Mean Height Standard Deviation Score Research Articles

The Manifestations and Complications of X-linked Hypophosphatemia in Saudi Arabia: A Retrospective Study

Background: X-linked hypophosphatemia (XLH) is a genetic disease of phosphate metabolism in which inactivating mutations of the phosphate regulating endopeptidase homolog, X-linked (PHEX) gene lead to local and systemic effects. In our pediatric clinics, XLH was observed to be associated with multiple complications despite conventional treatment. There is a need for novel treatment modalities to prevent disease progression and aid in the resolution of symptoms. Methods: This retrospective cross-sectional study aimed to understand the manifestations and complications of XLH in patients followed up at the endocrinology clinics in King Faisal Specialist Hospital and Research Center in Saudi Arabia. The study was conducted by reviewing the medical files of all XLH patients at the King Faisal Specialist Hospital and Research Center. Results: All the patients (N=24) who were included in this study had PHEX gene mutations. The mean age was 18.7 13.6 years and 68% were females. The mean height standard deviation score (HSDS) was ‑2.96 (-5.25 to -0.97) and 12 patients reached their final height (mean final HSDS, -3.28 [-1.39 to ‑5.39]). Skeletal deformities (mainly genu varum) were observed in 68% of the patients and 29% had craniosynostosis; 54% had undergone corrective osteotomy. Hyperparathyroidism was observed in 54% of the patients and 45% of the patients had nephrocalcinosis (grades 2/3). Conclusions: In our study, a majority of the XLH patients suffered from complications arising from the use of conventional therapy, thus indicating the need for novel treatment modalities for these patients. Additionally, no correlation between genotype and phenotype was found.

12256 Sustained Efficacy Of Weekly Somapacitan In Children With GHD: 3-year Results From Phase 3 REAL4 Study

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, BioMarin, Bristol-Myers Squibb, EMD Serono, Endo Pharmaceuticals, Novo Nordisk, Orchard Therapeutics, Pfizer, Provention Bio, Tolmar. Grant Recipient; Self; Alexion, Abbvie, Aeterna Zentaris, Amgen, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health Pfizer, Prevail Therapeutics, Sangamo Therapeutics. J.C. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A. Maniatis: Research Investigator; Self; Novo Nordisk, Ascendis, OPKO, Pfizer. J. Mori: Advisory Board Member; Self; Novo Nordisk. Consulting Fee; Self; JCR. Speaker; Self; Novo Nordisk, Pfizer, JCR. V. Böttcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring, Lilly, Merck, Novo Nordisk. H. Kim: None. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Sandoz, Merck, Sanofi. Speaker; Self; Novo Nordisk, Pfizer, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Ascendis, Lumos Pharma. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, JCR. Growth hormone (GH) replacement therapy for children with GH deficiency (GHD) traditionally required daily subcutaneous injections. Somapacitan (Novo Nordisk A/S) is a reversible albumin-binding GH derivative administered once-weekly and the only long-acting GH (LAGH) approved for the treatment of both adults and children with GHD. REAL4 is a randomized, open-label, multi-national, phase 3 trial, consisting of a 52-week main phase and a three-year (week 52 to 208) extension period (NCT03811535). The trial included 200 GH-treatment-naïve, prepubertal children with GHD. Participants received either once-weekly somapacitan (0.16 mg/kg; n=132) or once-daily GH (Norditropin® 0.034 mg/kg; n=68) for 52 weeks. Afterwards, participants receiving daily GH switched to 0.16 mg/kg/week somapacitan (switch group), while those receiving somapacitan continued treatment (soma/soma group). Growth-related endpoints included height velocity (HV), HV standard deviation score (SDS), height SDS, and bone age. The 3-year (156-week) results are presented here. A total of 188 participants (125 in the soma/soma group and 63 in the switch group) completed 3 years of treatment. Improvements in HV, HV SDS, height SDS, and bone age were similar between the groups. In year 3 (week 104 to 156), mean (SD) HV was 7.4 (1.5) cm/year in the soma/soma group and 7.8 (1.4) cm/year in the switch group. The mean (SD) change in height SDS from baseline to week 156 was 2.04 (0.85) in the soma/soma group and 2.38 (1.14) in the switch group, with mean (SD) height SDS at week 156 of -0.95 (0.98) and -1.08 (0.93) in the soma/soma and switch groups, respectively. Mean BMI SDS remained within normal range in both groups at week 156. No safety or tolerability issues were identified. During the extension period (week 52 to 156), a low proportion of the participants reported injection site reactions. No neutralizing antibodies were detected at any of the visits. In conclusion, once-weekly somapacitan showed sustained efficacy and tolerability for three years, as well as for two years following the switching from daily GH treatment in this pivotal phase 3 REAL4 trial. The safety profile of somapacitan was similar to the well-known safety profile of daily GH. Presentation: 6/3/2024

