the documentation of normal growth hormone secretion via a growth hormone (GH) stimulation test. All available GH stimulation tests have some disadvantages. The decision to initiate GH therapy is dependent on multiple factors, including the GH stimulation test result. However, many patients receive GH therapy, even if they have a normal GH stimulation test result, with the indication of a presumed idiopathic SS.ObjectiveIn this study, we investigated the use of the GH stimulation test result in initiating GH therapy.MethodA cross-sectional study was conducted with patients diagnosed with proportionate SS. Age, gender, insulin-like growth factor 1 (IGF-1) level, and GH stimulation test results were collected retrospectively from the electronic medical records. The main outcome variable was the decision related to prescribing GH therapy.ResultsA total of 286 patient charts were reviewed, and the majority (n = 201, 64.6%) were male. For just less than half (n = 136, 47.6%), the result of the GH stimulation test was ≥ 10 ng/mL, in a small proportion (n = 53, 18.5%) the result was < 5 ng/mL, and for the rest of the cohort, the result was 5.0 - 9.9 ng/mL. The majority (n = 219, 70.4%) received GH therapy, irrespective of the GH stimulation test result. The odds ratio (OR) for GH treatment was 3.9 (CI: 1.79 - 8.49) and 3.0 (CI: 1.21 - 7.42) for patients with a result < 5 ng/mL and 5.0 - 9.9 ng/mL, respectively, compared to the group with a result of ≥ 10 ng/mL.ConclusionGH therapy is frequently prescribed for patients with SS, irrespective of the GH stimulation test result. However, the group with SS with a result of < 9.9 ng/mL was more likely to receive GH therapy. The question of whether a GH stimulation test is required, in the context of SS, is debatable.

Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer.

Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN). To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986. Cohort study and nested case-control study. Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years). Occurrence of SN. In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2-1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4-1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9-4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2-3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9-5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case-control study. This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.

S0514 Growth Hormone Normalizes Gastrointestinal Symptoms in mTBI Patients

INTRODUCTION: Chronic inflammatory processes secondary to brain trauma have been hypothesized to significantly alter gastrointestinal metabolism, motility, and microbiome composition in patients with mild traumatic brain injuries (mTBI). This may be exacerbated by pituitary dysfunction and decreased growth hormone (GH) secretion resulting from injury. In this clinical trial, we analyzed the effects of GH treatment on gastrointestinal symptoms experienced by patients with concurrent mTBI and abnormal GH secretion. METHODS: Adult patients with mTBI and peak GH levels of < 10 ng/mL following glucagon stimulation test (n = 10) were given 0.6 mg injections of recombinant human growth hormone (rhGH) daily over a 6 month period. These patients were matched with healthy household controls (HHC) with whom they resided and shared meals with for comparison (Table 1). The Gastrointestinal Symptom Rating Scale (GSRS) measuring constipation, diarrhea, indigestion, abdominal pain, and acid reflux was administered to mTBI subjects (n = 10) and their healthy household controls (HHC; n = 10) every month for 6 months. RESULTS: GSRS scores within the treatment group dropped significantly after only one month of GH treatment (Figure 1, P < 0.01). Although GSRS scores were higher than the HCCs at baseline, the GSRS score of mTBI patients did not differ from the HHCs after receiving GH therapy. GSRS scores of the HHCs did not change significantly throughout the duration of the study (P > 0.05). CONCLUSION: Growth hormone may play a novel role in altering relationships in the gut-brain axis. Our results suggest that GH treatment helps to reduce a myriad of gastrointestinal symptoms in mTBI patients. We speculate this improvement may be attributable to changes in gut flora and overall gut microenvironment in mTBI, resembling that of healthy controls. Future studies can characterize the bacterial composition of gastrointestinal microbiomes of mTBI patients pre- and post-hormone supplementation compared to healthy controls to confirm this hypothesis.Table 1.: Demographics for healthy household controls and mTBI patients enrolled in the study (n = 20) a- Fisher's exact test; b- Parametric unpaired t-testFigure 1.: Gastrointestinal symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS) in mTBI patients receiving 6 months of growth hormone treatment compared to matched healthy household controls.

