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Background: The growth hormone-IGF (insulin-like growth factor) system plays a central role in hormonal growth regulation. Recombinant human (rh) growth hormone (GH) has been available since the late 1980s for replacement therapy in GH-deficient patients and for the stimulation of growth in patients with short stature of various causes. Growth promotion by GH occurs in part indirectly through the induction of IGF-1 synthesis. In primary disturbances of IGF-1 production, short stature can only be treated with recombinant human IGF-1 (rhIGF-1). rhIGF-1 was recently approved for this indication but can also be used to treat other conditions. Methods: Selective review of the literature on IGF-1 therapy, based on a PubMed search. Results and conclusion: In children with severe primary IGF-1 deficiency (a rare condition whose prevalence is less than 1:10 000), the prognosis for final height is very poor (ca. 130 cm), and IGF-1 therapy is the appropriate form of pathophysiologically based treatment. There is no alternative treatment at present. The subcutaneous administration of IGF-1 twice daily in doses of 80 to 120 µg/kg accelerates growth and increases final height by 12 to 15 cm, according to current data. There is, however, a risk of hypoglycemia, as IGF-1 has an insulin-like effect. As treatment with IGF-1 is complex, this new medication should only be prescribed, for the time being, by experienced pediatric endocrinologists and diabetologists. [ABSTRACT FROM AUTHOR]

Background : The increasing prevalence of severe obesity among children and adolescents poses a significant challenge for pediatricians and general practitioners. This study aimed to investigate the relationships between biochemical results, anthropometry, blood pressure measurements, and bioimpedance analysis (BIA)-derived parameters to identify potential cardiometabolic complications associated with severe obesity. Methods : This study included 347 children (162 boys, 185 girls) aged 0-19 years, meeting the criteria for severe obesity based on BMI thresholds for different age groups. The patients were recruited in four pediatric endocrinology centers in Poland (Zabrze, Cracow, Rzeszow, Szczecin). Each participant underwent anthropometric measurements, pubertal stage assessment, blood pressure measurement, biochemical and hormonal tests, and BIA. Results : BMI showed significant associations with fat mass percentage (FM%) and waist-to-height ratio (WHtR) but not waist-to-hip ratio (WHR). The relationship between BMI and FM% was stronger in girls and prepubertal children. The metabolic syndrome (MetS) Z-score showed a strong positive correlation with BMI in the pubertal children. A negative correlation between HDL and triglycerides was observed only in the boys. The prepubertal children exhibited more significant correlations, despite a smaller sample size and shorter duration of obesity. Conclusions : Considering multiple parameters beyond BMI alone provides a better understanding of cardiometabolic risks associated with severe obesity in children. MetS Z-score was not a reliable indicator of increased cardiometabolic risk in younger children. Early-onset severe obesity was associated with a higher risk of metabolic complications. Early intervention is crucial to mitigate metabolic complications in this population.

The Kabi International Growth Study (KIGS) was first established in 1987 and is the largest pharmaco-epidemiological study of recombinant human growth hormone (rhGH). KIGS is aimed at evaluating long-term safety and treatment outcomes in pediatric subjects who received Genotropin rhGH therapy (Pfizer, New York, NY, USA) as prescribed by physicians in real-world clinical practice settings. KIGS data have been used to answer multiple research questions related to growth, growth prediction, and growth hormone treatment, leading to the publication of 129 peer-reviewed manuscripts and 24 biannual reports, outcomes from 10 expert meetings, and 3 books. The KIGS has shown that rhGH is safe and increases both the short-term height gain and adult height in patients with GH deficiency (GHD) and multiple other non-GHD conditions associated with short stature.

Context: The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings., Objective: This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort., Methods: Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth., Results: The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls., Conclusion: Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Severe early-onset obesity (SEOO) in children is a common feature of monogenic obesity. Nowadays, mutations in at least 50 genes are known to be related to monogenic obesity, and many others are tested. Part of them is involved in the leptin-proopiomelanocortin pathway. The aim of the project is to establish the Polish database of severely obese children and adolescents and to evaluate the prevalence of monogenic forms of obesity in this cohort, with a special focus on leptin-proopiomelanocortin pathway abnormalities. The secondary project aim is to identify new population-specific mutations in obesity-related genes in severely obese Polish children and adolescents. This is a prospective multi-center clinical study performed in four Polish centers. The estimated sample size is 500 patients aged 1-18 years, with severe obesity, hyperphagia, and food-seeking behaviors. In each patient, the medical history regarding the obesity duration in the patient and obesity and its complication existence in the family will be taken. Next, the questionnaire regarding the symptom characteristic of specific mutations, which we are going to test, will be performed. Hyperphagia will be assessed on the basis of age-specific questionnaires. The physical examination with anthropometric measurement, basic biochemical and hormonal tests, and leptin and biologically active leptin measurements will be performed. Finally, genetic analysis will be performed using next-generation sequencing with sequencing libraries prepared to include obesity-related genes. The genotyping findings will be confirmed with the use of classic sequencing (Sanger's method). In the future, the pathogenicity of new mutations in obesity-related genes identified in our cohort is planned to be confirmed by functional testing in vitro . Nowadays, there are no data regarding the prevalence of severe obesity or monogenic obesity in Polish children. This project has the potential to improve understanding of obesity etiology and may contribute to implementing attribute mutation-specific treatment. Moreover, it may lead to a finding of new, population-specific mutations related to SEOO., Competing Interests: Author BF is employed by Mediagnost GmbH. The remaining authors declare that the research will be conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mierzwa, Bik-Multanowski, Ranke, Brandt, Flehmig, Małecka-Tendera, Mazur, Petriczko, Wabitsch, Wójcik and Zachurzok.)