Impact of Thyroid Autoimmunity on the Clinical and Biochemical Characteristics of Type 1 Diabetes Mellitus Patients.

Type 1 diabetes mellitus (T1DM) is frequently associated with other autoimmune disorders that are characterized by the presence of organ-specific autoantibodies. Autoimmune thyroid disease (AIT) is the most frequent autoimmune disorder associated with T1DM. Thyroid peroxidase antibodies (TPOAb) serve as a marker for diagnosing AIT. Prior research indicates that thyroid dysfunction can negatively impact linear growth and glycemic control in subjects with T1DM. The present study was done to determine the impact of thyroid autoimmunity on the clinical and biochemical characteristics of patients with newly diagnosed T1DM. In this single-center, hospital-based, observational cross-sectional study, we enrolled 70 patients with newly diagnosed T1DM ≤18 years of age. Type 1 diabetes mellitus was diagnosed based on the acute onset of osmotic symptoms with or without diabetic ketoacidosis (DKA), severe hyperglycemia (blood glucose >13.9 mmol/l (>250 mg/dl)), and insulin requirement from the onset of diabetes. Secondary diabetes, pancreatic diabetes (Type 3c), and maturity-onset diabetes of the young (MODY) were excluded. Participants were screened for AIT disease using TPOAb testing. Based on the presence or absence of TPOAb, the participants were categorized into two groups: Group A comprised individuals with T1DM who tested positive for TPOAb, while Group B consisted of those who tested negative for TPOAb. Out of 70 patients, 41.4% were girls and 58.6% were boys, with a mean age of 9.8±4.4 years. The prevalence of TPOAb among the cohort was 18.6%. A significant majority of patients (71.4%), presented with DKA. Group A showed significantly lower mean height standard deviation scores (SDS) compared to Group B (-0.3±0.6 vs. -0.8±0.5, p = 0.004), but no differences in weight SDS or BMI SDS. Hemoglobin A1C (HbA1c) levels, C-peptide levels, and frequency of DKA did not differ between groups. Group A had higher mean thyroid-stimulating hormone (TSH) levels (4.8±3.7 µU/ml vs. 2.6±1.5 µU/ml, p = 0.001) and a greater proportion of patients with TSH levels above the upper limit of normal compared to Group B (38.4% vs. 7.1%, p = 0.008). Additionally, Group A exhibited a higher frequency of glutamic acid decarboxylase antibody (GADA) positivity compared to Group B (46.1% vs. 17.5%, p = 0.04). Patients positive for TPOAb exhibited significantly lower height SDS compared to TPOAb-negative patients. Additionally, T1DM patients with TPOAb positivity showed an increased frequency of GADA compared to those without TPOAb. However, no significant differences were found in HbA1c levels, C-peptide levels, or hematological parameters between TPOAb-positive and TPOAb-negative patients. These findings emphasize the impact of TPOAb on growth parameters in T1DM and advocate for routine screening of TPOAb in all T1DM patients, starting at the time of diabetes diagnosis.

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome

BackgroundFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.MethodsClinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.ResultsHepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3−) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3− and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from − 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.ConclusionsEarly diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.

Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs). The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA). The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found. Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.

