Change In Height Standard Deviation Score Research Articles

A Clinical Trial of High Dose Growth Hormone in a Patient with a Dominant Negative Growth Hormone Receptor Mutation.

Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention. To determine whether high dose GH can overcome GH resistance in this specific patient resulting in normal IGF-1 levels and improved growth rates. Single patient trial of ascending doses of GH followed by dose stable phase; total 12 months of treatment. Patient has a heterozygous variant in GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH starting at 50 micrograms/kg/day and escalating to 250 micrograms/kg/day until goal IGF-1 achieved. Subject continued 250 micrograms/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the mid-point of the normal range. Secondary endpoints included height velocity and the change in height SDS during the 1st year of treatment. A dose of GH of 250 micrograms/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height. A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.

Imatinib treatment and longitudinal growth in pediatric patients with chronic myeloid leukemia: Influence of demographic, pharmacological, and genetic factors in the German CML-PAED cohort.

In children and adolescents, impaired growth due to tyrosine kinase inhibitor therapy remains an insufficiently studied adverse effect. This study examines demographic, pharmacological, and genetic factors associated with impaired longitudinal growth in a uniform pediatric cohort treated with imatinib. We analyzed 94 pediatric patients with chronic myeloid leukemia (CML) diagnosed in the chronic phase and treated with imatinib for >12 months who participated in the Germany-wide CML-PAEDII study between February 2006 and February 2021. During imatinib treatment, significant height reduction occurred, with medians of -0.35 standard deviation score (SDS) at 12 months and -0.76 SDS at 24 months. Cumulative height SDS change (Δheight SDS) showed a more pronounced effect in prepubertal patients during the first year but were similar between prepubertal and pubertal subgroups by the second year (-0.55 vs. -0.50). From months 12 to 18 on imatinib, only 18% patients achieved individually longitudinal growth adequate to the growth standard (Δheight SDS≥0). When patients were divided into two subgroups based on median Δheight SDS (classifier Δheight SDS > or ≤-0.37) after one year on imatinib therapy, cohort 1 (Δheight SDS extending -0.37) showed younger age at diagnosis, a higher proportion of prepubertal children, but also better treatment response and higher imatinib serum levels. Exploring the association of growth parameters with pharmacokinetically relevant single nucleotide polymorphisms, known for affecting imatinib response, showed no correlation. This retrospective study provides new insights into imatinib-related growth impairment. We emphasize the importance of optimizing treatment strategies for pediatric patients to realize their maximum growth potential.

THU169 Role Of Growth Hormone (GH) Therapy In Short Children With Skeletal Dysplasias And Pathogenic Variants In The COL2A1 Gene

Abstract Disclosure: L.D. Cellin: None. K.G. Guimaraes: None. N.L. Menezes De Andrade: None. G.A. Vasques: None. E.D. Goiano: None. M. Akkari: None. C. Santili: None. A.A. Jorge: None. A.C. Malaquias: None. Introduction: COL2A1 is the primary collagen synthesized by chondrocytes and plays a critical structural role in regulating cell growth, differentiation, and migration. Mutations in the COL2A1 gene may cause heterogeneous phenotypes ranging from skeletal dysplasia to nonsyndromic short stature. Clinical characteristics in COL2A1-related disorders are abnormalities in the ocular, skeletal, oro-facial, and audiological systems. Unfortunately, data were scarce about GH treatment in short children with pathogenic variants in COL2A1.Objective: To evaluate recombinant growth hormone (GH) treatment in short children carrying mutations in the COL2A1 gene. Methods: Retrospectively, we selected 8 prepubertal patients with short stature and pathogenic variants in the COL2A1 gene who were treated with GH (mean dose of 45.8 ± 7.9 µg/kg/d at the start). The primary outcomes were changes in height SDS and growth velocity in the 1st year and at the end of treatment. Results: Five patients were male; 3 were disproportionate, and 5 showed skeletal dysplasia signs. Two had familial short stature. At the start of the treatment, the mean calendar age was 8.1 ± 3.9 yr, and bone age was 6.9 ± 4.2 yr. The mean height SDS was -4.0 ± 0.9 for the CDC reference. In the 1st year of therapy, the growth velocity (GV) increased from baseline values of 5.2 ± 1.9 cm/yr to 7.4 ± 1.4cm/yr, an increment of 2.2 ± 2.2cm (p=0.02). GV SDS increased from -1.2 ± 1.5 to 1.2 ± 1.8 in the whole cohort during the 1st year of treatment (p=0.02). Height SDS showed a modest improvement after one year of therapy (from -4.0 ± 0.9 to -3.5 ± 0.9; p=0.005). To improve adult height, we treated two patients with GnRH analogs associated with GH. After a mean duration of therapy of 5.5 ± 2.5 years, 5 patients ended the treatment with rhGH (one prematurely stopped therapy due to poor growth response). No increment was observed in height SDS at the end of treatment (from -3.8 ± 0.9 to -3.4 ± 1.3; p=0.2). Four patients achieved adult height after 6.4 ± 1.7 years of therapy (height SDS ranging from -3.4 ± 0.4 to -2.9 ± 0.8; p=0.08). The mean gain in adult height SDS was 0.5 ± 0.4 (ranging from zero to 0,97). Conclusions: Our patients with COL2A1-associated disorders showed no response to GH therapy to improve adult height as a group. However, we need more studies to determine which patient will benefit from this treatment once there is considerable phenotype heterogeneity. GnRH analogs may help to improve adult height in association with GH. Also, alternative therapies might be evaluated to treat short children with these disorders. Presentation: Thursday, June 15, 2023

