Dutch Growth Research Foundation

Rotterdam, Netherlands

Dutch Growth Research Foundation

Rotterdam, Netherlands

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Smeets C.C.J.,Erasmus Medical Center | Renes J.S.,Erasmus Medical Center | Van Der Steen M.,Erasmus Medical Center | Van Der Steen M.,Dutch Growth Research Foundation | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2017

Context: Children with Silver-Russell syndrome (SRS) are born small for gestational age (SGA) and remain short. Growth hormone (GH) treatment improves height in short SGA children, including those with SRS. Data on metabolic health and long-term safety of GH treatment in SRS are lacking. Objective: To investigate metabolic health in SRS patients during and until 2 years after discontinuation of GH treatment. Design: Metabolic health was assessed longitudinally at GH-start, GH-stop, 6 months, and 2 years thereafter. Patients: Twenty-nine SRS patients vs 171 non-SRS subjects born SGA. Main Outcome Measures: Lean body mass (LBM), fat mass percentage (FM%), insulin sensitivity (Si), b-cell function, blood pressure, and serum lipids. Results: At GH-start [mean age (standard deviation) 5.4 (2.1) years in SRS and 6.7 (2.0) years in non-SRS (P = 0.003)], blood pressure, serum lipids, glucose, and insulin levels were similar and within normal ranges in SRS and non-SRS. LBM standard deviation score (SDS) and FM% SDS were lower than average in both groups. During treatment, LBM SDS remained stable whereas FM% SDS increased in both groups. During the 2 years after GH-stop, LBM decreased and FM% increased, whereas Si and b-cell function improved. At 2 years after GH-stop (mean age 18 years), all parameters were similar and within normal ranges in SRS and non-SRS. None of the SRS patients developed metabolic syndrome, diabetes mellitus type 2, or adverse events. Conclusion: GH-treated SRSpatients have a similarmetabolic healthandsafetyprofile as non-SRS subjects born SGA, both during and until 2 years after GH-stop. Copyright © 2017 by the Endocrine Society.


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.


Savendahl L.,Karolinska Institutet | Maes M.,Cliniques Universitaires St Luc | Maes M.,Belgian Study Group for Pediatric Endocrinology | Albertsson-Wikland K.,Gothenburg University | And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment. Objective: To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated withGH during childhood, in Belgium, The Netherlands, and Sweden. Design: Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands). Patients: All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation. Main Outcome Measure: Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed. Results: Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect. Conclusions: In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease. Copyright © 2012 by The Endocrine Society.


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.


Siemensma E.P.C.,Dutch Growth Research Foundation | Siemensma E.P.C.,Erasmus University Rotterdam | De Lind Van Wijngaarden R.F.A.,Dutch Growth Research Foundation | De Lind Van Wijngaarden R.F.A.,Erasmus University Rotterdam | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: The pathophysiology of hypogonadism in boys with Prader-Willi Syndrome( PWS) remains uncertain. Several reports described hypogonadotropic hypogonadism, some reported primary gonadal failure, and others a combination of both. Objectives: The aim of the study was to evaluate gonadal function over time in boys with PWS and the effect of GH treatment. Measurements: We made a longitudinal assessment of inhibin B, FSH, testosterone, and LH levels in prepubertal boys and male adolescents with PWS. Patients and Methods: We studied 68 boys participating in the Dutch PWS Cohort study. Serum inhibin B, FSH, LH, and testosterone levels were compared with reference values. Results: Boys with PWS had normal inhibin B levels between 6 months and 10 yr of age, but after onset of puberty, inhibin B levels declined to less than the 5th percentile, and FSH levels increased to more than the 95th percentile. Two years after the onset of puberty and in young adults, inhibin B levels were significantly lower (P = 0.008 and P < 0.0001), and FSH levels were significantly higher (P = 0.034 and P < 0.0001) than at onset of puberty. Testosterone levels increased but remained below the 5th percentile, and LH levels increased but not above the 95th percentile. Age showed a significant correlation with inhibin B levels (r = -0.31; P = 0.001) after 9 yr of age. GH treatment had no significant effect on inhibin B levels. Conclusion: Our study indicates that the majority of male patients with PWS have primary testicular failure, which becomes apparent after onset of puberty. Hypogonadotropic hypogonadism did not appear to be the main reason of hypogonadism in most boys. Copyright © 2012 by The Endocrine Society.


