Effects Of Growth Hormone Treatment Research Articles

Increased IGFBP proteolysis, IGF-I bioavailability and pappalysin levels in children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. We determined serum levels of PAPP-As and STCs in association with IGF axis components in pre- and pubertal patients with PWS, also analyzing the effect of GH treatment. Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at six months of treatment in 11 children. Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and higher concentrations of free IGF-I, IGFBP-5 and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment.

We aimed to describe the clinical characteristics of patients with congenital combined pituitary hormone deficiency (CPHD) and evaluate the first-year growth responses of individuals with CPHD and isolated growth hormone deficiency (IGHD) in order to establish the influence of other hormone deficiencies on growth response. This retrospective study was conducted in four tertiary care centers in Turkey. The records of patients diagnosed with CPHD (n=39) and severe IGHD (n=50) were collected. Cases with acquired lesions or chronic diseases were not included in the study. Data are presented as median (interquartile range). Among 39 patients (13 females; 33%) with a diagnosis of CPHD, the majority of patients (64%) presented initially with combined deficits at baseline examination, whereas isolated deficiencies (36%) were less prevalent. Among all patients with GH deficiency, TSH, ACTH, FSH/LH, and ADH deficiencies were present in 94%, 74%, 44%, and 9% of patients, respectively. Patients with CPHD were diagnosed at a younger age (4.9 (8.4) vs. 11.6 (4.1), p<0.001, respectively) and had lower peak GH concentrations (0.4 (1.8) vs. 3.7 (2.9), p<0.001, respectively) than patients with IGHD. Patients with IGHD and CPHD had similar first-year growth responses (Δheight SD score of 0.55 (0.63) vs. 0.76 (0.71), respectively, p=0.45). We established the nature and timing of numerous hormonal deficits emerging over time. We also identified that the existence of CPHD did not hinder growth response.

FRI454 The Effect Of Growth Hormone Treatment According To Karyotype Classification In Turner Syndrome Patients

Abstract Disclosure: J. Choi: None. J. Yu: None. H. Kim: None. OBJECTIVES Short stature is the main characteristics for Turner syndrome (TS) patients, and growth hormone (GH) therapy has been used as an essential treatment for developing final adult height. However, there are only a few studies on the difference responsiveness to GH therapy according to the karyotype of Turner syndrome in Korea. The aim of this study was to analyze the effect of different types of TS karyotype abnormality on the response of GH therapy. METHODS The clinical parameters of 194 TS patients registered in the LG Growth Study, who received rhGH therapy (Eutropin inj.,LG Chem Ltd.,Korea) between February 2001 and October 2021, were retrospectively reviewed. Data for four group of subjects were obtained as follow: Monosomy X (n=56); Mosaicism without X structural abnormality (n=41); Mosaicism with X structural abnormality (n=71); X Structural abnormality (n=26). Parameters of biochemical characteristics and growth responses were compared during 3-year GH treatment. RESULTS The baseline height standard deviation score (SDS) was -2.85±0.86 in total TS patients. The growth velocity (cm/year) in the second year was higher in the Mosaicism without X structural abnormality compared to the monosomy X patients. However, the change of Hight SDS over three years was not statistically different between karyotypes. The growth rate was the highest in the first year, and it showed a decreasing trend over time. There was an increase in Height SDS due to growth hormone treatment for three years. The variables affecting the 0-3rd Δ height SDS were not found in the regression analysis CONCLUSIONS Our results indicate that there are no difference in response to three years of growth hormone therapy according to karyotype of TS. It was found that the initial height SDS was the lowest in monosomy compared to the others group. Further studies should be performed on other factors influencing the efficacy of the therapy. Presentation Date: Friday, June 16, 2023

