Inflammatory markers in prepubertal children and their associations with abdominal fat.

OBJECTIVE: To evaluate the association between inflammatory markers and abdominal fat assessed by ultrasound in prepubertal children with and without excess weight. METHODS: A cross-sectional study involving 241 prepubertal children, 156 with obesity, 37 with overweight, and 48 with normal weight, aged five to ten years, who were followed at a research unit on Childhood Obesity from a teaching hospital belonging to a public health system. The concentration of interleukin-6, tumor necrosis factor-α and C-reactive protein were assessed and regression analyses, considering outcome variables such as abdominal wall and intra-abdominal fat thickness measured by ultrasound, were performed. RESULTS: The findings highlighted an association between abdominal fat and inflammatory markers, even in children at this young age group. Subcutaneous fat showed a stronger association with inflammatory biomarkers compared to intra-abdominal fat when performing logistic regression, with a positive association between tumor necrosis factor-α and abdominal wall thickness equal to or greater than the 75th percentile in adjusted logistic regression (OR: 18.12; CI 95 %: 1.57: 209.55). CONCLUSIONS: Abdominal wall fat, in contrast to what is often observed in adults, appears to have a greater impact on chronic inflammation related to excessive weight in very young children.

Daily physical activity, cardiorespiratory fitness, nutritional status, endothelial function, and autonomic modulation in school-age adolescents: A principal component analysis.

PURPOSE: This study evaluated the association between cardiorespiratory fitness, abdominal obesity, blood pressure, endothelial function, and autonomic modulation in school-age adolescents exhibiting different levels of habitual physical activity and nutritional status, through a multivariate statistical approach. METHODS: 101 adolescents aged 15-18 years (54 females) underwent assessments of daily physical activity, body mass index, cardiorespiratory fitness, reactive hyperemia, and heart rate variability. Based on BMI adjusted for age and sex (z-BMI), 21 adolescents were classified as 'overweight' (9 girls), and 9 as 'obese' (4 girls). The common variation between those variables was assessed through Principal Component Analysis (PCA). RESULTS: Main axis of common variation of outcomes analyzed defined four principal components (PCs) accounting for 69.7% of overall variance, related to 'abdominal obesity and blood pressure' (PC1; eigenvalue=2.76), 'cardiorespiratory fitness, endothelial function, and autonomic modulation' (PC2, eigenvalue=1.98), 'cardiorespiratory fitness' (PC3, eigenvalue=1.21), and 'sedentary behavior' (PC4, eigenvalue=1.02). Girls reported longer screen time and sedentary behavior than boys. Notwithstanding, in both sexes poorer cardiorespiratory fitness corresponded to lower reactive hyperemia and vagal modulation, irrespective of the nutritional status. Overall, adolescents classified as 'obese' and 'sedentary' exhibited poorer CRF concomitantly to autonomic and endothelial dysfunctions. CONCLUSION: In school-age adolescents, endothelial and autonomic dysfunctions related to poor cardiorespiratory fitness, irrespective of the nutritional status and physical activity level. However, endothelial and autonomic dysfunctions were more prevalent among adolescents combining poor cardiorespiratory fitness, reduced levels of daily physical activity, and overweight/obesity.

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.

IGF-I and IGF Binding Protein-3 Generation Tests and Response to Growth Hormone in Children with Silver-Russell Syndrome.

Objectives. To evaluate, in children with Silver-Russell Syndrome, the response to the IGF-I and IGFBP-3 generation test and compare results to the growth response after 6 months of rhGH. Methods. Eight children (6 males), with a mean age of 5.71 ± 2.48 years and height SDS of -3.88 ± 1.28 received rhGH for 6 months. IGF-I and IGFBP-3 were analyzed before and after 4 doses of rhGH. Results. The mean growth velocity (GV) before treatment was 5.28 ± 1.9 cm/year. GV increased after rhGH in five children to a mean GV of 10.3 ± 3.64 cm/year. Six children had normal basal IGF-I levels and two low levels. After 4 doses of rhGH, the IGF-I levels were normal in seven. There was no correlation between the growth response and the IGF-I generation test. Conclusions. Children with SRS have normal IGF-I generation test. There is no correlation between the generation test and the growth velocity after 6 months of rhGH.

Comparison between Actual and Perceived Height of Parents of Children with Short Stature and Controls.

Objectives. We investigate whether parents complaining of their children's short stature have misconception of their height. Methods. Parents were asked to report their own height and were then measured. We compared the difference between reported and actual height of parents of children with short stature (CSS) with that of parents coming for a well child care visit (WCC) and parents of children referred to the endocrinologist without short stature (Endo). The accuracy of reported height from short (below 25%) and tall (above 75%) parents was compared. Results. The CSS fathers were shorter than WCC (P < .01) fathers. The CSS mothers were shorter than the Endo (P < .01) and WCC (P < .001) mothers. There was no difference between reported and actual height when comparing the groups based on the reason for the visit or based on the parental height. Conclusions. Parents of CSS and short parents do not have a misconception of their height.

The role of recombinant human insulin-like growth factor-I in treating children with short stature.

