Automated bone age assessment in a German pediatric cohort: agreement between an artificial intelligence software and the manual Greulich and Pyle method.

OBJECTIVES: This study aimed to evaluate the performance of artificial intelligence (AI) software in bone age (BA) assessment, according to the Greulich and Pyle (G&P) method in a German pediatric cohort. MATERIALS AND METHODS: Hand radiographs of 306 pediatric patients aged 1-18 years (153 boys, 153 girls, 18 patients per year of life)-including a subgroup of patients in the age group for which the software is declared (243 patients)-were analyzed retrospectively. Two pediatric radiologists and one endocrinologist made independent blinded BA reads. Subsequently, AI software estimated BA from the same images. Both agreements, accuracy, and interchangeability between AI and expert readers were assessed. RESULTS: The mean difference between the average of three expert readers and AI software was 0.39 months with a mean absolute difference (MAD) of 6.8 months (1.73 months for the mean difference and 6.0 months for MAD in the intended use subgroup). Performance in boys was slightly worse than in girls (MAD 6.3 months vs. 5.6 months). Regression analyses showed constant bias (slope of 1.01 with a 95% CI 0.99-1.02). The estimated equivalence index for interchangeability was - 14.3 (95% CI -27.6 to - 1.1). CONCLUSION: In terms of BA assessment, the new AI software was interchangeable with expert readers using the G&P method. CLINICAL RELEVANCE STATEMENT: The use of AI software enables every physician to provide expert reader quality in bone age assessment. KEY POINTS: • A novel artificial intelligence-based software for bone age estimation has not yet been clinically validated. • Artificial intelligence showed a good agreement and high accuracy with expert radiologists performing bone age assessment. • Artificial intelligence showed to be interchangeable with expert readers.

Deeplasia: deep learning for bone age assessment validated on skeletal dysplasias.

BACKGROUND: Skeletal dysplasias collectively affect a large number of patients worldwide. Most of these disorders cause growth anomalies. Hence, evaluating skeletal maturity via the determination of bone age (BA) is a useful tool. Moreover, consecutive BA measurements are crucial for monitoring the growth of patients with such disorders, especially for timing hormonal treatment or orthopedic interventions. However, manual BA assessment is time-consuming and suffers from high intra- and inter-rater variability. This is further exacerbated by genetic disorders causing severe skeletal malformations. While numerous approaches to automate BA assessment have been proposed, few are validated for BA assessment on children with skeletal dysplasias. OBJECTIVE: We present Deeplasia, an open-source prior-free deep-learning approach designed for BA assessment specifically validated on patients with skeletal dysplasias. MATERIALS AND METHODS: We trained multiple convolutional neural network models under various conditions and selected three to build a precise model ensemble. We utilized the public BA dataset from the Radiological Society of North America (RSNA) consisting of training, validation, and test subsets containing 12,611, 1,425, and 200 hand and wrist radiographs, respectively. For testing the performance of our model ensemble on dysplastic hands, we retrospectively collected 568 radiographs from 189 patients with molecularly confirmed diagnoses of seven different genetic bone disorders including achondroplasia and hypochondroplasia. A subset of the dysplastic cohort (149 images) was used to estimate the test-retest precision of our model ensemble on longitudinal data. RESULTS: The mean absolute difference of Deeplasia for the RSNA test set (based on the average of six different reference ratings) and dysplastic set (based on the average of two different reference ratings) were 3.87 and 5.84 months, respectively. The test-retest precision of Deeplasia on longitudinal data (2.74 months) is estimated to be similar to a human expert. CONCLUSION: We demonstrated that Deeplasia is competent in assessing the age and monitoring the development of both normal and dysplastic bones.

Age- and weight group-specific weight gain patterns in children and adolescents during the 15 years before and during the COVID-19 pandemic.