Pregnancy outcomes in women receiving growth hormone therapy enrolled in NordiNet international outcome study (IOS) and American Norditropin Studies: Web Enabled Research (ANSWER Program)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Association between Insulin-Like Growth Factor-1 and Relative Skeletal Maturation: A Retrospective Cohort Study of Short Children and Adolescents

Objective Delays in skeletal maturity are related to bone mass and fracture risk in children, but the factors that determine it are unknown. We aimed to identify the association between insulin-like growth factor-1 (IGF-1) and skeletal maturation before and after growth hormone (GH) treatment. Methods In this retrospective cohort study, we observed 783 short children and adolescents, 229 of whom received GH therapy. Skeletal maturation was assessed based on the difference between bone age (BA) and chronological age (CA) (noted as BA-CA). Anthropometric data and laboratory values were measured, and BA was evaluated using the Greulich and Pyle method. Results The delayed BA group was defined as BA‐CA < −2 SD (n = 457), and the occurrence rate of BA delay was 58.37%. A nonlinear relationship was observed between the IGF-1 standard deviation score (IGF-1 SDS) and BA-CA before and after GH therapy. Before GH therapy, there was a significant positive association between the IGF-1 SDS and BA-CA when the IGF-1 level was greater than -2 SDS (β 0.17, 95% CI 0.08, 027; P < 0.001). However, we did not observe a significant relationship between the IGF-1 SDS and BA-CA when the IGF-1 level was lower than -2 SDS (β 0.07, 95% CI -0.12, 0.26; P = 0.454). After GH therapy, there was a significant positive association between the IGF-1 SDS and BA-CA when the IGF-1 level was lower than 2 SDS (β 0.20, 95% CI 0.12, 028; P < 0.001). However, we did not observe a significant relationship between the IGF-1 SDS and BA-CA when the IGF-1 level was greater than 2 SDS (β -0.03, 95% CI -0.33, 0.27; P = 0.866). Conclusion BA is more delayed in short children and adolescents. There is a nonlinear relationship between IGF-1 and BA maturation in short children before and after GH treatment. These findings suggest that a low level of IGF-1 may contribute to BA delay in short children and adolescents.

Growth hormone therapy for people with thalassaemia.

Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency. This review on the role of growth hormone was originally published in September 2017 and updated in April 2020. To assess the benefits and safety of growth hormone therapy in people with thalassaemia. We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 14 November 2019. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Date of latest search: 06 January 2020. Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity. Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The certainty of the evidence was assessed using GRADE criteria. We included one parallel trial conducted in Turkey. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The certainty of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate-certainty evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate-certainty evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period. A small single trial contributed evidence of moderate certainty that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.

SAT-106 Growth Hormone Treatment Response in Children

OBJECTIVES: Growth hormone (GH) therapy is an effective treatment in addressing growth failure in children with GH deficiency (GHD). It has also been increasingly used in non-GH deficient (nGHD) conditions. We sought to report the growth response of GHD and nGHD patients who received GH therapy at a tertiary care center. METHODS: Data was collected from health records of patients followed in the endocrinology clinic at Alberta Children’s Hospital, Calgary, Canada, from 2005 to 2019, and used to analyze clinical responses based on indication for GH treatment. RESULTS: A total of 167 patient records (87 males and 80 females) were used for analysis. The average age at the start of GH therapy was 7.3 years (range 0.25 to 16.98 yrs). 74 patients were in the GHD group while 93 were nGHD. Of the patients in the nGHD group, the most common diagnosis were: idiopathic short stature (ISS)(n=45), Turner syndrome (TS)(n=26), and Prader Willi Syndrome (PWS)(n=8). The mean height velocity (HV) in year 1 was highest in the GHD group at 11.68 cm/year (n= 62, sd = 5.93), followed by ISS at 9.41cm/year (n = 52, sd = 4.34). The mean first year HV of those who had received chemotherapy (n= 5, mean = 5.48, sd = 1.92) or had Turner syndrome (n= 24, mean = 7.20, sd = 2.15) was significantly lower than both the GHD and ISS groups. GH peak during a GH stimulation test at baseline was not correlated to the first year height velocity while on GH treatment. However there was a negative linear correlation between baseline IGF1 level and first year height velocity (Spearman’s rho = 0.312216, p-value= 0.01516). Age at GH initiation was negatively correlated with height velocity during GH treatment. Height velocity over time decreased sharply from year 1 to year 3, and became stable for the remaining years of GH therapy. For the entire group, HV for years 1-5 was 9.81 (sd=4.83), 7.40 (sd=2.89), 6.29 (sd=2.38), 5.92 (sd=2.56), 5.66 (sd=2.51). There is no significant correlation between GH dose and height velocity response after adjusting for diagnosis. CONCLUSION: In our population, the response to GH therapy was consistent with those reported in the literature. Response to GH therapy was not associated with GH peak on stimulation but rather to baseline IGF-1 level and age at initiation. Although peak GH to stimulation is required to obtain public funding for GH therapy, these findings demonstrate that GH stimulation test results may not indicate which patients may benefit the most from GH therapy. Follow-up until final adult height will allow us to have a better understanding of the efficacy of GH therapy in patients with both GHD and nGHD conditions.