Evaluation of the Relationship Between Peak Growth Hormone Response to Growth Hormone Stimulation Tests and Body Mass Index

Objective: A contrary relationship between body mass index (BMI) and growth hormone (GH) secretion has been demonstrated in adults. BMI-specific cutoff levels are suggested for identifying growth hormone deficiency (GHD) in adulthood. However, specific values for BMI and growth hormone stimulation test responses in the childhood age group are not certain. In this research, our purpose was to investigate the relationship between GH peak response and BMI in children who underwent GHST with a pre-diagnosis of GHD. Material and Methods: This was a retrospective study of stimulative GH testing with clonidine and L-dopa performed in 150 children 2–18 year-old with short stature (&lt; -2 SDS) in the Pediatric Endocrinology Unit at Bakırçay University Çiğli Training and Research Hospital from the years of 2018 to 2023. Anthropometric measurements, insulin-like growth factor-1 (IGF-I) and IGFBP- 3 levels, especially peak-stimulated GH, were evaluated. Results: A total of 150 patients [98 boys (65.3%) and 52 girls (34.7%)] were included in the study. The mean age of the individuals during testing was 10.26 ± 3.37 years, mean height standard deviation score (SDS) was -2.64 ± 0.89, mean weight SDS was -1.85 ± 1.01 and mean body mass index (BMI) SDS was -0.47 ± 1.07. Ninety-two of the patients (63%) were prepubertal. The mean value for maximum growth hormone serum level (GHmax) clonidine collected during the growth hormone stimulation test was 4.46 ± 2.83 ng/mL, while the mean value in L-dopa test was 3.29 ± 2.57 ng/mL. There was no statistical distinction in terms of both test responses. The correlation between peak GH and BMI-SDS, in terms of clonidine and L-dopa tests, was significantly negative [β = -0.257 (p = 0.010), β = -0.283 (p = 0.004), respectively]. Age, gender and puberty were not significantly associated with peak GH value. In terms of L-dopa peak GH level, the GH level in group 4 (&gt;1 SDS) was revealed to be statistically lower than that in group 1 (&lt; -1 SDS), nevertheless, similar relationship was not detected for clonidine. Conclusion: In our study, a negative correlation was found between GHmax and BMI-SDS in terms of clonidine and L-dopa tests. Therefore, keeping BMI-SDS in mind when evaluating growth hormone stimulation tests performed in short children may be guiding. Still, future studies are needed to make it a determining factor when deciding on treatment.

Growth, weight gain and BMI in virally suppressed children on antiretroviral therapy with specific reference to dolutegravir

BackgroundPediatric HIV infection cause retardation in height and weight. However, effective antiretroviral therapy (ART) result in desirable weight gain. Concerns have emerged regarding excessive weight gain related to the integrase inhibitor dolutegravir in adults but knowledge about the circumstances in children/adolescents is limited. We studied if dolutegravir containing ART or switch to dolutegravir affected body mass index (BMI) and described height development in the Stockholm pediatric/adolescent HIV cohort.MethodsA retrospective cohort study of height, weight and BMI in relation to ART in 94 children/adolescents living with HIV.ResultsAt last documented visit 60/94 children/adolescents were on dolutegravir, 50 had switched from a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Height standard deviation score (SDS) increased between first and last visit from mean height SDS -0.88 (16 had SDS < -2 and 6 SDS < -3) to -0.32 (four had SDS < -2). Mean BMI SDS increased from -0.15 to 0.62 in girls, but not (-0.20 to 0.09) in boys. The number of girls ≥ 12 years with BMI SDS ≥ 2 increased significantly from 0/38 to 8/38 and totally 9/50 (18%) girls and 4/44 (9%) boys had BMI SDS ≥ 2 at last visit. There was no difference in height or weight gain between different ART regimens. BMI SDS remained stable in 22/50 children switching to dolutegravir, decreased in 13 and increased in 15.ConclusionAdolescent girls gained weight to a greater extent than expected but independently of ART. We found no association between dolutegravir alone or combined with tenofovir alafenamide fumarate (TAF) and excessive weight gain. Height development was within normal range.

Benefits and risks evaluation of recombinant human growth hormone replacement therapy in children with GHD after craniopharyngioma surgery.