Context: Prediction of adult height (AH) is important in clinical management of short children. The conventional methods of Bayley-Pinneau (BP) or Roche-Wainer-Thissen (RWT) have limitations., Objective: We aimed to develop a set of algorithms for AH prediction in patients with idiopathic short stature (ISS) which are specific for combinations of predicting variables., Methods: Demographic and auxologic data were collected in childhood (1980s) and at AH (1990s). Data were collected by Dutch and German referral centers for pediatric endocrinology. A total of 292 subjects with ISS (219 male, 73 female) were enrolled. The population was randomly split into modeling (n = 235) and validation (n = 57) cohorts. Linear multi-regression analysis was performed with predicted AH (PAH) as response variable and combinations of chronological age (CA), baseline height, parental heights, relative bone age (BA/CA), birth weight, and sex as exploratory variables., Results: Ten models including different exploratory variables were selected with adjusted R² ranging from 0.84 to 0.78 and prediction errors from 3.16 to 3.68 cm. Applied to the validation cohort, mean residuals (PAH minus observed AH) ranged from -0.29 to -0.82 cm, while the conventional methods showed some overprediction (BP: +0.53 cm; RWT: +1.33 cm; projected AH: +3.81 cm). There was no significant trend of residuals with PAH or any exploratory variables, in contrast to BP and projected AH., Conclusion: This set of 10 multi-regression algorithms, developed specifically for children with ISS, provides a flexible tool for AH prediction with better accuracy than the conventional methods., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

The BoneXpert method for automated determination of bone age from hand X-rays was introduced in 2009 and is currently running in over 200 hospitals. The aim of this work is to present version 3 of the method and validate its accuracy and self-validation mechanism that automatically rejects an image if it is at risk of being analysed incorrectly. The training set included 14,036 images from the 2017 Radiological Society of North America (RSNA) Bone Age Challenge, 1642 images of normal Dutch and Californian children, and 8250 images from Tübingen from patients with Short Stature, Congenital Adrenal Hyperplasia and Precocious Puberty. The study resulted in a cross-validated root mean square (RMS) error in the Tübingen images of 0.62 y, compared to 0.72 y in the previous version. The RMS error on the RSNA test set of 200 images was 0.45 y relative to the average of six manual ratings. The self-validation mechanism rejected 0.4% of the RSNA images. 121 outliers among the self-validated images of the Tübingen study were rerated, resulting in 6 cases where BoneXpert deviated more than 1.5 years from the average of the three re-ratings, compared to 72 such cases for the original manual ratings. The accuracy of BoneXpert is clearly better than the accuracy of a single manual rating. The self-validation mechanism rejected very few images, typically with abnormal anatomy, and among the accepted images, there were 12 times fewer severe bone age errors than in manual ratings, suggesting that BoneXpert could be safer than manual rating., (© 2022. The Author(s).)

The new WHO reference standard allows for the definition of serum antibodies against various SARS-CoV-2 antigens in terms of binding antibody units (BAU/mL) and thus to compare the results of different ELISA systems. In this study, the concentration of antibodies (ABs) against both the S- and the N-protein of SARS-CoV-2 as well as serum neutralization activity were evaluated in three patients after a mild course of COVID-19. Serum samples were collected frequently during a period of over one year. Furthermore, in two individuals, the effects of an additional vaccination with a mRNA vaccine containing the S1-RBD sequence on these antibodies were examined. After natural infection, the antibodies (IgA, IgG) against the S1-protein remained elevated above the established cut-off to positivity (S-IgA 60 BAU/mL and S-IgG 50 BAU/mL, respectively) for over a year in all patients, while this was not the case for ABs against the N-protein (cut-off N-IgG 40 BAU/mL, N-IgA 256 BAU/mL). Sera from all patients retained the ability to neutralize SARS-CoV-2 for more than a year. Vaccination resulted in a rapid boost of antibodies to S1-protein but, as expected, not to the N-protein. Most likely, the wide use of the WHO reference preparation will be very useful in determining the individual immune status of patients after an infection with SARS-CoV-2 or after vaccination.