BACKGROUND/OBJECTIVES: There is a concern that measures aiming to limit a further spread of COVID-19, e.g., school closures and social distancing, cause an aggravation of the childhood obesity epidemic. Therefore, we compared BMI trends during the 15 years before and during the COVID-19 pandemic. SUBJECTS/METHODS: To assess the change in weight dynamics during the first months of COVID-19, we compared the trends of 3-month change in BMI-SDS (ΔBMI-SDS) and the proportions of children showing a high positive (HPC) or high negative (HNC) weight change between 2005 and 2019 and the respective changes from 2019 (pre-pandemic) to 2020 (after the onset of anti-pandemic measures) in more than 150,000 children (9689 during the pandemic period). The period of 3 months corresponds approximately to the first lockdown period in Germany. RESULTS: During the COVID-19 pandemic, we found a substantial weight gain across all weight and age groups, reflected by an increase in the 3-month change in BMI-SDS (ß = 0.05, p < 0.001), an increase in the proportion of children showing HPC (OR = 1.4, p < 0.001), and a decrease in the proportion of children showing HNC (OR = 0.7, p < 0.001). Besides, we found the same trends since 2005 on a low but stable level with a yearly increase of ΔBMI-SDS by ß = 0.001 (p < 0.001), the odds of HPC increased by ORhigh_pos = 1.01 (p < 0.001), and the odds of HNC decreased by ORhigh_neg = 0.99 (p < 0.001). These rather small effects accumulated to ß = 0.02, ORhigh_pos = 1.14, and ORhigh_pos = 0.85 over the whole period 2005-2019. Alarmingly, both the long-term and the short-term effects were most pronounced in the obese subgroup. CONCLUSIONS: There are positive dynamics in different measures of weight change, indicating a positive trend in weight gain patterns, especially within the group of children with obesity. These dynamics are likely to be escalated by COVID-19-related measures. Thus, they may lead to a significant further aggravation of the childhood obesity pandemic.

Acceleration of BMI in Early Childhood and Risk of Sustained Obesity.

BACKGROUND: The dynamics of body-mass index (BMI) in children from birth to adolescence are unclear, and whether susceptibility for the development of sustained obesity occurs at a specific age in children is important to determine. METHODS: To assess the age at onset of obesity, we performed prospective and retrospective analyses of the course of BMI over time in a population-based sample of 51,505 children for whom sequential anthropometric data were available during childhood (0 to 14 years of age) and adolescence (15 to 18 years of age). In addition, we assessed the dynamics of annual BMI increments, defined as the change in BMI standard-deviation score per year, during childhood in 34,196 children. RESULTS: In retrospective analyses, we found that most of the adolescents with normal weight had always had a normal weight throughout childhood. Approximately half (53%) of the obese adolescents had been overweight or obese from 5 years of age onward, and the BMI standard-deviation score further increased with age. In prospective analyses, we found that almost 90% of the children who were obese at 3 years of age were overweight or obese in adolescence. Among the adolescents who were obese, the greatest acceleration in annual BMI increments had occurred between 2 and 6 years of age, with a further rise in BMI percentile thereafter. High acceleration in annual BMI increments during the preschool years (but not during the school years) was associated with a risk of overweight or obesity in adolescence that was 1.4 times as high as the risk among children who had had stable BMI. The rate of overweight or obesity in adolescence was higher among children who had been large for gestational age at birth (43.7%) than among those who had been at an appropriate weight for gestational age (28.4%) or small for gestational age (27.2%), which corresponded to a risk of adolescent obesity that was 1.55 times as high among those who had been large for gestational age as among the other groups. CONCLUSIONS: Among obese adolescents, the most rapid weight gain had occurred between 2 and 6 years of age; most children who were obese at that age were obese in adolescence. (Funded by the German Research Council for the Clinical Research Center "Obesity Mechanisms" and others; ClinicalTrials.gov number, NCT03072537 .).

Childhood Dystonia-Parkinsonism Following Infantile Spasms-Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration.

