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Rotterdam, Netherlands

Renes J.S.,Erasmus Medical Center | Willemsen R.H.,Erasmus Medical Center | Wagner A.,Erasmus Medical Center | Finken M.J.J.,VU University Amsterdam | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Background: GH treatment has become a frequently applied growth-promoting therapy in short children born small for gestational age (SGA). In some disorders GH treatment is contraindicated, eg, chromosomal breakage syndromes. Bloom syndrome is a rare chromosomal breakage syndrome characterized by severe pre- and postnatal growth deficiency, a photosensitive facial erythema, immunodeficiency, mental retardation or learning disabilities, endocrinopathies, and a predisposition to develop a wide variety of cancers. Objective: We report 2 patients with Bloom syndrome illustrating the variety in clinical manifes-tations. They were initially diagnosed with shortstature after SGA birth and Silver Russell syndrome and treated with GH. Cases: Both patients presented with pre- and postnatal growth failure but no clear other characteristic features associated with Bloom syndrome. Photosensitive skin lesions developed only at a pubertal age and were minimal. Also, both children showed normal immunoglobulin levels, normal development, and no signs of endocrino pathiesat start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-1 levels increased to values greater than 3.5 SD score, with normal IGF binding protein-3 levels. Conclusion: Short children born SGA comprise a heterogeneous group. Bloom syndrome should be tested for in children with consanguineous parents, dysmorphic features (particularly resembling Silver Russell syndrome), skin abnormalities, and/or IGF-1 levels greater than 2.5 SD score during standard GH treatment with normal IGF binding protein-3 levels. Copyright © 2013 by The Endocrine Society. Source

Mehls O.,University of Heidelberg | Lindberg A.,Pfizer | Nissel R.,University of Rostock | Haffner D.,University of Rostock | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

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 pharmacoepidemiological 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. Copyright © 2010 by The Endocrine Society. Source

Lo S.T.,Dutch Growth Research Foundation | Collin P.J.L.,de Koraalgroep | Hokken-Koelega A.C.S.,Erasmus Medical Center
Journal of Intellectual Disability Research | Year: 2015

Background: Prader-Willi syndrome (PWS) is characterised by hypotonia, hypogonadism, short stature, obesity, behavioural problems, intellectual disability, and delay in language, social and motor development. There is very limited knowledge about visual-motor integration in children with PWS. Method: Seventy-three children with PWS aged 7-17 years were included. Visual-motor integration was assessed using the Beery Visual-motor Integration test at the start of the study and after 2 years. The association between visual-motor integration and age, gender, genetic subtype and intelligence was assessed. Results: Children with PWS scored 'very low' (-3 standard deviations) in visual-motor integration and 'below average' (-1 standard deviation) in visual perception and motor coordination compared with typically developing children. Visual-motor integration was higher in children with a deletion (β=-0.170, P=0.037), in older children (β=0.222, P=0.009) and in those with a higher total IQ (β=0.784, P<0.001). Visual perception was higher with a deletion (β=-0.193, P=0.044) and higher IQ (β=-0.618, P<0.001), but motor coordination was only higher with a higher total IQ (β=0.429, P=0.001). Visual perception and motor coordination were not associated with age or gender. There was a trend for visual-motor integration decline over the 2 year follow-up period (P=0.099). Visual perception and motor coordination did not change over the follow-up period. Conclusions: Visual-motor integration is very poor in children with PWS. Children scored higher on the time-limited subtests for visual perception and motor coordination than the combined test for visual-motor integration. Separation of visual-motor integration tasks into pure visual or motor tasks and allowing sufficient time to perform the tasks might improve daily activities, both at home and at school. © 2015 John Wiley & Sons, Ltd. Source

