Anita C S Hokken-Koelega

Erasmus MC, Rotterdam, South Holland, Netherlands

Are you Anita C S Hokken-Koelega?

Claim your profile

Publications (240)999.9 Total impact

  • N E Bakker, E P C Siemensma, C Koopman, A C S Hokken-Koelega
    [Show abstract] [Hide abstract]
    ABSTRACT: Dietary management is a difficult but key aspect of care in children with Prader-Willi syndrome (PWS). We therefore investigated the effect of growth hormone (GH) treatment on reported energy intake in children with PWS, in relation with body composition, resting energy expenditure (REE) and hormone levels. In a randomized controlled GH trial including 47 children with PWS, we assessed 5-day dietary records and dual-energy X-ray absorptiometry for body composition. REE was calculated by Müller's equation, based on fat mass, fat free mass and gender. Baseline energy intake of children with PWS was lower than normal daily energy requirements (p < 0.001), and decreased with age to 50% in prepubertal children. Energy intake in infants [m/f: 11/8; median (interquartile range [IQR]) age 2.7 years (1.5-3.2)] increased after 1 year of GH treatment (p = 0.008); this tended to be higher in the GH group than in the untreated group (p = 0.07). In prepubertal children [m/f: 14/14; median (IQR) age 6.8 years (5.1-8.1)], the increase in energy intake was higher in the GH group, but this was not different compared to the untreated group. REE was not different between the GH group and the untreated group. Increase in energy intake during 2 years of GH treatment was correlated with lower fat percentage standard deviation scores (p = 0.037) and higher adiponectin levels (p = 0.007). Our study demonstrates that parents of children with PWS are very well capable of restricting energy intake up to 50% compared to daily energy requirements for age- and sex-matched healthy children. GH treatment was associated with a slight increase in energy intake, but also improved body composition and adiponectin levels, which suggests a protective effect of GH treatment. © 2015 S. Karger AG, Basel.
    Hormone Research in Paediatrics 02/2015; DOI:10.1159/000374113 · 1.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Longitudinal data on bone mineral density (BMD) in children and adolescents with PWS during long-term GH treatment are not available. Objective: To determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS) and bone mineral apparent density of the lumbar spine (BMADLS) in children with PWS. Design: Prospective longitudinal study. Setting: Dutch PWS Cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years. Intervention: GH treatment 1 mg/m(2)/day (≅0.035 mg/kg/day). Main outcome measures: BMDTB, BMDLS and BMADLS by using the same dual-energy x-ray absorptiometry (DXA) machine for all annual measurements. Results: In the prepubertal group, BMDTBSDS and BMDLSSDS significantly increased during 4 years of GH treatment while BMADLSSDS remained stable. During adolescence, BMDTBSDS and BMADLSSDS decreased significantly, in girls from the age of 11 years and in boys from the age of 14 and 16 years, resp., but all BMDs remained within the normal range. Higher Tanner stage tended to be associated with lower BMDTB-SDS (P=0.083) and a significantly lower BMADLSSDS (P=0.016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS and BMADLS remains stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 in girls and 14 in boys, unless there is a normal progression of puberty.
    Journal of Clinical Endocrinology &amp Metabolism 02/2015; DOI:10.1210/jc.2014-4347 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Information on behavior of children with Prader-Willi syndrome (PWS) and the effect of growth hormone (GH) treatment is scarce. Parents report less problem behavior during GH treatment. Forty-two pre-pubertal children, aged 3.5-14 years were studied in a randomized controlled GH trial (RCT) during 2 years, followed by a longitudinal study during 8 years of GH treatment. Behavior was measured annually by the Developmental Behavior Checklist for children with intellectual disability (DBC) and a Dutch questionnaire to evaluate social behavioral problems in children, the Children's Social Behavior Questionnaire (CSBQ). Problem behavior measured by the DBC in children with PWS was similar compared to peers with comparable intellectual disability. Scores on 'Social disabilities' subscale were however significantly higher compared to the DBC total score (p < 0.01). A lower IQ was associated with more self-absorbed behavior, more communication problems and more problem behavior in general. Problem behavior measured by the CSBQ was similar compared to peers with a comparable intellectual disability, but children with PWS scored significantly higher on the 'Not tuned', 'Understanding', and 'Stereotyped' subscales than the CSBQ total score (p < 0.05 for all subscales and p = 0.001 for the 'Not tuned'-subscale). There were no significant effects of GH treatment during the RCT and 8 years of GH treatment. Children with PWS showed similar problem behavior as a reference population with a comparable intellectual disability. Social problems were the most pronounced within-problem behavior in PWS. In contrast to our expectations and parents reports, our study shows no improvement but also no deterioration of behavioral problems in children with PWS during long-term GH treatment.