THU049 Growth Hormone Treatment Reverses Deficits In POU1F1 Gene Mutation

Abstract Disclosure: S. Al-Samerria: None. J. Phelan: None. H. Xu: None. A. Negron: None. F. Wondisford: None. S. Radovick: None. Mutations in the Pit 1 gene, also known as POU1F1, have been linked to the deficient development of somatotrophs and the synthesis of growth hormone (GH) in the anterior pituitary gland. In a previous study, we reported a point mutation in the PIT1 gene caused by a substitution of a lysine (K) with a glutamic acid (E) at position 216 (K216E) on one allele in a patient presenting with combined pituitary hormone deficiency (CPHD). This patient had undetectable levels of GH, TSH, very low PRL, and severe mental retardation associated with short stature (SS). To study the effects of GH treatment on growth and metabolism in CPHD, we created a unique mouse model with the K216E mutation in the PIT1 gene using the CRISPR/Cas9 genome editing system. In this study, 4-week-old male and female homozygous mice were randomly divided into two groups. The treatment group received subcutaneous injections of GH (5 mg/g/day) for 5 consecutive days per week for 4 weeks, while the control group received saline injections on the same schedule. GH treatment significantly improved the growth and body composition of male and female mice bearing the K216E. GH treatment also increased metabolism as measured by oxygen consumption, carbon dioxide production, and energy expenditure. These effects were observed both during treatment and 4 weeks post-treatment, although some reversal of the changes in body composition was observed 4 weeks post-treatment. Our findings demonstrate the utility of this mouse model in studying the effects of GH deficiency and treatment on growth and metabolism. This model holds great promise in advancing our understanding of the underlying mechanisms of hypopituitarism and CPHD, potentially serving as a valuable tool in identifying metabolic biomarkers for these conditions. Presentation: Thursday, June 15, 2023

3M syndrome: Evaluating the clinical and laboratory features and the response of the growth hormone treatment: Single center experience

Introduction & objective3 M Syndrome is a rarely encountered autosomal recessive syndrome characterized by low birth weight, severe postnatal growth deficiency, and minor dysmorphic abnormalities. 3 M-related short stature has been attributed to the resistance to growth hormone (GH) to a certain extent rather than to GH deficiency. The resistance to GH, on the other hand, has been associated with impaired protein scaffolding, transport, and p53-mediated apoptosis at the IGF-1 post-receptor pathway. In this context, the objective of this study is to evaluate the clinical, laboratory, and genetic characteristics of the patients with 3 M syndrome, detect the mutations frequently observed in these patients, and assess their response to GH treatment. Material&methodsThe sample of this single-center study consisted of patients diagnosed with 3 M syndrome based on genetic tests between 2007 and 2021. Patients’ clinic, laboratory, and genetic characteristics pertaining to the time of admission and follow-up were recorded. All patients except one underwent a growth hormone stimulation test (GHST) (Levo-dopa or insulin tolerance test). Insulin-like growth factor (IGF) generation test was performed on those with sufficient GHST results (0.1 mg/kg/day for four days). ResultsThe median age of the patients, five females and three males, was 2.8 (0.25–8.12) years at admission. All but one patient were small for gestational age (SGA). The patient with normal birth weight was the baby of a diabetic mother. Obscurin-like 1 (OBSL1) variant was detected in all cases. The median height standard deviation score (SDS) at admission was −4.94 ((-5.63)- (−3.27)) SDS, and the median midparenteral height SDS was −1.27 SDS ((-3.1)- (0.34)). All patients were prepubertal at admission. The GHST response was sufficient in five cases. IGF generation test was performed in three cases. Seven patients received GH therapy (35–57 μg/kg/day). Five of these patients discontinued GH therapy since their growth velocity (GV) fell below normal during treatment. In addition, one case discontinued GH therapy because her IGF-1 value was>2 SDS, and another case received gonadotropin-releasing hormone (GnRH) analogs together with GH therapy. The median age and height SDS of the patients were 10.1 (1.79–18) years and −5.09 SDS ((-7.11)- (2.45)), respectively, as of the last follow-up visit. The height SDS values of the two cases that reached the final height were −7.11 SDS and −3.39 SDS. There were no side effects of GH treatment. ConclusionThe study findings indicated a good GV during the early stages of the long-term GH treatment administered to patients with 3 M syndrome. However, response to GH therapy decreased in the following years, and the desired improvement in height SDS could not be achieved in patients who reached their final heights. Taken together with the literature data, it has been concluded that initiating GH therapy in the prepubertal period provided better outcomes than after puberty.