Growth pattern in children with X-linked hypophosphatemia treated with burosumab and growth hormone

BackgroundX-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies.ResultsThirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy.ConclusionTo our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

Clinical characteristics and long-term outcomes of 12 children with vitamin D-dependent rickets type 1A: A retrospective study.

Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by deficiency of the CYP27B1 gene. This study aims to investigate the phenotypic and genotypic features of VDDR1A children in southern China and evaluate the long-term therapeutic effects. Twelve children from southern China with VDDR1A were enrolled in this study. Their clinical, radiological, biochemical, and molecular findings were analyzed retrospectively. The rickets severity score (RSS), biochemical parameters, and height standard deviation score (HtSDS) were used to evaluate clinical outcomes. Six males and six females were included in this VDDR1A cohort. The age of onset was from 6 months to 1.8 years, and the age at diagnosis was 2.1 ± 0.8 years. The most common clinical symptoms at diagnosis were delayed walking (10/12) and severe growth retardation (9/12). HtSDS at diagnosis was negatively associated with age (p < 0.05). All patients presented with hypocalcemia, hypophosphatemia, increased serum alkaline phosphatase and parathyroid hormone, and high RSS at diagnosis. Two allelic variants of the CYP27B1 gene were identified in all patients, including nine different variants, four known and five novel, with c.1319_1325dupCCCACCC(p.Phe443Profs*24) being the most frequent. All patients were treated with calcitriol and calcium after diagnosis, and all patients but one were followed-up from 6 months to 15.6 years. HtSDS, RSS, and biochemical parameters were found to be improved during the first few years of the treatment. However, only five patients had good compliance. Although RSS and biochemical parameters were significantly improved, the HtSDS change was not significant from the time of diagnosis to the last visit, and seven patients remained of a short stature (HtSDS < -2). Our study extends the mutational spectrum of VDDR1A and finds a hotspot variant of the CYP27B1 gene in southern China. The results reconfirm the importance of early diagnosis and treatment compliance and reveal the challenge of height improvement in VDDR1A patients.

RF26 | PMON334 Once-Weekly Somapacitan in Growth Hormone Deficiency: 4-Year Efficacy and Safety Results from REAL 3, a Randomised Controlled Phase 2 Trial

Abstract The current treatment for growth hormone deficiency (GHD) requires daily subcutaneous injections, which can be burdensome. Somapacitan is a long-acting growth hormone (GH) derivative in development for once-weekly use in children with GHD. REAL 3 (NCT02616562) is an ongoing, phase 2, multinational, randomised, open-label, controlled trial designed to investigate the efficacy and safety of somapacitan compared with daily GH (Norditropin®). Prepubertal children with GHD who were naïve to GH treatment received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (equivalent to 0.238 mg/kg/week; n=14) for 1 year. This was followed by a 2-year safety extension, in which all patients on somapacitan (n=45) received 0.16 mg/kg/week, while patients receiving daily GH remained on daily GH. In a further, ongoing 4-year long-term safety extension, patients treated with somapacitan remained on somapacitan (somapacitan/somapacitan, n=39) and all patients on daily GH switched to somapacitan 0.16 mg/kg/week (daily GH/somapacitan, n=11). Here, we present efficacy and safety results from the first year of the 4-year long-term safety extension. At year 4, the mean (SD) height velocity (HV) was 7.4 (1.6) cm/year for the somapacitan/somapacitan group and 6.6 (1.6) cm/year for the daily GH/somapacitan group, compared with 8.3 (1.7) and 7.6 (2.0) cm/year for the somapacitan/somapacitan and daily GH groups, respectively, at year 3. The mean (SD) HV standard deviation score (SDS) was 1.55 (1.70) for the somapacitan/somapacitan group and 0.88 (1.61) for the daily GH/somapacitan group, and the mean (SD) change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97), respectively. The mean (SD) insulin-like growth factor-I SDS at year 4 was 1.29 (1.23) and 0.94 (1.60) for the somapacitan/somapacitan and daily GH/somapacitan groups, respectively. During year 4, 20 patients (51.3%) experienced 84 adverse events (AEs) in the somapacitan/somapacitan group, and eight patients (72.7%) experienced 12 AEs in the daily GH/somapacitan group. The most common AE was nasopharyngitis, occurring in four patients (10.3%) in the somapacitan/somapacitan group and one patient (9.1%) in the daily GH/somapacitan group; all other AEs occurred in &amp;lt;10% of patients in either group. Most AEs were mild or moderate and unlikely related to GH treatment. One severe AE (surgery for elbow fracture) occurred in the somapacitan/somapacitan group. No serious AEs were reported in year 4. Since previously reported in year 3, one patient in the somapacitan/somapacitan group experienced five injection-site reactions; none occurred in the daily GH/somapacitan group. In conclusion, these year 4 data support the efficacy and safety results of somapacitan observed in the previous 3 years of the trial. In year 4, height-related outcomes were similar for patients who continued treatment with somapacitan and those who switched from daily GH to somapacitan. Somapacitan was well tolerated, and no safety signals were identified. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:44 p.m. - 12:49 p.m.