SUN-597 Healthcare Utilization Patterns Among Commercially Insured Patients with Prader-Willi Syndrome: A Retrospective Analysis of Administrative Claims

Prader-Willi syndrome (PWS) is a complex orphan endocrine disease characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity and early mortality along with a significant burden on patients and caregivers. Life-long medical care is required but the consistency of services rendered to this population has not been evaluated. This study characterized use of US hospital care, specialty physician care, and growth hormone (GH) therapy for PWS patients at different life stages. Methods: PWS ICD-9 codes in the IQVIA™ Health Plan Claims Data from 1/2006 to 9/2015 were used to identify PWS patients. Inclusion criteria considered patients <65 years of age with ≥12 months of continuous enrollment who received ≥2 PWS diagnostic codes. Observation time was segmented into 12-month patient-years for analysis. Standardized billing code conventions were used to identify and categorize services of interest from 1/2006 to 11/2018. Results: A total of 5,060 PWS patient years representing 1,461 unique patients were eligible. Mean annual visits to inpatient, emergency department, and physician office settings ranged by age-cohort in years from 0.2-1.6, 0.5-1.3, and 9.2-26.0, respectively. Younger (0-17) and older (50-64) age-cohorts utilized more services than early-mid adulthood age-cohorts. Use of pediatricians or endocrinologists ranged from 76% to 88% among patients under 18 years of age. Utilization of cardiologists, orthopedists, physical therapists, and otolaryngologists ranged by age-cohort from 8-44%, 7-21%, 3-21%, and 7-38%, respectively, with highest utilization among younger patients. GH use increased from 37% to 46% of PWS patients between 2007 and 2018. GH users <18 years of age were 3.0, 0.6, 1.9, 1.7, and 1.4 times as likely to utilize endocrinologists, cardiologists, orthopedists, physical therapists, and otolaryngologists, respectively, compared with non-GH users. Conclusions: Use of hospital services for PWS patients was bimodal with higher use among the youngest and oldest age-cohorts. Change in the utilization level of select specialists reflects the complexity of care for age-related clinical sequelae, such as orthopedic concerns in infancy and early-onset cardiovascular disease due to hyperphagia and obesity in adolescents, as well as syndrome-specific treatment protocols (e.g., specialty consults needed for GH treatment). That less than half of PWS patients <18 years of age received GH therapy despite growing clinical evidence on the benefits and tolerability of GH suggests a potential gap in provider knowledge of the standard of care for PWS. Our analysis suggests that GH use may be a surrogate for better access to a multidisciplinary care team and specialty services. Considerable variation of services indicates that more effort is required to optimize care in PWS.