CONTEXT: Recombinant human (rh) IGF-I is now available to treat children with short stature resulting from severe primary IGF-I deficiency. This review from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society discusses different aspects of rhIGF-I therapy, particularly with regard to potential advantages and disadvantages in comparison with the traditional use of rhGH for treatment of short stature. EVIDENCE ACQUISITION: We used the Entrez-PubMed search engine to conduct a review of publications addressing IGF-I deficiency, the use of rhIGF-I, and treatment for short stature. EVIDENCE SYNTHESIS: rhIGF-I, as a twice-daily sc injection, is now approved for treatment of short stature in children with severe primary IGF-I deficiency, which may occur as a consequence of mutations in the GH receptor, defects in the post-GH receptor signaling pathway, and IGF-I gene defects. It is also approved for children with GH deficiency who develop neutralizing antibodies to GH. rhIGF-I significantly improves growth in these conditions. However, adult height may still be suboptimal, possibly due to lack of direct GH effects. Dosing regimens for rhIGF-I administration are under investigation, as are other indications for use of rhIGF-I. CONCLUSION: The use of rhIGF-I is justified in conditions approved by the Food and Drug Administration. Until more substantial data become available, the use of rhIGF-I outside Food and Drug Administration recommendations should only be investigational.

IGF-I, IGFBP-3 and ALS generation test in Turner syndrome.

OBJECTIVES: The pathophysiology of the short stature in girls with Turner syndrome (TS) is not well understood. The "IGF-I generation test" is used to assess the sensitivity to growth hormone. We compared the biochemical response to four days of growth hormone of TS and controls. STUDY DESIGN: Pre-pubertal TS were recruited to participate in the study. Their siblings served as controls. IGF-I, IGFBP-3 and ALS were measured before and 5 days after using hGH (0.05mg/kg/day). Student-t test was used to compare the differences in their responses. RESULTS: Eleven TS (mean age of 8.5+/-2.4) and 11 siblings (6 females and 5 males) (mean age of 7.0+/-2.0) participated in the study. The basal serum levels of IGF-I, IGFBP-3 and ALS were normal and not different between groups (p=0.62 for IGF-I, p=0.91 for IGFBP-3 and p=0.51 for ALS). The IGF-I generation test was positive in all controls and in 10/11 TS. The IGFBP-3 generation test was positive in 6/11 controls and 4/11 TS. After hGH the mean IGFBP-3 was lower in TS than in controls (p=0.08). The ALS response to hGH was not uniform between groups. CONCLUSIONS: The IGF-I and ALS generation test results were not different between controls and TS. The IGFBP-3 results were higher in the control group but more than 50% of tested children did not pass. The IGF-I/IGFBP-3 generation tests, as presently done, did not help in the understanding of the short stature in TS. The use of different GH dosages and number of doses need to be investigated.

Short stature in children with sickle cell anemia correlates with alterations in the IGF-I axis.

Children with sickle cell anemia (SCA) frequently have short stature. We propose that alterations in the IGF-I axis are involved in their growth failure. We investigated the IGF-I axis in children with SCA and height below the 25th percentile (n = 15) and compared it with that of children with SCA and height above the 50th percentile (n = 7). IGF-I and IGFBP-3 levels were assessed by RIA. IGFBP-3 proteolysis was assessed by a protease activity assay and by Western immunoblots. IGF-I and IGFBP-3 SDS were low for both groups. In the short statured patients, IGF-I SDS correlated with height velocity SDS (p = 0.018). IGFBP-3 SDS, when corrected for bone age, decreased with age (p = 0.0054). IGFBP-3 was proteolyzed in both groups although the short statured patients had lower levels of absolute intact IGFBP-3 when compared with the normally growing group (p = 0.028). We demonstrated that children with SCA have abnormalities in the IGF-I axis, which worsen with age.

The correlation of the IGF-I, IGFBP-3, and ALS generation test to height velocity after 6 months of recombinant growth hormone therapy in girls with Turner syndrome.

BACKGROUND/AIMS: Girls with Turner syndrome (TS) have short stature and benefit from growth hormone therapy (hGH). Some TS present a significant change in height velocity in response to hGH while others have only a mild increment. Our objective was to correlate the response to hGH (height velocity after 6 months of therapy) to biochemical data prior to and after the beginning of hGH to try to define a tool to predict the response to hGH. METHODS: Thirteen TS participated in the study (ages 3.5-14 years). Levels of IGF-I and IGFBP-3 were measured before and 5, 30 and 90 days after starting hGH (0.05 mg/kg/day), ALS levels were measured only prior and after 5 days. RESULTS: The mean height velocity (+/-SD) increased from 4.27 (+/-1.18) cm/year to 8.46 (+/-2.17) cm/year (p=0.0001). There was no correlation between the height velocity encountered and the expected height velocity using published mathematical models. Basal ALS values correlated to height velocity SDS and IGF-I and IGFBP-3, after 90 days, correlated to height velocity. Most of the data was too scattered to be used individually for each patient. CONCLUSIONS: Even though we observed a relationship between biochemical markers and height velocity in TS treated with hGH, the response to hGH therapy in this condition is highly variable.

Asymmetrical closure of epiphyses in a patient with sickle cell anemia.

There is a high incidence of delayed sexual development and short stature during childhood in children with sickle cell anemia (SCA). We report a 15 year-old male with SCA who presented with significant short stature after a near death event (involving seizures and prolonged hypoxia). His evaluation showed growth hormone (GH) deficiency with low insulin-like growth factor-I (IGF-I), low IGF binding protein-3, and low GH response to stimulation. He was started on GH replacement with poor response in height gain although with normal response in terms of elongation of his arm span. Further studies showed premature closure of the epiphyses of the femora and tibiae bilaterally. This report demonstrates that children with SCA may present with growth failure not only due to nutritional and GH abnormalities but also due to abnormal growth plates, probably due to local anoxic events. Children with SCA should always have their arm span measured carefully.