    European Child & Adolescent Psychiatry 12/2014; DOI:10.1007/s00787-014-0662-4 · 3.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the effect of physical training combined with growth hormone (GH) on muscle thickness and its relationship with muscle strength and motor development in infants with Prader-Willi syndrome (PWS). In a randomized controlled trial, 22 infants with PWS (12.9 ± 7.1 months) were followed over 2 years to compare a treatment group (n = 10) with a waiting-list control group (n = 12). Muscle thickness of 4 muscle groups was measured by using ultrasound. Muscle strength was evaluated by using the Infant Muscle Strength meter. Motor performance was measured with the Gross Motor Function Measurement. Analyses of variance were used to evaluate between-group effects of GH on muscle thickness at 6 months and to compare pre- and posttreatment (after 12 months of GH) values. Multilevel analyses were used to evaluate effects of GH on muscle thickness over time, and multilevel bivariate analyses were used to test relationships between muscle thickness, muscle strength, and motor performance. A significant positive effect of GH on muscle thickness (P < .05) was found. Positive relationships were found between muscle thickness and muscle strength (r = 0.61, P < .001), muscle thickness and motor performance (r = 0.81, P < .001), and muscle strength and motor performance (r = 0.76, P < .001). GH increased muscle thickness, which was related to muscle strength and motor development in infants with PWS. Catch-up growth was faster in muscles that are most frequently used in early development. Because this effect was independent of GH, it suggests a training effect. Copyright © 2014 by the American Academy of Pediatrics.
  • Source
    Akvile Lukoshe, Anita C Hokken-Koelega, Aad van der Lugt, Tonya White
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with symptoms involving not only hypothalamic, but also a global, central nervous system dysfunction. Previously, qualitative studies reported polymicrogyria in adults with PWS. However, there have been no quantitative neuroimaging studies of cortical morphology in PWS and no studies to date in children with PWS. Thus, our aim was to investigate and quantify cortical complexity in children with PWS compared to healthy controls. In addition, we investigated differences between genetic subtypes of PWS and the relationship between cortical complexity and intelligence within the PWS group. Methods High-resolution structural magnetic resonance images were acquired in 24 children with genetically confirmed PWS (12 carrying a deletion (DEL), 12 with maternal uniparental disomy (mUPD)) and 11 age- and sex-matched typically developing siblings as healthy controls. Local gyrification index (lGI) was obtained using the FreeSurfer software suite. Results Four large clusters, two in each hemisphere, comprising frontal, parietal and temporal lobes, had lower lGI in children with PWS, compared to healthy controls. Clusters with lower lGI also had significantly lower cortical surface area in children with PWS. No differences in cortical thickness of the clusters were found between the PWS and healthy controls. lGI correlated significantly with cortical surface area, but not with cortical thickness. Within the PWS group, lGI in both hemispheres correlated with Total IQ and Verbal IQ, but not with Performance IQ. Children with mUPD, compared to children with DEL, had two small clusters with lower lGI in the right hemisphere. lGI of these clusters correlated with cortical surface area, but not with cortical thickness or IQ. Conclusions These results suggest that lower cortical complexity in children with PWS partially underlies cognitive impairment and developmental delay, probably due to alterations in gene networks that play a prominent role in early brain development.