Childhood-onset craniopharyngiomas (CPs) have a high incidence of growth hormone deficiency (GHD) leading to growth failure and metabolic disorders. We aim to evaluate the benefits and risks of recombinant human growth hormone replacement therapy (GHRT) in postoperative children. We retrospectively analyzed auxological and metabolic parameters and adverse events before and after GHRT of 44 children after CP surgery. The median duration of GHRT was 24months (IQR, 12.5-36). Growth velocity (GV) increased significantly after different treatment duration (TD) compared with baseline (p<0.001) and attained the greatest GV of 12.06±4.16cm/year at TD6. The mean height standard deviation score (HtSDS) from-3.20±1.16at baseline improved significantly to-1.51±1.32 at TD36 (p<0.001). There were significant increases in insulin-like growth factor-1 SDS (IGF-1SDS), insulin-like growth factor binding protein 3 SDS (IGFBP-3SDS), bone age (BA), and BA/chronological age (CA) (p<0.05). There was a significant reduction in waist-to-hip ratio (WHR), but there were no significant changes in weight SDS (WtSDS) or BMISDS. Low-density lipoprotein-cholesterol (LDL-C) levels and the incidence of hypercholesterolemia decreased (p<0.05). Three patients (6.8%) had tumor recurrence after 15, 30, and 42months, respectively. A patient had residual tumor enlargement after 3months. There was no adverse influence on glucose metabolism or any severe adverse events. GHRT effectively accelerates GV, increases HtSDS, and improves lipid profiles without unfavorable effects on glucose metabolism. The benefits are clear and the risks of adverse events are low.

RF26 | PMON332 Safety and Efficacy of Treatment with Lonapegsomatropin in Children with Growth Hormone Deficiency at Week 130 in the enliGHten Trial

Abstract Background Once-weekly lonapegsomatropin (TransCon hGH) is a long-acting prodrug of somatropin, recently approved for the treatment of pediatric growth hormone deficiency (GHD) by the US FDA. In the pivotal 52-week phase 3 heiGHt trial and the 26-week fliGHt trial, lonapegsomatropin demonstrated safety and efficacy in both treatment-naïve and treatment-experienced children with GHD. Methods Results are reported from Week 130 (data snapshot date: September 01, 2021) from the open-label extension trial enliGHten. Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available. Results A total of 298 participants (98% of parent trials) continued from the heiGHt or fliGHt trials into enliGHten. At Week 130, 36 participants had completed the trial and 248 participants remain enrolled. The height standard deviation score (SDS) mean (standard deviation [SD]) at Week 130 was -0.64 (0.85) compared with baseline value of -1.56 (0.88) at the start of enliGHten. Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS mean (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. For the 36 participants who had completed the trial, 14 had reached bone age of &amp;gt;14 years (girls) or &amp;gt;16 years (boys), and 24 had completed the study based on investigator judgement that treatment for growth hormone deficiency was no longer necessary. The difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75) for the 36 completers, and 61.1% of these participants had met or exceeded the average parental height SDS. The mean (SD) total duration of hGH treatment for participants who completed the trial (including daily treatment and lonapegsomatropin) was 3.53 (0.88) years, and the mean (SD) duration of treatment with lonapegsomatropin was 2.20 (0.66). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals. Conclusions Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy. Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Pre- and postdiagnosis growth failure, adult short stature, and untreated growth hormone deficiency in radiotherapy-treated long-term survivors of childhood brain tumor.

PurposeGrowth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed.MethodsA cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up.ResultsGrowth failure was evident at diagnosis, with a mean height decline of -0.6 SDS (standard deviation score) from birth (95% CI -1.15 to -0.05). Mean height SDS decline after the diagnosis was -1.09 SDS (95%CI -1.51 to -0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < -2 SDS). The mean height deficit corrected for target height was -1.9 SDS (95% CI -1.45 to -2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below -2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects.ConclusionLongitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common.

Association Between the Growth Hormone/Insulin-Like Growth Factor-1 Axis and Muscle Density in Children and Adolescents of Short Stature.

