Anita C S Hokken-Koelega

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (266)1144.87 Total impact

  • Laura M Breij · Régine P M Steegers-Theunissen · Daniela Briceno · Anita C.S. Hokken-Koelega ·
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    ABSTRACT: Background: Body composition in early life influences the development of obesity during childhood and beyond. It is, therefore, important to adequately determine neonatal body composition. Fetal growth and maternal factors might influence neonatal fat mass percentage (FM%), independent of birth weight. Methods: In 194 healthy neonates, we investigated neonatal body composition, measured by air-displacement plethysmography (PEAPOD), and its associations with estimated fetal weight (EFW), neonatal anthropometric data, maternal preconceptional body mass index (BMI) and maternal weight gain during pregnancy. Results: There was a large variation in neonatal FM%, even in case of a similar birth weight, corrected for gender and gestational age. Neonatal FM% was associated with EFW at 30 and 36 weeks of gestation and with catch-up in weight between 30 and 36 weeks of gestation, but not with EFW at 20 weeks (p < 0.01, p < 0.01 and p = 0.64, respectively). Neonatal FM% was also associated with preconceptional BMI of the mother (p < 0.01). There was no correlation with maternal weight gain. Conclusion: Our study shows that term neonates have a large variation in FM%. Neonatal FM% is associated with EFW at 30 and 36 weeks, catch-up in weight between 30 and 36 weeks of gestation and preconceptional BMI of the mother.
    Hormone Research in Paediatrics 10/2015; DOI:10.1159/000441298 · 1.57 Impact Factor
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    ABSTRACT: Growth hormone (GH) treatment is beneficial for children with Prader-Willi syndrome (PWS), but data about health-related quality of life (HRQOL) and effects of GH treatment are scarce. We, therefore, investigated the effects of GH treatment on HRQOL in PWS children. In a randomized controlled GH trial including 26 PWS children and during an 11-year longitudinal GH study in 76 children, we annually assessed HRQOL recorded by patients and parents, using a generic questionnaire (DUX25), containing 4 subdomains (Physical, Home, Social, and Emotional) and a PWS-specific questionnaire (DUXPW). At baseline, PWS children rated HRQOL similar to or higher than healthy and obese children. GH-treated children reported an increase in HRQOL in the Physical and Social subdomains and the DUXPW compared to untreated children. Parents reported an increase in the Physical and Emotional subdomains and borderline in the total DUX25 compared to parents of untreated children. During the 11 years of GH treatment, the Physical subdomain continued to improve, according to parents, whereas the Home, Social and Emotional subdomains, the total DUX25, and the DUXPW remained similar, according to children and parents. PWS children rated HRQOL equally to or better than healthy and obese children. HRQOL increased during GH treatment, in contrast to HRQOL of untreated children. This effect was sustained during long-term GH treatment. PWS children consider themselves quite happy, despite some difficulties related to the syndrome. © 2015 S. Karger AG, Basel.
    Hormone Research in Paediatrics 08/2015; 84(4). DOI:10.1159/000437141 · 1.57 Impact Factor
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    ABSTRACT: Context: Previously we showed that pubertal children born small for gestational age (SGA) with a poor adult height (AH) expectation can benefit from treatment with growth hormone (GH) 1mg/m(2)/day (∼0.033mg/kg/day) in combination with 2 years of GnRH analogue (GnRHa) and even more so with a double GH dose. GnRHa treatment is thought to have negative effects on body composition and blood pressure. Long-term effects and GH-dose effects on metabolic health in children treated with combined GH/GnRHa are unknown. Objective: To investigate body composition, blood pressure and lipid profile during GH treatment, either with or without 2 years of additional GnRHa. To assess whether GH 2mg/m(2)/day (∼0.067mg/kg/day) results in a similar or even more favorable metabolic health at AH than GH 1mg/m(2)/day. Methods: Longitudinal, randomized, dose-response GH trial involving 107 short SGA children (58 girls) treated with GH until AH (GH randomized 1 or 2mg/m(2)/day during puberty). Sixty-four children received additional GnRHa. At AH, metabolic parameters were compared between children treated with combined GH/GnRHa and those with only GH. The GH-dose effect on metabolic health was evaluated in a subgroup of 47 children who started GH treatment in early puberty (randomized 1 or 2mg/m(2)/day) with 2 years of GnRHa. Results: At AH, fat mass percentage (FM%) SDS, lean body mass (LBM) SDS, blood pressure SDS and lipid profile were similar between children treated with combined GH/GnRHa and those with only GH. In the pubertal subgroup, FM% SDS was lower during treatment with GH 2mg/m(2)/day. There was no GH dose-dependent effect on LBM SDS, blood pressure and lipid profile. Conclusions: Combined GH/GnRHa treatment has no long-term negative effects on metabolic health compared to only GH. Started in early puberty, a GH dose of 2mg/m(2)/day results in a similar metabolic health at AH and a more favorable FM% than GH 1mg/m(2)/day.