INTRODUCTION: Beta-propeller protein-associated neurodegeneration (BPAN) is a very rare, X-linked dominant (XLD) inherited member of the neurodegeneration with brain iron accumulation (NBIA) disease family. CASE REPORT: We present a female case of BPAN with infantile spasms in the first year, Rett-like symptomatology, focal epilepsy, and loss of motor skills in childhood. Menarche occurred at the age of 9, after precocious pubarche and puberty.Dystonia-parkinsonism as extrapyramidal sign at the age of 10 years resulted in radiological and genetic work-up. RESULTS: Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) measured 66/120 points in body part-related dystonia symptoms. Cerebrospinal fluid examination showed dopamine depletion.T2 and B0 sequences of the diffusion-weighted magnetic resonance imaging showed susceptibility artifacts with NBIA-typical hypointense globus pallidus (GP) and substantia nigra (SN). Next-generation sequencing revealed a BPAN-causing pathogenic variant in WDR45 (WD repeat-containing protein 45) gene (c.830 + 1G > A, XLD, heterozygous, de novo). Skewed X-inactivation was measured (2:98). CONCLUSIONS: Autophagy-related X-linked BPAN disease might still be underdiagnosed in female cases of infantile spasms.Skewed X-inactivation will have mainly influenced the uncommon, very early childhood neurodegenerative symptomatology in the present BPAN case. Oral levodopa substitution led to improvement in sleep disorder, hypersalivation, and swallowing.Reduced white matter and hypointense signals in SN and GP on susceptibility sequences in magnetic resonance imaging are characteristic radiological findings of advanced disease in NBIA. No BPAN-typical halo sign in T1-weighted scan at midbrain level was seen at the age of 11 years. NBIA panel is recommended for early diagnosis.

GH and IGF-1 Replacement in Children.

In this chapter, we want to give an overview on what we have learned from more than 30 years ago on the use of recombinant human growth hormone (rhGH) and later recombinant human IGF-1 which was introduced for the treatment of short children and what are the safety issues concerned with this treatment. However, rhGH is used not solely in conditions where short stature is the consequence of GH deficiency but also in various disorders without a proven GH deficiency. In clinical studies, growth responses to various forms of rhGH therapy were analyzed, adding to our concept about the physiology of growth. Most patients under rhGH treatment show a considerable short-term effect; however, the long-term gain of height in a child obtained by a year-long treatment until final height remains controversial in some of the growth disorders that have been treated with rhGH or IGF-1. Today the first studies on the long-term safety of rhGH treatment have been published and raising some questions whether this treatment is similarly safe for all the patient groups treated with rhGH. Although there is a long-standing safety record for these hormone replacement therapies, in the face of the considerable costs involved, the discussion about the risk to benefit ratio is continuing. Newer developments of rhGH treatment include long-term preparations, which have only to be injected once a week. Although some of these drugs already have proven their non-inferiority to conventional rhGH treatment, we have to await further results to see whether they show improvements in treatment adherence of the patients and prove their long-term safety.

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency.

PURPOSE: Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases. METHODS: To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed. RESULTS: We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype. CONCLUSION: These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.

Diagnosis and Clinical Course of Three Adolescents with Amiodarone-Induced Hyperthyroidism.

Amiodarone-induced hyperthyroidism is a known side effect of amiodarone treatment. In the pediatric population, long-term amiodarone treatment is rarely indicated because of its severe side effects including thyroid function impairment. Treatment is therefore restricted to therapy-resistant arrhythmias. In the literature, scarce data are available on the management and therapy of amiodarone-induced thyroid dysfunction at a young age. We present three adolescent patients developing amiodarone-induced thyrotoxicosis in the months after amiodarone therapy. A latency period for thyroid dysfunction has been described in adulthood but was not previously reported in pediatric patients. The gap between amiodarone treatment and the development of symptoms and the diagnosis of hyperthyroidism was between 3 and 10 months. In two patients, hyperthyroidism was transient and resolved without treatment. These two patients, one boy and on girl, were almost asymptomatic. In contrast, in one male patient overt and severe hyperthyroidism developed. We began treatment with thiamazole without benefit. Control of hyperthyroidism was achieved under prednisone treatment, which was continued for 9 months. Clinical evaluation proved an amiodarone-induced destructive thyroiditis in this patient. Amiodarone-induced thyroid dysfunction is frequent also in pediatric patients with long-term amiodarone treatment. Patients and clinicians should be aware of the impact of amiodarone on thyroid function during and also in the months and maybe years after treatment. Careful follow-up is needed, as symptoms might be associated with the underlying cardiac disease in these patients. Amiodarone-induced thyrotoxicosis often resolves without treatment but can be challenging in some cases.