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.


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.


Lem A.J.,Dutch Growth Research Foundation | Lem A.J.,Erasmus Medical Center | De Rijke Y.B.,Erasmus Medical Center | Van Toor H.,Erasmus Medical Center | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Age-appropriate reference ranges for thyroid hormones are required for detecting pediatric thyroid dysfunction. Data on thyroid hormones and peripheral thyroid metabolism in short children born small for gestational age (SGA) before and during GH treatment are lacking. Objectives: Our objectives were to obtain pediatric thyroid hormone reference ranges; to investigate thyroid hormones in short SGA children before puberty, during puberty, and during postponement of puberty by GnRH analog; and to evaluate thyroid hormones during GH treatment. Patients and Design: In 512 healthy children (225 females; 0-18 yr), free T4 (FT4), TSH, total T4, T3, rT3, and T4-binding globulin were determined. Reference ranges were calculated using the linearity, median, and skewness method. In 125 short SGA children (62 females; mean age 11.3 yr), thyroid hormones were analyzed before and after 2 yr of GH treatment and additional GnRH analog. Results: Thyroid references showed wide ranges postnatally and age-specific patterns thereafter, similar in boys and girls. Untreated short SGA children had similar FT4 and T4 levels as the reference population but significantly higher T3, rT3, and T4-binding globulin levels. During puberty and during GH treatment, FT4 and rT3 significantly decreased, whereas T3 significantly increased. Conclusion: Age-specific thyroid reference ranges are presented. Puberty and GH treatment both induce changes in peripheral thyroid metabolism, resulting in more biologically active T3 at the expense of less inactive rT3, possibly mediated by IGF-I. GH treatment induces altered peripheral thyroid metabolism but does not result in thyroid dysfunction. Copyright © 2012 by The Endocrine Society.


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.


Lem A.J.,Dutch Growth Research Foundation | Lem A.J.,Erasmus Medical Center | Van Der Kaay D.C.M.,Erasmus Medical Center | Hokken-Koelega A.C.S.,Dutch Growth Research Foundation | Hokken-Koelega A.C.S.,Erasmus Medical Center
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Postponement of puberty by GnRH analog (GnRHa) in addition to GH treatment might increase adult height (AH) in short adolescents born small for gestational age (SGA). GnRHa treatment is thought to have negative effects on bone mineral density (BMD) and body composition. Objective: The objective of the study was to assess the BMD of total body (BMDTB), lumbar spine (BMDLS), bone mineral apparent density lumbar spine (BMAD LS), lean body mass, fat mass, and fat distribution during GH treatment, with or without an additional 2 yr of GnRHa. Patients and Design: This was a prospective GH trial involving short SGA adolescents (≥8 yr). Eighty-eight children (50 girls) were treated until AH (GH randomized 1 or 2 mg/m2·d during puberty); 52 of these children received additional GnRHa. BMD and body composition were longitudinally assessed by dual-energy X-ray absorptiometry. Results: Baseline BMDTB SD score (SDS) and BMDLS SDS were significantly reduced (both P<0.001), but BMADLS SDS was comparable with zero (P = 0.129). BMDTB SDS and BMDLS SDS improved (both P<0.001) from the start until AH, whereas BMADLS SDS remained similar (P = 0.168). At AH, 93% of patients had a normal BMDTB, 99% a normal BMDLS, and 98% a normal BMADLS (>-2 and <+2 SDS). From the start until AH, lean body mass SDSheight and fat mass SDS increased significantly toward zero (both P < 0.001). Multiple regression analyses showed that additional GnRHa treatment had no adverse effect on the changes in BMD and body composition during GH treatment, also after correction for influencing variables. Conclusion: Untreated short SGA adolescents had reduced BMDTB and BMDLS but normal bone size-corrected BMADLS. During GH treatment, BMDTB and BMDLS increased significantly, leading to a normal adult BMD in almost all patients. Two years of GnRHa in addition to GH treatment had no adverse effect on BMD or body composition. Copyright © 2013 by The Endocrine Society.

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