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Purpose: 17α Hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, typically diagnosed in late adolescence with symptoms of pubertal delay and hypertension. This study aimed to determine the clinical and laboratory characteristics of 17OHD cases and gather data on disease management., Methods: Data from 97 nationwide cases were analyzed using the CEDD-NET web system. Diagnostic, follow-up findings, and final heights of patients were evaluated., Results: Mean age at admission was 13.54 ± 4.71 years, with delayed puberty as the most common complaint. Hypertension was detected in 65% at presentation; hypokalemia was present in 34%. Genetic analysis revealed Exon 1-6 homozygous deletion as the most frequent mutation, identified in 42 cases. Hydrocortisone replacement was universal; pubertal replacement was administered to 66 cases. Antihypertensive treatment was required in 57 (90%) patients. Thirty-seven cases reached final height, with an average SD of 0.015 in 46,XX and -1.43 in 46,XY. Thelarche and pubarche did not develop properly in some cases despite estradiol treatment., Conclusion: This study represents the largest cohort of pediatric cases of 17-hydroxylase deficiency (17OHD) documented in the literature. Hypertension and hypokalemia can serve as guiding indicators for early diagnosis.The final height is typically considered to be normal. The relationship between genotype and phenotype remains elusive. The initial genetic test for exon 1-6 deletions may be MLPA in our region., (© 2024. The Author(s).)

Introduction: Most children with adrenocortical tumors (ACTs) present with accelerated growth and skeletal maturation at diagnosis, which potentially compromises their adult heights (AHs). Knowledge about growth and pubertal patterns after ACT resection is scarce. This study presents the pubertal and auxological development of patients treated for ACT and followed up at a single pediatric endocrinology service in Brazil., Methods: Retrospective cohort study including 63 patients (47 girls) followed up between 1966 and 2021. Pubertal and auxological data from ACT diagnosis to AH were analyzed., Results: At diagnosis, the patients had median values of bone age (BA) more advanced than chronological age (CA), height standard deviation score greater than target height (TH-SDS), and predicted adult height (PAH-SDS) lower than TH-SDS. The difference between BA and CA decreased gradually during follow-up and the PAH-SDS moved closer to the TH-SDS 7 years after tumor resection. Puberty started at a median CA of 9.3 (8.3-11.3) years in girls and 9.9 (9.2-13.6) years in boys. Nine patients (6 girls) developed central precocious puberty (CPP), which was influenced by a CA >4 years at diagnosis. The difference between AH-SDS and TH-SDS was not significant (p = 0.3). The factors independently associated with AH below TH were CA >4 years at diagnosis, time between clinical manifestation and diagnosis >1 year, and development of CPP., Conclusion: Most patients treated for ACT during childhood attained AH within the TH despite presenting with advanced skeletal maturation at diagnosis. Development of CPP was not infrequent., (© 2024 S. Karger AG, Basel.)

Objectives: Clinical benefits of growth hormone (GH) in Prader-Willi syndrome (PWS) are proven and scoliosis is a known association of both PWS and GH therapy. The aims of this study were to assess GH prescribing practices and growth outcomes over time, the prevalence and predictors of scoliosis in GH-treated PWS children, and the near-final height of GH-treated PWS patients., Design and Methods: This is a retrospective, descriptive study evaluating data from all clinic visits of patients aged 0-18 years with PWS, seen through the Children's Hospital at Westmead between March 1992 and May 2022 (n=75)., Results: A total of 64 patients were treated with GH (visits = 1,414). In the recent decade, the diagnosis of PWS and GH commencement were made significantly earlier in life. The prevalence of scoliosis was 41 %, in which age was the only significant predictor for scoliosis (odds ratio 1.19: 95 % CI [1.08-1.31; p=0.001]) adjusted for other predictors. In patients with data available at the age 16 years (23/28 treated with GH), those who were GH treated had significantly higher height SDS vs. nontreated group (SDS -0.67 vs. -2.58; p=0.0001) and lower BMI SDS (1.18 vs. 2.37; p<0.001)., Conclusions: Significant improvements in growth and body composition were seen in the GH-treated group vs. non-treated group of children with PWS. There were no significant modifiable clinical predictors of scoliosis in children with PWS, but our findings confirm the high prevalence of scoliosis in GH-treated children with PWS reinforcing the need for close surveillance., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Central precocious puberty (CPP) is the onset of puberty before the age of 8 in girls and 9 in boys. The primary goal of CPP treatment is control and arrest of puberty development. In this study, it was aimed to determine the factors associated with final height in patients who received gonadotropin-releasing hormone analogs (GnRHa) treatment and reached their final height., Methods: From the medical records of the patients, age on admission, bone age (BA), weight-standard deviation score (SDS), height-SDS, BMI-SDS, target height-SDS, basal LH, FSH, E2, age at menarche, and pelvic USG findings were obtained., Results: The mean age on admission of the 67 female patients was 7.5 ± 0.60 years. On admission, 4.5 % of the patients were obese and 19.4 % were overweight. There was no difference between BMI-SDS at admission and after treatment. The mean age at menarche was 11.57 ± 0.78 years. About 58.2 % of the patients reached the target height, 35.8 % exceeded the target height, and 6 % were below the target height. The mean height-SDS and predicted adult height (PAH) on admission were better in patients who exceeded the target height. It was determined that target height-SDS had a positive effect on delta height-SDS, while BA/CA ratio had a negative effect., Conclusions: It was found that GnRHa treatment did not have a negative effect on BMI-SDS. It was shown that 94 % of the patients who received GnRHa treatment reached the target height, and in fact, 35.8 % exceeded the target height. A greater final height may be associated with good height-SDS and PAH values on admission., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Direct comparisons of both short-term and long-term auxological outcomes of growth hormone therapy (GHT) between growth hormone deficiency (GHD) and small for gestational age (SGA) are scarce., Methods: One hundred three patients with GHD and 53 patients with SGA treated at our tertiary center were investigated. Short-term and long-term outcomes were compared between these groups using multivariable linear regression models with adjustment for age, sex, and height at therapy start, also allowing for sex-specific group comparisons., Results: Mean delta height standard deviation scores (SDS) after 1 year of treatment were significantly higher in GHD (0.90, CI: 0.82-0.99) compared to SGA (0.67, CI: 0.54-0.79) (p = 0.003) with no sex difference. As expected, the mean increase in height SDS at final height (FH) was significantly higher in GHD (2.21, CI: 2.00-2.42) compared to SGA (1.05, CI: 0.75-1.35) (p &lt; 0.001), leading to a target height corrected FH of -0.39 SDS (CI: -0.62 to -0.15) in GHD and -1.22 SDS (CI: -1.57 to -0.87) in SGA (p &lt; 0.001). Girls with GHD had a better long-term outcome, as did boys with SGA when compared to the respective opposite sex. The cut-off of delta height of 0.5 SDS during the first year had a low sensitivity to detect long-term non-responders. We found a relation between short-term and long-term outcomes in GHD but not in SGA (adjusted R2 = 0.66 vs. 0.01)., Conclusion: In contrast to GHD, we observed practically no relationship between 1st-year and long-term outcomes in SGA patients treated with GH., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Considering the high prevalence of type 1 diabetes mellitus (T1DM) together with the importance of improved physical growth and the significance of promoting healthcare quality among T1DM children, this meta-analysis aims to determine mean final height in this population group., Methods: We systematically searched PubMed, EMBASE, Web of Science, Scopus, and Cochrane databases for all studies published until May 2023 and reviewed references of published articles. Meta-analytic procedures were used to estimate the effect size (mean final height Z-score) among T1DM children in a random effects model. Significance values, weighted effect sizes, 95% CIs, and tests of homogeneity of variance were calculated. The included studies consisted of data from 3274 patients., Results: The mean final height Z-score for T1DM children was -0.201 (n = 25 studies, 95% CI: -0.389, -0.013; I2 = 97%), -0.262 in males (n = 20 studies, 95% CI: -0.539, 0.015, I2 = 97.1%), and -0.218 in females (n = 18 studies, 95% CI: -0.436, 0, I2 = 94.2%). The non-significant negative association between age at diagnosis, HbA1c levels, and final height Z-score is suggested by the findings of the univariate meta-regression., Conclusion: Our findings indicated that children with T1DM have impaired linear growth and that monitoring of growth in these patient populations is an important issue in the management of T1DM. Due to a scarcity of studies providing data on the relationship between uncontrolled diabetes (increased HbA1c) and early diagnosis and final height, further investigation is warranted to determine whether there is indeed a correlation. Consequently, any conclusion regarding the association between uncontrolled diabetes (elevated HbA1c), early diagnosis of T1DM, and the increased risk of impaired linear growth or final height remains uncertain., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Objectives: The aim was to estimate the pubertal growth height of children and adolescents living in a high-altitude region of Peru using the Preece-Baines model 1 (1 PB)., Methods: A cross-sectional study was conducted in schoolchildren from the department of Puno (Peru) between 3841 and 3874 masl. The age range was between 4 and 17 years. Standing height was evaluated. 1 PB was used to infer the mathematical and biological parameters of stature., Results: Mathematical parameters estimated by the 1 PB model reflected small residual standard error (RSE) values in both sexes (0.25 in boys and 0.27 in girls). In boys, the age at which peak velocity was reached (APHV) was estimated at 13.21 ± 0.33years. While in girls it was 9.96 ± 0.26years (p < 0.05). In general, girls reached APHV (y) 3.25 years earlier than boys. On the other hand, the growth velocity of maximum height [APHV (cm/y)] of boys was higher (6.33 ± 6.06 cm/y) relative to girls (6.06 ± 0.32 cm/y). Estimated final adult height (EFAH) in boys was reached at 166.020 ± 0.99 cm and height at maximum growth velocity (HPHV) was 153.07 ± 0.67 cm, while in girls they were significantly lower (EFAH; 153.74 ± 0.44 cm and HPHV: 139.73 ± 0.84 cm)., Conclusions: This study showed that girls living in Puno at a high altitude in Peru reached APHV 3 years earlier than boys and at the same time reflected slower PHV. These results suggest that pubertal growth at high altitudes is slower in both sexes and especially in girls. Thus, modeling physical growth may be an important step in understanding the onset of puberty at different latitudes., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Editora Ltda.)