The syndrome of impaired GH secretion (GH deficiency) in childhood and adolescence had been identified at the end of the 19 th century. Its non-acquired variant (naGHD) is, at childhood onset, a rare syndrome of multiple etiologies, predominantly characterized by severe and permanent growth failure culminating in short stature. It is still difficult to diagnose GHD and, in particular, to ascertain impaired GH secretion in comparison to levels in normally-growing children. The debate on what constitutes an optimal diagnostic process continues. Treatment of the GH deficit via replacement with cadaveric pituitary human GH (pit-hGH) had first been demonstrated in 1958, and opened an era of therapeutic possibilities, albeit for a limited number of patients. In 1985, the era of recombinant hGH (r-hGH) began: unlimited supply meant that substantial long-term experience could be gained, with greater focus on efficacy, safety and costs. However, even today, the results of current treatment regimes indicate that there is still a substantial fraction of children who do not achieve adult height within the normal range. Renewed evaluation of height outcomes in childhood-onset naGHD is required for a better understanding of the underlying causes, whereby the role of various factors - diagnostics, treatment modalities, mode of treatment evaluation - during the important phases of child growth - infancy, childhood and puberty - are further explored., Competing Interests: The author declares 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 Ranke.)

Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.

Objective: We hypothesized that modelling catch-up growth (CUG) as developed for coeliac disease (CD), might also fit CUG in adequately treated children with juvenile hypothyroidism (JHT) or growth hormone deficiency (GHD)., Methods: We used a monomolecular function for all available prepubertal data on height standard deviation score (HSDS) minus target height SDS (adjHSDS) in children with JHT (n=20) and GHD (n=18) on a conventional (CoD) or high GH dose (HD), based either on a national height reference with an age cut-off of 10 (girls) and 12 (boys) years (model 1) or prepubertal height reference values, if age (0) was ≥3, with no upper age limit (model 2)., Results: The models could be fitted in 83-90% of cases; in other cases the HSDS decreased after several measurements, which violated the assumption of an irreversible growth process. In JHT, the rate constant (k) and adjHSDS (0) were lower than in CD (p=0.02), but adjHSDS (end) was similar. In GHD (model 1), k was lower than for CD (p=0.004) but similar to JHT, while adjHSDS (0) and adjHSDS (end) were similar to CD and JHT. Thus, the shape of CUG is similar for children with JHT and GHD, while children with CD had less growth deficit at start and a faster CUG. The differences in CUG parameters between GH dose subgroups did not reach statistical significance., Conclusion: Modelling CUG of prepubertal children with JHT and GHD can be used for assessing the adequacy of CUG and the influence of clinical treatment modalities on its speed and magnitude.

The relationship between the nasopharyngeal virus load, IgA and IgG antibodies to both the S1-RBD-protein and the N-protein, as well as the neutralizing activity (NAbs) against SARS-CoV-2 in the blood of moderately afflicted COVID-19 patients, needs further longitudinal investigation. Several new serological methods to examine these parameters were developed, validated and applied in three patients of a family which underwent an ambulatory course of COVID-19 for six months. The virus load had almost completely disappeared after about four weeks. Serum IgA levels to the S1-RBD-protein and, to a lesser extent, to the N-protein, peaked about three weeks after clinical disease onset but declined soon thereafter. IgG levels rose continuously, reaching a plateau at approximately six weeks, and stayed elevated over the observation period. Virus-neutralizing activity reached a peak about 4 weeks after disease onset but dropped slowly. The longitudinal associations of virus neutralization and the serological immune response suggest immunity in patients even after a mild clinical course of COVID-19.

Context: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness., Objective: To identify genetic variants associated with GH responsiveness., Design: Genome-wide association study (GWAS)., Setting: Cohorts from multiple academic centers and a clinical trial., Patients: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age., Intervention: Association of more than 2 million variants was tested., Main Outcome Measures: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness., Results: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score., Conclusions: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height., (© Endocrine Society 2020.)

In light of the growing number of surviving children born very preterm, there is an increasing focus on their long-term outcomes in terms of growth, metabolic status, and neurocognitive development. Therefore, it is of importance to follow such children from birth onwards with the aim of identifying the causes of atypical development, developing preventative measures, and improving outcomes. Since such long-term follow-up needs to be conducted with the least possible burden, clinical investigations such as anthropometry and neurocognitive tests, if conducted rigorously, will continue to have a predominant role. The aim of this review is to discuss the complexity of longitudinal anthropometry in children born very preterm and to provide an overview of the main studies that have examined associations between growth, in particular head growth, and neurocognitive outcomes at around school age., (© 2014 Mac Keith Press.)

Objective: While in adults not total body- or visceral fat mass, but liver fat content was found to independently determine insulin resistance, it is unclear whether these relationships are already present in obese adolescents., Methods: Thirty-nine overweight/obese adolescents were matched for sex and BMI with 39 adults. To compare the age- and sex-specific BMI values of adolescents and adults, the percentile value of each adolescent was projected to the age of 18. Body fat depots were quantified by whole-body magnetic resonance (MR) imaging. Liver fat content was measured with (1)H-MR spectroscopy. Insulin resistance was estimated from the homeostasis model assessment of insulin resistance (HOMA-IR)., Results: Compared to overweight and obese adults, adolescents had higher HOMA-IR (P < 0.001) and lower lean body mass (P = 0.002). Furthermore, they had higher total body- (P = 0.02), but lower visceral- (P < 0.001) fat mass, while liver fat content was not significantly different between the groups (P = 0.16). In both groups liver fat content (both P ≤ 0.007), but not total body- or visceral fat mass (all P ≥ 0.64) was an independent predictor of insulin resistance., Conclusions: Having lower visceral fat mass, overweight and obese adolescents are more insulin resistant than sex- and BMI-matched adults. Liver fat content, but not total body- or visceral fat mass, is an independent determinant of insulin resistance in adolescents., (Copyright © 2013 The Obesity Society.)