    PLoS ONE 09/2014; 9(9):e107320. DOI:10.1371/journal.pone.0107320 · 3.53 Impact Factor
  • N E Bakker, K P Wolffenbuttel, L H J Looijenga, A C S Hokken-Koelega
    [Show abstract] [Hide abstract]
    ABSTRACT: Boys with Prader-Willi syndrome (PWS) often have undescended testes. Prospective studies on treatment of cryptorchidism in boys with PWS are lacking. Our aim was to evaluate the effects of human Chorionic Gonadotropin (hCG) treatment on testis position. In those who underwent orchidopexy, biopsy was taken and testis histology studied.
    The Journal of Urology 08/2014; 193(1). DOI:10.1016/j.juro.2014.07.113 · 3.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Active rheumatoid arthritis (RA) during pregnancy and the presence of rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) are related with a lower birth weight. Prednisone reduces the gestational age. Rapid catch-up in weight for length during the first year of life has been related to worse cardiovascular and metabolic profile in adults. We want to assess the influence of RA disease activity, medication and the presence of RF or ACPA during pregnancy on the growth of the child in the first year of life. Methods Tempo of catch-up in weight during the first year of life was studies. All 180 children were born to mothers with RA. Independent variables were RA disease activity (DAS28), medication and presence of RF or ACPA during pregnancy. Results 31% (52/167) of the children showed catch-up in weight in the first year of whom 90% (47/52) showed rapid catch-up. Elevated DAS28 was associated with rapid catch-up in weight independent of medication or the presence of RF or ACPA during pregnancy (OR, 1.44; 95% CI, 1.07- 1.95; for one point increase in DAS28). Medication had no influence on postnatal growth. Conclusion Elevated RA disease activity during pregnancy should be avoided because it is associated with rapid postnatal catch-up in weight, a risk factor for worse cardiovascular and metabolic profile in adults. Medication during pregnancy, including prednisone, had no effect on growth. Continuation or extension of medication will not only improve maternal health during pregnancy, but could be beneficial for the future health of the unborn child. © 2014 American College of Rheumatology.
    07/2014; 66(7). DOI:10.1002/art.38519
  • J S Renes, J vanDoorn, A C S Hokken-Koelega
    [Show abstract] [Hide abstract]
    ABSTRACT: Background IGF-I is mainly sequestered in a 150 kD ternary complex with IGFBP-3 and the acid-labile subunit (ALS). 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 SGA children have lower IGF-I and IGFBP-3 levels compared to healthy peers. Objective To determine complex formation in healthy normal statured children, and assess variables influencing complex formation. Secondly, we determined complex formation in short SGA children Design/methods Complex formation was assessed using (125)I-hIGF-I column chromatography in 70 controls (40 boys), median age 10.6 years, and 40 short SGA children (25 boys), median age 8.6 years. IGFBP-3 was determined by Western immunoblotting. Results (125)I-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 to IGFBP-3 levels (P<0.001), and lower serum IGF-II (P<0.001) and IGFBP-1 levels (P<0.001). In addition, a higher presence of proteolyzed IGFBP-3 negatively influenced 150 kD complex formation (P=0.006). At a young age, healthy children showed considerable IGFBP-3 proteolytic activity which declined with aging (P<0.001). IGFBP-3 proteolytic activity was negatively correlated with IGF-I levels (P<0.001). Compared to healthy controls, short SGA children showed reduced IGF-I levels (-1.3 vs. 0.1 SDS) and increased proteolyzed IGFBP-3 (35.1% vs. 12.2%). Conclusion Age-specific normative values for (125)I-hIGF-I 150 kD 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 (125)I-hIGF-I ternary complex formation. Our results suggest that in conditions were 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.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(10):jc20133814. DOI:10.1210/jc.2013-3814 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prednisone use and active disease are associated with reduced bone mineral density (BMD) in patients with rheumatoid arthritis (RA). Either or both of these factors may be inevitable during pregnancy in women with RA, but it is unknown whether they variables influence the BMD of the offspring. This study was undertaken to investigate whether medication use or disease activity during pregnancy in RA patients influences the BMD of their prepubertal offspring. Mothers (n = 255) participated in a prospective cohort study of RA and pregnancy, and 108 children of these mothers (ages 5-10 years) were included in this followup study. Information on features known to influence BMD in children, i.e., calcium intake, physical activity, serum 25-hydroxyvitamin D level, sex, height, and weight, was collected. In addition, pre- and postnatal variables known to influence BMD, i.e., gestational age, maternal smoking, birth weight, postnatal rate of growth, and type of feeding, were recorded. Independent variables were prednisone use, sulfasalazine use, and RA disease activity during pregnancy. We found no association of BMD in the children with either prednisone use or RA disease activity during pregnancy, even after correcting for all known associated variables. Sulfasalazine use during pregnancy had a positive effect on the total-body BMD of the offspring (difference in standard deviation score 0.53, P = 0.005). Our findings indicate that neither medication use nor high RA disease activity during pregnancy is associated with decreased BMD in offspring at age ∼7 years. The maternal benefit of medication use for RA during pregnancy outweighs the effect on BMD in the offspring.