The Effects of Growth Hormone on Nerve Regeneration and Alloimmunity in Vascularized Composite Allotransplantation.

Poor outcomes in functional recovery following upper extremity transplantation are largely due to denervation-induced muscle atrophy that occurs during the prolonged period of nerve regeneration. Growth hormone (GH) has well-established trophic effects on neurons, myocytes, and Schwann cells and represents a promising therapeutic approach to address this challenge. This study sought to confirm the positive effects of GH treatment on nerve regeneration and functional recovery and to evaluate the effects of GH treatment on the immune response in the setting of vascularized composite allotransplantation. Rats underwent orthotopic forelimb transplantation across a full MHC-mismatch and received either porcine-derived growth hormone or no treatment (n=18 per group). Functional recovery was measured using electrically-stimulated grip strength testing. Animals were monitored for clinical and subclinical signs of rejection. Neuromuscular junction reinnervation and grip strength were improved in GH-treated animals (p=0.005; p=0.08). No statistically significant differences were seen in muscle atrophy, degree of myelination, axon diameter, and axon counts between groups. The rates of clinical and histological rejection did not significantly differ among groups. Our findings alleviate concern for increased risk of transplant rejection during GH therapy and therefore support the translation of growth hormone as a therapeutic method to promote improved functional recovery in upper extremity transplantation.

Schaaf-Yang Syndrome: Clinical Phenotype and Effects of 4 years of Growth Hormone Treatment

Introduction: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder caused by truncating mutations of the MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region. PWS and SYS have phenotypic overlap. Patients with SYS are often treated with growth hormone (GH), but evidence for the effectiveness of the treatment in patients with SYS is limited. Methods: This study describes 7 children with SYS. We studied their phenotype, genotype, and the effect of GH treatment on height and body mass index (BMI) during 4 years and on body composition during 1 year. Results: All patients had a normal birth weight. Most patients had hypotonia and feeding difficulties after birth (86%). Full-scale IQ ranged from <50 to 92. All patients above the age of 2 years had psycho-behavioral problems. There were no apparent correlations between the phenotype and the location of the defect in the MAGEL2 gene. Mean (95% CI) height SDS increased significantly from −1.74 (−3.55; 0.07) at start to −0.05 (−1.87; 1.77) after 4 years of GH treatment. Mean (95% CI) BMI SDS decreased significantly from 2.01 (1.02; 3.00) to 1.22 (0.18; 2.26) after 6 months and remained the same during the rest of the follow-up. Fat mass percentage SDS decreased and lean body mass did not change during 1 year of treatment in 3 patients. Conclusion: Patients presented with a phenotype of hypotonia, respiratory insufficiency, and feeding difficulties after birth, endocrine disorders, intellectual disability, and behavioral problems. Treatment with GH significantly improved height SDS and BMI over the course of 4 years.

The Effects of 5 Years of Growth Hormone Treatment on Growth and Body Composition in Patients with Temple Syndrome