Study Question: In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy?, Summary Answer: Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy., What Is Known Already: Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood., Study Design, Size, Duration: Cross-sectional study investigating 270 karyotype proven TS patients aged 0-20 years between 2009 and 2010., Participants/materials, Settings, Methods: Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF. RESULTS AND THE ROLE OF CHANCE: Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with 'other' karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1-175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8-472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9-8.8; P < 0.001)., Limitations, Reasons for Caution: The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis.

Objective: The aim of this study was to identify the prevalence of eating disorder symptoms in obese adolescents participating in a lifestyle intervention for weight loss and to investigate possible relationships with weight change, general psychopathology, and health-related quality of life (HRQOL)., Method: At the beginning and after completion of a 6-month lifestyle intervention, 41 participants (20 females; age: 13.7 ± 1.4 years) reported on core symptoms of eating disorders (SCOFF), self-esteem (Rosenberg Self-Esteem Scale, RSES), and HRQOL (Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents, KINDL), while parents filled in a questionnaire assessing their children's internalizing and externalizing behavioral problems (Child Behavior Checklist, CBCL)., Results: Compared to age-matched normative samples, patients showed increased behavior problems and an impaired HRQOL. 43% of the patients were screened positive for an eating disorder pathology, and this subgroup showed an increased psychopathological burden compared to patients that were screened negative. The lifestyle intervention resulted in a significant weight loss which was unaffected by the presence of an eating disorder pathology. The screening rate for eating disorders remained stable after the intervention., Conclusion: The large overlap, mutual interaction, and high burden of eating and weight problems in children and adolescents underpin the need for an integrated view in both prevention and treatment approaches in pediatric obesity.

Background: Mathematical models can be developed to predict growth in short children treated with growth hormone (GH). These models can serve to optimize and individualize treatment in terms of height outcomes and costs. The aims of this study were to compile existing prediction models for short children born SGA (SGA), to develop new models and to validate the algorithms., Methods: Existing models to predict height velocity (HV) for the first two and the fourth prepubertal years and during total pubertal growth (TPG) on GH were applied to SGA children from the KIGS (Pfizer International Growth Database)--1st year: N = 2340; 2nd year: N = 1358; 4th year: N = 182; TPG: N = 59. A new prediction model was developed for the 3rd prepubertal year based upon 317 children by means of the all-possible regression approach, using Mallow's C(p) criterion., Results: The comparison between the observed and predicted height velocity showed no significant difference when the existing prediction models were applied to new cohorts. A model for predicting HV during the 3rd year explained 33% of the variability with an error SD of 1.0 cm/year. The predictors were (in order of importance): HV previous year; chronological age; weight SDS; mid-parent height SDS and GH dose., Conclusions: Models to predict growth to GH from prepubertal years to adult height are available for short children born SGA. The models utilize easily accessible predictors and are accurate. The overall explained variability in SGA is relatively low, due to the heterogeneity of the disorder. The models can be used to provide patients with a realistic expectation of treatment, and may help to identify compliance problems or other underlying causes of treatment failure.

Context: The association between IGFs and cancer in adults with GH deficiency (GHD) receiving GH replacement requires investigation., Objective: The objective was to examine the association between IGF-I, IGF-binding protein 2 (IGFBP-2), and IGFBP-3 SD scores (SDSs) in GH-deficient adults receiving GH therapy and the occurrence of de novo malignancies., Design: Serum IGF-I, IGFBP-2, and IGFBP-3 levels in GH-deficient patients who developed a malignancy since receiving GH were compared with patients with idiopathic GHD but without malignancy. Measurements were related to age-, sex-, and body mass index-specific SDS reference regions., Setting: The setting included the KIMS (the Pfizer International Metabolic Database)., Patients: One hundred patients with de novo malignancy during GH therapy were compared with 325 patients with idiopathic GHD without malignancy., Intervention(s): Serum samples were obtained as close as possible to the diagnosis of malignancy, or after approximately 2 yr of GH replacement in KIMS., Main Outcome Measures: Associations between relative risk (RR) of malignancy and IGF-I, IGFBP-2, and IGFBP-3 SDSs were assessed in multiple log-linear Poisson working regression models, controlling for age, sex, onset of GHD, and GH naivety at KIMS entry., Results: No association between IGF-I SDSs and RR was observed (P = 0.48). Increasing IGFBP-2 and IGFBP-3 SDSs were associated with increasing RRs [18% per unit IGFBP-2 SDSs (95% confidence interval, 7-30%; P = 0.0006), 13% per unit IGFBP-3 SDS (2-26%; P = 0.01)]., Conclusions: IGF-I levels targeted to within normal age-related reference ranges during GH replacement were not associated with the occurrence of malignancies. Higher IGFBP-2 and/or IGFBP-3 SDSs may be associated with increased cancer risk.