    03/2014; 66(3):533-7. DOI:10.1002/art.38281
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: To determine acid-labile subunit (ALS) levels in short small for gestational age (SGA) children and to assess the relationship between ALS levels and several clinical and laboratory characteristics. Also, to assess whether adding ALS levels to a growth prediction model might improve the long-term growth prediction. Design/Methods: ALS levels were measured in 312 short SGA children at the start of growth hormone (GH) treatment. Results: Median (interquartile range) ALS of all subjects was -0.5 SDS, significantly below the 0 SDS (p < 0.001). In 34 children (11%), ALS levels were ≤-2 SDS. ALS SDS correlated significantly with height SDS (r = 0.24, p < 0.001), weight SDS (r = 0.30, p < 0.001), BMI SDS (r = 0.20, p = 0.001), IGF-I SDS (r = 0.56, p < 0.001) and IGFBP-3 SDS (r = 0.67, p < 0.001). ALS SDS was also positively correlated with fasting insulin (r = 0.41, p < 0.001) and glucose levels (r = 0.33, p < 0.001), and HOMA-IR (r = 0.35, p < 0.001). Baseline ALS levels contributed to the long-term growth prediction of GH treatment (5%, p < 0.001). Conclusion: Short SGA children tend to have lower ALS levels compared to controls, albeit less reduced than IGF-I and IGFBP-3 levels. Our data suggest that ALS may be involved in glucose homeostasis. Determination of ALS levels before the start of GH treatment in short SGA children contributes moderately to a more accurate prediction of the growth response to GH treatment. © 2014 S. Karger AG, Basel.
    Hormone Research in Paediatrics 01/2014; 81(2):126-132. DOI:10.1159/000356926 · 1.71 Impact Factor
  • Laura M Breij, Gerthe F Kerkhof, Anita C S Hokken-Koelega
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic metabolic syndrome. Some studies demonstrated an association between small size at birth and NAFLD. Rapid catch-up in weight often follows small birth size and has been associated with metabolic syndrome, but its association with NAFLD remained unknown. Patients and Methods: In 268 adults aged 18-24 yrs, BMI, waist circumference, triglyceride, gamma-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), alanine aminotranserase (ALT), and aspartate aminotransferase (AS) levels were determined. Fatty liver index (FLI, 0-100) was calculated. Associations of birth weight SDS and first year gain in weight- and length SDS were determined with FLI and other liver markers. Comparisons were performed between subjects with and without rapid catch-up in weight in the first year of life. Furthermore, a FLI-score (low, intermediate, high risk for NAFLD) was assigned to each participant to determine clinical relevance, and ordinal regression analyses were performed. Results: Gain in weight in the first three months of life was associated with FLI as a continuous variable, whereas low birth weight was not. There were no significant associations with γ-GT, ALT, or AST. Of the subjects with rapid catch-up in weight for length, 27.8% had an intermediate or high FLI at the age of 21 years, compared with 5.3% of subjects with slow catch up. Rapid catch-up was also associated with a higher FLI-score after adjustments (odds ratio:11.7, p-value:0.016). Conclusion: Accelerated gain in weight for length in the first three months of life is associated with a higher risk for NAFLD in early adulthood, whereas small size at birth is not.