ObjectiveTo evaluate the association between the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis and muscle density in children and adolescents of short stature.MethodsParticipants were children and adolescents of short stature hospitalized in the Affiliated Hospital of Jining Medical University between January 2020 and June 2021. All participants had CT scan images available. We performed an analysis of the images to calculate the muscle density or skeletal muscle attenuation (SMA), skeletal muscle index (SMI), and fat mass index (FMI). Bioelectrical impedance analysis (BIA) was used to ensure that chest CT is a credible way of evaluating body composition.ResultsA total of 297 subjects were included with the mean age of 10.00 ± 3.42 years, mean height standard deviation score (SDS) of -2.51 ± 0.53, and mean IGF-1 SDS of -0.60 ± 1.07. The areas of muscle and fat tissues at the fourth thoracic vertebra level in the CT images showed strong correlation with the total weights of the participants (R2 = 0.884 and 0.897, respectively). The peak of GH was negatively associated with FMI (r = - 0.323, P <.01) and IGF-1 SDS was positively associated with SMI (r = 0.303, P <.01). Both the peak GH and IGF-1 SDS were positively associated with SMA (r = 0.244, P <.01 and r = 0.165, P <.05, respectively). Multiple stepwise linear regression analysis demonstrated that the GH peak was the predictor of FMI (β = - 0.210, P < .01), the IGF-1 SDS was the predictor of SMI (β = 0.224, P < .01), and both the peak GH and IGF-1 SDS were predictors of SMA (β = 0.180, P < .01 and β = 0.222, P < .01).ConclusionsA chest CT scan is a credible method of evaluating body composition in children and adolescents of short stature. In these patients, peak GH and IGF-1 SDS are independent predictors of muscle density and the GF/IGF-1 axis may regulate body composition through complex mechanisms.

Clinical characteristics and effects of enzyme replacement therapy with elosulfase alfa in Korean patients with mucopolysaccharidosis type IVA

Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase, which results in skeletal and connective tissue abnormalities, as well as various non-skeletal manifestations. Although enzyme replacement therapy (ERT) is recommended as the first-line treatment, the outcomes of ERT on bone pathology remain controversial. We report clinical characteristics and outcomes of ERT in 9 patients with MPS IVA (6 males and 3 females) from 7 unrelated families. During ERT, results from pulmonary function tests, echocardiography, the 6-min walk test, and the Functional Independence Measure were monitored biannually. Anthropometric data were compared with previously reported growth charts of subjects with MPS IVA.Among the 9 patients (5 severe, and 4 slowly progressive form), 7 patients (5 severe, 2 slowly progressive) commenced ERT at a median age of 3.8 years (range: 0.8–13.7 years) and were treated for a median duration of 1.9 years (range: 1.2–5.7 years). Mean height standard deviation scores using MPS IVA growth charts were + 0.4 (+0.0 in severe phenotypes) at initiation and + 0.7 (+0.2 in severe phenotypes) at the last follow-up. Four patients with severe phenotypes underwent surgery for cervical myelopathy and 1 patient with a slowly progressive phenotype underwent a bilateral pelvic osteotomy for hip pain during ERT. The parameters of pulmonary and heart function, endurance, and Functional Independence Measure scores were maintained or increased after ERT. Overall, ERT was well tolerated without deterioration of cardiorespiratory and functional outcomes during treatment, although skeletal outcomes, including growth, were limited.

Safety and effectiveness of Omnitrope® (somatropin) in PATRO Children: a multi-center, post-marketing surveillance study comparison of US and international cohort data