Renes J.S.,Erasmus Medical Center | Van Doorn J.,University Utrecht | Hokken-Koelega A.C.S.,Erasmus Medical Center | Hokken-Koelega A.C.S.,Dutch Growth Research Foundation
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Background: IGF-I is mainly sequestered in a 150-kDa ternary complex with IGF binding protein (IGFBP)-3 and the acid-labile subunit. Data on complex formation and factors influencing formation have not been established. Dissociation of IGF-I from the ternary complex is in part regulated by proteolysis of IGFBP-3, which reduces its affinity for IGF-I. Short small for gestational age (SGA) children have lower IGF-I and IGFBP-3 levels compared with healthy peers.Objective: The objective of the study was to determine complex formation in healthy normalstatured children and assess variables influencing complex formation. Second, we determined complex formation in short SGA children.Design/Methods: Complex formation was assessed using 125I-hIGF-I column chromatography in 70 controls (40 boys), median age 10.6years, and 40 short SGA children (25 boys), median age 8.6years. IGFBP-3 was determined by Western immunoblotting.Results: 125I-hIGF-I complex formation showed an age-specific pattern in healthy controls. Variables positively influencing ternary complex formation were higher serum IGF-I levels compared with IGFBP-3 levels (P <.001) and lower serum IGF-II (P <.001) and IGFBP-1 levels (P <.001). In addition, a higher presence of proteolyzed IGFBP-3 negatively influenced 150-kDa complex formation (P =.006). At a young age, healthy children showed considerable IGFBP-3 proteolytic activity, which declined with aging (P<.001). IGFBP-3 proteolytic activity was negatively correlated with IGF-I levels (P <.001). Compared with healthy controls, short SGA children showed reduced IGF-I levels (-1.3 vs 0.1 SD score) and increased proteolyzed IGFBP-3 (35.1% vs 12.2%).Conclusion: Age-specific normative values for 125I-hIGF-I 150-kDa ternary complex formation are presented. A decrease in IGF-I and an increase in IGF-II, IGFBP-1, and IGFBP-3 proteolytic activity associate with reduced 125I-hIGF-I ternary complex formation. Our results suggest that in conditions in which IGF-I levels are low, such as young age and in short SGA children, IGFBP-3 proteolytic activity is increased to ensure IGF-I bioavailability. Copyright © 2014 by the Endocrine Society. Source

Siemensma E.P.C.,Dutch Growth Research Foundation | Siemensma E.P.C.,Erasmus University Rotterdam | Van Alfen-van Der Velden A.A.E.M.,Radboud University Nijmegen | Otten B.J.,Radboud University Nijmegen | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: The etiology of hypogonadism in girls with Prader-Willi syndrome (PWS) remains uncertain. Objectives:Theaimof the study was to evaluate gonadal function longitudinally in girls and female adolescents with PWS. Measurements: We performed a longitudinal assessment of anti-Müllerian hormone (AMH), gonadotropins, estradiol (E2), inhibin B and A, and pubertal development in girls and female adolescents with PWS. Patients and Methods: Sixty-one girls participating in the Dutch PWS Cohort study participated in the study. Serum AMH, gonadotropins, E2, and inhibin B and A levels were compared with reference values. Results: AMH levels in girls and female adolescents with PWS were comparable to reference levels between 6 months and 22 yr of age. From 10 yr of age, FSH and LH levels increased to above the 5th percentile compared to reference levels. E2 and inhibin B levels were in the low normal range in the majority, and inhibin A levels were low but detectable in almost half the female adolescents with PWS. The median age at puberty onset was comparable, but the median ages at attaining Tanner M3 (P=0.05) and M4 (P<.0001) were significantly higher in girls with PWS than in healthy references. Conclusion: Our study shows that the primordial follicle pool and number of small antral follicles are conserved in girls and female adolescents with PWS. We found no classical hypogonadotropic hypogonadism. However, maturation of follicles and progression of pubertal development are impaired, which might be due to dysregulation of LH secretion. Because these impairments are not absolute, ovulation and thus conception cannot be ruled out in individual female adolescents with PWS. Copyright © 2012 by The Endocrine Society. Source

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