Introduction: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal uniparental disomy of chromosome 14, paternal deletion of 14q32.2, or an isolated methylation defect. Most patients with TS14 develop precocious puberty. Some patients with TS14 are treated with growth hormone (GH). However, evidence for the effectiveness of GH treatment in patients with TS14 is limited. Methods: This study describes the effect of GH treatment in 13 children and provides a subgroup analysis of 5 prepubertal children with TS14. We studied height, weight, body composition by dual-energy X-ray absorptiometry, resting energy expenditure (REE), and laboratory parameters during 5 years of GH treatment. Results: In the entire group, mean (95% CI) height SDS increased significantly during 5 years of GH treatment from −1.78 (−2.52; −1.04) to 0.11 (−0.66; 0.87). Fat mass percentage SDS decreased significantly during the first year of GH, and lean body mass (LBM) SDS and LBM index increased significantly during 5 years of treatment. IGF-1 and IGF-BP3 levels rose rapidly during GH treatment, and the IGF-1/IGF-BP3 molar ratio remained relatively low. Thyroid hormone levels, fasting serum glucose, and insulin levels remained normal. In the prepubertal group, median (interquartile range [IQR]) height SDS, LBM SDS, and LBM index also increased. REE was normal at start and did not change during 1 year of treatment. Five patients reached adult height and their median (IQR) height SDS was 0.67 (−1.83; −0.01). Conclusion: GH treatment in patients with TS14 normalizes height SDS and improves body composition. There were no adverse effects or safety concerns during GH treatment.

Role of growth hormone in orthodontics

Human growth hormone (Somatotropin) is produced by acidophilic growth hormone cells in the anterior pituitary gland, stimulated by hypothalamus. Its production is regulated by several complex feedback mechanisms in response to stress, exercise, diet, sleep and growth hormone itself. Growth hormone plays a major role in linear body growth and craniofacial growth. In Orthodontics, it induces orthodontic tooth movement by activating specific cytokines to regulate osteoclast &amp; osteoblast activity. It mediates STAT signalling in liver &amp; pancreas to produce JAK-IGF-1. IGF-1 has stimulatory effects on osteoblasts and chondrocytes for endochondral ossification to promote bone growth. Growth hormone mediates mitogenic stimulus to odontoblast lineage cells by epidermal growth factor (EGF) to differentiate into odontoblasts. It also stimulates production of alkaline phosphatase and osteocalcin in osteoblasts to improve osteoblast proliferation and differentiation. It also induces osteoclastic activity indirectly by production of IGF-1 and IL- 6 thereby activating RANK-RANKL/OPG phenomenon. It also promotes myofibrillar diameter expansion so it increases muscle mass with strength. Growth Hormone Replacement therapy reduces facial convexity and its main effect appears to be on condylar growth. Since deficiencies of growth hormone can adversely affect orthodontic treatment, effects of growth hormone treatment on craniofacial structures should be considered in order to maximize the effectiveness of orthodontic treatment with appliances and it is more important to understand.

MAY GROWTH HORMONE HAVE A ROLE IN THE TREATMENT OF SEVERE OLIGOASTHENOZOOSPERMIA? A CONTROLLED TRIAL EVALUATING THE IGF-I SERUM LEVELS

It is established that Growth Hormone (GH) affects gonadal function at hypothalamic, pituitary and gonadal sites, and the effect of GH/IGF-I axis on spermatogenesis is well known. IGF-I is secreted by Sertoli Cells, secondary spermatocytes, spermatids and spermatozoa, and abnormal sperm parameters seem to correlate with lower serum IGF-I serum levels. Some authors reported a beneficial effect of GH treatment in infertile men, with the increase of spermatozoa number and motility in cases of oligoasthenoteratozoospermia. On the other hand, other authors did not confirm these findings. The aim of this study was to evaluate the role of GH treatment in normogonadotropic oligoasthenozoospermic patients no responsive to gonadotropins treatment in improving semen characteristics, evaluating the role of patients IGF-I serum levels

Copeptin in Growth Hormone-Treated Patients.

Growth hormone (GH) changes body composition, including increasing body water. GH is known to have an anti-natriuretic effect in the kidney, but little is known of its effect on arginine-vasopressin (AVP) release. We studied the effect of GH on AVP release by measurement of copeptin, a fragment from the same precursor protein, in GH-treated patients with GH deficiency. The study was designed as a retrospective cohort study of biobank samples from 34 patients substituted with GH between 1999 and 2004. Copeptin and insulin-like growth factor 1 (IGF-1) results were compared with previously obtained data. An increase in IGF-1 and copeptin was seen at 3 and 6 months’ treatment compared to baseline. Between the 3 and 6 months follow up, copeptin levels were stable. There was a difference in HbA1c between 3 and 6 months (p < 0.01) and between baseline and 6 months (p = 0.042), with higher levels at 6 months. In addition, LDL levels were lower at the 6 months follow up (p = 0.046). The waist circumference at 3 months was lower (p = 0.02). To conclude, three months of GH treatment increased the levels of copeptin and the increase remained at 6 months. This could be a compensatory mechanism balancing the anti-natriuretic effect of GH treatment seen in previous studies.