There are known geographical differences in growth hormone deficiency (GHD) patient populations and treatment practices. Here, we present a comparison of safety and effectiveness data from patients treated with recombinant human growth hormone (rhGH) in the USA versus other countries. PAtients TReated with Omnitrope® (PATRO) Children is an international, non-interventional study with Omnitrope® (somatropin, Sandoz Inc.). All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. By September 2018, 294 patients had been enrolled in the USA (53% rhGH-naïve) and 6206 patients had been enrolled across 13 other countries (international group; 86% rhGH-naïve). The most common indication in both groups was GHD. Overall, 194 US patients (66%) and 2977 international patients (48%) experienced adverse events (AEs; 886 and 11,716 events, respectively), most of which were of mild or moderate intensity. The AEs were suspected to be treatment-related in five US patients (1.7%) and 452 international patients (7.3%). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No cases of diabetes mellitus or hyperglycemia were reported. In rhGH-naïve GHD patients, after 3 years of rhGH therapy, the improvement in mean height SD score from baseline was + 1.25 and + 1.35 in US and international patients, respectively.Conclusion: Omnitrope® treatment appears to be well tolerated and effective in US patients and those from other countries. Across the pediatric indications included, there was no evidence of an increased risk of developing uncommon or unexpected AEs with rhGH.Trial registration: NA.What is Known:• Continued monitoring of patients treated with recombinant human growth hormone (rhGH) is important, particularly in terms of diabetogenic potential and the risk of malignancies.• The PAtients TReated with Omnitrope® (PATRO) Children study is a long-term, post-marketing surveillance program for the rhGH Omnitrope®.What is New:• Omnitrope® is well tolerated and effective in US patients, and those from other countries.• Across all indications included, there were no unexpected adverse events and there was no evidence of an increased risk of developing malignancies or diabetes.

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status.

IntroductionMutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated.MethodsThis analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S).ResultsA total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was −1.9 (1.1) and −1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses.ConclusionsGHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Abstract 2: Effectiveness and safety of early growth hormone treatment in children born small for gestational age: Long-term data from NordiNet® International Outcome Study (IOS) and ANSWER program

Background: Growth hormone (GH) is indicated for the treatment of short stature in children born small for gestational age (SGA) who fail to show catch-up growth. In pilot studies, early initiation of GH has been associated with favorable growth responses in short SGA children. However, few studies have examined the short- and long-term effects of initiating GH in children born SGA who are <4 years (yr) of age, compared with those starting later. This analysis therefore investigated the effect of age at GH initiation on long-term effectiveness and safety in children born SGA.Methods: The NordiNet IOS (NCT00960128) and ANSWER (NCT01009905) programs are complementary, noninterventional, multicenter studies that evaluated the long-term effectiveness and safety of Norditropin (somatropin; Novo Nordisk A/S, Denmark) as prescribed in real-life clinical practice. In this analysis, children born SGA who were prepubertal at GH initiation were grouped according to age at GH start: <4 yr, 4-6 yr, and ≥6 yr. Patient characteristics at birth and at GH start, auxological measurements, and adverse events were evaluated in each group.Results: Overall, 3351 SGA patients were included in the effectiveness set (age at GH start: <4 yr [n=389, 54.8% male]; 4-6 yr [n=1048, 57.6% male]; and ≥6 yr [n=1914, 56.6% male]). The proportion of patients born pre-term (<37-week gestation) was 38.6% in the <4 yr group, 36.1% in the 4-6 yr group, and 28.2% in the ≥6 yr group. Mean (SD) birth length standard deviation score (SDS) and birth weight SDS were: −2.9 (1.6) and −2.3 (1.2) in the <4 yr group, −2.8 (1.3) and −2.2 (1.1) in the 4-6 yr group, and −2.5 (1.4) and −2.0 (1.2) in the ≥6 yr group. Mean (SD) age at GH start was 3.1 (0.7), 4.9 (0.6), and 9.3 (2.2) years in the <4 yr, 4-6 yr, and ≥6 yr groups, respectively. Mean (SD) GH duration and daily GH dose in the study were: 3.5 (3.1) yr and 0.044 (0.016) mg/kg in the <4 yr group, 4.1 (3.1) yr and0.039 (0.012) mg/kg in the 4-6 yr group, and 3.5 (2.5) yr and 0.042 (0.012) mg/kg in the ≥6 yr group. Mean (SD) height SDS (HSDS) at GH start was −3.3 (1.2) in the <4 yr group, −3.1 (0.9) in the 4-6 yr group, and −2.8 (0.8) in the ≥6 yr group. After 4 and 8 yr of GH, mean (SD) ÄHSDS from baseline was 1.7 (0.7) and 2.5 (0.6) in the <4 yr group, 1.6 (0.7) and 2.2 (0.8) in the 4-6 yr group and 1.3 (0.7), and 1.7 (0.6) in the ≥6 yr group. Among patients who reached near-adult height in the study, mean (SD) HSDS was −1.9 (0.6) in the <4 yr group (n=3), −1.9 (0.8) in the 4-6 yr group (n=10), and −1.8 (1.0) in the ≥6 yr group (n=220). In the safety set (n=5643), the most commonly reported non-serious adverse reactions (AR) were headache (n=20) and arthralgia (n=5). The most common serious ARs were headache (n=3) and epiphysiolysis (n=4). ARs and serious ARs were distributed equally among groups.Conclusions: This analysis of real-world data confirms the effectiveness and safety of GH in children born SGA, irrespective of patient age at treatment initiation.

