Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study.

Objectives: To investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings. Methods: This case-control study, conducted at the Schneider Children's Medical Center's Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation. Results: Fecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (p<0.001). ISS children with higher levels of Methanobrevibacter, the dominant species in the archaeal gut community, were significantly shorter in stature than those with lower levels (p=0.022). Mice receiving fecal transplants from ISS children did not experience stunted growth, probably due to the eradication of Methanobrevibacter caused by exposure to oxygen during fecal collection. Discussion: Our findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS.

Clinical and immunological characteristics of children diagnosed with-Type 1 diabetes during the COVID-19 pandemic.

AIMS: To find clinical and immunological signatures of the SARS-CoV-2 and the COVID-19 pandemic on children newly diagnosed with type 1 diabetes (T1D). METHODS: A single-centre, retrospective, observational study comparing the clinical and immunological characteristics of children diagnosed with T1D the year before and during the first 2 years of the COVID-19 pandemic. Data extracted from the medical records included clinical and demographic parameters, COVID-19 PCR results and the presence of anti-islet, thyroid and celiac-related antibodies. Also obtained from the medical records was a family history of T1D, celiac disease and autoimmune thyroid disease in a first-degree family member. RESULTS: A total of 376 children were diagnosed with T1D during the study period. A total of 132 in the pre-COVID era and 246 in the first 2 years of the pandemic. At diagnosis, the pH in children with DKA was lower, and HbA1c tended to be higher in the COVID-19 group compared to the pre-COVID-19 group (7.30 [7.18, 7.35] vs 7.33 [7.19, 7.36], p = 0.046) and (110.9 [86.9, 129.5] vs 100 [80.3, 129.5], p = 0.067]) respectively. Multiple islet antibodies (IA) were significantly more common among patients in the pre-COVID-19 group compared to the COVID-19 group (72% vs 61%, p = 0.032). Tissue transglutaminase antibodies were more common among children diagnosed in the COVID-19 compared to the pre-COVID group (16.6% vs 7.9%, p = 0.022). CONCLUSIONS: Our findings suggest that SARS-CoV-2 and the environmental alterations caused by the pandemic affected the clinical characteristics and the immunological profile of children diagnosed with T1D. It is, therefore, plausible that the virus plays a role in the autoimmune process causing T1D.

Blood pressure in girls with central precocious puberty receiving GnRH analogue therapy.

OBJECTIVES: Case reports show hypertension in children treated with GnRH analogues for central precocious puberty (CPP). However, relevant data on blood pressure are scarce. We aimed to evaluate blood pressure (BP) among girls with idiopathic CPP and early-onset puberty before and during GnRH analogue therapy; and to examine associations of blood pressure with clinical parameters. METHODS: For this retrospective longitudinal cohort study, demographic, anthropometric, clinical, and laboratory data were collected from electronic files. The study group included 112 girls with idiopathic CPP or early-onset puberty followed in a tertiary pediatric endocrinology institute, and a control group of 37 healthy pre-pubertal girls. The main outcome measures were BP percentile, before, and during treatment with GnRH analogue. RESULTS: At baseline, similar proportions of the study and control groups had BP values>90th percentile: 64 (53 %) and 17 (46 %), respectively (p=0.57). The mean systolic and diastolic BP percentiles measured under treatment remained unchanged. In the study group, baseline BP>90th percentile compared to normal baseline BP was associated with lower birthweight and a higher body mass index-standard deviation score: 2,821 ± 622 vs. 3,108 ± 485 g and 1.0 ± 0.7 vs. 0.70 ± 0.8, respectively, p=0.01 for both. CONCLUSIONS: GnRH analogue therapy for precocious or early puberty was not associated with increased blood pressure. The stability of mean blood pressure percentile during treatment is reassuring.

Compromised Adult Height in Females with Non-Classical Congenital Adrenal Hyperplasia Diagnosed in Childhood.