Objective: This research aimed to evaluate retrospectively the effect of anastrozole on height gain and sex hormone levels in pubertal boys receiving growth hormone (GH)., Materials and Methods: Pubertal boys who received both GH and anastrozole (GH+A) were one-to-one matched with boys who received only GH (GH-Only) for chronological and bone age, pubertal stage and height before the GH initiation, treatment duration and midparental height. Anthropometric measurements throughout treatment and adult heights were compared between the groups. Sex hormone levels were evaluated longitudinally in the GH+A group., Results: Forty-eight cases (24 in each group) were included. There was no statistical difference in adult height between the GH+A and GH-Only (p = 0.071). However, when the analysis was limited to those receiving anastrozole for at least 2 years, mean adult height was higher in the GH+A than in the GH-Only group (173.1 ± 6.2/169.8 ± 5.6 cm, p = 0.044). Despite similar growth rates between the two groups, bone age advancement was slower in the GH+A than in the GH-Only in a mean anastrozole treatment period of 1.59 years (1.37 ± 0.80/1.81 ± 0.98 years, p = 0.001). The greatest increase for FSH, LH, total and free testosterone and decrease for estradiol levels were observed in the third month after anastrozole was started, albeit remaining within the normal ranges according to the actual pubertal stages., Conclusion: Using anastrozole with GH for at least 2 years decelerates the bone age advancement resulting in adult height gain with no abnormality in sex hormone levels. These results suggest anastrozole can be used as an additional treatment to GH for further height gain in pubertal boys.

Purpose: The appropriate evaluation of height and accurate estimation of bone age are crucial for proper assessment of the growth status of a child. We developed a bone age estimation program using a deep learning algorithm and established a model to predict the final adult height of Korean children., Materials and Methods: A total of 1678 radiographs from 866 children, for which the interpretation results were consistent between two pediatric endocrinologists, were used to train and validate the deep learning model. The bone age estimation algorithm was based on the convolutional neural network of the deep learning system. The test set simulation was performed by a deep learning program and two raters using 150 radiographs and final height data for 100 adults., Results: There was a statistically significant correlation between bone age interpreted by the artificial intelligence (AI) program and the reference bone age in the test set simulation (r=0.99, p <0.001). In the test set simulation, the AI program showed a mean absolute error (MAE) of 0.59 years and a root mean squared error (RMSE) of 0.55 years, compared with reference bone age, and showed similar accuracy to that of an experienced pediatric endocrinologist (rater 1). Prediction of final adult height by the AI program showed an MAE of 4.62 cm, compared with the actual final adult height., Conclusion: We developed a bone age estimation program based on a deep learning algorithm. The AI-derived program demonstrated high accuracy in estimating bone age and predicting the final adult height of Korean children and adolescents., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2023.)

Objectives: The aim of this study is to analyze height after cessation of growth (final height [FH]) and its evolution over the last decades in X-linked hypophosphatemia (XLH) patients in France, as the data on natural history of FH in XLH are lacking., Design: We performed a retrospective observational study in a large cohort of French XLH patients with available data on FH measurements., Materials and Methods: We divided patients into 3 groups according to their birth year: group 1 born between 1950 and 1974, group 2 born between 1975 and 2000, and group 3 born between 2001 and 2006, respectively, and compared their FHs., Results: A total of 398 patients were included. Mean FHs were the following: for group 1, -2.31 ± 1.11 standard deviation score (SDS) (n = 127), 156.3 ± 9.7 cm in men and 148.6 ± 6.5 cm in women; for group 2, -1.63 ± 1.13 SDS (n = 193), 161.6 ± 8.5 cm in men and 153.1 ± 7.2 cm in women; and for group 3, -1.34 ± 0.87 SDS (n = 78), 165.1 ± 5.5 cm in men and 154.7 ± 6 cm in women. We report a significant increase in mean FH SDS over 3 generations of patients, for both men and women (P < .001). Final height SDS in male (-2.08 ± 1.18) was lower than in female (-1.70 ± 1.12) (P = .002)., Conclusion: The FH of XLH patients in France increased significantly over the last decades. Even though men's FHs improved more than women's, men with XLH remain shorter reflecting a more severe disease phenotype. While the results are promising, most patients with XLH remain short leaving room for improvement., Competing Interests: Conflict of interest: D.-A.E. reports receiving travel grants and honoraria from Novo Nordisk, Pfizer and Merck Serono. A.L. and A.R. report receiving research grants, consulting fees and/or honoraria from Kyowa Kirin, Alexion, Novo Nordisk, Pfizer, and Merck Serono. All disclosures mentioned are unrelated to this research project. The other authors have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The aim of the present study was to determine the efficiency of three different predictive models [Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner-Whitehouse 2 (TW2)] by comparing their predictions with near-adult height data of girls receiving gonadotropin-releasing hormone agonist (GnRHa) therapy., Methods: Clinical findings were retrospectively analyzed. Bone ages obtained before treatment were evaluated from left hand and wrist radiographs by three researchers. Predicted adult height (PAH) was calculated using the BP, RWT, and TW2 methods for each patient at the beginning of therapy., Results: The median age at diagnosis of the 48 patients included in the study was 8.8 (8.9-9.3) years. There was no significant difference between the mean bone ages evaluated separately with the Greulich-Pyle atlas and the TW3-RUS method (p=0.34). Among the PAH methods, only PAH measured by the BP method was very close to and no different from near adult height (NAH) [159.8±6.3 vs. 158.8±9.3 cm. p=0.3; (-0.5±1.1) vs. (-0.7±1.6) standard deviation score, p=0.1]. Accordingly, the BP method was found to be the most accurate prediction tool in girls with puberty treated with GnRHa., Conclusion: The BP method is more effective at predicting adult height than the RWT and TW2 methods in female patients who will receive GnRHa treatment., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: Early puberty suppression (ePS; Tanner stages 2 and 3) through gonadotropin-releasing hormone agonists (GnRHas) and gender-affirming hormones (GAHs) interferes with growth and may impact final height (FH)., Aim: To investigate the impact of ePS and GAH on FH in trans boys and trans girls., Methods: Retrospective study, including 10 trans boys and 22 trans girls at FH. Bone age (BA) was determined at the start of ePS and at the start of GAH according to Greulich and Pyle; predicted adult height (PAH) was calculated according to Bayley and Pinneau's tables; target height (TH) was calculated as adjusted mean of maternal and paternal height. Target height, PAH, and BA were determined according to sex registered at birth (SRAB) and experienced gender (EG)., Results: The age at the start of PS was 12.37 ± 0.74 years in trans boys and 13.10 ± 1.12 years in trans girls. Total height gain since the start of ePS in trans boys was 14.62 ± 4.08 cm, with 70% achieved before the start of GAH. In trans girls, it was 20.68 ± 7.66 cm, with 61% achieved before GAH. Target height for SRAB was the most accurate predictor for FH in both trans boys and girls: the difference with FH was 1.57 cm ± 3.1 (P = .168) and -0.98 cm ± 4.17 (P = .319), respectively. Also the difference between FH and PAH at the start of PS for SRAB was nonsignificant in both trans boys and girls (2.62 cm ± 3.79, P = .056 and -2.35 cm ± 5.2, P = .051, respectively)., Conclusion: Early puberty suppression and GAH do not impact FH, supporting the safety of the treatment; however, trans adolescents achieve a FH in line with SRAB, rather than EG., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64-82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved., Methods/design: Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario., Discussion: If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8-4.6 million (€2.05-5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects., Trial Registration: EudraCT number: 2020-001006-39., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Narcolepsy Type 1 (NT1) is a rare hypersomnia of central origin linked to hypocretin deficiency, most frequently arising at pediatric age. NT1 could be associated with endocrine comorbidities involving the neuroendocrine axis, predominantly obesity, and Central Precocious Puberty (CPP). The primary aim of this study is the evaluation of endocrine and auxological parameters at diagnosis and during follow-up in patients with NT1, treated with Sodium Oxybate (SO) or not., Methods: We retrospectively evaluated the auxological, biochemical, and radiological parameters of 112 patients referred to our Center between 2004-2022. The design of our study is cross-sectional at the time of diagnosis followed by a longitudinal follow-up., Results: Our study confirms an increased frequency of CPP and obesity in patients with NT1. At first evaluation, obesity was found in 31.3% of patients, while overweight was found in 25.0%. A diagnosis of CPP was made in 19.6% of patients. Interestingly, this group showed a significantly lower level of CSF-hypocretin (hrct-1) at diagnosis compared to others. We found an improvement in BMI SDS in the SO-treated group compared to untreated patients, and this trend persisted also at 36 months of follow-up (0.0 ± 1.3 vs 1.3 ± 0.4; p<0.03). Sixty-three patients reached their final height, with a median SDS of 0.6 ± 1.1 in boys and 0.2 ± 1.2 in girls., Discussion: To our knowledge, these are the first results regarding the final height in a large series of pediatric patients with NT1, with a normal range of IGF1-SDS levels and stature SDS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Casale, Assirelli, Pizza, Balsamo, Gennari, Pession, Plazzi and Cassio.)