Factors Associated With Height Among Pediatric Kidney Transplant Recipients Aged ≤16 Years: A Retrospective, Single-Center Cohort Study of 60 Transplants.

The aim of this study was to describe the factors associated with growth before and after kidney transplant. We retrospectively reviewed 60 pediatric patients with end-stage kidney disease aged ≤16 years who underwent kidney transplant at our facility between November 2001 and March 2018. Height standard deviation score and possible associated factors were also compared. Among the 60 patients, median age was 11 years (interquartile range, 5.3-14 years), and 24 (40%) were female. All patients were alive during the observational period. The 2-, 5-, and 15-year graft survival rates were 96.7%, 94.4%, and 77.8%, respectively. Mean height standard deviation score for preoperative kidney transplant was -2.1 ± 1.5. Duration of dialysis (months) was associated with preoperative height standard deviation score (β = -0.020; standard error = 0.006; t = -3.23; P = .002).Higher age andepisode of rejection were significant factors for loss of catch-up growth (P < .001 and P = .023, respectively). In total, 26 patients (43.3%) and 19 patients (31.7%) had short stature preoperatively and at 2 years after kidney transplant, respectively. Although 23 patients (38.3%) presented with catch-up growth after kidney transplant, 14 (53.9%) remained with short stature even 2 years after kidney transplant.Height standard deviation score 2 years after kidney transplant was associated with age, preoperative height standard deviation score, and episodes of rejection (P = .032, P < .001, and P = .005, respectively). Our study suggests that, although kidney transplant results in catch-up growth in pediatric patients, short stature often persists even 2 years after kidney transplant and is affected by age, preoperative height standard deviation score, and episodes of rejection.

Phenotypic and genotypic characteristics of children with Bartter syndrome.

Bartter syndrome (BS) is a group of autosomal-recessive tubular disorders and it is classified into five genetic subtypes. BS can also be classified by phenotype (antenatal, classic). Patients with mutations in the same gene can present different phenotypes. In the present study, target gene sequencing was performed to evaluate the genotype-phenotype relationship. Biochemical, clinical and renal ultrasonography results were collected at presentation and the last clinic visit. Genetic analyses were performed. The findings of patients with classical BS (cBS) and antenatal BS (aBS) at presentation and the last visit were compared. Our study included 21 patients (12 female, 57.1%) from 20 families with BS. The median age at diagnosis was 8 months and the median follow-up period was 39 months. The most frequent complaint was growth failure. We have found 18 different types of mutations in four genes, including nine in the CLCNKB gene, seven in the SLCA12A1 gene, one in the KCNJ1 gene and one in the BSND gene. In ten patients, nine different types of CLCNKB gene mutations were detected, five of them were novel. Seven different mutations in the SLC12A1 gene were detected in eight patients, five of them were novel. Compared to patients with aBS and cBS, prematurity was significantly higher in the group with aBS. Nephrocalcinosis was present in only one patient with cBS, all the ten hypercalciuric patients with aBS had nephrocalcinosis at the time of diagnosis and the last visit. The mean height standard deviation score (SDS) of patients with aBS were significantly lower than the cBS group at the time of presentation. The mean weight SDS at the time of presentation was worse in patients with aBS than in patients with cBS. The mean plasma potassium and chloride concentrations were significantly lower in the patients with cBS at the time of diagnosis. This investigation revealed the mutation characteristics and phenotype-genotype relationship of our patients and provided valuable data for genetic counseling.