LBMON197 Predictors Of Response To Growth Hormone Treatment In Pediatric Growth Disorders: Analysis From The Answer Program And Nordinet® IOS

Abstract Background The American Norditropin® Studies: Web-Enabled Research (ANSWER) Program and the NordiNet® International Outcome Study (NordiNet® IOS) were large-scale, non-interventional studies intended to gather long-term data on the effectiveness and safety of Norditropin® (somatropin) treatment in the real-world setting. Data were collected in the US and Europe from 2006 to 2016. Objective To determine predictors of response to daily growth hormone (GH) for height outcomes using a longitudinal analysis across 5 years of real-world data from pediatric patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS). Methods Data were combined for ANSWER and NordiNet® IOS studies for GH-treatment-naïve pediatric patients on daily somatropin. Descriptive statistics for baseline demographics, outcomes, and GH (mg/kg/d) data were analyzed for each indication; statistics for outcome and GH data were analyzed over time for absolute values and change from baseline values at year 1 through year 5. A longitudinal statistical approach was used to identify factors, including age at treatment start and HSDS at baseline, significantly associated with change in height SDS from baseline (ΔHSDS) in a regression model. Repeated-measures regression analyses were performed on ΔHSDS, adjusting for covariates. Longitudinal growth responses over the follow-up years were evaluated. Results Overall, 14,295 patients were included in the analyses: 3766 females and 8917 males with GHD, 1307 patients with TS, 55 females and 148 males with NS, and 52 females and 50 males with PWS. Mean (SD) GH dose for patients with GHD was 0. 037 (0. 012) mg/kg/d (females) and 0. 038 (0. 012) mg/kg/d (males), for those with TS was 0. 045 (0. 011) mg/kg/d, those with NS was 0. 042 (0. 012) mg/kg/d, and those with PWS was 0. 031 (0. 013) mg/kg/d. HSDS improved over time across all indications. Greater improvement in HSDS was observed for years 1 and 2 of follow-up, with a plateau in years 4 and 5; this plateau was most apparent in patients with TS. Age at start of GH therapy had a significant effect on ΔHSDS for all indications (P&amp;lt;0. 001 for all). Lower baseline HSDS on average resulted in lower HSDS improvement over time. In a regression model, the GH dose (mg/kg/d) from the previous year was positively associated with ΔHSDS, with a significant positive slope for GHD and TS (P&amp;lt;0. 0001 for both). A 0. 01 increase in GH mg/kg/d increased the average HSDS improvement by 0. 02 to 0. 03 units in GHD and 0. 03 units in TS. Slopes for NS (P=0.3534) and PWS (P=0.1485) were not significant. Conclusions On average, GH treatment resulted in HSDS improvements over baseline across all indications; patients with GHD had the highest improvement, while patients with TS had the lowest improvement. Earlier treatment with GH led to better outcomes in HSDS. Increasing the dose of GH also led to better outcomes in HSDS. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PSAT104 Predicting Response to Growth Hormone Therapy with Pituitary Volume and The Growth Hormone Stimulation Test

Abstract Background Patients with diminished growth hormone (GH) secretion are candidates for GH therapy (GHT). The GH stimulation test (GHST) is considered the gold standard for the diagnosis of GH deficiency (GHD), yet its efficacy has been questioned. In this study we explore the GHST and PV's ability to define GHD and determine their individual ability to predict GHT outcomes. Subjects and Methods A database at a Pediatric Endocrinology center was queried for patients aged 6-18 yrs who underwent a GHST, MRI, and GHT between 1/2018 - 1/2021. Patients with a first follow up (FU) between 3 and 9 months were included; of these patients, second FUs were included if they occurred between 9 and 15 months. Patients with relevant comorbidities, those with GHST peak ≥ 10.0 ng/mL, and nonadherent patients were excluded. MRIs were acquired on a Philips 1.5 or 3.0 T scanner (2mm slices) and PV was calculated using the ellipsoid formula (LxWxH/2). PV and height were converted to SDS. Response to treatment was defined as change in height SDS over the assessed time interval. A multiple linear regression was utilized to analyze the response to GHT relative to peak GH and PV, with initial height and age at stimulation included as covariates. The relationship between peak GH and PV SDS was analyzed with a Pearson correlation Results The first FU ranged between 3.1 and 8.9 months, and the second FU ranged between 9.0 and 14.9 months. 145 patients had one FU, and 83 patients had two FUs. Peak GH and PV SDS were not correlated (r=0.03). Patients who were relatively shorter for their age and gender at stimulation had higher growth rates in the first interval, but not in the second interval. Both PV and peak GH provided information about response to GHT. PV SDS negatively predicted the relative growth response to treatment in the first interval (slope=-0.03, p=0.048). However, PV only explained 3.7% of variation in growth. PV SDS was not a useful predictor of response in the second interval (slope=-0.01, p=0.693). Peak GH was a predictor of response to GHT in the first interval only after accounting for age at stimulation and initial height (slope=-0.01, p=0.032; r2=0.01). Peak GH was a predictor of response in the second interval (slope=-0.02, p=0.040), explaining 5.1% of the variation in growth. Conclusion Since peak GH and PV were not correlated, they likely reflect different physiological processes. PV and peak GH both provide information about response to GHT, so they should both be utilized to determine eligibility for GHT. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The long-term growth, cost-effectiveness, and glycemic effects of growth hormone therapy on children born small for gestational age over 10years: a retrospective cohort study.