Background/aim: Despite optimal conventional treatment (oral phosphate supplements and active vitamin D analogs), about 40-50% of children with well-controlled X-linked hypophosphatemia (XLH) show linear growth failure, making them less likely to achieve an acceptable final height. Here, we studied the hypothesis that rhGH treatment improves final height in children with XLH and growth failure., Methods: Two cohorts of children with XLH were included in this retrospective longitudinal analysis: (1) a cohort treated with rhGH for short stature (n = 34) and (2) a cohort not treated with rhGH (n = 29). The mean duration of rhGH treatment was 4.4 ± 2.9 years. We collected the auxological parameters at various time points during follow-up until final height., Results: In rhGH-treated children, 2 years of rhGH therapy was associated with a significant increase in height from - 2.4 ± 0.9 to - 1.5 ± 0.7 SDS (p < 0.001). Their mean height at rhGH discontinuation was - 1.2 ± 0.9 SDS and at final height was - 1.3 ± 0.9 SDS corresponding to 165.5 ± 6.4 cm in boys and 155.5 ± 6.3 cm in girls. Notably, the two groups had similar final heights; i.e., the final height in children not treated with rhGH being - 1.2 ± 1.1 SDS (165.4 ± 6.8 cm in boys and 153.7 ± 7.8 cm in girls), p = 0.7., Conclusion: Treatment with rhGH permits to improve final height in children with XLH and growth failure, despite optimal conventional treatment. We propose therefore that rhGH therapy could be considered as an option for short stature in the context of XLH., (© 2022. The Author(s).)

Background: Gonadotropin-releasing hormone analogs (GnRHas) are effective in increasing the final height of children with idiopathic central precocious puberty (ICPP). However, in previous years, some transient metabolic complications have been described during this treatment, for which there are no long-term outcome data. Our study aimed to evaluate the efficacy of GnRHas and clarify if body mass index (BMI) at diagnosis of ICPP could influence long-term outcomes., Methods: This was an observational, retrospective study that recruited a cohort of girls with ICPP. Data for anthropometric measures, fasting lipid profile, and glucose metabolism were collected at baseline [when GnRHas treatment started (T1)], at the end of the treatment (T2), and near-final height (nFH) or final height (FH) (T3). Predicted adult height (PAH) was calculated at T1 following Bayley and Pinneau's method. Analysis was carried out using BMI standard deviation score (SDS) categories at T1 (group A, normal weight, vs. group B, overweight/obese)., Results: Fifty-seven girls with ICPP who were treated with GnRHas were enrolled in the study (group A vs. group B: 33 vs. 24 patients, aged 7.86 ± 0.81 vs. 7.06 ± 1.61 years, respectively; p < 0.05). In the study population, nFH/FH was in line with the target height (TH) ( p = 0.54), with a mean absolute height gain of 11.82 ± 5.35 cm compared with PAH. Even if the length of therapy was shorter (group A vs. group B: 1.84 ± 2.15 vs. 2.10 ± 0.81 years, respectively; p < 0.05) and the age at menarche was younger (group A vs. group B: 10.56 ± 1.01 vs. 11.44 ± 0.85 years, respectively; p < 0.05) in group B than in group A, the nFH/FH gain was still comparable between the two groups ( p = 0.95). At nFH/FH, BMI SDS was still greater in group B than in group A ( p = 0.012), despite the fact that BMI SDS significantly increased in group A only ( p < 0.05). Glucose metabolism got worst during GnRHa with a complete restoring after it, independently from pre-treatment BMI. The ratio of low-density to high-density lipoprotein cholesterol transiently deteriorated during treatment with GnRHas in group A only ( p = 0.030)., Conclusions: Our results confirm the effectiveness of treatment with GnRHas on growth and do not support the concern that being overweight and obese can impair the long-term outcomes of GnRHas therapy. However, the observed transient impairment of metabolic parameters during treatment suggests that clinicians should encourage ICPP girls treated with GnRHas to have a healthy lifestyle, regardless of their pretreatment BMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bruzzi, Valeri, Sandoni, Madeo, Predieri, Lucaccioni and Iughetti.)