Effects of growth hormone treatment on sleep-related parameters in adults with Prader-Willi syndrome

Effects of growth hormone treatment on sleep-related parameters in adults with Prader-Willi syndrome

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.

Effect of Growth Hormone Treatment on the Concentration of Selected Metabolic Markers in Girls With Turner Syndrome.

BackgroundAs Turner syndrome (TS) predisposes to obesity and metabolic disorders, and their complications, such as cardiovascular diseases, are the main causes of shortened life expectancy in patients with TS, new metabolic markers that could serve as early predictors of dysmetabolic state are sought.ObjectiveAssessment of MMP-1 (matrix metalloproteinase-1), MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metallopeptidase-9), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), and VEGF (vascular endothelial growth factor) before the onset of growth hormone (GH) therapy and then during GH treatment as well as markers assessment during GH medication in girls with TS to establish marker stability and repeatability, and the impact of GH on markers concentration.MethodThe concentrations of circulating MMP-1, MMP-2, MMP-9, BDNF, GDNF, and VEGF were measured in nine girls with TS before the onset of GH therapy and then after at least 3 months of treatment period. Subsequently, markers concentration was determined in 17 girls during GH medication, with the first determination after at least a 3-month treatment period. The patients’ clinical and biochemical phenotypes were determined by weight, height, BMI, total cholesterol, HDL cholesterol, triglycerides, and glucose concentration.ResultsComparison of markers concentration revealed a significantly higher concentration of MMP-2 in patients undergoing GH treatment (132.1 ± 42.05) than before the onset of therapy (105.0 ± 45.5, p=0.045). The values of the first measurement of VEGF in girls with TS undergoing GH therapy were significantly higher than those during the second measurement (30.9 ± 33.4 vs. 12.5 ± 11.7, p=0.029). There were no statistically significant differences between the measurements of the remaining markers concentration at any stage of the analysis.ConclusionIncrease in MMP-2 concentration is visible during GH therapy in comparison to the pre-GH period in girls with TS which demands confirmation in subsequent tests. The role of VEGF requires further studies in the context of carbohydrate-lipid disturbances in girls with TS and its association with GH treatment.

Molecular Genetics and Pathogenesis of the Floating Harbor Syndrome: Case Report of Long-Term Growth Hormone Treatment and a Literature Review.

Introduction: Floating Harbor syndrome (FHS) is an extremely rare disorder, with slightly more than a hundred cases reported worldwide. FHS is caused by heterozygous mutations in the SRCAP gene; however, little is known about the pathogenesis of FHS or the effectiveness of its treatment. Methods: Whole-exome sequencing (WES) was performed for the definitive molecular diagnosis of the disease. Identified variants were validated using Sanger sequencing. In addition, systematic literature and public data on genetic variation in SRCAP and the effects of growth hormone (GH) treatment was conducted. Results: We herein report the first case of FHS in the Russian Federation. The male proband presented with most of the typical phenotypic features of FHS, including short stature, skeletal and facial features, delayed growth and bone age, high pitched voice, and intellectual impairment. The proband also had partial growth hormone deficiency. We report the history of treatment of the proband with GH, which resulted in modest improvement in growth prior to puberty. WES revealed a pathogenic c.7466C>G (p.Ser2489*) mutation in the last exon of the FHS-linked SRCAP gene. A systematic literature review and analysis of available genetic variation datasets highlighted an unusual distribution of pathogenic variants in SRCAP and confirmed the lack of pathogenicity for variants outside of exons 33 and 34. Finally, we suggested a new model of FHS pathogenesis which provides possible basis for the dominant negative nature of FHS-causing mutations and explains limited effects of GH treatment in FHS. Conclusion: Our findings expand the number of reported FHS cases and provide new insights into disease genetics and the efficiency of GH therapy for FHS patients.

