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Reinehr T.,Witten/Herdecke University | Bechtold-Dalla Pozza S.,Ludwig Maximilians University of Munich | Bettendorf M.,University of Heidelberg | Doerr H.-G.,University Hospital for Children and Adolescents | And 8 more authors.
Experimental and Clinical Endocrinology and Diabetes | Year: 2011

Background: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests. Methods: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years). Results: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0g/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97 th centile; n=71) and moderate overweight children (BMI>90 th to 97th centile, n=93) demonstrated no significant difference in any parameter. Conclusions: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart. Source


Kraft M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Cirstea I.C.,Heinrich Heine University Dusseldorf | Voss A.K.,Walter and Eliza Hall Institute of Medical Research | Voss A.K.,University of Melbourne | And 21 more authors.
Journal of Clinical Investigation | Year: 2011

Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway. Source


Lell M.M.,Friedrich - Alexander - University, Erlangen - Nuremberg | May M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Deak P.,Friedrich - Alexander - University, Erlangen - Nuremberg | Alibek S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 6 more authors.
Investigative Radiology | Year: 2011

Objectives: Computed tomography (CT) is considered the method of choice in thoracic imaging for a variety of indications. Sedation is usually necessary to enable CT and to avoid deterioration of image quality because of patient movement in small children. We evaluated a new, subsecond high-pitch scan mode (HPM), which obviates the need of sedation and to hold the breath. Material and Methods: A total of 60 patients were included in this study. 30 patients (mean age, 14 A± 17 month; range, 0-55 month) were examined with a dual source CT system in an HPM. Scan parameters were as follows: pitch ≤ 3.0, 128 Ã- 0.6 mm slice acquisition, 0.28 seconds gantry rotation time, ref. mAs adapted to the body weight (50-100 mAs) at 80 kV. Images were reconstructed with a slice thickness of 0.75 mm. None of the children was sedated for the CT examination and no breathing instructions were given. Image quality was assessed focusing on motion artifacts and delineation of the vascular structures and lung parenchyma. Thirty patients (mean age, 15 A± 17 month; range, 0-55 month) were examined under sedation on 2 different CT systems (10-slice CT, n ≤ 18; 64-slice CT, n ≤ 13 patients) in conventional pitch mode (CPM). Dose values were calculated from the dose length product provided in the patient protocol/dose reports, Monte Carlo simulations were performed to assess dose distribution for CPM and HPM. Results: All scans were performed without complications. Image quality was superior with HPM, because of a significant reduction in motion artifacts, as compared to CPM with 10- and 64-slice CT. In the control group, artifacts were encountered at the level of the diaphragm (n ≤ 30; 100%), the borders of the heart (n ≤ 30; 100%), and the ribs (n ≤ 20; 67%) and spine (n ≤ 6; 20%), whereas motion artifacts were detected in the HPM-group only in 6 patients in the lung parenchyma next to the diaphragm or the heart (P < 0,001). Dose values were within the same range in the patient examinations (CPM, 1.9 ± 0.6 mSv; HPM, 1.9 ± 0.5 mSv; P ≤ 0.95), although z-overscanning increased with the increase of detector width and pitch-value. Conclusion: High-pitch chest CT is a robust method to provide highest image quality making sedation or controlled ventilation for the examination of infants, small or uncooperative children unnecessary, whereas maintaining low radiation dose values. © 2011 by Lippincott Williams & Wilkins. Source


Dorr H.G.,University Hospital for Children and Adolescents | Bettendorf M.,University of Heidelberg | Hauffa B.P.,University of Duisburg - Essen | Mehls O.,University Hospital for Children and Adolescents | And 4 more authors.
Clinical Endocrinology | Year: 2011

Background There has been controversy in recent years on whether the d3 polymorphism of the GH receptor is associated with a better growth response to GH in idiopathic short children born small for gestational age (SGA). Methods In this prospective study, we evaluated exon 3-GHR polymorphisms in 142 (62 f, 80 m) short prepubertal children born SGA (birth length and/or weight of ≤-2 SD for GA) and treated with rhGH (mean dose of 0·30 mg/kg/week) in 24 centres in Germany. A growth prediction for the first year of therapy was calculated for each child according to Ranke and co-workers. The index of responsiveness (IOR) was calculated by dividing the response (observed growth minus predicted growth) by the standard error of the prediction. All analyses were performed in one centre on samples collected and shipped on filter paper. The DNA fragment containing or missing exon 3 of the GHR was amplified by multiplex PCR. Results The fl-GHR isoform was most common with a frequency of 47·8%, followed by the d3/fl isoform with 38% and the d3-GHR isoform with 14·2%. There were no significant differences regarding gestational age, birth weight and birth length, mid parental height-SDS, chronological age at start of therapy, height-SDS, BMI-SDS, height velocity and GH dose between the different subgroups according to the genotype. After the first treatment year, height (H)-SDS (P < 0·05), height velocity (HV) (P < 0·01), HV-SDS (P < 0·001) and delta-H-SDS (P < 0·05) were significantly higher in patients with d3-GHR than in those with fl-GHR. The mean IOR was above 0 in children with at least one d3 allele, and highest, with 0·54, in those with the d3-GHR isoform. After the second year on GH, no differences between the different GHR-isoforms were found. Conclusions According to our results, the exon 3-deleted GHR explains the better growth response to GH only for the first and not for the second year. © 2011 Blackwell Publishing Ltd. Source


Schuster S.,University Hospital for Children and Adolescents | Hechler C.,University Hospital for Children and Adolescents | Gebauer C.,University Hospital for Children and Adolescents | Kiess W.,University Hospital for Children and Adolescents | Kratzsch J.,University of Leipzig
Pediatric Research | Year: 2011

The adipokine leptin has been detected in human breast milk, but its effect on postnatal growth and development remains largely unclear. We hypothesized that leptin could affect infant's body weight gain during early lactation in the first 6 mo of life. Therefore, we evaluated leptin levels in maternal serum and breast milk of 23 healthy, lactating mothers and their neonates in a prospective, longitudinal study. Leptin concentration was quantified by a commercially available human leptin RIA. Our results showed that leptin levels in breast milk were 22-fold lower than in maternal serum, but both parameters were positively correlated to each other (r = 0.431, p = 0.001) and to maternal BMI (serum: r = 0.512, p < 0.001; milk: r = 0.298, p < 0.001) over 6 mo of lactation. A negative association was found between breast milk leptin levels during the first week after delivery and the infant weight gain from the end of the first to the sixth month (r =-0.681, p = 0.007). This suggests that milk-borne leptin provides a link between maternal body composition and infant growth and development and plays a critical role in regulating appetite and food intake during early infancy. © 2011 International Pediatric Research Foundation, Inc. Source

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