    The Journal of Clinical Endocrinology and Metabolism 01/2014; 99(4):jc20133199. DOI:10.1210/jc.2013-3199 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pregnant women suffering from autoimmune disease use glucocorticoids. Glucocorticoids can partly diffuse to the fetus, and may influence the development of the fetal hypothalamic-pituitary-adrenal axis, especially in early stage of pregnancy. The objective was to investigate whether prednisone-exposure in utero influences the cortisol levels of the prepubertal children. Mothers participated in a prospective cohort study on rheumatoid arthritis (RA) and pregnancy. Children were exposed (n=44) or non-exposed (n=65) to prednisone in utero. Salivary cortisol levels were taken from all children during one day: at awakening, 30 minutes after awakening, 1pm and, bedtime. Cortisol levels between groups were also analyzed using area under the curve (AUC), cortisol awakening response (CAR), and slope. The mean age (SD) of the children was 6.98 (1.23). The difference in mean (SD) cortisol level at '1pm' was 5.42 nmol/L (4.08) in the prednisone-exposed and 3.97 nmol/L (4.00) in the non-exposed (p=0.03). Prednisone-exposed children had a higher AUC (β=13.28; p=0.02), even after correction for RA disease activity. No differences were found on CAR, slope or blood pressure. The cortisol levels of the non-exposed were more similar to the age-specific references than the prednisone-exposed. Prednisone use during pregnancy is associated with a higher daytime cortisol level, in the prepubertal offspring, not yet accompanied with clinical outcomes. This conclusion will have no consequences at this moment, but is does raise questions concerning prednisone-exposure in utero and the long-term consequences for the offspring, This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 12/2013; DOI:10.1111/cen.12388 · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Fetal growth failure has been associated with an increased risk of hypertension, cardiovascular disease and diabetes in adulthood. Exploring the mechanisms underlying this association should improve our understanding of these common adult diseases. Patients and Methods: We investigated 225 SNPs in 10 genes involved in growth and glucose metabolism (GH1, GHR, IGF1, IGF1R, STAT5A, STAT5B, MAPK1, MAPK3, PPARγ and INS) in 1,437 children from the multinational NESTEGG consortium: 345 patients born small for gestational age who remained short (SGA-S), 288 who showed catch-up growth (SGA-Cu), 410 idiopathic short stature (ISS) and 394 controls. We related genotype to pre- and/or postnatal growth parameters, response to growth hormone (if applicable) and blood pressure. Results: We found several clinical associations for GH1, GHR, IGF1, IGF1R, PPARγ and MAPK1. One SNP remained significant after Bonferroni's correction: IGF1R SNP rs4966035's minor allele A was significantly more prevalent among SGA and associated with smaller birth length (p = 0.000378) and birth weight (weaker association), independent of gestational age. Conclusion: IGF1R SNP rs4966035 is significantly associated with birth length, independent of gestational age. This and other associations suggest that polymorphisms in these genes might partly explain the phenotype of short children born SGA and children with ISS. © 2013 S. Karger AG, Basel.
    Hormone Research in Paediatrics 11/2013; 80(6). DOI:10.1159/000355409 · 1.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prader--Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD.
    Journal of Neurodevelopmental Disorders 10/2013; 5(1):31. DOI:10.1186/1866-1955-5-31 · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition.Objectives:The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment.Setting:This was a multicenter prospective cohort study.Methods:We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≅ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat.Results:After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = 0.06, P = 0.14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation.Conclusion:This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.
    The Journal of Clinical Endocrinology and Metabolism 09/2013; DOI:10.1210/jc.2013-2012 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Growth hormone (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, e.g. 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 two patients with Bloom syndrome illustrating the variety in clinical manifestations. They were initially diagnosed with short stature after SGA birth and Silver Russell syndrome and treated with GH.CasesBoth 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 endocrinopathies at start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-I levels increased to values >3.5 SDS, with normal IGFBP-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-I levels >2.5 SDS during standard GH treatment with normal IGFBP-3 levels.