Height and body mass index in molecularly confirmed Silver-Russell syndrome and the long-term effects of growth hormone treatment.

ObjectiveSilver–Russell syndrome (SRS) causes short stature. Growth hormone (GH) treatment aims to increase adult height. However, data are limited on the long‐term outcomes of GH in patients with molecularly confirmed SRS. This study evaluated height, body mass index (BMI) and GH treatment in molecularly confirmed SRS.DesignAn observational study with retrospective data collection.PatientsIndividuals with molecularly confirmed SRS aged ≥13 years.MeasurementsData were collected on height, height gain (change in height standard deviation score [SDS] from childhood to final or near‐final height), BMI and gain in BMI (from childhood to adulthood) and previous GH treatment.ResultsSeventy‐one individuals (40 female) were included. The median age was 22.0 years (range 13.2–69.7). The molecular diagnoses: H19/IGF2:IG‐DMR LOM in 80.3% (57/71); upd(7)mat in 16.9% (12/71) and IGF2 mutation in 2.8% (2/71). GH treatment occurred in 77.5% (55/71).Total height gain was greater in GH‐treated individuals (median 1.53 SDS vs. 0.53 SDS, p = .007), who were shorter at treatment initiation (−3.46 SDS vs. −2.91 SDS, p = .04) but reached comparable heights to GH‐untreated individuals (−2.22 SDS vs. −2.74 SDS, p = .7). In GH‐treated individuals, BMI SDS was lower at the most recent assessment (median −1.10 vs. 1.66, p = .002) with lower BMI gain (2.01 vs. 3.58, p = .006) despite similar early BMI SDS to GH‐untreated individuals (median −2.65 vs. −2.78, p = .3).ConclusionsThese results support the use of GH in SRS for increasing height SDS. GH treatment was associated with lower adult BMI which may reflect improved metabolic health even following discontinuation of therapy.

Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height.

ObjectivesGrowth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children.MethodsRetrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with PTPN11 mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement.ResultsANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages (p<0.001), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from −3.10 ± 0.84 to −2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH.ConclusionsrhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of PTPN11 gene and in the less common genotypes.

The Effects of Growth Hormone Treatment in Patients with Isolated Growth Hormone Deficiency on Hematological Parameters

Objective: A small number of studies were reported regarding the direct and indirect effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) especially on the erythrocyte series. The purpose of this study was to examine the effects of GH treatment (GHT) used in patients with isolated GH deficiency (IGHD) on hematological parameters. Methods: The records of the patients who were diagnosed as having IGHD in our clinic and received GHT for at least two years between 2013 and 2019 were retrospectively examined. Height, height standard deviation scores (SDS), weight, weight SDS, IGF-1, annual growth rates, and changes in blood count parameters before and after the GHT were recorded. The statistical analyses were made using SPSS v.20 Package Program, and the significance level was accepted as p&lt;0.05. Results: A total of 37% (n=23) of the 62 patients that were included in the study were female, and 63% (n=39) were male. It was determined that the age of the patients was between 2-16 years at the time of diagnosis, and the median age at diagnosis was 10.8. After the GHT, a significant increase was detected in the distribution and volume of hemoglobin, hematocrit, and red sphere count (p&lt;0.05). A statistically significant but clinically insignificant decrease was detected in the platelet count and there was an increase in the platelet volumes (p&lt;0.001). A clinically significant decrease was detected in the number of white sphere, lymphocyte and neutrophil counts (p&lt;0.05). Conclusion: It was determined that GHT had a stimulating effect on erythropoiesis in IGHD. It was also shown that GHT caused a number of changes on the platelet count, white sphere count, and the lymphocyte and neutrophil parameters, which were not clinically important. We believe that studies at in vitro and molecular level are needed to explain the effects of GHD and GHT on the hematopoietic system.