INTRODUCTION: Data on adult height (AHt) in individuals with non-classical congenital adrenal hyperplasia (NCCAH) are inconsistent. METHODS: We conducted a retrospective study of 109 females diagnosed with NCCAH at age <18 years who reached AHt. We studied AHt compared to target height (THt) and the correlation of AHt with clinical parameters. RESULTS: The mean age at diagnosis was 9.7 ± 4.4 years; the mean follow-up was 10.9 ± 6.3 years. Hydrocortisone treatment (11.0 ± 5.0 mg/m2) was initiated at age 9.7 ± 4.0 years. Bone age was more advanced in girls who presented with central precocious puberty or early puberty (CPP/EP) (n = 43) than with timely puberty. AHt-standard deviation score (SDS) was lower than Ht-SDS at diagnosis (-0.8 ± 1.0 vs. +0.2 ± 1.3; p < 0.001) and -0.3 SDS shorter than THt (p < 0.001). Height, weight, and body mass index-SDS at last visits were similar between patients treated with glucocorticoids (n = 92) and those never treated (n = 17). AHt was comparable between patients with timely puberty and with CPP/EP, with no difference between those treated or not by GnRH analogue. AHt was similar between patients who were fully pubertal (Tanner 5), pre-pubertal (Tanner 1), and pubertal (Tanner 2-4) at diagnosis (158.0 ± 7.6, 158.1 ± 6.1, and 157.5 ± 6.5, respectively; p = 0.9). AHt-SDS was correlated with THt (R = 0.67, p < 0.001) and Ht-SDS at diagnosis (R = 0.7, p < 0.001) but not with age at diagnosis (R = -0.05, p = 0.6), the extent of bone age advancement (R = -0.04, p = 0.72), glucocorticoid treatment duration (R = -0.11, p = 0.34), or dose (R = -0.04, p = 0.70). CONCLUSION: AHt of females diagnosed with NCCAH in childhood was lower than their THt. Glucocorticoid treatment duration and dose, pubertal status at diagnosis, and having CPP or EP were not correlated with AHt.

Infertility and Pregnancy Rates in Female Thyroid Cancer Survivors: A Retrospective Cohort Study Using Health Care Administrative Data from Israel.

Background: Thyroid cancer (TC) is one of the most common carcinomas in young women. Concerns have been raised regarding the impact of the disease and its treatment on reproductive function. The aim of the study was to investigate the association of TC diagnosis and radioactive iodine (RAI) treatment on infertility and pregnancy rates in women. Methods: The comprehensive computerized database of a health management organization in Israel was screened for all female patients who were diagnosed with TC at age ≤40 years in 2000-2020. Rates of infertility (based on a documented diagnosis or purchase of fertility medications in the patient files) and pregnancy were compared with healthy age-matched controls. Results: The cohort included 1164 patients with TC (median age at diagnosis 31.6 years; interquartile range [IQR]: 26.7-35.4) and 5030 controls, followed for a median period of 10 years (IQR: 5.0-15.0). The infertility rate was higher in the TC group than in the control group (23.9% vs. 20.4%, p = 0.008). Still, the postdiagnosis/referent date pregnancy rates were comparable in the whole cohort (46.9/47.7%, p = 0.625) and across all age quartiles. The median time to the first pregnancy postdiagnosis/referent date was longer in TC patients than in controls (37 vs. 31 months, p < 0.001). Within the TC group, women who received repeated radioactive iodine treatment (n = 611, 52.5%) had comparable rates of infertility and pregnancy as those who did not. However, their time to the first postdiagnosis pregnancy was longer (median 45 vs. 29 months, p = 0.020). Conclusions: Our study provides reassuring evidence about the reproductive characteristics of women treated for TC. Pregnancy rates in TC survivors were comparable with controls. However, a higher infertility rate and a longer time to conceive were observed in the TC group compared with the control group. These findings were consistent in women who received single or repeated RAI treatments.

The Effect of a Nutritional Supplement on Growth and Body Composition in Short and Lean Preadolescent Boys following One Year of Intervention.

INTRODUCTION: Adequate nutrition plays an important role in linear growth throughout childhood, including puberty. However, not all children are willing or able to consume an adequate and balanced diet daily. We aimed to evaluate the 1-year effectiveness and safety of nutritional supplementation on linear growth, weight gain, and changes in body composition in short and lean peripubertal boys. METHODS: A 1-year, 2-phase multicenter interventional study comprising 1-6 months of a double-blinded intervention with nutritional formula or placebo, followed by 6-12 months of an open-label extension with the nutritional formula for all participants. RESULTS: The outcomes of the double-blinded intervention were reported previously. A total of 79/98 (81%) boys, aged ≥10 years, Tanner stages 1-3, completed the open-labeled extension phase. For this phase, a significant dose-response correlation (p < 0.05) was found of the consumption of the formula with Δ height-SDS, Δ weight-SDS, and Δ muscle mass (crude correlations and after adjustment for baseline age and end-of-study Tanner stage). In the extension phase and in the 12-month analysis, participants who were good formula consumers (intake ≥50% of the recommended dose) maintained their height-SDS, while poor consumers had a significant decline in their height-SDS (p = 0.028 and p = 0.009, between group difference in the extension phase and 12-month analysis, respectively). Between-group differences were not observed in the Tanner stage at any point of the study. No serious adverse events were reported. CONCLUSIONS: An intervention in healthy peripubertal boys suggests that 1-year consumption of a multi-nutrient, protein-rich nutritional supplement is efficacious and safe. The induced changes in growth and body composition, although modest, may be clinically significant. The effect of the formula on growth parameters was not mediated by enhancement of the pubertal tempo.

Symptoms and Glycemic Control in Young People With Type 1 Diabetes Following SARS-CoV-2 Infection: An Observational Study.

CONTEXT: Data is needed regarding the effect of SARS-CoV-19 infection on young people with established type 1 diabetes. Identifying the disease outcomes, short and long-term sequelae may help to establish an evidence-based prevention and education policy for sick days management and DKA prevention. OBJECTIVE: This work aims to describe clinical manifestations of SARS-CoV-2 infection in children, adolescents, and young adults with established type 1 diabetes (T1D) and explore the effects of COVID-19 on glycemic control and disease course. METHODS: An observational study was conducted at 3 pediatric diabetes clinics in Israel between mid-March 2020 and mid-March 2021. Included were young people with established T1D, age younger than 30 years, who tested positive for SARS-CoV-2 (quantitative real-time polymerase chain reaction). Data were collected from medical files, diabetes devices, and COVID-19 questionnaire. Outcome measures were analyzed by the presence/absence of clinical symptoms (symptomatic/asymptomatic) and by age group (pediatric, < 19 years/young adults, 19-30 years). RESULTS: Of 132 patients, mean age 16.9 ±â€…5.3years, with COVID-19-confirmed infection, 103 (78%) had related symptoms; the most common were headaches, fatigue, fever, and loss of sense of smell. All had a mild disease course, but 4 required hospitalization and 2 cases were directly related to COVID-19 infection (pleuropneumonia in a patient with immunodeficiency syndrome, 1 case of diabetic ketoacidosis). Logistic regression analysis showed that age (odds ratio [OR] = 1.11; 95% CI, 1.01-1.23; P = .033), elevated glucose levels (OR = 5.23; 95% CI, 1.12-24.41; P = .035), and comorbidities (OR = 8.21; 95% CI, 1.00-67.51; P = .050) were positively associated with symptomatic infection. Persistent symptoms occurred in 16.5% of the cohort over a median of 6.7 months; age (OR = 1.14; 95% CI, 1.01-1.29; P = .030) and elevated glucose levels (OR = 3.42; 95% CI, 1.12-10.40; P = .031) were positively associated with persistent symptoms. Usually, no change was reported in glucose levels (64%) except for a temporary deterioration in glycemic control during the short infection period. CONCLUSION: Young people with established T1D experience mild COVID-19 infection. Elevated glucose levels during COVID-19 infection and older age were associated with prolonged disease course.

Effect of a nutritional supplementation on growth and body composition in short and lean preadolescent boys: A randomised, double-blind, placebo-controlled study.

AIM: To evaluate the effect of nutritional supplementation on height, weight and body composition in short and lean male preadolescents. METHODS: A randomised, double-blinded, placebo-controlled trial of nutritional supplementation of short and lean prepubertal 10-14.5-year-old boys. Primary outcomes included Δheight-SDS and Δweight-SDS. Secondary outcomes included changes in body composition and BMI-SDS. RESULTS: Of 160 boys enrolled, 126 (80%) completed 6 months' intervention. Baseline age, height-SDS, weight-SDS, BMI-SDS, body composition and dietary intake were similar in the formula and placebo groups. 'Good' formula consumers (intake of ≥50% of the recommended dose, n = 30) gained significantly more in weight-SDS, BMI-SDS, fat-free-mass and muscle mass (p < 0.05) than did 'poor' consumers (n = 35) and the placebo group (n = 61). Only in the formula group, positive dose-response correlations were found between consumption of the formula and changes in the outcome parameters examined, including Δheight-SDS (r = 0.301, p = 0.015). Boys aged >11.4 years who were 'good' formula consumers maintained their Δheight-SDS, while Δheight-SDS declined in 'poor' consumers and the placebo group of the same age (p = 0.033). CONCLUSION: Intervention with a multi-nutrient, protein-rich formula was effective in increasing weight-SDS, fat-free-mass, muscle mass and BMI-SDS in short and lean prepubertal male adolescents. Good consumption of the formula prevented Δheight-SDS decline in the older participants.

Diagnosing Growth Hormone Deficiency: Can a Combined Arginine and Clonidine Stimulation Test Replace 2 Separate Tests?

OBJECTIVE: Given the large number of false-positive growth hormone deficiency (GHD) diagnoses from a single growth hormone (GH) stimulation test in children, 2 different pharmacologic tests, performed on separate days or sequentially, are required. This study aimed to assess the reliability and safety of a combined arginine-clonidine stimulation test (CACST). METHODS: This was a retrospective, single-center, observational study. During 2017-2019, 515 children aged >8 years underwent GH stimulation tests (CACST: n = 362 or clonidine stimulation test [CST]: n = 153). The main outcome measures used to compare the tests were GH response (sufficiency/deficiency) and amplitude and timing of peak GH and safety parameters. RESULTS: Population characteristics were as follows: median age of 12.2 years (interquartile range [IQR]: 10.7, 13.4), 331 boys (64%), and 282 prepubertal children (54.8%). The GHD rate was comparable with 12.7% for CACST and 14.4% for CST followed by a confirmatory test (glucagon or arginine) (P = .609). Peak GH was higher and occurred later in response to CACST compared with CST (14.6 ng/mL [IQR: 10.6, 19.4] vs 11.4 ng/mL [IQR: 7.0, 15.8], respectively, P < .001; 90 minutes [IQR: 60, 90] vs 60 minutes [IQR: 60, 90], respectively, P < .001). No serious adverse events occurred following CACST. CONCLUSION: Our findings demonstrate the reliability and safety of CACST in detecting GHD in late childhood and adolescence, suggesting that it may replace separate or sequential GH stimulation tests. By diminishing the need for the second GH stimulation test, CACST saves time, is more cost-effective, and reduces discomfort for children, caregivers, and medical staff.

Management of Fully Pubertal Girls With Nonclassical Congenital Adrenal Hyperplasia: Glucocorticoids Versus Oral Contraceptives.

OBJECTIVE: To compare clinical outcomes of 3 treatment regimens-glucocorticoids (GCs), oral contraceptives (OCs), or a combination of both-administered to adolescents and young women diagnosed in childhood with nonclassical congenital adrenal hyperplasia (NCCAH), who had been treated with GCs until their adult height was achieved. METHODS: A retrospective study of medical records of 53 female patients with NCCAH followed in 3 tertiary pediatric endocrinology institutes. The 3 treatment groups were compared for the prevalence of hirsutism and acne, standardized body mass index (BMI)-standard deviation score (SDS), and androgen levels at the attainment of adult height (baseline), 1-year later, and at the last documented visit. RESULTS: At baseline, there were no significant differences among groups in BMI-SDS, androgen levels, hirsutism prevalence, acne, or irregular menses. From baseline to the last visit, the rate of hirsutism declined significantly only in the OC group (37.5% vs 6.2%, respectively; P = .03). The rate of acne declined in the combined group (50% vs 9%, respectively; P = .03) with a similar tendency in the OC group (50% vs 12.5%, respectively; P = .05). No significant changes were observed in BMI-SDS for the entire cohort or any subgroup during follow-up. A significant rise in androstenedione (P < .001), testosterone (P < .01), and 17-hydroxyprogesterone (P < .01) levels was observed only in the OC group. CONCLUSION: In girls diagnosed in childhood with NCCAH, who require treatment for hyperandrogenism following completion of linear growth, management should be tailored individually using a patient-centered approach. Treatment with OCs might be better than that with GCs for regression of hirsutism and acne. The long-term effects of elevated levels of androgens associated with this treatment regimen should be further studied.

Good glycemic control at puberty in boys with type 1 diabetes is important for final height.

BACKGROUND: Poor glycemic control in children with type 1 diabetes (T1D) may hinder sexual development and the associated growth spurt. This study aims to identify factors that may affect the timing of puberty, total pubertal growth (TPG), and final height (F-Ht) in boys with T1D. METHODS: This was a retrospective longitudinal study of 68 boys diagnosed with T1D during 1996 to 2009, who were prepubertal at diagnosis and had completed puberty at the time of data collection. Data were accessed regarding anthropometric measurements, Tanner stage, and glycosylated hemoglobin (HbA1c) levels from diagnosis to F-Ht. F-Ht was compared to parental height and Israeli National Health Survey data. RESULTS: The mean F-Ht standard deviation score (F-Ht-SDS) was lower than the mean Ht-SDS at diagnosis (P < .006) but similar to the mean target height SDS (P = .3) and to values from the national survey (P = .12). Mean HbA1c levels in the year preceding pubertal onset were associated with the age at onset of puberty (R = 0.33, P = .009) and inversely with TPG (R = -0.3, P = .03). Mean HbA1c levels during puberty were inversely associated with TPG (R = -0.26, P = .035) and F-Ht (R = -0.28, P = .02). Boys who presented with diabetic ketoacidosis at diagnosis were shorter than those who did not throughout the follow-up. CONCLUSIONS: We found associations of age of pubertal onset, pubertal growth spurt, and F-Ht with target height and glycemic control before and during puberty. Targeted interventions to achieve optimal metabolic control during these time periods are needed for normal, timely puberty and for achieving optimal adult height within the genetic target height.

Growth assessment of children during the COVID-19 pandemic-Can we rely on parental measurements?

AIM: The COVID-19 pandemic prompted the rapid development of remote medical services. During lockdown periods, children's growth data were obtained from parents' home assessments. This study aimed to assess the accuracy of home height and weight measurements and analyse their utility in clinical decision-making. METHODS: A retrospective, single-centre observational study. Children aged 3-18 years were measured for weight and height at home using guidance provided to parents on proper measurements techniques before subsequent professional re-evaluation at our endocrine institution clinic. The two sets of measurements were compared and analysed according to various clinical parameters. RESULTS: Height measurements at home and in the clinic were comparable (diff = 0.1 ± 1.3cm, p = 0.42) amongst the 107 children (mean age 10.2 ± 3.7, 56.1% males) participating in the study, except in overweight and obese children where they were significantly higher in the clinic (diff = 0.86 ± 1.48cm, p = 0.018). Weight and BMI were significantly higher in the clinic (diff = 0.45 ± 0.8kg and diff = 0.3 ± 0.6kg/m2 , p<0.001 and p<0.001, respectively). CONCLUSIONS: Height measurements of children by their parents were accurate except in obese and overweight children, whereas weight measurements tended to be lower than in the clinic. With proper guidance, parents' home measurements of height and weight are accurate and suitable for clinical decision-making.

Dyslipidemia and cardiovascular disease risk factors in patients with type 1 diabetes: A single-center experience.

BACKGROUND: Type 1 diabetes (T1D) contributes to altered lipid profiles and increases the risk of cardiovascular disease (CVD). Youth with T1D may have additional CVD risk factors within the first decade of diagnosis. AIM: To examine risk factors for dyslipidemia in young subjects with T1D. METHODS: Longitudinal and cross-sectional retrospective study of 170 young subjects with T1D (86 males; baseline mean age 12.2 ± 5.6 years and hemoglobin A1c 8.4% ± 1.4%) were followed in a single tertiary diabetes center for a median duration of 15 years. Predictors for outcomes of lipid profiles at last visit (total cholesterol [TC], triglycerides [TGs], low-density lipoprotein-cholesterol [LDL-c], and high-density lipoprotein-cholesterol [HDL-c]) were analyzed by stepwise linear regression models. RESULTS: At baseline, 79.5% of the patients had at least one additional CVD risk factor (borderline dyslipidemia/dyslipidemia [37.5%], pre-hypertension/hypertension [27.6%], and overweight/obesity [16.5%]) and 41.6% had multiple (≥ 2) CVD risk factors. A positive family history of at least one CVD risk factor in a first-degree relative was reported in 54.1% of the cohort. Predictors of elevated TC: family history of CVD (ß[SE] = 23.1[8.3], P = 0.006); of elevated LDL-c: baseline diastolic blood pressure (DBP) (ß[SE] = 11.4[4.7], P = 0.003) and family history of CVD (ß[SE] = 20.7[6.8], P = 0.017); of elevated TGs: baseline DBP (ß[SE] = 23.8[9.1], P = 0.010) and family history of CVD (ß[SE] = 31.0[13.1], P = 0.020); and of low HDL-c levels: baseline DBP (ß[SE] = 4.8[2.1], P = 0.022]). CONCLUSION: Our findings suggest that elevated lipid profiles are associated with DBP and a positive family history of CVD. It is of utmost importance to prevent and control modifiable risk factors such as these, as early as childhood, given that inadequate glycemic control and elevation in blood pressure intensify the risk of dyslipidemia.

Pediatric reference values of TSH should be personalized according to BMI and ethnicity.

OBJECTIVE: The need for personalization of the reference values of thyroid function tests has been previously suggested. We aimed at determining TSH reference values in a large cohort of children according to age, sex, BMI, and ethnicity. DESIGN: A population-based cohort study. METHODS: The study cohort included 75 549 healthy children aged 5-18 years. Data analyzed included age, gender, TSH, FT4 levels, BMI and ethnicity. Multivariate logistic regression analysis examined the associations between the study parameters. RESULTS: TSH in the Jewish population is lower than in the non-Jewish population (median: 2.1 IU/L (IQR: 1.5) vs 2.2 IU/L (IQR: 1.5), P < 0.0001). TSH is significantly affected by BMI for children defined as underweight, normal weight, overweight or obese, levels increased as weight diverged from the normal range (median levels: 2.1 IU/L (IQR: 1.4), 2.0 IU/L (IQR: 1.3), 2.1 IU/L (IQR: 1.4), 2.4 (IQR: 1.5), respectively, P < 0.001). The 2.5 percentile is affected by gender and BMI (P < 0.02 and P < 0.001, respectively), while the 97.5 percentile is affected by ethnic origin and BMI (P < 0.001 for both). New TSH reference intervals (RI) adjusted according to BMI and ethnicity are suggested. Comparison of the old and new RI demonstrate the significance of RI personalization: 25.1% of the children with TSH levels above the old RI are within the new RI, while 2.3% of the children who were in the old RI are below the new RI. CONCLUSIONS: TSH reference values in children are affected by BMI and ethnicity. Reference values should be individualized accordingly to improve future clinical decision-making and treatment.

Diagnosis of Growth Hormone Deficiency in Children: The Efficacy of Glucagon versus Clonidine Stimulation Test.

INTRODUCTION: The diagnosis of childhood growth hormone deficiency (GHD) requires a failure to respond to 2 GH stimulation tests (GHSTs) performed with different stimuli. The most commonly used tests are glucagon stimulation test (GST) and clonidine stimulation test (CST). This study assesses and compares GST and CST's diagnostic efficacy for the initial evaluation of short children. METHODS: Retrospective, single-center, observational study of 512 short children who underwent GHST with GST first or CST first and a confirmatory test with the opposite stimulus in cases of initial GH peak <7.5 ng/mL during 2015-2018. The primary outcome measure was the efficacy of the GST first or CST first in diagnosing GHD. RESULTS: Population characteristics include median age of 9.3 years (interquartile range 6.2, 12.1), 78.3% prepubertal, and 61% boys. Subnormal GH response in the initial test was recorded in 204 (39.8%) children: 148 (45.5%) in GST first and 56 (30%) in CST first, p < 0.001. Confirmatory tests verified GHD in 75/512 (14.6%) patients. Divergent results between the initial and confirmatory tests were more prevalent in GST first than CST first (103/148 [69.6%] vs. 26/56 [46.4%], p < 0.001) indicating a significantly lower error rate for the CST first compared to the GST first. In multivariate analysis, the only significant predictive variable for divergent results between the tests was the type of stimulation test (OR = 0.349 [95% CI 0.217, 0.562], p < 0.001). CONCLUSIONS: Screening of GH status with CST first is more efficient than that with GST first in diagnosing GHD in short children with suspected GHD. It is suggested that performing CST first may reduce the need for a second provocative test and avoid patients' inconvenience of undergoing 2 serial tests.

The Beneficial Effect of Combined GH/GnRHa Therapy in Increasing Adult Height Outcome in Children With ISS.

CONTEXT: Management of GH-treated children with idiopathic short stature (ISS) with early puberty and adolescents in midpuberty at initiation of treatment is challenging. OBJECTIVE: To assess the effect of combined GH/GnRHa therapy during puberty on achieved adult height (AHt) in these children with ISS and to determine whether outcome depended on sex and pubertal status at initiation of GH therapy. DESIGN: Retrospective, single-center observational study from 2003-2018. SETTING: Tertiary endocrine center. PATIENTS: One hundred ninety-two GH-treated children with ISS; 58 of 192 were treated by GH/GnRHa during puberty; 31 of 58 were prepubertal (19 girls) and 27 of 58 pubertal (19 girls) at initiation of GH. MAIN OUTCOME MEASURES: AHt, gain-in-height standard deviation score (SDS), AHt vs predicted adult height (PAHt), AHt vs target height (THt). RESULTS: Most boys and girls attained AHt SDS within the normal range (-0.73 ± 0.60 and -0.85 ± 0.65, respectively). Treatment modality, pubertal status, and sex were tested for their joint effect on growth outcome measures. Combined GH/GnRHa therapy increased AHt vs PAHt (P < 0.001) and AHt vs THt (P = 0.035). Prepubertal status at onset of GH treatment increased AHt (P = 0.049), gain-in-height SDS (P < 0.001), AHt vs PAHt (P < 0.001), and AHt vs THt (P = 0.042). Female sex increased AHt vs PAHt (P < 0.001). CONCLUSIONS: Our study demonstrated a beneficial effect of combined GH/GnRHa therapy in increasing AHt outcome in children with ISS with early/normal puberty and in adolescents naïve to GH treatment who are in midpuberty at initiation of therapy. This effect was more pronounced in the prepubertal group and in girls. Prospective randomized controlled trials are needed to assess whether GnRHa can increase AHt in GH-treated children with ISS.

Growth hormone therapy and short stature-related distress: A randomized placebo-controlled trial.

CONTEXT: Growth hormone (GH) treatment of short healthy children is based on the belief that short stature is associated with psychosocial problems and a diminished quality of life. OBJECTIVE: To determine the impact of GH therapy on psychosocial well-being and the ability of psychological metrics to define short stature-related distress. METHODS: Sixty prepubertal boys with idiopathic short stature (age: 10.0 ± 1.4 years, height-SDS: -2.38 ± 0.3) were enrolled in this 4-year intervention study (1-year double-blinded, randomized, placebo-controlled [GH/placebo-2:1] and 3-year open-labelled GH therapy). Explicit (conscious/voluntary) psychological metrics (Pediatric Quality of Life Inventory [PedsQL], Silhouette Apperception Test [SAT], Rosenberg Self-Esteem Scale [RSES], Child Behavior Checklist [CBCL]) and implicit (unconscious/involuntary) psychological metrics (Single-Category Implicit Association Test for height [SC-IAT-H], Height Perception Picture Test [HPPT]). Psychosocial evaluations were performed at study entry, after 1 and 4 years. RESULTS: At study entry, PedsQL of boys with idiopathic short stature was lower than Israeli norms (P = 0.001). After 1-year blinded intervention, only the GH-treated boys improved their actual and anticipated adult height perception (SAT, P < 0.001 and P = 0.022) with reduced short stature-related distress (SC-IAT-H, P < 0.001). At study end, RSES and SC-IAT-H improved significantly (P < 0.001), with no change in PedsQL and CBCL. CONCLUSIONS: Our finding of improved psychosocial functioning only in the GH-treated boys after 1-year blinded intervention suggests that it was the GH therapy, rather than being enrolled in a clinical trial, which contributed to the outcome. Long-term open-labelled GH treatment significantly improved height perception and self-esteem. Future studies are needed to fully assess the relevance of complementing the routinely used explicit self-report measures with the implicit measures.

Central Precocious Puberty as a Presenting Sign of Nonclassical Congenital Adrenal Hyperplasia: Clinical Characteristics.

CONTEXT: Central precocious puberty (CPP) may be the first presentation of nonclassical congenital adrenal hyperplasia (NCCAH) in girls. Data on the prevalence and the clinical phenotype of CPP associated with NCCAH are sparse. OBJECTIVES: To study the clinical and laboratory characteristics that could differentiate idiopathic CPP from CPP associated with NCCAH and to determine the prevalence of NCCAH among girls with CPP. DESIGN: Case-control study. SETTING: Tertiary pediatric endocrinology institute. PARTICIPANTS AND METHODS: From 2008 to 2017, 147 girls who had undergone stimulation tests with gonadotropin-releasing hormone and ACTH were diagnosed with CPP; of these, seven (4.8%) were eventually diagnosed with NCCAH. These seven patients together with 30 girls who presented with CPP during 1984 to 2008 and were later diagnosed with NCCAH comprised the NCCAH group. Demographic, anthropometric, clinical, and laboratory data were compared between the NCCAH group and the 140 girls with idiopathic CPP (ICPP group). RESULTS: No between-group differences were found in height, weight, body mass index, bone age, and Tanner stage. Mean basal levels of androstenedione, dehydroepiandrosterone-sulphate, and 17-hydroxyprogesterone were significantly higher in the NCCAH group, although ranges overlapped between the groups, and stimulated cortisol level was higher in the ICPP group. CONCLUSION: NCCAH was found in 4.8% of girls presenting with true CPP over 10 years, and no single parameter could differentiate between the diagnoses. Thus, in girls with true CPP from populations in which NCCAH is prevalent, assessment of adrenal androgens is required, and ACTH test should be considered.

Growth hormone therapy in children with idiopathic short stature - the effect on appetite and appetite-regulating hormones: a pilot study.

AIM: To investigate the effect of growth hormone (GH) therapy on appetite-regulating hormones and to examine the association between these hormones and the response to GH, body composition, and resting energy expenditure (REE). METHODS: Nine pre-pubertal children with idiopathic short stature underwent a standard meal test before and 4 months following initiation of GH treatment. Ghrelin, GLP-1, leptin, and insulin levels were measured; area under the curve (AUC) was calculated. Height, weight, body composition, REE, and insulin-like growth factor levels were recorded at baseline and after 4 and 12 months. RESULTS: Following 4 months of GH therapy, food intake increased, with increased height-standard deviation score (SDS), weight-SDS, and REE (p < .05). Significant changes in appetite-regulating hormones included a decrease in postprandial AUC ghrelin levels (p = .045) and fasting GLP-1 (p = .038), and an increase in fasting insulin (p = .043). Ghrelin levels before GH treatment were positively correlated with the changes in weight-SDS (fasting: r = .667, p = .05; AUC: r = .788, p = .012) and REE (fasting: r = .866, p = .005; AUC: r = .847, p = .008) following 4 months of GH therapy. Ghrelin AUC at 4 months was positively correlated with the changes in height-SDS (r = .741, p = .022) and fat-free-mass (r = .890, p = .001) at 12 months of GH treatment. CONCLUSIONS: The reduction in ghrelin and GLP-1 following GH treatment suggests a role for GH in appetite regulation. Fasting and meal-AUC ghrelin levels may serve as biomarkers for predicting short-term (4 months) changes in weight and longer term (12 months) changes in height following GH treatment. The mechanisms linking GH with changes in appetite-regulating hormones remain to be elucidated. ABBREVIATIONS: SDS: standard deviation score; REE: resting energy expenditure; SMT: standard meal test; AUC: area under the curve; ISS: idiopathic short stature; SGA: small for gestational age; FFM: fat-free-mass; FM: fat mass; EER: estimated energy requirements; DRI: dietary reference intakes; IQR: inter-quartile range.