Context: Information about the expected growth response of children to GH therapy is currently inadequate., Objectives: The aim of the study was to compare observed and expected growth in response to GH in prepubertal children and to propose how these parameters can be used to optimize GH therapy. Indices considered were observed growth, observed growth relative to reference data [height sd score (Ht SDS), change in (Delta) Ht SDS, height velocity (HV)], and observed growth relative to growth predicted from prediction models [Studentized residual (SR)]. Design/Setting/Patients/Intervention: Growth data from KIGS-Pfizer International Growth Database-on prepubertal children aged 1-13 yr with severe GH deficiency (GHD; maxGH <5 microg/liter; n = 2129), with less-severe GHD (maxGH of 5-10 microg/liter; n = 3075), and with Turner syndrome (n = 2350), and short children born small for gestational age (n = 993) were analyzed before and during 2 yr of GH treatment., Main Outcome Measure: For each patient group, growth responses during the first 2 yr of GH treatment were established. The relationships of HV and DeltaHt SDS with SR were determined., Results: Reference data were generated for assessing adequate individual responses. Responses to GH in terms of HV and DeltaHt SDS were greatest in children with severe GHD. HV and DeltaHt SDS were highly correlated with SR during only the first year of GH treatment (R approximately 0.7; P < 0.001)., Conclusions: Decisions on GH therapy regimens should be made using both traditional (HV or DeltaHt SDS) and prediction model-derived (SR) indices of growth response.

Context: Short stature in children with chronic kidney disease (CKD) is due to various underlying congenital or acquired renal disorders resulting in variable impairment of renal function and variable response to GH treatment., Objective: It was the aim to develop a mathematical model that allows the prediction of the individual growth response and to identify nonresponders., Design: Data from 208 prepubertal children on conservative or dialysis treatment in a large pharmaco-epidemiological survey, the KIGS (Pfizer International Growth Database), were used for the model and data from 67 similar CKD patients registered at the Dutch Growth Research Foundation for validation., Results: Annualized height velocity (centimeters per year) during the first year of GH treatment was best predicted by age at start, weight sd score, underlying renal disorder (hereditary kidney disorder), glomerular filtration rate (at baseline), and GH dosage. Using these parameters, the final model explained 37% of the overall variability of growth response. Standard error of the estimates was 1.6 cm. Age was the most important predictor of growth response (20.3% of variability) followed by weight sd score at start, and 27.2% of the variability of the second-year response could be predicted by the first-year response and glomerular filtration rate. Nonresponders of the validation group could be correctly identified., Conclusion: Based on simple clinical variables, a robust prediction model was developed that provides realistic expectations of individual growth response to GH in short children with CKD. The model will help in identifying nonresponders and to tailor treatment strategies.

Objective. Retrospective single-centre analysis of growth characteristics in 182 healthy short children born small for gestational age (SGA) or appropriate for gestational age (idiopathic short stature, ISS). Methods. Birth size references from the USA and Sweden were compared, and for the classification as SGA or ISS the Swedish reference was chosen. Height, target height (TH), bone age (BA), predicted adult height (PAH), IGF-I and IGFBP-3 values were compared between SGA and ISS. Results. In the combined group, birth weight and length showed a symmetric Gaussian distribution. The American reference overestimates the percentage of short birth length and underestimates that of low birth weight. In childhood, SGA children were shorter than ISS (-3.1 versus -2.6 SDS, P < .001), also in comparison to TH (-2.6 versus -1.9 SDS, P < .001). TH, height SDS change over time, BA delay, and PAH were similar. IGF-I and IGFBP-3 were lower in ISS (P = .03 and .09). Conclusions. SGA children represent the left tail of the Gaussian distribution of birth size in short children. The distinction between SGA and ISS depends on birth size reference. Childhood height of SGA is lower than of ISS, but the other auxological features are similar.

Context: Adult height prediction is a common procedure in pediatric endocrinology, but it is associated with a considerable variability and bias from the bone age rating., Objective: A new method for adult height prediction is presented, based on automated bone age determination., Method: The method predicts the fraction of height left to grow from age and BoneXpert bone age. This is refined by drawing the prediction toward the population mean, or alternatively toward the height predicted from the parents' heights. Boys' body mass index and girls' height at menarche can be included optionally as predictors., Participants: A total of 231 normal children from the First Zurich Longitudinal Study (1ZLS) were followed from age 5 until cessation of growth with annual x-rays of the left hand. A total of 198 normal children from the Third Zurich Longitudinal Study were used for validation., Results: The root mean square error of adult height prediction (Tanner-Whitehouse 3 method in parentheses considered as standard for accuracy) on the 1ZLS was 3.3 cm (3.5 cm) for boys aged 10-15 yr and 2.7 cm (3.1 cm; P < 0.005 for difference to Tanner-Whitehouse 3) for girls aged 8-13 yr. High body mass index before puberty negatively affected adult height of boys, independent of bone age., Conclusions: With the new method, adult height prediction has become objective because the dependence on manual bone age rating is eliminated. The method is well-suited to analyze large studies and provide a consistent body of evidence regarding the relation between maturation, body mass, and growth across populations, conditions, and ethnicities.

Background: Formula milk-fed infants show faster rates of growth and weight gain than do breastfed infants, and they have higher concentrations of insulin-like growth factor I (IGF-I)., Objective: Our objective was to determine the influence of IGF-I concentrations on gains in weight, length, body mass index (BMI), and adiposity in the first year of life., Design: IGF-I concentrations were measured in 953 capillary blood samples from 675 unselected infants at ages 3 and 12 mo. These infants were born between 2002 and 2008 in one center and were participating in a prospective longitudinal birth cohort. Weight, length, and 4 skinfold thicknesses as an indicator of adiposity were measured at ages 0, 3, and 12 mo. Analyses were adjusted for age and sex., Results: Infants who were formula milk-fed had higher IGF-I concentrations at 3 mo, and they showed greater gains in weight, length, BMI, and adiposity between age 3 and 12 mo. IGF-I concentrations at 3 mo were unrelated to subsequent overall weight gain (P = 0.5). However, higher IGF-I concentrations at age 3 mo predicted greater subsequent gains in body length (P < 0.001 and P = 0.007 in formula milk-fed and breastfed infants, respectively) and slower gains in BMI (P < 0.001 and P = 0.004, respectively) and adiposity (P = 0.03 and P = 0.003, respectively)., Conclusions: Our findings support a key role for IGF-I in the partitioning of overall infant weight gain into statural growth compared with adiposity. In formula milk-fed infants, higher IGF-I concentrations may lead to faster gains in length; however, other mechanisms likely explain their faster gains in weight, BMI, and adiposity.

Context and Objective: The efficacy of oral dehydroepiandrosterone (DHEA) in the treatment of atrichia pubis and psychological distress in young females with central adrenal insufficiency is unknown. Our study aimed to evaluate this therapy., Design and Patients: A total of 23 young females (mean age 18 yr, range 13-25) was enrolled in a double-blind randomized placebo-controlled trial. Inclusion criteria were ACTH deficiency plus two or more additional pituitary deficiencies, serum DHEA less than 400 ng/ml, and pubertal stage more than B2. Exclusion criteria were cerebral radiation with more than 30 Gy, tumor remission less than 1 yr, amaurosis, hypothalamic obesity, psychiatric disorders, and unstable hormone medication., Intervention: Patients were randomized to placebo (n = 12) or 25 mg HPLC-purified DHEA/d (n = 11) orally for 12 months after stratification into a nontumor (n = 7) and a tumor group (n = 16)., Main Outcome Measures: Clinical scoring of pubic hair stage was performed at 0, 6, and 12 months (primary endpoint), and psychometrical evaluation (Symptom Check-List-90-R and the Centre for Epidemiological Studies-Depression Scale) at 0 and 12 months (secondary endpoint). Androgen levels and safety parameters were measured at 0, 6, and 12 months; 24-h androgen urinary excretion rates were calculated at 0 and 12 months., Results: In the placebo group, four patients dropped out because of recurrence of craniopharyngioma, manifestation of type 1 diabetes, and change of residence (n = 2); in the DHEA group, one patient dropped out because of recurrent anxiety attacks. DHEA substitution resulted in normalization of DHEA sulfate and androstanediol glucuronide morning serum levels 2 h after drug intake (P < 0.006), and of its 24 h urinary metabolite levels (P < 0.0001), placebo had no effect. Morning serum levels of androstenedione increased in the DHEA group (P < 0.02) but did not normalize. The DHEA group exhibited significant progress in pubic hair growth from Tanner stage I-III to II-V (mean: +1.5 stages), whereas the placebo group did not (relative risk 0.138; 95% confidence interval 0.021-0.914; P = 0.0046). Importantly, eight of the 10 Symptom Check-List-90-R scores, including those for depression, anxiety, and interpersonal sensitivity, and the global severity index improved in the DHEA group in comparison to the placebo group (P < 0.048). DHEA was well tolerated., Conclusions: In adolescent girls with central adrenal insufficiency, daily replacement with 25 mg DHEA orally is beneficial: atrichia pubis vanishes, and psychological well-being improves significantly.