Purpose: We aimed to evaluate the near-final height (nFHt) in a large cohort of pediatricpatients with growth hormone deficiency (GHD) and to elaborate a new predictive method of nFHt., Methods: We recruited GHD patients diagnosed between 1987 and 2014 and followed-up until nFHt. To predict the values of nFHt, each predictor was run in a univariable spline., Results: We enrolled 1051 patients. Pre-treatment height was -2.43 SDS, lower than parental height (THt) (-1.09 SDS, p < 0.001). The dose of recombinant human GH (rhGH) was 0.21mg/kg/week at start of treatment. nFHt was -1.08 SDS (height gain 1.27 SDS), higher than pre-treatment height (p < 0.001) and comparable to THt. 1.6% of the patients were shorter than -2 SDS from THt. The rhGH dose at nFHt was 0.19 mg/kg/week, lower than at the start (p < 0.001). The polynomial regression showed that nFHt was affected by gender, THt, age at puberty, height at puberty, age at the end of treatment (F = 325.37, p < 0.0001, R 2 87.2%)., Conclusion: This large national study shows that GHD children can reach their THt. The rhGH/kg/day dose significantly decreased from the start to the end of the treatment. Our model suggests the importance of a timely diagnosis, possibly before puberty, the beneficial effect of long-term treatment with rhGH, and the key-role of THt. Our prediction model has a very acceptable error compared to the majority of other published studies., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Purpose: This study aimed to investigate the utility of annual growth velocity (GV) standard deviation scores (SDSs) and compatibility and effectiveness of biochemical parameters in long-term treatment monitoring and management of 21-hydroxylase deficiency (21-OHD) in children., Methods: Fifty children with 21-OHD were included in this study, and the biochemical parameters obtained during 402 visits were retrospectively evaluated. The follow-up period was divided between two GV SDS groups (GV SDS < 2 and GV SDS ≥ 2) and compared with auxological, biochemical, and clinical findings., Results: Elevation of 17-hydroxyprogesterone (17-OHP) values was observed at 193/402 visits, and both adrenocorticotropic hormone (ACTH) and total testosterone (tT) were observed at 53 of 193 (27.5%) visits. The calculated cut-off value for 17-OHP was > 4.3 ng/ml, with a sensitivity of 85.48% and specificity of 37.59% in the GV SDS ≥ 2 group. In the GV SDS ≥ 2 group, the corrected final height SDS (cFH SDS) was lower, and the delta height was higher than in the GV SDS < 2 group (p = 0.005 and p = 0.008, respectively). Linear regression analysis of the GV SDSs revealed that 17-OHP values and the hydrocortisone dose (mg/m 2 ) were affected (β = 0.037, p = 0.035, and β =  - 0.147, p = 0.001, respectively)., Conclusions: Annual GV was critical in the final height (FH) of children with 21-OHD. However, we observed inconsistency between the biochemical parameters in the follow-ups, and there were difficulties in evaluating these markers. Therefore, annual GV SDSs and biochemical findings should be used together in patients with 21-OHD at follow-ups., (© 2022. Hellenic Endocrine Society.)

Poor linear growth is common in children with cystic fibrosis (CF) and predicts pulmonary status and mortality. Growth impairment develops in infancy, prior to pulmonary decline and despite aggressive nutritional measures. We hypothesized that growth restriction during early childhood in CF is associated with reduced adult height. We used the Cystic Fibrosis Foundation (CFF) patient registry to identify CF adults between 2011 and 2015 (ages 18-19 y, n = 3655) and had height for age (HFA) records between ages 2 and 4 y. We found that only 26% CF adults were ≥median HFA and 25% were <10th percentile. Between 2 and 4 years, those with height < 10th percentile had increased odds of being <10th percentile in adulthood compared to children ≥ 10th percentile (OR = 7.7). Of HFA measured between the 10th and 25th percentiles at ages 2-4, 58% were <25th percentile as adults. Only 13% between the 10th and 25th percentile HFA at age 2-4 years were >50th percentile as adults. Maximum height between ages 2 and 4 highly correlated with adult height. These results demonstrate that low early childhood CF height correlates with height in adulthood. Since linear growth correlates with lung growth, identifying both risk factors and interventions for growth failure (nutritional support, confounders of clinical care, and potential endocrine involvement) could lead to improved overall health.

Introduction: Treatment with growth hormone (GH) is not approved for idiopathic short stature (ISS) in Europe., Objectives: To compare the growth of children treated with isolated GH deficiency (IGHD) vs. ISS-treated and untreated children., Methods: A retrospective descriptive study of patients treated in the last 14 years for IGHD (Group A), in comparison with ISS-treated (Group B) and untreated (Group C) subjects., Results: Group A had 67 males, who showed a height gain of 1.24 SD. Group B had 30 boys, who showed a height gain of 1.47 SD. Group C had 42 boys, who showed an improvement of 0.37 SD. The final heights were -1.52 SD, -1.31 SD, and -2.03 SD, respectively. Group A and C did not reach their target heights (with differences of 0.27 SD and 0.59 SD, respectively). Group B surpassed their target height by 0.29 SD., Conclusions: The final heights of the IGHD and treated ISS are similar. Treated groups were taller than untreated groups.

Objective: Knowledge of the biological parameters of pubertal growth spurt allows verification of secular changes and exploration of the timing of puberty. The aim of the study was to estimate final height, age at peak height velocity (APHV), and peak height velocity PHV (cm/y) in children and adolescents living at moderate altitude in Colombia., Methods: A cross-sectional study was designed in 2.295 schoolchildren from Bogotá (Colombia) with an age range from 5.0 to 18.9 years. Height (cm) was assessed. Preece-Baines model 1 (1PB) was used to make inferences about mathematical and biological parameters., Results: The five mathematical parameters estimated in general have reflected quality in the fit to the model, reflecting a small residual error. Final height was reached in boys at 170.8 ± 0.4 cm and in girls at 157.9 ± 0.2 cm. APHV was estimated at 12.71 ± 0.1 years in boys and 10.4 ± 0.2 years in girls. Girls reached APHV 2.2 years earlier than boys. In relation to PHV (cm/y), boys reached higher growth speed in height (7.4 ± 0.4 cm/y), and in girls it was (7.0 ± 0.2 cm/y)., Conclusion: It was determined that final height was reached at 170.8 ± 0.4 cm in boys and 157.9 ± 0.2 cm in girls, and APHV (years) and PHV (cm/ye) were reached relatively early and with average peak velocity similar to Asian and Western populations. A large-scale longitudinal study is needed to confirm these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cossio-Bolaños, Vidal-Espinoza, Minango-Negrete, Olivares, Urzua-Alul, de Campos, Fuentes-López, Sanchez-Macedo, Diaz-Bonilla, Torres-Galvis and Gomez-Campos.)

Objective: Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood., Design: It is a retrospective case series., Methods: Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height., Results: Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI., Conclusions: This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus., (© 2021 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background : In patients with growth hormone (GH) deficiency, the prediction of adult height before initiation of GH treatment can be helpful to guide clinicians and families. However, data regarding the effectiveness of prediction methods in such patients are limited. Objective : We aimed to investigate the accuracy of the three most used adult height prediction methods [Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner-Whitehouse 2 (TW2)] by comparing their results with the near-adult height (NAH) data of children treated with GH. Methods : A single-center retrospective study was conducted including patients treated with somatotropin due to GH deficiency. Bone age radiographs were reread by three authors. Adult height predictions were made using BP, RWT, and TW2 methods for each patient. Results : Forty-nine patients with GH deficiency [median age at diagnosis 10.8 (9.2-12.0) years, 63.3% girls, 69.4% prepubertal] were included. Median differences between predicted adult height (PAH) and NAH standard deviation (SD) scores were -0.5, 0.0, and 0.3 for BP, RWT, and TW2 methods, respectively. The rates of PAH within ±1 SD score of NAH were 54.7%, 62.3%, and 77.4% for BP, TW2, and RWT methods, respectively. RWT was the most accurate method in girls, however, it showed a similar efficiency with TW2 in prepubertal patients or those with delayed bone age between 1-2 years, independent of gender. Conclusions : We found that RWT and TW2 methods may be preferable rather than the BP method for predicting adult height in patients with a diagnosis of GH deficiency.

Growth retardation is a major complication in children with chronic kidney disease (CKD) and on kidney replacement therapy (KRT). Conversely, better growth in childhood CKD is associated with an improvement in several hard morbidity-mortality endpoints. Data from pediatric international registries has demonstrated that improvements in the overall conservative management of CKD, the search for optimal dialysis, and advances in immunosuppression and kidney transplant techniques have led to a significant improvement of final height over time. Infancy still remains a critical period for adequate linear growth, and the loss of stature during the first years of life influences final height. Preliminary new original data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry confirm an association between the final height and the height attained at 2 years in children on KRT.