Combined pituitary hormone deficiency due to gross deletions in the POU1F1 (PIT-1) and PROP1 genes.

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

Further stabilization and even decrease in the prevalence rates of overweight and obesity in German children and adolescents from 2005 to 2015: a cross-sectional and trend analysis.

OBJECTIVE: Recently several industrialized countries reported a stabilization or even a decrease in childhood overweight and obesity prevalence rates. In Germany, this trend started in 2004. The present study therefore aimed to evaluate whether this trend has continued or even leads in a clear direction. Design/Setting/Subjects BMI (>90th percentile (overweight), >97th percentile (obesity)) from the CrescNet database was analysed in 326 834 children and adolescents according to three age groups (4-7·99, 8-11·99 and 12-16 years), gender and between time points (2005-2015). RESULTS: Trend analysis from 2005 to 2010 demonstrated that the prevalence of overweight and obesity decreased significantly in boys and girls in the entire group (4-16 years) and in 4-7·99-year-olds. From 2010 to 2015 there was a significant decrease in boys for overweight and obesity in the entire group and for overweight among 8-11·99-year-olds. Within the cross-sectional analysis, prevalence rates for overweight decreased significantly for both genders in the age groups of 4-7·99 and 8-11·99 years (2005 v. 2015). For obesity, prevalence rates showed a significant decrease for boys (2005 v. 2015) and girls (2005 v. 2010) in 4-7·99-year-olds. CONCLUSIONS: We observed a further stabilization of overweight and obesity prevalence rates for all age groups and even a decrease in the rates for the younger ages (4-7·99 years, 8-11·99 years). As other industrialized countries have also reported similar trends, it seems that the epidemic of childhood overweight and obesity is reaching a turning point in the industrial part of the world.

Clinical and biochemical consequences of an intragenic growth hormone receptor (GHR) deletion in a large Chinese pedigree.

OBJECTIVE: Growth hormone insensitivity (GHI) may be caused by failure of GH receptor function. Some patients bearing specific GHR mutations differ from classical GHI individuals by extremely elevated GH-binding protein (GHBP) serum concentrations. We investigated clinical, genetic and biochemical characteristics of a severely growth-retarded Chinese boy with classical Laron syndrome manifestations. PATIENTS AND MEASUREMENTS: DNA and mRNA from blood cells of the patient and 11 family members were investigated for GHR mutations. Basal GH, GHBP, IGF-1 and IGFBP-3 concentrations were determined in serum samples. The impact of the aberrant mRNA on GHR protein expression and secretion was analysed in vitro by transfection studies in HEK293 cells. RESULTS: The proband and seven relatives had excessively elevated GHBP serum concentration. Basal GH in these individuals was significantly greater compared with family members with normal GHBP. The GHBP increase originated from a novel GHR intragenic deletion comprising parts of exon and intron 8 that caused exon 8 skipping from the GHR mRNA transcript. Transfection studies revealed that the predicted loss of plasma membrane anchorage results in direct secretion of the mutant GHR. CONCLUSIONS: The partial GHR deletion causes excessively elevated GHBP serum concentrations regardless of the state of zygosity of the mutation. The increase in GHBP is associated with significantly elevated basal GH levels. Clinically, only homozygous carriers exhibit classical GHI manifestations. The truncated GHR protein resulting from exon 8 skipping is directly secreted out of the cell.

High birth weights but not excessive weight gain prior to manifestation are related to earlier onset of diabetes in childhood: 'accelerator hypothesis' revisited.