    The Journal of Clinical Endocrinology and Metabolism 08/2013; 98(10). DOI:10.1210/jc.2013-2491 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although severe motor problems in infants with Prader-Willi syndrome (PWS) are striking, motor development has never been studied longitudinally and the results of growth hormone (GH) treatment on motor development are contradictory. The authors studied whether GH treatment can enhance the effect of physical training on motor development in infants with PWS. Twenty-two infants were followed for two years during a randomized controlled trial. The treatment and control groups began GH after baseline or following a control period, respectively. Both groups followed a child-specific physical training program. Motor performance was measured every three months. Multi-level regression analysis revealed that motor development differed significantly between infants (p<.001), and this could be partially explained by baseline motor developmental level (p<.01). GH treatment enhanced the effects of child-specific physical training on both motor developmental rate and motor developmental potential. Moreover, this effect was more pronounced when GH treatment was initiated at a younger age.
    Research in developmental disabilities 07/2013; 34(10):3092-3103. DOI:10.1016/j.ridd.2013.05.043 · 4.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In order to evaluate the social cognitive functioning in children with Prader-Willi syndrome (PWS), Theory of Mind (ToM) and symptoms of Autism Spectrum Disorder were evaluated. Sixty-six children with PWS aged 7-17 years were tested using the Theory of Mind test-R and the Diagnostic Interview for Social Communication disorders. We tested the correlation between Total ToM Standard Deviation Score (Total ToM SDS) and genetic subtype of paternal deletion or maternal uniparental disomy, and total IQ, verbal IQ and performal IQ. Prevalence and symptoms of Autism Spectrum Disorder were assessed. Median (interquartile range) of total ToM SDS of those aged 7-17 years was -3.84 (-5.73, -1.57). Their Total ToM SDS correlated with total IQ (β=0.662, p<0.001, adj.R(2)=0.407), in particular with verbal IQ (β=0.502, p=0.001, adj.R(2)=0.409), but not with performal IQ (β=0.241, p>0.05, adj.R(2)=0.259). No difference in Total ToM SDS was found between children with deletion and maternal uniparental disomy (β=-0.143, p>0.05, adj.R(2)=-0.016). Compared to the reference group of healthy children aged 7-12 years, children with PWS in the same age group had a median ToM developmental delay of 4 (3-5) years. One third of children with PWS scored positive for Autism Spectrum Disorder. Most prominent aberrations in Autism Spectrum Disorder were focused on maladaptive behavior. Our findings demonstrate a markedly reduced level of social cognitive functioning, which has consequences for the approach of children with PWS, i.e. adjustment to the child's level of social cognitive functioning.
    Research in developmental disabilities 06/2013; 34(9):2764-2773. DOI:10.1016/j.ridd.2013.05.024 · 4.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.
    Hormone Research in Paediatrics 05/2013; 79(5):257-270. DOI:10.1159/000351025 · 1.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: STUDY QUESTION: In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy? SUMMARY ANSWER: Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy. WHAT IS KNOWN ALREADY: Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood. STUDY DESIGN, SIZE, DURATION: Cross-sectional study investigating 270 karyotype proven TS patients aged 0-20 years between 2009 and 2010. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF. RESULTS AND THE ROLE OF CHANCE: Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with 'other' karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1-175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8-472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9-8.8; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis. WIDER IMPLICATIONS OF THE FINDINGS: Serum AMH levels are a useful marker of the follicle pool and thus ovarian function in pediatric patients with TS. These findings are in line with the published literature. The finding that GH therapy may affect AMH levels is novel, but must be confirmed by future longitudinal studies.
    Human Reproduction 03/2013; 28(7). DOI:10.1093/humrep/det089 · 4.59 Impact Factor

Publication Stats

5k Citations
999.90 Total Impact Points


  • 2003–2014
    • Erasmus MC
      • • Department of Pediatrics
      • • Department of Endocrinology
      Rotterdam, South Holland, Netherlands
  • 2013
    • St Jansdal Hospital
      Harderwijk, Gelderland, Netherlands
    • Radboud University Medical Centre (Radboudumc)
      • Department of Rehabilitation
      Nymegen, Gelderland, Netherlands
  • 1990–2012
    • Erasmus Universiteit Rotterdam
      • Department of Endocrinology
      Rotterdam, South Holland, Netherlands
  • 2009
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 1994–2008
    • Het Oogziekenhuis Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2007
    • University Medical Center Utrecht
      • Department of Metabolic and Endocrine Disease
      Utrecht, Utrecht, Netherlands