    Journal of Clinical Endocrinology &amp Metabolism 08/2015; DOI:10.1210/jc.2015-2619 · 6.21 Impact Factor
  • Laura M Breij · Gerthe F Kerkhof · Anita C.S. Hokken-Koelega ·
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. Accelerated catch-up in weight during infancy in subjects born at full term has been associated with increased risk for NAFLD in adulthood, but this association has not been studied in subjects born preterm. In 162 young adults born at a gestational age <36 weeks, we assessed the associations between fatty liver index (FLI, 0-100) and birth weight standard deviation score and first-year weight gain. We performed comparisons between subjects with and without accelerated catch-up in weight in the first year after term age. An FLI score was assigned to each participant to determine the clinical relevance, and regression analyses were performed. Accelerated weight gain in the first 3 months after term age was associated with FLI as a continuous variable, whereas gestational age and low birth weight were not. Of the subjects with accelerated catch-up in weight-for-length after term age, 7.3% had a high FLI at the age of 21 years, whereas none of the subjects without accelerated catch-up in weight had a high FLI. Our study shows that accelerated weight gain after term age is associated with an increased risk of developing NAFLD in young adults born preterm. © 2015 S. Karger AG, Basel.
    Hormone Research in Paediatrics 08/2015; DOI:10.1159/000437054 · 1.57 Impact Factor
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    ABSTRACT: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country. © 2015 S. Karger AG, Basel.
    Hormone Research in Paediatrics 07/2015; 84(3). DOI:10.1159/000435856 · 1.57 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the effect of growth hormone treatment on adaptive functioning in children with Prader-Willi syndrome. Vineland Adaptive Behavior Scale (VABS) was assessed during a randomized controlled trial (RCT) and after 7 years of growth hormone treatment. In the RCT, 75 children (42 infants and 33 prepubertal children) with Prader-Willi syndrome were included. Subsequently, 53 children were treated with long-term growth hormone. Our study demonstrates a marked delay in adaptive functioning in infants and children with Prader-Willi syndrome, which was associated with older age and lower intelligence. Results of the repeated measurements show that the earlier growth hormone treatment was started during infancy, the better the adaptive skills were on the long-term.
    American Journal on Intellectual and Developmental Disabilities 07/2015; 120(4):315-327. DOI:10.1352/1944-7558-120.4.315 · 2.08 Impact Factor
  • N E Bakker · J van Doorn · J S Renes · G H Donker · A C S Hokken-Koelega ·
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    ABSTRACT: Children with Prader-Willi syndrome (PWS) attain high serum immunoreactive IGF-I levels during standard dose growth hormone (GH) treatment, which leads to concern, but lowering the dose, deteriorates their body composition. To evaluate serum IGF-I, IGFBP-3 and acid-labile subunit (ALS) levels, complex formation and IGF-bioactivity in GH-treated PWS children. Cross-sectional study. Dutch PWS Cohort Participants: Forty GH-treated PWS children compared with 41 age- and sex-matched healthy controls. GH treatment (1.0 mg/m(2)/day≅0.035 mg/kg/day). Serum IGF-I, IGFBP-3 and ALS levels, complex formation and IGF-bioactivity by IGF1 receptor kinase activation assay (KIRA). Serum IGF-I, IGFBP-3, ALS levels and IGF-I/IGFBP-3 ratio were significantly higher in GH-treated PWS children than in healthy controls. The 150 kD ternary complex formation was, however, also significantly higher than in controls, indicating that most of serum IGF-I is sequestered in the ternary 150 kD complex with ALS and IGFBP-3. Young GH-treated PWS children, median (IQR) age 5.2 (4.3 to7.2) years, exhibited higher serum IGF-bioactivity than controls, but no difference was observed in IGF-bioactivity between older GH-treated PWS children, age 14.9 (13.8 to 16.2) years, and controls. The proportion of IGF-bioactivity of total serum IGF-I was, however, lower in GH-treated PWS children than in controls. Serum immunoreactive IGF-I levels did not correlate with IGF-bioactivity in GH-treated children with PWS, in contrast to a strong positive correlation in healthy controls. In GH-treated PWS children, most serum IGF-I is sequestered in the 150 kD complex. Higher IGF-bioactivity was only found in young GH-treated PWS children and not in the older ones. IGF-bioactivity during GH showed a wide variation and there was a disrupted correlation with immunoreactive IGF-I levels, which makes immunoreactive IGF-I levels an inappropriate indicator for GH-dosing in PWS children.