AIMS/HYPOTHESIS: Aim of this study was to test Wilkin's 'accelerator hypothesis': whether excessive weight gain accelerates the onset of type 1 diabetes. SUBJECTS AND METHODS: Anthropometric birth data of 1117 children who developed diabetes between 1988 and April 2013 were compared with those of a sex, age, and gestational age matched, contemporary regional control group (n = 54 344). Cases were divided into three manifestation groups (G1:0-4.9 yr, G2:5-9.9 yr, and G3: 10-20 yr). Furthermore, growth data of 540 children with diabetes were compared with controls (n = 134 249) in pre-, peri-, and post-onset intervals (interval: 1-6). Also, correlation of age at onset and body mass index (BMI) standard deviation score (SDS) at this point of time were examined. RESULTS: Cases had significantly higher SDSs for birth weight when compared with controls (boys: p = 0.007, girls: p = 0.002). Children with early manifestation had the highest mean of birth weight SDS (G1>G2>G3), (p = 0.22, adjusted r(2) = 0.001). BMI SDS trend curves of cases are slightly higher compared with those of the healthy controls. This was only significant in years after diagnosis (interval 6, p < 0.000). Cases did not show excessive weight gain in any of the examined intervals before the onset of diagnosis (interval 1-3). One year after diagnosis, we found an inverse correlation between age at diagnosis and BMI SDS at diabetes manifestation. The youngest children at diagnosis (G1) had the lowest BMI SDS at manifestation and vice versa (G1

Potential for Optimization of Growth Hormone Treatment in Children with Growth Hormone Deficiency, Small for Gestational Age, and Turner Syndrome in Germany: Data from the PATRO® Children Study.

INTRODUCTION: Growth hormone (GH) treatment in children with growth hormone deficiency (GHD), short children born small for gestational age (SGA), and Turner syndrome (TS) is well established. However, a variety of parameters are still under discussion to achieve optimal growth results and efficiency of GH use in real-world treatment. METHODS: German GH-treatment naïve patients of the PATRO Children database were grouped according to their start of treatment into groups of 3 years from 2007 to 2018. Time trends in age, gender, GH dose, height standard deviation score (SDS), first-year growth response, and Index of Responsiveness (IoR) were investigated in children with GHD, short children born SGA, and TS starting GH treatment in the German patient population of the PATRO Children database from 2007 to 2018 to determine specific parameters for GH treatment optimization. RESULTS: All patient groups started GH treatment at a relatively high chronological age (2007-2009: GHD 8.33 ± 3.19, SGA 7.32 ± 2.52, TS 8.65 ± 4.39) with a slight but not significant trend towards younger therapy start up to 2016-2018 (GHD 8.04 ± 3.36, SGA 6.67 ± 2.65, TS 7.85 ± 3.38). In the GHD and SGA groups, female patients were underrepresented compared to male patients (GHD 32.3%, SGA 43.6%) with no significant change over the 4 time periods. Patients with GHD started GH treatment at a low dose (0.026 mg/kg/day). In SGA and TS patients, GH therapy was started below the registered dose recommendation (30.0 µg/kg/day and 33.7 µg/kg/day, respectively). In the first year of treatment, the mean GH dose was increased moderately (GHD: 30.7, SGA: 35.7, TS: 40.8 µg/kg/day). There was no significant change of GH dosing over time from 2007 to 2018. The IoR was comparable between time-groups for all 3 diagnoses. DISCUSSION: This study shows potential for improvement of GH treatment results in GHD, SGA, and TS patients in terms of early dose adjustment and younger age at the start of treatment. This is in accordance with important parameters used in prediction models.

Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency.

BACKGROUND: The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. METHODS: We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. RESULTS: Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. CONCLUSIONS: A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.

Blood pressure tracking in children and adolescents.