We aimed to report our 10-year experience of treating short children born small for gestational age (SGA) by comparing the long-term growth, metabolic safety, and cost-effectiveness of recombinant human growth hormone (rhGH) therapy in short children born SGA with those in rhGH-treated children with growth hormone deficiency (GHD) and Turner syndrome. We performed a 10-year retrospective cohort study at King Saud University Medical City. We included children aged 3-16years who received rhGH for GHD, SGA, or Turner syndrome for >1year. A total of 166 children received rhGH therapy for GHD, 58 for SGA, and 16 for Turner syndrome. During the last study visit, the average height change was 21cm for GHD children and 14cm for children born SGA (p-value <0.001). The height SDS change was 0.84 forGHD children and 0.55 for SGA children (p-value=0.004). The average cost-effectiveness ratios for treating GHD and SGA children were USD 1,717.22 and USD 1,157.19 per centimeter gained, respectively. Moreover, the mean incremental cost-effectiveness ratio for GHD vs. SGA patients was USD 2,820.39 per centimeter gained. Dysglycemia developed in 70 patients: 43 (36.44%), 22 (40.74%), and 5 (13%) in the GHD, SGA, and Turner syndrome groups, respectively. rhGH is effective in height improvement of short children. However, pursuing rhGH treatment for children born SGA requires a shared decision-making approach to balance the modest benefit of final adult height gain with the long-term metabolic effects, considering the acceptable costs on the Saudi healthcare system.

Maternal Factors in Pregnancy and Ethnicity Influence Childhood Adiposity, Cardiac Structure, and Function.

ImportanceThe links between maternal and offspring adiposity and metabolic status are well established. There is much less evidence for the impact of these relationships combined with ethnic background on cardiac structure and function in childhood.ObjectiveTo test the hypothesis that ethnicity, maternal adiposity and glycemic status, and child adiposity affect cardiac structure and function.DesignA prospective cohort study.SettingA single-center mother-child cohort study. The cohort is a subset of the international multi-center Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.ParticipantsThis study included 101 healthy pre-pubertal British-born children [56 White Europeans (WEs) and 45 South Asians (SAs)] with a median age of 9.1 years, range 6.0–12.2 years, at the time of the investigation.Main Outcomes and MeasuresAnthropometric and echocardiographic measurements were made on the cohort. Maternal pregnancy and birth data were available. Relationships between maternal parameters (BMI and glucose status), child adiposity, and echo measures were assessed.ResultsDespite no ethnic difference in BMI SDS at a median age of 9.1 years, SA children exhibited higher levels of body fat than WE children (whole body, right arm, and truncal fat all p < 0.001). SA children also exhibited greater changes in weight and height SDS but not BMI SDS from birth than WE children. As expected, maternal BMI correlated with child BMI (r = 0.28; p = 0.006), and body fat measures (e.g., whole body fat r = 0.25; p = 0.03). Maternal fasting glucose levels were associated with child body fat measures (r = 0.22–0.28; p = 0.02–0.05). Left ventricular (LV) indices were not different between SA and WE children, but E/A and E′/A′ (measures of diastolic function) were lower in SA when compared with WE children. LV indices correlated positively to BMI SDS and body fat markers only in SA children. Maternal fasting and 2-h glucose were negatively correlated with E′/A′ in SA children (r = −0.53, p = 0.015, and r = −0.49, p = 0.023, respectively) but not in WE children.Conclusion and RelevanceSA and WE children exhibit differences in adiposity and diastolic function at a median age of 9.1 years. Novel relationships between maternal glycemia, child adiposity, and cardiac structure and function, present only in SA children, were identified.

Short-term effect of growth hormone treatment in childhood leukemia survivors with growth hormone deficiency.

Survivors of childhood leukemia are at risk of growth impairment due to intensive chemotherapy and radiation treatments. This study investigated the auxological and biochemical characteristics of childhood leukemia survivors diagnosed with growth hormone deficiency (GHD) and the changes in these parameters after 1 year of growth hormone (GH) treatment. A total of 24 children diagnosed with GHD after leukemia treatment was analyzed. Clinical and biochemical data were collected retrospectively at leukemia diagnosis, GHD diagnosis, and 1 year after GH treatment. Standard deviation score (SDS) was calculated based on the age- and gender-adjusted population. Of the 24 children included in this study, 19 received GH treatment. The median age at GHD diagnosis was 12.3 years, and the median delay in bone age was 1.46 years. Height SDS decreased from -0.69 at leukemia diagnosis to -2.58 at GHD diagnosis (P<0.001). The change in height SDS with and without GH for 1 year was 0.35 and -0.21, respectively (P=0.044). In regression analyses, higher height SDS at GHD diagnosis and a smaller decrease of the height SDS between leukemia and GHD diagnoses were positively correlated with height SDS after GH treatment. GH treatment could be beneficial and safe for improving height in childhood leukemia survivors with GHD. Height SDS at GHD diagnosis and reduction of height SDS between leukemia and GHD diagnosis could be potential factors in predicting the therapeutic effects. Close auxological monitoring is recommended for any childhood leukemia survivors who experience posttreatment height decline.

Metabolic Changes across Tertiles of Delta Changes in Height SDS during Growth Hormone Therapy in Children with Growth Hormone Deficiency

Introduction: Obesity, dyslipidemia, hypertension, and insulin resistance are components of the metabolic syndrome and in adults are positively affected by growth hormone (GH) treatment. Few data are available on youth, especially evaluating the improvement of metabolic features after starting GH treatment. The aim of this study was to evaluate changes in metabolic profile in GHD children across tertiles of h-SDS changes after at least 20 months of GH therapy. Methods: Data from 51 normal-weight children and adolescents with GHD (age: 11.4 ± 2.3 years; h-SDS: −2.25 ± −1.94) who had performed a complete metabolic profile including IGF-1, lipid profile (total cholesterol, triglycerides, HDL cholesterol), glucose metabolism (fasting glycemia, insulin, hemoglobin A1c levels), and insulin resistance indices (HOMA, TG/HDL ratio) before and after start GH treatment were analyzed. Subjects who had received GH therapy for at least 20 months were eligible. Delta changes were calculated for each variable. Subjects were divided according to tertiles of delta changes of h-SDS (1st tertile, 2nd tertile, 3rd tertile) before and after a period of GH treatment. Results: In each tertile group, a significant increase in height SDS was documented. Delta changes in glucose metabolism, lipid profile, and insulin resistance indices significantly improved across tertiles groups, showing the highest tertile a better metabolic pattern. Discussion/Conclusions: GH therapy is associated with improvement of metabolic profile. Delta changes seem to be more evident in those children with a higher tertile of delta h-SDS after starting GH therapy. A tailored therapy aimed to reach a proper goal in h-SDS after GH treatment might be necessary in order to reduce cardiovascular risk in GHD children.

Growth and Nutritional Outcomes in Children Post-Haematopoietic Stem Cell Transplant without Exposure to Total Body Irradiation

AimsPoor growth in childhood cancer survivors who undergo haematopoietic stem cell transplant (HSCT) without exposure to radiation is reported anecdotally, although literature to support this is limited. The aims of this study were to assess the change in height standard deviation score (SDS) and the final adult height (FAH) in children who underwent chemotherapy-only conditioned HSCT and to identify predictors of poor growth. Materials and methodsWe conducted a retrospective hospital medical record review (1984–2010) of children (1–10 years) who underwent chemotherapy-only conditioned HSCT, noting anthropology measurements at cancer diagnosis, HSCT, 10 years old and FAH. ResultsThe median age at HSCT of the 53 patients was 4.5 years, 75% had a haematological malignancy and 25% a solid tumour. Half of the cohort underwent allogenic HSCT and most (89%) conditioned with busulphan. The mean change in height SDS from primary cancer diagnosis to FAH was –1.21 (±1.18 SD), equivalent to 7–8.5 cm loss, with a mean FAH of –0.91 SDS (±1.10 SD). The greatest height loss occurred between diagnosis and HSCT (–0.77 SDS, 95% confidence interval –1.42, –0.12, P = 0.01), with no catch-up growth seen by FAH. Patients with solid tumours had the greatest height loss. Overall body mass index SDS did not change significantly over time, or by cancer type. ConclusionsChemotherapy-only conditioned HSCT during childhood can impact FAH, with the greatest height loss occurring prior to HSCT and no catch-up growth after treatment finishes. Children transplanted for a solid tumour malignancy seem to be more at risk, possibly due to intensive treatment regimens, both pre-transplant and during conditioning.

A Real-World Study of Recombinant Human Growth Hormone in the Treatment of Idiopathic Short Stature and Growth Hormone Deficiency.

ObjectiveThis study aimed to evaluate the clinical efficacy of recombinant human growth hormone (rhGH) in the treatment of children with idiopathic short stature (ISS) and growth hormone deficiency (GHD) and to explore the related factors affecting treatment efficacy.MethodsThe current research reflects a real-world study. A total of 79 patients with ISS and 95 patients with GHD (both groups pre-puberty) who had been treated with rhGH for more than one year from January 2010 to September 2019 were included in this study. The patients were divided into two groups, ie, an ISS and a GHD group, respectively. The growth indexes, such as chronological age (CA), bone age (BA), height standard deviation score (HtSDS), insulin-like growth factor-1 (IGF-1) SDS, and body mass index were recorded and compared between the two groups before and after treatment. The treatment efficacy was evaluated according to changes in HtSDS before and after treatment, and the influencing factors of clinical efficacy were analyzed using a multivariate regression model.ResultsAt the start of treatment, the differences in CA, BA, height, weight, sexual development stage, HtSDS, mid-parental height SDS, and IGF-1 SDS between the two groups were not statistically significant (P > 0.05). However, the initial dose of rhGH in the GHD group was significantly lower than in the ISS group (P < 0.001). Following rhGH treatment, the differences in CA, BA, BA/CA ratio, and IGF-1 SDS measured at 6, 12, 18, and 24 months between the ISS and GHD groups were not statistically significant, while the difference in HtSDS measured at 6 months was statistically significant. With the extension of rhGH treatment time, the annual growth rate (GV) gradually decreased, and the difference between HtSDS and the baseline gradually increased; however, the differences between the ISS and GHD groups were not statistically significant. The most important factor affecting the treatment efficacy for patients with ISS was age at the start of treatment; the most important factors affecting the treatment efficacy for patients with GHD were age and IGF-1 SDS.ConclusionRecombinant human growth hormone treatment can significantly improve the height of patients with ISS and GHD. There was no significant difference in growth rate between patients with ISS and those with GHD at relatively high doses. The common factor affecting the treatment efficacy of the two groups was the age at the start of treatment. During treatment, monitored data indicated that rhGH treatment of GHD and ISS thyroid function showed a clinical phenomenon in the form of increased free triiodothyronine, rather than hypothyroidism, which was rarely reported in existing studies.

Role of ZBTB38 Genotype and Expression in Growth and Response to Recombinant Human Growth Hormone Treatment.

ContextSingle-nucleotide polymorphisms (SNPs) in ZBTB38 have been associated with idiopathic short stature (ISS) and adult height.ObjectiveThis study sought to (a) characterize the phenotype of ISS patients and their response to recombinant human growth hormone (rhGH) by ZBTB38 SNP genotype; (b) describe the relationship of ZBTB38 expression with normal growth; and (c) describe the in vitro effects of ZBTB38 knockdown on cell proliferation and MCM10 expression.MethodsThe genotype-phenotype relationship of rs6764769 and rs724016 were explored in 261 ISS patients and effects of genotype on response to rhGH were assessed in 93 patients treated with rhGH. The relationship between age and ZBTB38 expression was assessed in 87 normal children and young adults. Knockdown of ZBTB38 in SiHA cells was achieved with siRNAs and cell proliferation assessed with a WST-8 assay.ResultsWe found that rs6764769 and rs724016 are in linkage disequilibrium. The rs724016 GG genotype was associated with lower birth length (P = 0.01) and a lower change in height SDS over the first year of treatment (P = 0.02). ZBTB38 expression was positively correlated with age (P < 0.001). siRNA-mediated knockdown of ZBTB38 resulted in increased cell proliferation at 72 and 96 hours posttransfection but did not alter expression of MCM10.ConclusionsSNPs within ZBTB38 associated with ISS are linked to higher birth size within a cohort of ISS patients and a better response to rhGH therapy while ZBTB38 expression is positively related to age.

A 4-hour Profile of 17-hydroxyprogesterone in Salt-wasting Congenital Adrenal Hyperplasia: Is the Serial Monitoring Strategy Worth the Effort?

Objective:Since there is no gold standard laboratory variable for adjustment of treatment in congenital adrenal hyperplasia (CAH), the aim was to assess the use of a 4-hour profile of serum 17-hydroxyprogesterone (17-OHP) to determine the most appropriate sample time and level of 17-OHP in predicting the metabolic control and evaluate the role of sex hormone-binding globulin (SHBG) in hyperandrogenemia.Methods:This study included children with salt-wasting CAH. Measurements for 17-OHP and cortisol were made from samples obtained before and 1, 2, and 4 hours after the morning dose of hydrocortisone. Patients were designated to have poor metabolic control when androstenedione levels according to age and sex-specific reference intervals were high and annual height standard deviation score (SDS) changes were ≥0.5.Results:The study cohort was 16 children (9 girls) with a median age of 7-years old. Premedication 17-OHP levels were strongly correlated with 17-OHP levels 1, 2, and 4 hours after the morning dose (rs=0.929, p<0.01; rs=0.943, p<0.01; rs=0.835, p<0.01, respectively). 17-OHP profiles (0, 1, 2, 4 hours) of poor (n=6) and good (n=10) metabolically controlled cases were similar. Among the patients with poor metabolic control, two cases had 17-OHP levels <2 ng/mL at all times. The remaining patients with poor metabolic control had median 17-OHP levels above 104 ng/mL, 82 ng/mL, 14 ng/mL, and 4 ng/mL, for baseline and 1, 2, and 4 hours, respectively. Differences between the poor and well-controlled group were androstenedione levels with respect to upper limit of normal [1.8 (1.5) and 0.5 (1.5) ng/mL, respectively p=0.03], annual change in height SDS [0.7 (0.2) and -0.03 (0.8) SDS, respectively, p=0.001], and daily hydrocortisone doses [7 (6) and 16 (8) mg/m2/day, respectively, p=0.02]. Androstenedione and SHBG levels were negatively correlated in the pubertal children (rs=-0.7, p=0.04).Conclusion:We conclude that: (i) a 4-hour 17-OHP profile is not useful in predicting hyperandrogenemia; (ii) suppressed levels of 17-OHP do not always indicate overtreatment; (iii) reference intervals of 17-OHP for different time periods might be of importance; (iv) low hydrocortisone doses should be avoided; and (v) SHBG could be used in pubertal children as an indicator of hyperandrogenemia.