Possible Effects of Growth Hormone Therapy on the Eye

AbstractBackground: Human growth hormone therapy in children may affect the eye due to its growth promoting properties.Aim of the Study: To detect possible effects of growth hormone therapy on ocular axial length, refraction and posterior segment.Patients and Methods: This study included 30 Growth Hormone (GH) deficient children scheduled for human GH therapy. Before GH treatment patients ocular examination included: Dilated fundus, cycloplegic spherical equivalent and axial length using A-scan ultra sound. All the previous examination items were repeated and documented 6 months after treatment start.Results: 30 GH deficient children were included; 17 (56.7%) males and 13 (43.3%) females of whom 3 had turner syndrome. Mean age was 11 .39±3.64 years. Mean spherical equivalent of cycloplegic refraction was +0.81-}0.85 diopter pre-therapy and +0.26-}0.6 diopter 6 months after therapy (p-value=0.2). Mean axial length was 21.04-}1.33mm pre-therapy and 21.421.39mm 6 months after therapy (p-value=0. 12). Right sided papilledema occurred in 1 patient with turner syndrome (1.66%) 6 months after therapy, while no other retinal complications were found.Conclusion: We found no significant change in ocular axial length and refraction 6 months after GH therapy. One case of pseudotumour cerebri was documented. We recommend routine fundus examination for patients receiving GH therapy and stop of therapy once papilloedema encountered.

PF349 57 PATIENTS WITH HAX1 ASSOCIATED CONGENITAL NEUTROPENIA: AN ANALYSIS OF THE EUROPEAN SEVERE CHRONIC NEUTROPENIA INTERNATIONAL REGISTRY (SCNIR)

Background:Congenital neutropenia (CN) is a heterogeneous group of rare inborn genetic defects with different gene mutations and different patterns of inheritance. Mutations in the HCLS1 associated Protein X‐1 (HAX1) make up the largest cohort of autosomal recessive CN in Europe. There are two HAX1 splice isoforms. Mutations affecting one isoform (p.W44X) only can be found in consanguineous families of Turkic or Arabic origin while mutations affecting both isoforms were found in the original pedigree from Sweden (p.Q190X) and in Japanese pts (p.R86X). Independent of the mutation, HAX1 pts benefit from G‐CSF treatment, which improved the life expectancy and quality of life significantly. However, a significant risk of secondary leukemia has been unmasked for pts with HAX1 mutations (comparable to pts with ELANE mutations).Aims:Here we report on the genotype – phenotype correlation and outcome of pts revealing different HAX1 mutations.Methods:We identified 57 pts with HAX1 mutations within the CN cohort documented by the European Branch of the SCNIR since 1994.Results:HAX1 mutations have been identified in 57 (25 female; 32 male) of 501 pts with CN. The median age is 9.49 years (range 0.28–38.69 years), with 664.83 pt years under observation. 45 of 57 pts reveal homozygous mutations in one transcript variant (p.W44X), in 1pt with an additional heterozygous ELANE mutation. In 2 of 57 pts, both isoforms are affected (p.Q190X). 5 of 57 pts have mutations at other sites of the HAX1 gene and in 5 pts the position was not reported. At diagnosis, all HAX1 pts presented with severe neutropenia and a maturation arrest at the promyelocyte/myelocyte stage in the bone marrow. All pts received long‐term G‐CSF treatment with a median dose of 4.25 μg/kg/day compared to 4.61 μg/kg/day for the total CN cohort of the SCNIR Europe. Median ANC increased from 160 to 1775/μL during G‐CSF treatment. Additional clinical features included cardiac defects in 4 pts, hypogonadism in 5 female pts and growth retardation in 6 pts, of whom 2 pts received growth hormone therapy. In addition to the 2 pts affecting both HAX1 isoforms, neurological involvement like mental retardation or epilepsia was identified in 3 pts. 8 of the 57 pts (14.04 %) developed secondary MDS or leukemia (age at diagnosis 0.98–15.98 years, median 8.59 years). 7 of the 8 pts carry mutation p.W44X, 1 pt carries p.Q190X. All 8 pts were treated with allogeneic SCT. In addition, 2 pts (age 0.88 and 18.11 years) received SCT for other reasons (prior to G‐CSF availability; cure of primary disease), but none for G‐CSF non‐responsiveness. G‐CSF doses were higher in pts with leukemia (7.05 μg/kg/day) compared to non‐leukemic pts (3.64 μg/kg/day) as previously reported for other CN pts. 54 of 57 pts are alive, 1 pt expired from sepsis at age 2 years after developing hemophagocytic lymphohistiocytosis, 2 pts transplanted for leukemia expired (1 of TRM at age 13 years; 1 of alveolar haemorrhage after leukemia relapse at age 11 years).Summary/Conclusion:All pts with HAX1 mutations present with profound neutropenia, but respond well to long‐term G‐CSF treatment. There are additional organ involvements in subsets of pts. All pts with HAX1 mutations have a significant risk for secondary leukemia. Registry and biobanks are extremely valuable for understanding the consequences of rare hematological diseases such as congenital neutropenia.