Background: Short small for gestational age (SGA) children can be affected by a lack of muscle mass rather than fat mass. They also face a high risk of the metabolic syndrome developing after childhood. It is not known whether low muscle mass influences muscle function., Aim: Our aim was to investigate muscle-fat distribution and muscle function before and during GH treatment in short SGA children., Patients: A total of 34 prepubertal short SGA children (11 females, seven with Silver-Russell syndrome) were included in the study. Mean values were: age at GH start 7.3 yr; height sd score (SDS) -3.3; and birth weight SDS -2.7., Methods: Investigations over 24 months on GH treatment (57 microg/kg.d) were performed. Body composition, including fat area and muscle area (MA), was assessed through peripheral quantitative computed tomography (XCT 2000; Stratec, Inc., Pforzheim, Germany). Maximal isometric grip force was performed with a Jamar dynamometer (Preston, Jackson, MI). Comparison with height-dependent reference values (SDS(Height)) was calculated., Results: MA SDS(Height) at GH start was -1.8 and increased to -0.8 (P < 0.001) and -0.8, and fat area SDS(Height) decreased from -0.6 to -2.0 (P < 0.001) and -1.5 after 12 and 24 months on GH. Maximal isometric grip force SDS(Height) increased from -0.9 to 0.3 (P < 0.001) and 0.5. MA at start correlated negatively with height velocity (R = -0.54; P < 0.001) and MA SDS at start and Delta-height SDS during the first year of GH treatment (R = -0.40; P < 0.001)., Conclusions: Short stature in SGA children is associated with low muscle mass and function. Supraphysiological GH doses led to a concomitant increment in height, muscle mass, and function, whereas fat mass decreased. Furthermore, body composition at GH start gives insight into GH responsiveness and the individual risk of metabolic syndrome.

Imprinting defects have meanwhile been described in nearly all human imprinting disorders among them Silver-Russell syndrome (SRS). In this disorder, 11p15 epimutations and maternal Uniparental Disomy of chromosome 7 (UPD7) are detectable in approximately 50% of patients. To find out whether isolated imprinting defects on chromosome 7 play a role in the aetiology of SRS we screened a cohort of 54 SRS patients without 11p15 epimutations. Methylation-specific PCR was carried out for the PEG1/MEST locus in 7q31. This test detects all known segmental and complete UPD7 cases. The exclusion of isolated imprinting defects in our study population shows that this type of epimutation at the PEG1/MEST locus in 7q31 does not play a relevant role in SRS. However, the role of imprinting disturbances in other genes cannot be excluded.

Background: IGF-I immunoassays are primarily used to estimate IGF-I bioactivity. Recently an IGF-I-specific kinase receptor activation assay (KIRA) has been developed as an alternative method. However, no normative values have been established for the IGF-I KIRA., Objective: The objective of the study was to establish normative values for the IGF-I KIRA in healthy adults., Design: This was a cross-sectional study in healthy nonfasting blood donors., Study Participants: Participants included 426 healthy individuals (310 males, 116 females; age range 18-79 yr)., Main Outcome Measures: IGF-I bioactivity determined by the KIRA was measured. Results were compared with total IGF-I, measured by five different IGF-I immunoassays., Results: Mean (+/- sd) IGF-I bioactivity was 423 (+/- 131) pmol/liter and decreased with age (beta = -3.4 pmol/liter.yr, P < 0.001). In subjects younger than 55 yr, mean IGF-I bioactivity was significantly higher in women than men. Above this age this relationship was inverse, suggesting a drop in IGF-I bioactivity after menopause. This drop was not reflected in total IGF-I levels. IGF-I bioactivity was significantly related to total IGF-I (r(s) varied between 0.46 and 0.52; P < 0.001)., Conclusions: We established age-specific normative values for the IGF-I KIRA. We observed a significant drop in IGF-I bioactivity in women between 50 and 60 yr, which was not perceived by IGF-I immunoassays. The IGF-I KIRA, when compared with IGF-I immunoassays, theoretically has the advantage that it measures net effects of IGF-binding proteins on IGF-I receptor activation. However, it has to be proven whether information obtained by the IGF-I KIRA is clinically more relevant than measurements obtained by IGF-I immunoassays.

Context: Around 50% of children with Silver-Russell syndrome (SRS) carry a hypomethylation of the imprinting control region 1 at the IGF2/H19 locus on 11p15, the functional significance of which is unknown., Objective: We aimed to compare the genotype in SRS with the endocrine phenotype., Design: The retrospective study included all SRS children who were treated during the last 18 yr at our hospital and for comparison a cohort of GH treated nonsyndromic short children born small for gestational age (SGA)., Patients: The 61 patients with SRS included were defined by the presence of intrauterine growth retardation, lack of catch-up growth, and at least two of the criteria: typical face, relative macrocephaly, and skeletal asymmetry. Routine karyotype and GH secretion was normal in all children studied. A subgroup of 53 patients was treated with GH., Materials and Methods: Genomic DNA was available from 44 children. Multiplex ligation probe-dependent amplification analysis was performed to detect hypomethylation at the imprinting control region 1 on 11p15. Uniparental disomy of chromosome 7 (UPD7) was analyzed by short tandem repeats typing. Serum levels of GH, IGF-I, and IGF-binding protein (IGFBP)-3 were measured by RIA., Results: Epimutations at 11p15 were found in 19 of 44, UPD7 in five of 44, and small structural aberrations of the short arm of chromosome 11 in two of 44 children. Of 44 cases, 18 were negative for any genetic defect known (41%). The most severe phenotype was found in children with 11p15-SRS. Children with UPD7-SRS had a significantly higher birth length (P < 0.004) but lost height sd score (SDS) postpartum, whereas children with 11p15-SRS showed no change in height SDS. IGF-I and IGFBP-3 serum levels were inadequately high in 11p15-SRS at -0.02 SDS (1.07, sd) and +1.38 SDS (1.01), compared with the low levels in UPD7-SRS and in the cohort of 58 nonsyndromic SGA children (P < 0.0009). During GH therapy, IGFBP-3 serum levels increased above normal values in 11p15-SRS (P < 10(-4)), whereas IGF-I increase was moderate. There was a trend toward more height gain in children with UPD7 than in those with 11p15 epimutation under GH therapy (+2.5 vs. +1.9 height SDS after 3 yr) (P = 0.08)., Conclusions: Children with SRS and an 11p15 epimutation have IGFBP-3 excess and show endocrine characteristics suggesting IGF-I insensitivity, whereas children with SRS and UPD7 were not different from nonsyndromic short children born SGA. This phenotype-genotype correlation implicates divergent endocrine mechanisms of growth failure in SRS.