    The Journal of Clinical Endocrinology and Metabolism 05/2015; 100(8):jc20151410. DOI:10.1210/jc.2015-1410 · 6.21 Impact Factor
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    ABSTRACT: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. Hyperghrelinemia may be involved in the underlying mechanisms of the switch. The purpose of this study is to evaluate acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in PWS and investigate their associations with hyperphagia. This is a cross-sectional clinical study conducted in three PWS expert centers in the Netherlands and France. Levels of AG and UAG and the AG/UAG ratio were determined in 138 patients with PWS (0.2-29.4 years) and compared with 50 age-matched obese subjects (4.3-16.9 years) and 39 healthy controls (0.8-28.6 years). AEBSF was used to inhibit deacylation of AG. As a group, PWS patients had higher AG but similar UAG levels as healthy controls (AG 129.1 vs 82.4 pg/ml, p = 0.016; UAG 135.3 vs 157.3 pg/ml, resp.), resulting in a significantly higher AG/UAG ratio (1.00 vs 0.61, p = 0.001, resp.). Obese subjects had significantly lower AG and UAG levels than PWS and controls (40.3 and 35.3 pg/ml, resp.), but also a high AG/UAG ratio (1.16). The reason for the higher AG/UAG ratio in PWS and obese was, however, completely different, as PWS had a high AG and obese a very low UAG. PWS patients without weight gain or hyperphagia had a similar AG/UAG ratio as age-matched controls, in contrast to those with weight gain and/or hyperphagia who had an elevated AG/UAG ratio. The switch to excessive weight gain in PWS seems to coincide with an increase in the AG/UAG ratio, even prior to the start of hyperphagia.
    Endocrine 05/2015; DOI:10.1007/s12020-015-0614-x · 3.88 Impact Factor
  • S T Lo · P J L Collin · A C S Hokken-Koelega ·
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    ABSTRACT: 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. 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. 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. 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 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.
    Journal of Intellectual Disability Research 04/2015; 59(9). DOI:10.1111/jir.12197 · 2.41 Impact Factor
  • N E Bakker · E P C Siemensma · C Koopman · A C S Hokken-Koelega ·
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    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; 83(5). DOI:10.1159/000374113 · 1.57 Impact Factor
  • S T Lo · P J L Collin · A C S Hokken-Koelega ·
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    ABSTRACT: Psychiatric disorders such as psychosis are highly prevalent in adults with Prader-Willi syndrome (PWS). However, knowledge about the presence and progression of psychiatric disorders in children with PWS is very limited. Sixty-one children with PWS aged 7-17 years were tested using the Diagnostic Interview Schedule for Children (DISC) and Compulsive Behaviour Checklist (CBC), and 38/61 were retested after 2 years. Prevalence of psychiatric disorders and the association with age, gender, genetic subtype, and total IQ were assessed. In addition, occurrence and characteristics of compulsions were determined. Prior to the study, two boys were known with psychotic symptoms and treated with antipsychotics. At baseline, none scored positive for psychotic disorder. During the follow-up, only one boy with known psychotic symptoms required a dose adjustment of his antipsychotic medication. After 2 years, none of the children had a psychotic disorder according to the DISC. Oppositional defiant disorder (ODD) was the most common diagnosis and present in 20% of children with PWS, and this was not associated with age (β = -0.081, P = 0.546), gender (β = 0.013, P = 0.923), genetic subtype (β = -0.073, P = 0.584), or total IQ (β = -0.150, P = 0.267). The most common compulsions were hoarding and fixed hygiene sequences. In our large group of 61 children with PWS, the majority had no psychotic disorder and no progression was found during 2-year follow-up. ODD was present in 20% of children. No changes in the prevalence of psychiatric disorders were found during the 2-year follow-up study and genetic subtype was not related to psychosis, depression, or ODD. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(5). DOI:10.1002/ajmg.a.36998 · 2.16 Impact Factor
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    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; 100(4):jc.2014-4347. DOI:10.1210/jc.2014-4347 · 6.21 Impact Factor
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    Pediatric Transplantation 01/2015; 19:145-145. · 1.44 Impact Factor
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    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; 24(9). DOI:10.1007/s00787-014-0662-4 · 3.34 Impact Factor
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    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.