BACKGROUND: High blood pressure is a major risk factor for cardiovascular disease. Blood pressure tracking could help to identify individuals with potential hypertension. Therefore, we have asked whether or not tracking was of predictive value for the development of hypertension in early life. METHODS: Blood pressure was routinely measured in 13,261 children and adolescents in outpatient clinics as well as during hospitalization. In one analysis, 568 individuals with elevated and normotensive blood pressure values were evaluated after 2, 4, and 6 years of follow-up. In a second analysis, 2,157 individuals with normotensive blood pressure were examined in a paired t test. RESULTS: The follow-up analysis showed a significant tracking effect. However, the Pearson correlation coefficients of the systolic and diastolic blood pressure standard deviation scores (SDS) decreased over time. Upon the follow-up after 6 years, 35.6 % of the children and adolescents with elevated blood pressure values remained in the elevated range group. Of the children within the normotensive blood pressure range, 80.4 % remained normotensive after 6 years. Children with normotensive blood pressure showed a stronger tracking than those who had had one hypertensive blood pressure reading. Children with higher body mass index (BMI) at follow-up changed blood pressure SDS track from initially normal to higher blood pressure values. CONCLUSIONS: Blood pressure tracking in children and adolescents is moderate. We conclude that the predictive power of a single hypertensive blood pressure measurement during a single visit is rather small, and thus repetitive measurements across several consecutive visits are necessary.

Influence of seasonal variation on blood pressure measurements in children, adolescents and young adults.

BACKGROUND: Seasonal fluctuations in outdoor temperature have been shown to affect blood pressure in adults. The aim of our study was to determine whether blood pressure measurements in children and adolescents in Central Europe undergo seasonal variation or are influenced by outdoor temperature. METHODS: The blood pressure of 6,714 subjects (3,497 boys, 3,237 girls) aged 3 to 21 (median age 10.6) years was routinely measured. The study cohort comprised both healthy and sick children and adolescents visiting outpatient clinics and during hospitalisation. RESULTS: Cross-sectional analysis showed a significant seasonal variation in blood pressure measurements. The mean increase of systolic/diastolic blood pressure was 4.45/2.42 mmHg during the winter. A significant correlation between average outdoor temperature and systolic blood pressure was found (ρ = -0.074 p < 0.001). However, the effect was only detectable at an average temperature below 0 °C/32 °F and above 10 °C/50 °F. For each 1 °C increase in average outdoor temperature, the systolic blood pressure fell by 0.12 mmHg. CONCLUSIONS: Blood pressure measurements in children and adolescents, even in a temperate climate, are influenced by temperature and subject to seasonal variation. Considering seasonal variations in blood pressure could be of clinical interest.

Early Growth Hormone Initiation Leads to Favorable Long-Term Growth Outcomes in Children Born Small for Gestational Age.

CONTEXT: Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed. OBJECTIVE: We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA. METHODS: Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated. RESULTS: The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported. CONCLUSION: Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

BMI and Contraceptives Affect New Age-, Sex-, and Puberty-adjusted IGF-I and IGFBP-3 Reference Ranges Across Life Span.

CONTEXT: Various clinical factors influencing serum levels of insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are not entirely consistently described. OBJECTIVE: We asked whether body mass index (BMI), contraceptive drugs (CDs), and hormone replacement therapy (HRT) have potential effects on data for interpreting new age-, sex-, and puberty-adjusted reference ranges for IGF-I and IGFBP-3 serum levels. DESIGN AND SETTING: Subjects were mainly participants from 2 population-based cohort studies: the LIFE Child study of children and adolescents and the LIFE Adult study. PARTICIPANTS: We investigated 9400 serum samples from more than 7000 healthy and 1278 obese subjects between 3 months and 81 years old. MAIN OUTCOME MEASURES: Associations between IGF-I or IGFBP-3, measured with a new electrochemiluminescence immunoassay, and the predictors BMI and CDs were estimated using hierarchical linear modeling. RESULTS: During infancy, obese children had up to 1 SD score (SDS) higher mean predicted IGF-I values, converging with levels of normal-weight subjects up to 13 years old. Between 20 and 40 years of age, obesity was related to up to -0.5 lower IGF-I SDS values than the predicted values. Obesity had less impact on IGFBP-3. Estrogen- and progestin-based CDs, but not HRT, decreased IGF-I and increased IGFBP-3 (P < 0.01) in adolescents (ß IGF-I = -0.45, ß IGFBP-3  = 0.94) and adults (ß IGF-I = -0.43, ß IGFBP-3  = 1.12). Conversely, progestin-based CDs were significantly positive associated with IGF-I (ß IGF-I  =0.82). CONCLUSIONS: BMI and CDs must be considered when assessing and interpreting the clinical relevance of IGF-I and IGFBP-3 measurements.