Prevalence of low lean mass in patients with adult growth hormone deficiency with or without low-dose growth hormone therapy.

The importance of muscle mass has been emphasized in various studies, and growth hormone (GH) deficiency is tightly associated with lean mass loss. Therefore, we aimed to investigate the prevalence of low lean mass in patients with adult growth hormone deficiency (AGHD) who received or did not receive GH therapy. In this retrospective study, we included patients diagnosed with AGHD by using the insulin tolerance test (ITT) in our hospital. Patients without completed follow-up data were excluded, and data for 56 patients were analysed. Twenty-six patients who had received GH therapy for more than 6months, based on the medical record, were included in the GH group and received recombinant human growth hormone (rhGH) at a dose of 0.5IU/d. Thirty patients who had not previously received GH treatment were included in the non-GH group. Many anthropometric and blood biochemical indicators were measured. Body composition was measured on a dual-energy X-ray-absorptiometry (DXA) scanner. Low lean mass was defined as a skeletal muscle index (SMI) <7.0kg/m2 in males or 5.7kg/m2 in females. Statistical analyses were performed using GraphPad Prism 5.0. Compared to the non-GH group, the patients who received GH therapy had significantly lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and fasting plasma glucose (FPG). The percentage of patients with low lean mass in GH and non-GH groups was 30.77% and 60%, respectively. The percentage of total lean was lower in the GH group than in the non-GH group, but the difference in total lean mass was not statistically significant. Conversely, patients with GH treatment had significantly lower fat mass and percentage than non-GH-treated patients (P<0.05). The GH group had significantly higher serum levels of both IGF-1 and IGFBP3. Moreover, both IGF-1 and IGFBP3 were significantly correlated with SMI (r2 =0.275, P=0.003, and r2 =0.138, P=0.005, respectively). Our data showed that AGHD patients who received low-dose GH treatment had a lower prevalence of low lean mass than those who did not receive GH treatment. Patients with GH treatment had significantly lower cardiovascular risk factors, especially the lipid profile.

Growth hormone therapy in patients with Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder that involves multiple organ systems, with short stature as the most common presentation (>70%). Possible mechanisms of short stature in NS include growth hormone (GH) deficiency, neurosecretory dysfunction, and GH resistance. Accordingly, GH therapy has been carried out for NS patients over the last three decades, and multiple studies have reported acceleration of growth velocity (GV) and increase of height standard deviation score (SDS) in both prepubertal and pubertal NS patients upon GH therapy. One year of GH therapy resulted in almost doubling of GV compared with baseline; afterwards, the increase in GV gradually decreased in the following years, showing that the effect of GH therapy wanes over time. After four years of GH therapy, ~70% of NS patients reached normal height considering their age and sex. Early initiation, long duration of GH therapy, and higher height SDS at the onset of puberty were associated with improved final height, whereas gender, dosage of GH, and the clinical severity did not show significant association with final height. Studies have reported no significant adverse events of GH therapy regarding progression of hypertrophic cardiomyopathy, alteration of metabolism, and tumor development. Therefore, GH therapy is effective for improving height and GV of NS patients; nevertheless, concerns on possible malignancy remains, which necessitates continuous monitoring of NS patients receiving GH therapy.

The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center.

45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4±1.1 to -1.4±0.9 in adulthood (P<0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy.