Growth Hormone Treatment In Short Children Research Articles

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

The association between idiopathic scoliosis and growth hormone treatment in short children.

PurposeIdiopathic scoliosis is the most common form of scoliosis, and the risk of onset and progression has been found to correlate with growth spurts. Therefore, treatment with recombinant human growth hormone (GH) treatment in short children may initiate and/or aggravate scoliosis. The aim of this study was to investigate the relationship between idiopathic scoliosis and GH treatment in short children.MethodsThe medical records of 113 subjects seen at the participating institution between January 2010 and December 2020 and who were diagnosed with GH deficiency and small for gestational age, had idiopathic short stature, and were treated with GH for at least one year were reviewed. Scoliosis was defined as a Cobb angle greater than 10 degrees as assessed using a spine x-ray. Clinical data and laboratory findings before and 12 months after GH treatment were compared.ResultsThere was significant increase in height, height-standard deviation score, insulin-like growth factor 1, and insulin-like growth factor binding protein 3 (P<0.001) with GH treatment. However, there were no significant differences in the average Cobb angle (6.2°±3.3° vs. 6.1°±3.5°, P=0.842) and the prevalence of scoliosis (9.7% vs. 13.3%, P=0.481) before and after one year of GH treatment. A comparative analysis of both initial Cobb angle and change in Cobb angle during GH treatment showed no relationship with other factors.ConclusionsAlthough GH treatment in short children increased height and growth velocity, it was not associated with development or aggravation of idiopathic scoliosis.

Short Stature in Isodicentric Y Chromosome and Three Copies of the SHOX Gene: Clinical Report and Review of Literature

Short stature homeobox gene (SHOX) mutations and pseudoautosomal region 1 (PAR1) deletions encompassing SHOX are known causes of Léri-Weill dyschondrosteosis and isolated short stature, while 3 copies of SHOX in cases with triple sex chromosome constitution are responsible for tall stature. Duplications involving SHOX have been rarely reported, and they were found in individuals with short, normal and tall stature. An adopted boy with short stature, isodicentric Y chromosome and 3 copies of SHOX is described. Normal growth hormone (GH) secretion and insulin-like growth factor 1 (IGF1) increase during an IGF1 generation test were found, ruling out impaired GH-IGF1 axis. No other organic or psychiatric causes of impaired growth were found. GH treatment improved linear growth, as reported in children with SHOX haploinsufficiency. This new report and the review of literature support that SHOX duplication may cause short stature, especially in those children with duplications of the 5′SHOX regulatory elements. Chromosome analysis and detailed molecular characterization of the duplicated region should be warranted in individuals with SHOX duplications in order to investigate the presence of occult chromosome imbalance. Additional reports and follow-up till adult height are needed to give conclusions on long-term efficacy and safety of GH treatment in short children with SHOX duplication.

Rapid cardiovascular effects of growth hormone treatment in short prepubertal children: impact of treatment duration

Previous studies show that growth hormone (GH) treatment increases cardiac dimensions in short children with GH deficiency (GHD) and has diverse cardiac effects in children with idiopathic short stature (ISS). This study was performed to assess the effect of GH on the cardiovascular system in short children with a broad range of GH secretion and GH sensitivity/responsiveness. In this prospective, multicentre study, short prepubertal children diagnosed with isolated GHD (89) or ISS (38) were followed during 2 years of GH treatment. They were randomized to receive either a standard (43 μg/kg/day) or an individualized GH dose (range 17-100 μg/kg/day) based on GH responsiveness estimated by a prediction model and distance to target height. Echocardiography, blood pressure and electrocardiography were performed at baseline, 3, 12 and 24 months. Left ventricular mass (LVM) indexed to body surface area increased significantly during 2 years of GH treatment in both GHD and ISS irrespective of randomized dose. This change was already apparent at 3 months, when standard deviation scores (SDS) of wall thickness and diameter were increased. At 24 months, left ventricular diameter SDS remained increased, whereas myocardial thickness SDS returned to baseline values. There was no impairment of systolic or diastolic function. There was no correlation with treatment dose and LVM SDS at 24 months. Irrespective of GH status, there was a rapid increase in LVM during GH treatment in short children. At 3 months, wall thickness and diameter were increased, whereas only diameter remained increased at 24 months.

Adult height and health-related quality of life after growth hormone therapy in small for gestational age subjects

Objective: To estimate health-related quality of life (HRQoL) in non-growth hormone deficient (GHD) small for gestational age (SGA) children before and after growth hormone (GH) treatment to adult height (AH).Methods: This was a multicentre, two-arm trial. Following an initial 2-year double-blind study period, patients entered a 2-year extension period followed by treatment to AH. At baseline patients were randomised to GH (0.033 or 0.067 mg/kg/day) and continued treatment at that dose until AH. Height was assessed at baseline and 3-monthly intervals to AH (height velocity <2 cm/year). Height standard deviation score (SDS) before and after GH therapy was mapped onto estimated HRQoL scores up to AH.Results: Of the 79 children randomised into the study 53 were non-GHD (defined as peak GH >20 mU/L [peak 24-h GH value and peak arginine tolerance test]). At baseline these children had a mean (mean [±SD]) height SDS of −3.2 (0.7), height velocity SDS −0.6 (1.2) and age, 8.1 (1.9) years. Estimated HRQoL scores were significantly (p < 0.001) increased from baseline at AH (ΔHRQoL, 95% CI) (0.033 mg/kg/day, 0.112 [0.092, 0.132]; 0.067 mg/kg/day, 0.115 [0.094, 0.136]). HRQoL was not different between treatment groups. A significant gain in AH, relative to an SGA reference population, was reported in GH-treated patients. Mean (95% CI) ΔAH SDS (0.033 mg/kg/day, +1.4 [1.1, 1.6]. 0.067 mg/kg/day, +1.7[1.4, 2.0]).Limitations: The analysis assumes HRQoL can be mapped onto height SDS.Conclusions: GH treatment in short children born SGA without signs of persistent catch-up growth was associated with significant improvement in HRQoL and normalisation of AH.

Models predicting the growth response to growth hormone treatment in short children independent of GH status, birth size and gestational age

BackgroundMathematical models can be used to predict individual growth responses to growth hormone (GH) therapy. The aim of this study was to construct and validate high-precision models to predict the growth response to GH treatment of short children, independent of their GH status, birth size and gestational age. As the GH doses are included, these models can be used to individualize treatment.MethodsGrowth data from 415 short prepubertal children were used to construct models for predicting the growth response during the first years of GH therapy. The performance of the models was validated with data from a separate cohort of 112 children using the same inclusion criteria.ResultsUsing only auxological data, the model had a standard error of the residuals (SDres), of 0.23 SDS. The model was improved when endocrine data (GHmax profile, IGF-I and leptin) collected before starting GH treatment were included. Inclusion of these data resulted in a decrease of the SDres to 0.15 SDS (corresponding to 1.1 cm in a 3-year-old child and 1.6 cm in a 7-year old). Validation of these models with a separate cohort, showed similar SDres for both types of models. Preterm children were not included in the Model group, but predictions for this group were within the expected range.ConclusionThese prediction models can with high accuracy be used to identify short children who will benefit from GH treatment. They are clinically useful as they are constructed using data from short children with a broad range of GH secretory status, birth size and gestational age.

Effects of Growth Hormone Treatment for Short Stature on Calcium Homeostasis, Bone Mineralisation, and Body Composition

We investigated the effect of growth hormone (GH) treatment on mineral and vitamin D homeostasis, bone mineralisation, and body composition in short-statured children without GH deficiency (GHD). 11 children received GH (0.50 +/- 0.08 IU/kg/week) for 24 weeks. 1,25-Dihydroxyvitamin D3 levels (mean +/- SD in pmol/l) rose from a baseline of 73.7 +/- 39.2 to 114.0 +/- 32.7 at 8 weeks (p < 0.05) and 111.9 +/- 39.7 at 24 weeks (p < 0.01). Body composition evaluation using dual-energy X-ray absorptiometry revealed increased lean tissue mass and a reduction in fat tissue. As a percentage of total body mass, fat decreased from 19.0 +/- 11.8% at baseline to 17.3 +/- 11.5% at 8 weeks (p < 0.005) and 16.8 +/- 11.5% at 24 weeks (p < 0.05). L2-L4 bone mineral density was 0.637 +/- 0.155 g/cm2 at baseline and 0.666 +/- 0.160 g/cm2 at 24 weeks (NS). We conclude that recombinant human GH treatment of short children without GHD has significant effects on vitamin D homeostasis and body composition.

PREDICTION OF GROWTH RESPONSE IN GROWTH HORMONE (GH) TREATED SHORT PREPUBERTAL CHILDREN - INFLUENCE OF GROWTH IN EARLY LIFE

There is a need for better criteria for initiation of growth hormone (GH) treatment in children. The aim of this study was therefore to identify possible predictors of the growth response to GH treatment in short children of different GH staus, especially growth data from birth to two years of age. Prepubertal children (n=206) treated for at least two years with GH (0.1 U/g x day) were included. Their maximal GH response to provocation test ranged from 0-80 mU/L. At start of treatment the mean age was 8.4 years (range 2.6-15.4 years) and mean height −3.0 SDS. The individual 2 years growth response was correlated with the log GHmax at AITT (r=−0.40), the midparental height SDS (r=0.33), the age at start of treatment (r=−0.32), the height SDS at start of treatment (r=−0.21), delta SDS value (r=−0.21) and the difference between the height SDS at onset of GH treatment of an individual child and the midparental height SDS, (diff SDS; r = −0.42). The growth response during the first two years of treatment could be predicted in a multiple regression model to 33% in terms of GH^max at AITT and the diff SDS. We also found that the GHmax at AITT and the diff SDS both were positively correlated to birth length and height velocity during the first and second year of life as well as to the pretreatment height velocity, The complex etiology of being short, involving genetic potential, growth disturbances in the past, and GH secretion may explain the relatively low prediction of the growth response using ordinary multivariable analysis. Another approach would be to subgroup the children in terms of background variables before applying some predictive models. For instance on two years of CH treatment the children with low GHmax increased 1.8 SDS independently of birthlenght, whereas the growth response in children with high GHmax was positively related to birthlenght; 1.2 SDS in normal birthlength children vs 0.8 SDS in low birthlenglh children.