Molecular diagnosis for growth hormone deficiency in Chinese children and adolescents and evaluation of impact of rare genetic variants on treatment efficacy of growth hormone

BackgroundGrowth hormone is an effective therapy for growth hormone deficiency (GHD) but with a rather variable individual sensitivity. It is unclear whether rare genetic variants may contribute to the differential GH responsiveness. MethodsThe present study aims to investigate the molecular etiology of GHD in Chinese children and adolescents and evaluate the impact of rare variants on therapeutic efficacies of GH. ResultsTwenty-one rare heterozygous variant were classified as promising uncertain significance (n = 14), pathogenic (n = 5) or likely pathogenic (n = 2) for 21 of the 93 GHD patients. After GHD patients harboring these rare variants were excluded, inter-individual variability in the response to GH therapy obviously reduced and the negative correlation between initiation age of treatment and height SDS change became stronger in the group without rare variants. Among rare variants, 7 (likely) pathogenic variants (7.5%, 7/93) involved a total of 6 genes not only associated with GH secretion (PROKR2, LZTR1), but also growth plate chondrocyte signaling (ACAN, FBN1, COL9A1) or genetic syndromes (PTPN11). ConclusionsRare genetic variants are an important factor contributing to differential GH responsiveness and genetic testing should be factored into accurate diagnosis and treatment decision making in the future.Clinical Trial Registration Number: ChiCTR1900026510.

Growth Disturbances in Pediatric Patients Receiving Long-Term Tyrosine Kinase Inhibitor Therapy

Background:Since their approval in 2003, Tyrosine Kinase Inhibitors (TKIs) targeting bcr-abl1 kinase activity have changed the treatment paradigm for children with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). However, off-target inhibition of kinases, such as src and c-kit, can result in impaired osteoblast function, cause an imbalance in calcium and phosphate metabolism, and result in growth impairment in children. The aim of our study was to examine growth over time in pediatric patients receiving TKIs for CML or Ph+ ALL.Description: This is a single institutional retrospective longitudinal cohort study of patients (≤ 21 years of age) diagnosed with CML or Ph+ ALL between January 2000 and December 2015 who received a TKI and had ≥ 1 year of growth data available as of May 31, 2016. Patient demographics, treatment details including the type and duration of TKI therapy and details of concomitant conventional therapy (chemotherapy and radiation) were abstracted. Growth data was abstracted from the start of TKI at yearly intervals up to a maximum of five years or age 20 and from their last available appointment. Specific variables for growth included height, height percentile, height-SDS (height - standard deviation score or z score) and BMI-SDS (body mass index - standard deviation score). Height-SDS and BMI-SDS were determined using the CDC growth chart by age and gender. Age at diagnosis was used as a surrogate for expected pubertal status: pre-pubertal (3 - 8.9 years), pubertal/peri-pubertal (9 - 15.9 years), post-pubertal (16+ years). Overall change in height-SDS / BMI-SDS from baseline to 1-year and last follow-up were compared by diagnosis, gender, and pubertal age using ANOVA. Statistical analysis was performed using SAS® v9.3 (Cary, NC). For all analyses, a p-value of <0.05 was considered to be statistically significant.Results: Our cohort included 48 patients who received a TKI (n=29 CML, n=19 Ph+ ALL) - 46% were male and 38% were non-Hispanic white. The mean age at diagnosis was 12.1 ± 3.7 years for CML and 9.0 ± 4.6 years for Ph+ ALL patients (p=0.01). As expected, mean duration of TKI treatment was longer in CML (4.3 ± 2.8 years) versus Ph+ ALL (2.7 ± 1.7 years). The average duration of follow-up was similar in both groups (CML 4.6 ± 3.54 years vs Ph+ ALL 4.1 ± 2.9 years, p=0.60). At time of diagnosis, the mean Height-SDS for the entire cohort was 0.13 ± 1.28 with no difference between patients by diagnosis (p=0.92). At one year following treatment with TKI a decrease in mean height-SDS was noted, with a more significant difference in Ph+ ALL patients (-0.54 ± 0.21) compared to CML patients (-0.18 ± 0.39) (p=0.002). This difference remained significant at last follow-up (Ph+ ALL -0.96 ± 0.70, CML -0.52 ± 0.74, p=0.05) (Figure 1). There was no significant difference in mean change in height-SDS at 1 year or last follow-up by gender. Overall, the decrease in height-SDS at 1 year was most significant in the pre-pubertal age group (-0.51 ± 0.27) as compared to pubertal/peri-pubertal and post-pubertal groups (-0.26 ± 0.46 and -0.10 ± 0.24 respectively; p=0.04). BMI-SDS at baseline did not differ by diagnosis but did show a significant decrease at one year in Ph+ ALL versus CML patients (-0.18 ± 0.65 and 0.39 ± 0.54 respectively, p=0.003); this stabilized at the time of last follow up (-0.01 ± 0.75 and 0.38 ± 0.80 respectively, p=0.11).Conclusions: Our data underscores the concern of growth disturbances following prolonged TKI exposure in children, the role of exposure relative to pubertal change in bone growth, and the need for understanding off-target mechanisms in childhood survivors. Stabilization of BMI-SDS at the end of follow up with accompanying drop in mean height-SDS points to a mechanism of growth disturbance beyond nutritional deficiencies. This large pediatric cohort treated with TKIs is the first to include Ph+ ALL patients who were younger at onset of TKI treatment, and more likely to be pre/peripubertal at the start TKI exposure. Future directions will focus on a prospective study of musculoskeletal and other organ toxicities in patients treated with TKIs in childhood. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Is a Two-Year Growth Response to Growth Hormone Treatment a Better Predictor of Poor Adult Height Outcome Than a First-Year Growth Response in Prepubertal Children With Growth Hormone Deficiency?

ObjectiveThe first year response to growth hormone (GH) treatment is related to the total height gain in GH treated children, but an individual poor first year response is a weak predictor of a poor total GH effect in GH deficient (GHD) children. We investigated whether an underwhelming growth response after 2 years might be a better predictor of poor adult height (AH) outcome after GH treatment in GHD children.Design and methodsHeight data of GHD children treated with GH for at least 4 consecutive years of which at least two prepubertal and who attained (near) (n)AH were retrieved from the Belgian Register for GH treated children (n = 110, 63% boys). In ROC analyses, the change in height (ΔHt) SDS after the first and second GH treatment years were tested as predictors of poor AH outcome defined as: (1) nAH SDS <−2.0, or (2) nAH SDS minus mid-parental height SDS <−1.3, or (3) total ΔHt SDS <1.0. The cut-offs for ΔHt SDS and its sensitivity at a 95% specificity level to detect poor AH outcome were determined.ResultsEleven percent of the cohort had a total ΔHt SDS <1.0. ROC curve testing of first and second years ΔHt SDS as a predictor for total ΔHt SDS <1.0 had an AUC >70%. First-year ΔHt SDS <0.41 correctly identified 42% of the patients with poor AH outcome at a 95% specificity level, resulting in respectively 5/12 (4.6%) correctly identified poor final responders and 5/98 (4.5%) misclassified good final responders (ratio 1.0). ΔHt SDS after 2 prepubertal years had a cut-off level of 0.65 and a sensitivity of 50% at a 95% specificity level, resulting in respectively 6/12 (5.5%) correctly identified poor final responders and 5/98 (4.5%) misclassified good final responders (ratio 1.2).ConclusionIn GHD children the growth response after 2 prepubertal years of GH treatment did not meaningfully improve the prediction of poor AH outcome after GH treatment compared to first-year growth response parameters. Therefore, the decision to re-evaluate the diagnosis or adapt the GH dose in case of poor response after 1 year should not be postponed for another year.

Changes in height standard deviation scores during early life are affected by nutrition.

BackgroundLarge changes in height standard deviation score (SDS) have been reported from birth to 3 years of age. We analyzed how early these changes start and whether they are affected by nutrition.MethodsThe longitudinal growth of 1,849 children born between March 1 2007 and August 31 2007 or between March 1, 2009 and August 31 2009 with five records from birth to 3 years of age was analyzed.ResultsThe height SDS at birth was positively correlated with body mass index (BMI) SDS at birth (r = 0.224, P < 0.0001). The height SDS at birth decreased among children with a positive height SDS and increased among children with a negative height SDS. The changes occurred immediately after birth and became more modest as children aged. Regarding the change in the height SDS from birth to 3 years of age, 33.4% of children increased more than 0.5 SDs, 39.8% of children decreased more than 0.5 SDs, and 34.4% of children remained within ±0.5 SDs. The change in height SDS displayed a strong positive correlation with the change in weight during the four periods. From birth till 3 months, from 3 months till 6 months, from 6 months till 1.5 years, and from 1.5 years till 3 years.ConclusionsThe significant positive correlation between height SDS and BMI SDS suggests an effect of children’s nutrition status in utero. The height SDS change started immediately after birth and the change was largest from birth to 3 months. A positive correlation between changes in height SDS and weight suggest that growth during early childhood depends on nutritional status.