Lack of Catch-Up Growth with Growth Hormone Treatment in a Child Born Small for Gestational Age Leading to a Diagnosis of Noonan Syndrome with a Pathogenic PTPN11 Variant

Background Growth hormone (GH) treatment increases the adult height of short children born small for gestational age (SGA). Catch-up growth is associated with a younger age, shorter height, and prepubertal status at the onset of GH treatment. We report a 12 11/12-year-old girl born SGA who received GH for 5 years without catch-up growth and was diagnosed with Noonan Syndrome (NS). Results A 5-year-and-9-month-old 46, XX girl born SGA was started on GH treatment at a dose of 0.32 mg/kg/week. Her midparental target height is 158.6 cm. Endocrine work up showed an IGF-1 level 69 ng/ml (Normal (N): 55–238 ng/ml), IGFBP3 2.6 mg/L (N: 1.9–5.2 mg/L), TSH 3.2 mIU/L (N: 0.35–5.5 mIU/L), and a normal skeletal survey. Height was 96 cm (0.1%; Ht SDS −2.9), weight 14 kgs (1%; Wt SDS −2.3), and Tanner 1 breast and pubic hair were observed. Due to the poor catch-up growth on GH treatment, she was referred to Genetics to elucidate genetic or syndromic causes of short stature. She was noted to have posteriorly rotated ears and slight down slanting of the palpebral fissures. Genetic findings showed a heterozygous pathogenic variant in PTPN11 (c.922A > G (p.Asn308Asp)) diagnostic for NS. This finding is de novo given negative parental testing. She was noted to have a heterozygous missense variant of unknown significance (VUS) in FGFR3: c.746C > A (p.Ser249Tyr). FGFR3 is associated with multiple skeletal dysplasias including thanatophoric dysplasia, achondroplasia, and Crouzon syndrome and hypochondroplasia. Clinical correlation is poor for these syndromes. Conclusion Diminished catch-up growth and response to GH treatment in a child born SGA led to the diagnosis of NS. The concomitant diagnosis of SGA and NS may have affected the responsiveness of this child to the growth promoting effect of GH treatment.

Effects of Growth Hormone Treatment on Sleep-Related Parameters in Adults With Prader-Willi Syndrome.

ContextPrader-Willi syndrome (PWS) is a rare, genetic, multisymptom, neurodevelopmental disease due to lack of the expression of the paternal genes in the q11 to q13 region of chromosome 15. The main characteristics of PWS are muscular hypotonia, hyperphagia, obesity, behavioral problems, cognitive disabilities, and endocrine deficiencies, including growth hormone (GH) deficiency. Sleep apnea and abnormal sleep patterns are common in PWS. GH treatment might theoretically have a negative impact on respiration.ObjectiveHere we present the effect of GH treatment on polysomnographic measurements.MethodsThirty-seven adults, 15 men and 22 women, with confirmed PWS were randomly assigned to 1 year of GH treatment (n = 19) or placebo (n = 18) followed by 2 years of GH treatment to all. Polysomnographic measurements were performed every 6 months. A mixed-effect regression model was used for comparison over time in the subgroup that received GH for 3 years.ResultsAt baseline median age was 29.5 years, body mass index 27.1, insulin-like growth factor 115 µg/L, apnea-hypopnea index (AHI) 1.4 (range, 0.0-13.9), and sleep efficiency (SE) 89.0% (range, 41.0%-99.0%). No differences in sleep or respiratory parameters were seen between GH- and placebo-treated patients. SE continuously improved throughout the study, also after adjustment for BMI, and the length of the longest apnea increased. AHI inconsistently increased within normal range.ConclusionSE improved during GH treatment and no clinical, significantly negative impact on respiration was seen. The etiology of breathing disorders is multifactorial and awareness of them should always be present in adults with PWS with or without GH treatment.