Silver-Russell syndrome (SRS) describes a malformation syndrome with severe intrauterine and postnatal growth retardation. Currently, two major (epi)mutations have been described: while approximately 10% of patients carry a maternal uniparental disomy of chromosome 7 (UPD7), 35-60% show a hypomethylation at the H19 differentially methylated regions (DMRs) in 11p15. Until recently, a Southern-blot based test was routinely used to identify epimutation carriers. Nevertheless, this test was time consuming and hampered by the huge amount of genomic DNA needed. With the methylation-specific multiplex ligation-dependent probe amplification assay (MLPA) for SRS, a PCR-based test is now available, allowing the analysis also of small amounts of DNA. Probes in this assay hybridize to the H19 DMRs but do not cover the genomic target of the Southern-blot probe. We now screened 72 patients with SRS by MLPA. Hypomethylation of the H19 DMRs was confirmed in all patients analyzed by Southern blot. In addition, we identified six individuals with hypomethylation of the H19 DMR who had previously normal blot results. This discrepancy can be explained by the observed generally lower degree of demethylation in this group, possibly not detectable by the less sensitive Southern-blot method but also with a varying degree of methylation at different DMRs in the same individual. Apart from hypomethylation in the H19 DMR, we observed a slight demethylation for one of the IGF2 probes. The total detection rate of 11p15 hypomethylation is now increased to >38%. Considering maternal UPD7 and chromosomal aberrations, (epi)genetic alterations now account for more than 50% of SRS patients. In summary, MLPA represents an easy, low cost and reliable system in the molecular diagnostics of SRS.

Children born with very low birth weight (VLBW) are at risk of impaired growth. We aimed to study VLBW survivors (90.8%) born in 1998/1999 in the state of Baden-Württemberg (n = 2103) for whom growth data were available up to age six. Classification as appropriate for gestational age (AGA) or small for gestational age (SGA) depended on size at birth. Models to predict height SDS at 5 y were developed using data for 1 yr (Model 1) and 2 yrs (Model 2). The data of 1320 (63%) children were available: SGA: n = 730, AGA: n = 590. At 6 yrs, 8.3% AGA and 13.4% SGA children were short (<-2.0 SDS). The following factors explained Ht SDS at 5 (and 6) yrs (order of importance): (a) Model 1 (n = 1033; R2 = 0.52; error: 0.84 SDS): 1st yr Ht SDS, mid-parental height (MPH) SDS, 1 yr weight SDS, birth weight SDS; (b) Model 2 (n = 991; R2 = 0.72; error: 0.65 SDS): 1st yr Ht SDS; change (2nd yr) in Ht and weight SDS; MPH SDS; 1st yr weight SDS; birth weight SDS. Thus, some AGA and SGA children born VLBW remain short and preventive strategies need to be developed for those at risk.

Zinc (Zn(2+)) binding by human GH through amino acid residues His18, His21, and Glu174 has been described as a prerequisite for GH dimerization and storage in secretory granules. Our aim was to investigate in vitro whether disturbed Zn(2+) binding of mutant GH inhibits wild-type GH (wtGH) secretion and contributes to the pathogenetic mechanisms involved in dominantly transmitted isolated GH deficiency type II. Seven expression vectors harboring mutated human GH cDNAs were constructed in which nucleotide triplets encoding histidine or glutamine at positions 18, 21, and 174 were mutated to triplets encoding alanine: H18A, H21A, G174A, H18A-G174A, H21A-G174A, H18A-H21A, and H18A-H21A-G174A. These vectors were transiently cotransfected with a vector encoding wtGH or were singly transfected into rat pituitary GH(4)C(1) cells. Plasmids encoding beta -galactosidase were cotransfected. 48h after transfection, GH in media and cell extracts was measured using a GH-specific RIA, and results were normalized for transfection efficiency by means of beta -galactosidase activity. In comparison with the control transfection (wtGH/wtGH set at 100%), GH secretion remained unaffected when coexpressing wtGH and any of the GH mutants in which Zn(2+) binding was partially or completely prevented. When these mutants were singly expressed, the amount of GH in both media and cell extracts was decreased by about 50% when compared with cells expressing only wtGH. Our in vitro data do not support the hypothesis of disturbed Zn(2+) binding as a major pathogenetic mechanism in dominantly transmitted GH deficiency.