Study Design: Retrospective cohort study., Objectives: To explore the possibility of predicting final body height at maturity based on associating parameters at the time of diagnosing adolescent idiopathic scoliosis (AIS), while examining the effect of curve magnitude and deterioration., Methods: A total of 284 female patients with AIS (mean age 12.2 ± 1.1 years, 52.5% premenarchal) were followed till skeletal maturity, indicated by ≥Risser stage 4, static body height and arm span over the past 6 months, and postmenarche 2 years. Standing body height, arm span, menarchal status, Risser staging, distal radius and ulna (DRU) classification, Sanders staging (SS), Cobb angles (major and minor curves), and Lenke curve types at initial presentation were examined. Patients with/without curve deterioration were compared. Multiple linear regression was used for predicting final body height (cm), and remaining height increase (%)., Results: Baseline body height was 152.1 ± 7.1 cm and major curve Cobb angle was 27.1° ± 7.4°, whereas at maturity they were 159.5 ± 5.4 cm and 32.5° ± 9.3°, respectively. For patients presented at Risser stage 0 or 1, radius grade (R) 6, ulnar grade (U) 5, or SS3, those with curve deterioration exhibited greater height increase potential at initial presentation ( P < .05) than those without deterioration. No intergroup difference was found for patients presented at ≥Risser 2, R7, U6, SS4. Predictive baseline parameters were age, body height, Cobb angle (major curve), curve type, and DRU grades. Prediction models of final body height ( R 2 = 0.735, P < .001) and remaining height increase ( R 2 = 0.742, P < .001) were established., Conclusions: Final body height prediction model was derived for female patients with AIS, with baseline body height and ulnar grading having larger impacts than other parameters.

Objective: To retrospectively evaluate the follow-up data in patients with 46,XX congenital adrenal hyperplasia (CAH) who were raised male., Methods: A national database was created. The data of patients were asked to be recorded in the data form., Results: The median (range) age of diagnosis was three (0.1-18.3) years in 44 patients. Twenty nine cases were diagnosed after the age of two years. Most (95.4%) cases were stage 4-5 virilized. Hysterectomy and bilateral salpingoopherectomy, at a median age of 7.25 (2.4-25.3) years, was performed in 35 cases. Testicular prostheses were placed in 11 (25%) cases at a median age of 11.2 (2.8-17) years. The median final height was 149.2 (132.8-172) cms in 38 patients, including simple virilizing (n=18), salt-wasting (n=6), and 11-beta hydroxylase (n=12). Of the 16 patients above the age of eighteen, university education was completed in 25%., Conclusion: It was seen that most (65.9%) of the 46,XX CAH cases raised male were diagnosed after two years of age. In these cases, hysterectomy and bilateral salpingoopherectomy, genital corrective surgeries and testicular prosthesis operations were performed in a very wide age rage.

The recent COVID-19 pandemic poses the general question on how infectious diseases can persistently affect human health. A growing body of literature has found a significant amount of evidence on the long-term adverse effects of infectious diseases, such as influenza, typhoid fever, and yellow fever. However, we must be careful about the fact that little is known about the long-term consequences of the acute diarrheal disease pandemic cholera - Vibrio cholerae bacillus - which still threatens the health of the population in many developing countries. To bridge this gap in the body of knowledge, we utilized unique census-based data on army height at age 20 in early 20th-century Japan, with a difference-in-differences estimation strategy using regional variation in the intensity of cholera pandemics. We found that early-life exposure to a cholera pandemic had heterogeneous stunting effects on the final height of men; the magnitude of the stunting effects increased as the intensity of exposure increased., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Gonadotropin-releasing hormone agonist treatment is important for optimal growth in girls with central precocious puberty (CPP). Data are lacking regarding benefit to height outcome when treatment is started after chronological age (CA) of 7 years, and if continued beyond CA of 10 years or bone age (BA) of 12 years., Methods: Forty-eight girls with CPP were treated with monthly leuprolide depot. Change in predicted adult height (PAH) during treatment was assessed. Changes in PAH and growth velocity were compared between girls initiating treatment at CA <7 vs. ≥7 years, and BA ≥12 vs. BA <12 years., Results: Mean baseline CA was 6.8 years, BA, 10.2 years; and PAH, 156.4 cm. BA/CA ratio decreased from pretreatment values, averaging 1.5 to 1.2 at the end of treatment. Proportion of girls with >5 cm PAH change during treatment was similar, and PAH increased throughout treatment in most girls, regardless of age at treatment initiation. PAH continued to increase in 16/19 girls who continued treatment after BA of 12 years, and also in 16/22 girls who continued treatment after CA of 10 years., Conclusions: PAH improved in most girls who initiated treatment after CA of 7 years. It continued to improve in most girls with longer treatment, even past BA of 12 years or CA of 10 years, which suggests that no absolute CA or BA limit should define initiation or end of treatment. Treatment plans need to be individualized, and neither treatment initiation nor cessation should be based on BA or CA alone., (© 2021 Marcela Vargas Trujillo et al., published by De Gruyter, Berlin/Boston.)

Objectives: Sex steroids, administered as a priming before GH stimulation tests (GHST) to differentiate between growth hormone deficiency (GHD) and constitutional delay of growth and puberty (CDGP) or as growth-promoting therapy using low-dose sex steroids (LDSS) in CDGP, are much debated. We aimed to compare auxological outcomes of CDGP or GHD children undergoing primed or unprimed GHST and to evaluate LDSS treatment in CDGP., Design: Retrospective study among three paediatric University Hospitals in Italy and UK., Methods: 184 children (72 females) aged 12.4 ± 2.08 years underwent primed (/P + ) or unprimed (/P - ) GHST and were followed up until final height (FH). CDGP patients were untreated (CDG P - ) or received LDSS (CDGP + ). The cohort included 34 CDG P - /P + , 12 CDGP + /P + , 51 GHD/P + , 29 CDG P - /P - , 2 CDGP + /P - and 56 GHD/P - . FH standard deviation score (SDS), Δ SDS FH-target height (TH) and degree of success (-1 ≤ Δ SDS FH-SDS TH ≤ +1) were outcomes of interest., Results: GHD/P + had better FH-SDS (-0.87 vs -1.49; P = .023) and ΔSDS FH-TH (-0.35 vs -0.77; P = .002) than CDGP - /P + . Overall, GHD/P + showed the highest degree of success (90%, P = .006). Regardless of priming, both rhGH and LDSS improved degree of success compared to no treatment (89% and 86% vs 63%, P = .0009). GHD/P + showed a trend towards a higher proportion of permanent GHD compared to GHD/P - (30.43% vs 15.09%; P = .067)., Conclusion: In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP., (© 2020 John Wiley & Sons Ltd.)

Introduction: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH., Materials and Methods: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy., Results: We included 252 patients with an average birth length of -2.0 ± 0.7 SD and birth weight of -1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from -2.2 ± 0.9 SD to -1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively)., Conclusion: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment., (© 2021 S. Karger AG, Basel.)

Introduction: In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters., Methods: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups., Results: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>-2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = -0.30; p = 0.016]). No new safety concerns arose., Conclusion: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood., (© 2021 S. Karger AG, Basel.)

Aim: To determine the effects of gonadotropin-releasing hormone analog treatment on final height and body mass index in girls with central precocious puberty., Material and Methods: All cases with diagnosis age <8 years constituted group 1 (n=19) and those with ≥8 years constituted group 2 (n=35)., Results: There was no significant difference in height standard deviation score, body mass index standard deviation score, bone age/chronologic age, predicted final height at the time of diagnosis, and follow-up between group 1 and group 2. There was no significant difference in final height (standard deviation score) between the groups. The number of obese and overweight cases at diagnosis and final height was similar. The target height (standard deviation score), predicted final height (standard deviation score), and final height (standard deviation score) were similar in both Group 1 and Group 2., Conclusion: We found that between the ages of 6-9.8 years, girls with central precocious puberty who received gonadotropin-releasing hormone analog treatment reached a final height within their target height range. It is concluded that gonadotropin-releasing hormone analog treatment increases body mass index during treatment and when patients reach the final height, they return to their pretreatment body mass index. Younger age and greater height at the time of diagnosis are the positive factors on final height., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright: © 2020 Turkish Archives of Pediatrics.)