Growth Patterns of Children With Short Stature in Adulthood According to Auxological Status and Maturity at Birth.

CONTEXT: Prematurity carries a risk for impaired postnatal growth and long-term growth restriction. Especially children born SGA seem vulnerable for poor growth, as a persistent short stature can be observed in app 10-15% of these children. OBJECTIVE: In this study we aimed to recognize differences in growth patterns of children according to sex, maturity, and auxological status at birth facilitating earlier identification of small-for-gestational-age (SGA) children with adult short stature. METHODS: The growth data of 44 791 infants born between January 1, 1980, and December 30, 2012, among 2 pediatric cohorts with follow-up through December 31, 2020, were analyzed. A total of 5698 children with birth data had measurements at near final height (nfh) and at least 2 further points. RESULTS: Preterm children (gestational age < 37 weeks) had a significantly lower mean nfh SDS than term children (preterm, -0.61; term, -0.18) and a higher likelihood of nfh < third percentile (preterm, 20.5%; term, 12.2%). SGA born children also had a lower mean nfh SD score (SDS) than children born appropriate for gestational age (AGA) (SGA, -1.06; AGA, -0.15) and a higher likelihood of nfh < third percentile (SGA, 28.2%; AGA 10.1%). Of 1204 SGA children, 672 (56%) showed successful catch-up growth (CUG) to nfh greater than or equal to the 10th percentile (SGA-CU), and 532 children (44%) did not (SGA-S). The difference in their mean nfh SDS (SGA-CU, -0.12; SGA-S -2.26) can only partly be explained by the differences in mean mid-parental height SDS (SGA-CU, -0.3; SGA-S, -1.19). During the first year, SGA-CU showed higher CUG (SGA-CU, +1.2 SDS; SGA-S, +0.45 SDS), which helps to discriminate between groups earlier. CONCLUSION: Final growth outcome was influenced by prematurity and auxological status at birth, but not by sex. Height/length SDS increments during year 1 are instrumental to discern SGA children with later normal or short stature. While observing CUG until year 2 and 3 can add specificity, discrimination thereafter becomes difficult.

The Influence of Body Mass Index on the Growth Hormone Peak Response regarding Growth Hormone Stimulation Tests in Children.

INTRODUCTION: Several studies have analyzed the association between the maximal growth hormone serum level obtained during a growth hormone stimulation test (GHMax) and the body mass index-standard deviation score (BMI-SDS). However, as sample sizes were quite small, our study aimed to analyze the association between GHMax and BMI-SDS within a large cohort of 991 children. Further, we investigated other influencing factors, like test type, age, sex, puberty, and preterm birth. METHODS: Children with short stature (height <10th percentile) received growth hormone stimulation tests with arginine or glucagon at the Department of Paediatric Endocrinology of the University of Leipzig Medical Center. The study population included a total of 1,438 tests (633 tests on girls, 805 tests on boys), with the majority consisting of prepubertal children (tests = 1,138). The mean age at testing was 7.74 years. Analyses were carried out on the entire cohort as well as stratified by test types. We performed univariate and multivariate analyses using linear mixed-effect models to assess the effects on GHMax. RESULTS: GHMax and BMI-SDS were significantly negatively associated with an effect size of ß = -1.10 (p < 0.001), independent from the test type. The GHMax values were significantly (p < 0.001) higher for glucagon (mean value: 9.65 ng/mL) than those for arginine tests (mean value: 8.50 ng/mL). Age, sex, premature birth, and puberty were not significantly related to GHMax values. CONCLUSION: We confirmed the negative association between GHMax and weight status of short children found in previous studies. Therefore, considering BMI-SDS may be helpful in the assessment of growth hormone stimulation tests in short-statured children, but it should not be the determining factor for a treatment decision.