Pediatric adrenocortical tumors cohort characteristics and long-term follow-up at a single Argentinian tertiary center.

To report clinical, biochemical, and histological features, staging, and therapeutic interventions in a cohort of 28 patients treated at a single tertiary center. A retrospective review of medical records of children with PACT (diagnosed before <18 years of age) followed between 1987-2018 at Hospital de Pediatría Garrahan, Buenos Aires, Argentina. Mean age at diagnosis was 4.6 years (range, 0.3-17.3 years) and median follow-up was 4.17 years (range, 0-12 years). Female to male ratio was 2.5:1. Signs and symptoms that prompted medical intervention were hormonal overproduction (57%), abdominal complaints (36%), and hypertensive encephalopathy (7%). In patients with clinically virilizing tumors (n=16) mean height standard deviation score (SDS) and bone age advance were significantly higher while body mass index (BMI) SDS was significantly lower than in those with clinical Cushing's (n=10) (p<0.05). Serum dehydroepiandrosterone sulfate (DHEAS) levels were significantly higher in stage IV than in stage I (p=0.03). Total adrenalectomy was performed in 26 patients. Eight patients (stage III-IV) received adjuvant chemotherapy. Five-year overall and disease-free survival were 100% for ST I-II, and 51% (95%CI 21-82) and 33% (95% CI 1.2-65) for ST III-IV, respectively (p=0.002). No statistical difference was found when comparing 2-year parameters with and without adjuvant chemotherapy. Height SDS and BMI SDS seem to mirror hormonal secretion in pediatric adrenocortical tumors. Higher DHEAS levels were found in patients with more advanced disease. Further large-scale studies are needed to validate a possible role for DHEAS as a biochemical marker of tumor stage and to draw robust conclusions on the use of adjuvant chemotherapy.

Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Effectiveness and Overall Safety of NutropinAq® for Growth Hormone Deficiency and Other Paediatric Growth Hormone Disorders: Completion of the International Cooperative Growth Study, NutropinAq® European Registry (iNCGS).

ObjectiveThe International Cooperative Growth Study, NutropinAq® European Registry (iNCGS) (NCT00455728) monitored long-term safety and effectiveness of recombinant human growth hormone (rhGH; NutropinAq® [somatropin]) in paediatric growth disorders.MethodsOpen-label, non-interventional, post-marketing surveillance study recruiting children with growth disorders. Endpoints included gain in height standard deviation score (SDS), adult height, and occurrence of adverse events (AEs).Results2792 patients were enrolled. 2082 patients (74.6%) had growth hormone deficiency (GHD), which was isolated idiopathic in 1825 patients (87.7%). Non-GHD diagnoses included Turner syndrome (TS) (n=199), chronic renal insufficiency (CRI) (n=10), other non-GHD (n=498), and missing data for three participants. Improvements from baseline height SDS occurred at all time points to Month 132, and in all subgroups by disease aetiology. At Month 12, mean (95% CI) change in height SDS by aetiology was: idiopathic GHD 0.63 (0.61;0.66), organic GHD 0.71 (0.62;0.80), TS 0.59 (0.53; 0.65), CRI 0.54 (-0.49;1.56), and other non-GHD 0.64 (0.59;0.69). Mean height ( ± SD) at the last visit among the 235 patients with adult or near-adult height recorded was 154.0 cm ( ± 8.0) for girls and 166.7 cm ( ± 8.0) for boys. The most frequent biological and clinical non-serious drug-related AEs were increased insulin-like growth factor concentrations (314 events) and injection site haematoma (99 events). Serious AEs related to rhGH according to investigators were reported (n=30); the most frequent were scoliosis (4 events), epiphysiolysis (3 events), and strabismus (2 events).ConclusionsThere was an improvement in mean height SDS in all aetiology subgroups after rhGH treatment. No new safety concerns were identified.