Context: GnRHa treatment has been a standard of care in progressive early puberty (EP). Choice of the GnRHa formulation is dependent on the preference of the clinician., Objective: To compare the effects of triptorelin acetate (TA) and leuprolide acetate (LA) on anthropometry in girls with EP., Design: A descriptive observational study., Subjects and Methods: Girls diagnosed with central EP and treated with GnRHa at least for one year were included; treated with TA (n=46) and LA (n=35). First year anthropometric response and final height were evaluated., Results: The mean age at the initiation of GnRHa treatment of girls was 8.5±0.5 years. The ratio of obesity and of overweight was 7.4 and 25.9%, respectively. In both TA and LA groups, anthropometric data of the patients at initiation and at the first year of treatment were similar. Although growth velocity was similar in each group, in LA group height SDS at the first year of the treatment showed a significant decrease (p=0.045), but not in TA group (p=0.317). No significant ΔBMI was observed with treatment. The differences between FH - PAH at initiation (height gain) in TA and LA groups were 2.9±4.7 and 4.0±5.8 cm, respectively (p=.316). Height gain per treatment year was 1.7±3.0 cm., Conclusions: There was a significant decrease in height SDS at the first year of leuprolid treatment, but not in triptorelin. Although these two analogs show similar effects on treatment, a not significant but slightly better benefit in leuprolide was observed., (©by Acta Endocrinologica Foundation.)

Background: The management of children and adolescents with chronic kidney disease (CKD) and growth failure candidate for recombinant human growth hormone therapy (rhGH) is based on an appraisal of the literature established on a 2006 consensus statement and 2019 Clinical practice recommendations. The performance of these guidelines has never been tested. Aims: The objective of this study was to establish the level of adherence to international guidelines based on the 2006 consensus and the 2019 criteria that lead to the initiation of growth hormone treatment by both pediatric endocrinologists and pediatric nephrologists. Methods: A multidisciplinary team of pediatric endocrinologists and pediatric nephrologists, members of the Italian Society of Pediatric Endocrinology or of the Italian Society of Pediatric Nephrology, discussed and reviewed the main issues related to the management of pediatric patients with CKD who need treatment with rhGH. Experts developed 11 questions focusing on risk assessment and decision makings in October 2019 and a survey was sent to forty pediatric endocrinologists ( n = 20) and nephrologists ( n = 20) covering the whole national territory. The results were then analyzed and discussed in light of current clinical practice guidelines and recent recommendations. Results: Responses were received from 32 of the 40 invited specialists, 17 of whom were pediatric endocrinologists (42.5%) and 15 pediatric nephrologists (37.5%). Although all the centers that participated in the survey agreed to follow the clinical and biochemical diagnostic work-up and the criteria for the treatment of patients with CKD, among the Italian centers there was a wide variety of decision-making processes. Conclusions: Despite current guidelines for the management of children with CKD and growth failure, its use varies widely between centers and rhGH is prescribed in a relatively small number of patients and rarely after kidney transplantation. Several raised issues are not taken into account by international guidelines and a multidisciplinary approach with mutual collaboration between specialists will improve patient care based on their unmet needs., (Copyright © 2020 Cappa, Maghnie, Carbone, Chioma, Errichiello, Giavoli, Giordano, Guazzarotti, Klain, Montini, Murer, Parpagnoli, Pecoraro, Pesce and Verrina.)

Objective: The aim was to determine the final adult height (FAH) achieved by recombinant human growth hormone (rhGH) treatment, the factors affecting FAH and the success of attaining the genetic potential., Methods: Data of 133 patients treated with rhGH therapy were reviewed retrospectively. Patients were grouped according to diagnosis, either isolated GH deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD), and by sex, and pubertal status at the beginning of treatment., Results: The mean age of initiation of treatment was 12.3±2.18 years, and the mean duration of rhGH treatment was 3.65±1.5 years. The mean height standard deviation score (SDS) at diagnosis was -3.11±0.75 SD. All patients received a standardized GH dose of 0.033 mg/kg/day. Mean FAH-SDS was -1.8±0.77 and delta height-SDS (the change in height SDS between the beginning and end of treatment) was 1.28±0.94 SD. FAH-SDS was -1.79±0.86 SD in males; -1.82±0.64 in females (p=0.857); -1.94±0.71 at the beginning of treatment in pubertal patients and -1.68±0.81 in prepubertal patients (p=0.056); -1.84±0.89 in patients with IGHD and -0.47±0.2 in patients with MPHD (p˃0.05). In multiple regression analysis, First year delta height-SDS was the most predictive factor for both FAH-SDS and delta height-SDS., Conclusion: The majority of our patients achieved a final height compatible with their genetic potential as well as population standards when treated with rhGH even having started at a relatively late age. First year delta height-SDS was a predictive factor for FAH.

Objective: Adverse prenatal conditions can exert a long-lasting impact on growth up to final height (FH). Due to different prenatal nutrient availability, monozygotic twin pairs with discordant birth weight (bw) provide an excellent model to examine the impact of genes and environment and to analyse the predictive value of bw, birth length (bl) and cord blood (cb) concentration of IGF-I on FH., Patients and Methods: Twenty eight monozygotic twin pairs with intra-twin bw-/bl-differences were studied at birth and longitudinally until FH. Intra-twin bw difference >1 SDS was defined "discordant" (n = 10 pairs). IGF-I was analysed in cord blood in all twins. Intra-twin differences (∆) in bw, bl and cord blood IGF-I were correlated with ∆FH., Results: Throughout growth and up until FH intra-twin length/height differences remained for all but two (26/28) twins and for all (10/10) discordant twins. In the discordant group, a highly significant intra-twin difference for FH-SDS was found with a mean intra-twin Δheight- SDS of 1.23 (range, 0.29-2.34). This corresponds to a mean Δintra-twin difference at FH of 7.9 cm (3.1 inch; range, 2-15 cm [0.79-5.9 inch]). Correlation coefficients were calculated to identify factors predicting FH: ∆bw (r = .678; P = .0005), ∆bl (r = .333; P = .0002) and ∆IGF-I in cb (r = .418; P = .0023). Interaction terms showed that IGF-I is an additional factor to the auxological data, leading to an improvement of the ∆FH modelling., Conclusion: Prenatal environment leading to bw-/bl- and cbIGF-I differences in monozygotic twins had a long-lasting impact on growth until FH. Both, anthropometric data at birth and cbIGF-I are predictive of FH., (© 2020 John Wiley & Sons Ltd.)

Despite recent improvements in the composition of the diet, lower mineral bone density and overweight tendencies are incoherently described in patients with phenylketonuria (PKU). The impact of dietary factors and plasma phenylalanine levels on growth, BMI, body composition, and bone mineral density was investigated in our cohort of patients with hyperphenylalaninemia (HPA) with or without dietary treatment. The anthropometric, metabolic, BMI and other nutritional indicators and bone mineral density were compared between the group of 96 treated patients with PKU (58 classic PKU (cPKU) and 38 patients with moderate-mild PKU defined as non-classic PKU (non-cPKU)) and the untreated group of 62 patients with benign HPA. Having compared the treated and untreated groups, there were normal outcomes and no statistically significant differences in BMI, body composition, and bone mineral density. Lower body height standard deviation scores were observed in the treated as compared to the untreated group (P < 0.001), but the difference was not significant when analyzing patients older than 18 years; however, cPKU adults were shorter compared to non-cPKU treated adults (P = 0.012). Interestingly, the whole-body fat was statistically higher in non-cPKU as compared to cPKU patients. In conclusion, the dietary treatment ensured adequate nutrition without significant consequences in BMI, body composition, and bone mineral density. A low protein diet may have delayed the growth in childhood, but the treated patients gained a normal final height. Mild untreated hyperphenylalaninemia characteristic for benign HPA had no negative physiological effect on bone mineral density.

Context: Pituitary hormonal deficiencies in patients with craniopharyngioma may impair their bone health., Objective: To investigate bone health in patients with craniopharyngioma., Design: Retrospective cross-sectional study., Setting: Dutch and Swedish referral centers., Patients: Patients with craniopharyngioma (n = 177) with available data on bone health after a median follow-up of 16 years (range, 1-62) were included (106 [60%] Dutch, 93 [53%] male, 84 [48%] childhood-onset disease)., Main Outcome Measures: Fractures, dual X-ray absorptiometry-derived bone mineral density (BMD), and final height were evaluated. Low BMD was defined as T- or Z-score ≤-1 and very low BMD as ≤-2.5 or ≤-2.0, respectively., Results: Fractures occurred in 31 patients (18%) and were more frequent in men than in women (26% vs. 8%, P = .002). Mean BMD was normal (Z-score total body 0.1 [range, -4.1 to 3.5]) but T- or Z-score ≤-1 occurred in 47 (50%) patients and T-score ≤-2.5 or Z-score ≤-2.0 in 22 (24%) patients. Men received less often treatment for low BMD than women (7% vs. 18%, P = .02). Female sex (OR 0.3, P = .004) and surgery (odds ratio [OR], 0.2; P = .01) were both independent protective factors for fractures, whereas antiepileptic medication was a risk factor (OR, 3.6; P = .03), whereas T-score ≤-2.5 or Z-score ≤-2.0 was not (OR, 2.1; P = .21). Mean final height was normal and did not differ between men and women, or adulthood and childhood-onset patients., Conclusions: Men with craniopharyngioma are at higher risk than women for fractures. In patients with craniopharyngioma, a very low BMD (T-score ≤-2.5 or Z-score ≤-2.0) seems not to be a good predictor for fracture risk., (© Endocrine Society 2020.)

Purpose: Growth hormone deficiency (GHD) is the most prevalent hypothalamic-pituitary (HP) disorder found in childhood cancer survivors (CCS). The published studies assessing GHD in CCS concluded that recombinant human GH (rhGH) does not restore final height (FH) to that predicted from mid-parental height (MPH). Thus, wider analyses on final height outcomes after rhGH in CCS are needed., Methods: Retrospective study on final height (FH) in 87 CCS treated with rhGH. Patients were divided into: Group A (n =48) who underwent cranial radiotherapy or had non-irradiated tumours of HP area, and B (n =39) who were treated with craniospinal or total body irradiation (TBI). 19/87 patients with central precocious/early puberty also received GnRH analogues., Results: Height (HT) gain after 1 and 2 years of rhGH was 0.38 ± 0.35 SDS and 0.18 ± 0.30 SDS, respectively (P < 0.0001); mean FH was in the normal range (- 0.85 ± 1.34 SDS), though not significantly different from HT SDS at baseline. 67% overall failed to reach MPH especially in Group B (P < 0.0001). However, height loss (HT SDS-MPH SDS) at FH improved or remained stable compared to baseline in 26/45 patients (58%). On stepwise regression analysis, major determinants of FH were HT at baseline (P < 0.0001) and delay before start of rhGH (P = 0.012). There was no significant difference in FH when GnRHa was added to rhGH., Conclusion: rhGH and GnRH analogues therapy, when indicated, though failing to induce catch-up growth, prevented further height loss leading to a FH within the normal range but still below MPH, this latter being statistically significant in children who received craniospinal and TBI.

Introduction: Loss-of-function mutation of MKRN3 represents the most frequent genetic cause of familial central precocious puberty (CPP). The outcomes of gonadotropin-releasing hormone analog (GnRHa) treatment in CPP patients with MKRN3 defects are unknown., Objective: To describe the clinical and hormonal features of patients with CPP with or without MKRN3 mutations after GnRHa treatment. Anthropometric, metabolic and reproductive parameters were evaluated., Patients and Methods: Twenty-nine female patients with CPP due to loss-of-function mutations in the MKRN3 and 43 female patients with idiopathic CPP were included. Their medical records were retrospectively evaluated for clinical, laboratory, and imaging study, before, during, and after GnRHa treatment. All patients with idiopathic CPP and 11 patients with CPP due to MKRN3 defects reached final height (FH)., Results: At the diagnosis, there were no significant differences between clinical and laboratory features of patients with CPP with or without MKRN3 mutations. A high prevalence of overweight and obesity was observed in patients with CPP with or without MKRN3 mutations (47.3 and 50%, respectively), followed by a significant reduction after GnRHa treatment. No significant differences in the values of mean FH and target height were found between the 2 CPP groups after GnRHa treatment. Menarche occurred at the expected age in patients with or without CPP due to MKRN3 mutations (11.5 ± 1.3 and 12 ± 0.6 years, respectively). The prevalence of polycystic ovarian syndrome was 9.1% in patients with CPP due to MKRN3 mutations and 5.9% in those with idiopathic CPP., Conclusion: Anthropometric, metabolic, and reproductive outcomes after GnRHa treatment were comparable in CPP patients, with or without MKRN3 mutations, suggesting the absence of deleterious effects of MKRN3 defects in young female adults' life., (© 2019 S. Karger AG, Basel.)

Purpose: The definition of growth response in growth hormone (GH)-treated children is controversial. This study aims at: (1) evaluating short-term and long-term efficacy of GH treatment in a cohort of short children with GH deficiency (GHD); (2) assessing and compare various poor response criteria; (3) identifying predictive factors of growth response., Methods: Our study included 94 children, affected by isolated GHD and treated with GH until they reached final height. Criteria used for calculating the proportion of poor responders to GH for the first year were gain in height (ΔHt) SDS < 0.5 ("Bang criterion"), <0.3 or <0.4 SDS for less-severe and severe GHD, respectively ("Ranke criterion"), height velocity (HV) < mean -1 SDS ("Bakker criterion"); for adult height "Cianfarani criterion" was total ΔHt < 1 SDS., Results: After 1 year of treatment we defined "poor responders" 55.3% of patients according to Bang criterion, 40.9% according to Bakker criterion and 23.4% according to Ranke criterion. At the end of the treatment, poor responders according to Cianfarani criterion were 22.34%; almost everyone in our population (97.9%) achieved mMid-parental height (MPH). Median final Ht was -1.11 SDS. Our analysis revealed a significant negative association between ΔHt and age at diagnosis., Conclusions: Bang criterion generated the highest number of poor responders, but had a low negative predictive value (67.5%); Ranke and Cianfarani criteria displayed similar rate of poor response. There is no reliable predictive factor of growth hormone response. However, almost all children treated reached MPH, suggesting good treatment efficacy.

Background: Children with congenital adrenal hyperplasia (CAH) because of 21 hydroxylase deficiency (21OHD) are at risk for early or precocious puberty and a short adult height compared to population means and midparental height. The effect of histrelin in suppressing puberty and improving growth in these children has not been reported., Methods: Retrospective cohort analysis of all patients (age ≤ 20) at our institution who underwent histrelin implantation between 2008 and 2017. Treated patients with CAH (classic and nonclassic forms of 21OHD) were identified and their growth data analyzed., Results: Fifteen children with CAH were treated with histrelin for a median of 3 years (range 2-5; age at first implantation 7.7 ± 1.5 years). Bone age (BA) to chronologic age (CA) decreased from 1.57 ± 0.4 to 1.25 ± 0.25 ( P < .01), while predicted adult height (PAH) increased by 7.1 ± 6.6 cm ( P < .01). A subgroup of 10 children reached adult height. Similar changes in BA/CA and PAH were observed with therapy ( P = .02). Adult height z improved compared to pretreatment PAH z (-1.42 ± 0.9 vs. -1.96 ± 1.1 respectively, P < .01), but remained lower than midparental height z ( P = .01)., Conclusion: In this retrospective cohort study of children with CAH due to 21OHD and early or precocious puberty, histrelin implantation resulted in a decrease in BA progression compared to CA and an improvement in PAH. In the subgroup who completed growth, adult height remained significantly lower than midparental. These results need to be confirmed with prospective controlled studies., (© Endocrine Society 2019.)

Introduction: The inhibitory effect of aromatase on predicted adult height and near final height has been studied in patients with constitutional delay of growth and puberty (CDGP)., Aim: This is the first study aimed at verifying the letrozole (Lz) effect on final height of patients with CDGP., Material and Methods: In this study 8 patients with CDGP underwent treatment with Lz (2.5 mg/day) for a year, and 8 patients with CDGP, who did not receive Lz were followed -up to reaching final height. Height discrepancy was calculated by subtracting PAH from final height measurement., Results: the final height for Lz and Control Groups were 171± 4.5 cm and 168.8±4.1Cm respectively. The final heights for Lz group were significantly (p=0.04) higher than the control group. Final height in comparison with PAH at the beginning of the study showed significant difference (p=0.022) in Lz group whereas the difference was not significant (p=0.8) in control group. For height discrepancy the measurements were +1.9 cm and +0.1 cm for Lz and control group respectively with significant difference (p=0.04)., Conclusion: Our study, which is the first one in evaluating the impact of Lz on FH, illustrated that Lz treatment will ultimately lead to augmentation of FH in boys with CDGP., Competing Interests: There are no conflicts of interest., (© 2019 Farzaneh Rohani, Ramin Asadi, Amir Ahmad Mirboluk , Fahimeh Soheilipour.)

Background: Early puberty (EP) is due to the activation of gonadotropin-releasing hormone (GnRH) pulse generator in lower ages; EP may be a potential cause for impairment of adult height, leading to short stature. The aim of this study was to determine the effects of GnRH analog (GnRHa) and GnRHa plus recombinant human growth hormone (rhGH) treatment on final height in healthy girls with EP., Materials and Methods: Fifty EP girls (sexual maturity rating: 2-3) with chronological age (CA) 9.22 ± 0.56 and bone age (BA) 9.74 ± 0.59 years were treated with GnRHa (Triptorelin) at a dose of 100 μg/kg body weight (BW) as intramuscular every 28 days for 2.82 ± 0.57 years; 45 EP girls with CA 9.84 ± 0.57 and BA 10.14 ± 1.02 years were also treated with the same GnRHa plus rhGH (Norditropin) at a dose of 0.1 unit/kg BW daily for 6 days in a week for 2.55 ± 0.6 years. In the control group, 33 EP girls followed for the same period without treatment. Height, weight, and body mass index of girls and parents were assessed. Predicted adult height (PAH) at the start and the end of the study and target height were assessed., Results: PAH at the end of the study in the GnRHa group was not different with untreated girls. PAH at the end of the treatment in GnRHa plus rhGH group was significantly higher than both untreated and GnRHa group. PAH at the end of therapy in GnRHa plus rhGH group was significantly more than their target height., Conclusion: GnRHa therapy has a benefit effect in achievement of target height. Combination therapy with GnRHa plus rhGH increased their PAH more than both untreated and GnRHa groups., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Advanced Biomedical Research.)

Background: We aimed to assess whether final height in children with cystic fibrosis (CF) is affected by body mass index (BMI), BMI increase, pulmonary function, and cystic fibrosis-related diabetes (CFRD)., Study Design: A longitudinal, retrospective study was performed in a cohort of 57 patients with CF (30 boys, 27 girls) born between 1997 and 2001. Height and weight were recorded annually from ages 0.5 to 10 years and biannually up to the age of 18. Measurements were converted to height-for-age-adjusted-for-target-height (HFA-TH) and BMI-for-age z-scores. Analyses were performed using the independent t tests and the Pearson's correlation., Results: For both boys and girls, HFA-TH and BMI-for-age z-scores were significantly lower in the first year of life, these scores increased rapidly until the age of 11 and 8 years, respectively. In boys, HFA-TH z-scores declined during puberty, with subsequently significantly impaired final height (z-score, -0.56, n = 30, standard deviation [SD] = 0.81, P = 0.001). In girls, HFA-TH z-scores briefly declined after the age of 8 years, but then increased to a z-score of -0.21 (n = 27, SD = 0.87) at age 18, which is not significantly lower than the national average (P = 0.22). Pulmonary function and the presence of CFRD were not associated with final height. However, rapid BMI increase between ages 1 and 6 was negatively associated with final height in boys (n = 29, r =-0.420; P = 0.023) and girls (n = 25, r =-0.466; P = 0.019)., Conclusions: In boys and girls, early BMI increase was associated with impaired final height. We suggest that early childhood serves as a "window" in which nutritional variations may program subsequent growth. Further refinement of nutritional strategies could be needed., (© 2019 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.)

A retrospective evaluation of growth in 112 patients (68 males, 44 females) with Hb E ( HBB : c.79G>A)/β-thalassemia (β-thal), classified as 88 transfusion-dependent thalassemia (TDT) and 24 non transfusion-dependent thalassemia (NTDT), is reported. Patients with TDT have received regular transfusions of red blood cells (RBCs) 15 mL/kg every 4 weeks to maintain pre transfusion hemoglobin (Hb) levels of at least 9.0 g/dL and were categorized according to age at initiation of regular RBC transfusion as subgroup 1, <4 years; subgroup 2, 4-10 years, and subgroup 3, >10 years. Iron chelation was initiated at the mean age of 7 years. The results revealed that patients in subgroups 1 and 2, receiving RBC transfusions at a young age (2.9 and 6.9 years, respectively), had normal prepubertal growth at enrollment and last follow-up. Patients in subgroup 3, with the lowest initial height Z-score of -2.10, were able to achieve comparable final adult height as those in subgroups 1 and 2. The mean final height of 21 males and 13 females with TDT at the ages of 18.9 and 18.7 years was 168.1 and 157.7 cm, respectively, which did not significantly differ from their midparental height and those with NTDT. Early initiation of optimal transfusion and iron chelation promoted normal prepubertal growth. However, delayed initiation of transfusion at age 12 years impaired prepubertal growth but they could achieve normal final adult height.

Objective: To investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood., Methods: Retrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared., Results: The study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (-3.6 to 3.9) and bone age advancement, 14.7 months (-27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17-14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04-8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17-14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12-8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to -0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75)., Conclusions: Gonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.

Background We previously reported improved persistence and adherence to daily recombinant growth hormone (rGH) in children using jet transjection delivery compared to using needle-based devices. This study examines the relationship between improved adherence and medium-term growth outcomes in children receiving jet-delivered rGH (JrGH) at a single centre. Methods This was a retrospective longitudinal follow-up study of children (<16 years) treated with daily JrGH (somatropin; Ferring Pharmaceuticals) in the form of Zomacton® with the Zomajet® device. Delivery schedules of home distribution services were utilised to calculate adherence, quantified as the proportion of days covered (PDC) index (PDC > 0.8 adherent, PDC ≤ 0.8 less adherent). Demography, patient history, height standard deviation scores (HTSDS) and difference from mid-parental height SDS (MPHSDS - HTSDS) were extracted from hospital records for up to 3 years of treatment. Results Of 75 patients eligible for JrGH, 52 had PDC treatment and height data for at least 1 year and 22 for 3 years. A greater proportion of patients were classified as adherent in both 1- and 3-year treated cohorts (adherent 30 [57.7%] and 14 [63.6%], less adherent 22 [42.3%] and 8 [36.4%]). After 1 year of JrGH treatment, HTSDS was not significantly different in either adherence group. After 3 years, only adherent patients demonstrated sustained year-on-year increments in HTSDS and significant improvement in target HTSDS positions (by 1.32 SDS) compared to baseline (p = 0.0008). MPHSDS - HTSDS showed a similar significant improvement at 3 years in adherent patients only (p = 0.0043). Conclusions Patients adherent to JrGH demonstrate significant growth improvement compared to baseline over 3 years.

Background: The effect on final height of gonadotropin-releasing hormone analogues (GnRHa) used in the treatment of precocious puberty is controversial. The aim of this study was to determine whether or not GnRHa therapy would make any contribution to final height in precocious puberty of girls with onset of pubertal characteristic development aged 6 - 8 years., Methods: Age at start of puberty, target height standard deviation score (SDS) presentation, follow-up height SDS, body mass index (BMI) SDS, bone age and predicted adult height of 34 female subjects who had reached their final height and with pubertal findings beginning at the ages of 6 - 8 were evaluated. These subjects were divided into two groups: treatment and non-treatment groups. The treatment group was further divided into two subgroups, receiving monthly or three-monthly depot GnRHa., Results: Age at onset of puberty was 7.2 ± 0.9 years. Twenty-five cases were started on GnRHa and nine were followed-up without treatment. Fourteen cases received monthly 3.75 mg depot triptorelin acetate and 11 received three-monthly 11.25 mg depot. Mean age at start of treatment in the treatment group was 9.1 ± 1.2 years and mean bone age was 9.7 ± 2.3 years. Age at presentation in the non-treatment group was 8.4 ± 1.4 years and bone age was 10.3 ± 2.1 years. Target and final height SDS were similar in all the groups (P > 0.05). No difference was determined between the treatment groups in terms of initial height SDS, bone age, length of treatment, final height SDS or BMI SDS (P > 0.05)., Conclusions: GnRHa therapy did not make a positive contribution to final height in precocious puberty of girls with onset of puberty aged 6 - 8 years., Competing Interests: The authors declare that there is no conflict of interest.