    Pediatrics 11/2014; 134(6). DOI:10.1542/peds.2013-3607 · 5.47 Impact Factor
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    Akvile Lukoshe · Anita C Hokken-Koelega · Aad van der Lugt · Tonya White ·
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    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 · 3.23 Impact Factor
  • N E Bakker · K P Wolffenbuttel · L H J Looijenga · A C S Hokken-Koelega ·
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    ABSTRACT: Purpose: Boys with Prader-Willi syndrome often have undescended testes. Prospective studies on the treatment of cryptorchidism in these patients are lacking. We evaluated the effects of human chorionic gonadotropin administration on testis position in 16 males with Prader-Willi syndrome. In patients who subsequently underwent orchiopexy biopsy was taken and testis histology was evaluated. Materials and methods: A total of 16 boys (median age 1.6 years, IQR 1.2 to 1.8) with Prader-Willi syndrome and cryptorchidism underwent human chorionic gonadotropin stimulation test. After a positive test human chorionic gonadotropin treatment was initiated. Patients received 250 to 500 IU (depending on age) intramuscularly twice weekly for 6 weeks. Results: We found 1 testis in a stable scrotal position, 1 vanished testis and 1 atrophic abdominal testis. Of 29 testes responding to human chorionic gonadotropin 23% reached a stable scrotal position, 62% reached a lower position and 14% did not change position. Thus, 22 testes required orchiopexy. Of 17 obtained biopsies in 12 patients 2 showed germ cells in more than 60% of seminiferous tubules, 3 in 30% to 60% and 7 in less than 30%. In addition, 4 boys had Sertoli cell only syndrome and 1 had a vanished testis. In patients undergoing orchiopexy younger age and increased inhibin B and testosterone levels after human chorionic gonadotropin stimulation were associated with a greater number of germ cell containing tubules. Conclusions: Human chorionic gonadotropin administration resulted in an anatomically lower testis position in most of our patients with Prader-Willi syndrome, and 23% of testes reached a stable scrotal position. Of the cases 76% required orchiopexy to ensure a stable position in the scrotum.
    The Journal of Urology 08/2014; 193(1). DOI:10.1016/j.juro.2014.07.113 · 4.47 Impact Factor
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    ABSTRACT: Objective: Active rheumatoid arthritis (RA) during pregnancy and the presence of rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPAs) are associated with lower birth weight of the child. Moreover, treatment of the mothers with prednisone may shorten the gestational age at birth. Rapid catch-up in weight for length during the first year of life has been related to a worse cardiovascular and metabolic profile in early adulthood. This study was therefore undertaken to assess the influence of RA disease activity, medication use, and presence of RF or ACPAs during pregnancy on the growth of the child in the first year of life. Methods: Among 180 children born to mothers with RA, the tempo of catch-up in weight during the first year of life was studied. Independent variables were the extent of RA disease activity (according to the Disease Activity Score in 28 joints [DAS28]), medication use, and presence of RF or ACPAs during pregnancy. Results: Of 167 children with available data, 52 (31%) showed catch-up in weight in the first year of life, of whom 90% (47 of 52) showed rapid catch-up. An elevated DAS28 score in the mother was associated with rapid catch-up in weight of the offspring, independent of maternal medication use or the presence of RF or ACPAs during pregnancy (odds ratio 1.44 [95% confidence interval 1.07-1.95] per 1-point increase in the DAS28). Use of medications during pregnancy 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 a worse cardiovascular and metabolic profile in adults. Medication for RA 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.
    Arthritis and Rheumatology 07/2014; 66(7). DOI:10.1002/art.38519
  • J S Renes · J vanDoorn · A C S Hokken-Koelega ·
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    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 · 6.21 Impact Factor
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    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.
    Arthritis and Rheumatology 03/2014; 66(3):533-7. DOI:10.1002/art.38281

Publication Stats

6k Citations
1,144.87 Total Impact Points


  • 2003-2015
    • Erasmus MC
      • • Department of Pediatrics
      • • Department of Endocrinology
      Rotterdam, South Holland, Netherlands
  • 1990-2015
    • Het Oogziekenhuis Rotterdam
      Rotterdam, South Holland, Netherlands
  • 1991-2012
    • Erasmus Universiteit Rotterdam
      • Department of Endocrinology
      Rotterdam, South Holland, Netherlands
  • 2009
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands