Boudewijn Bakker

Increase in Prevalence of Overweight in Dutch Children and Adolescents: A Comparison of Nationwide Growth Studies in 1980, 1997 and 2009

Objective To assess the prevalence of overweight and obesity among Dutch children and adolescents, to examine the 30-years trend, and to create new body mass index reference charts. Design Nationwide cross-sectional data collection by trained health care professionals. Participants: 10,129 children of Dutch origin aged 0–21 years. Main Outcome Measures Overweight (including obesity) and obesity prevalences for Dutch children, defined by the cut-off values on body mass index references according to the International Obesity Task Force. Results In 2009, 12.8% of the Dutch boys and 14.8% of the Dutch girls aged 2–21 years were overweight and 1.8% of the boys and 2.2% of the girls were classified as obese. This is a two to three fold higher prevalence in overweight and four to six fold increase in obesity since 1980. Since 1997, a substantial rise took place, especially in obesity, which increased 1.4 times in girls and doubled in boys. There was no increase in mean BMI SDS in the major cities since 1997. Conclusions Overweight and obesity prevalences in 2009 were substantially higher than in 1980 and 1997. However, the overweight prevalence stabilized in the major cities. This might be an indication that the rising trend in overweight in the Netherlands is starting to turn.

Bioelectrical impedance analysis to estimate body composition in children and adolescents: a systematic review and evidence appraisal of validity, responsiveness, reliability and measurement error

Bioelectrical impedance analysis (BIA) is a practical method to estimate percentage body fat (%BF). In this systematic review, we aimed to assess validity, responsiveness, reliability and measurement error of BIA methods in estimating %BF in children and adolescents.We searched for relevant studies in Pubmed, Embase and Cochrane through November 2012. Two reviewers independently screened titles and abstracts for inclusion, extracted data and rated methodological quality of the included studies. We performed a best evidence synthesis to synthesize the results, thereby excluding studies of poor quality. We included 50 published studies. Mean differences between BIA and reference methods (gold standard [criterion validity] and convergent measures of body composition [convergent validity]) were considerable and ranged from negative to positive values, resulting in conflicting evidence for criterion validity. We found strong evidence for a good reliability, i.e. (intra‐class) correlations ≥0.82. However, test‐retest mean differences ranged from 7.5% to 13.4% of total %BF in the included study samples, indicating considerable measurement error. Our systematic review suggests that BIA is a practical method to estimate %BF in children and adolescents. However, validity and measurement error are not satisfactory.

Efficacy and Safety of Long-Term Continuous Growth Hormone Treatment in Children with Prader-Willi Syndrome

BACKGROUND Children with Prader-Willi syndrome (PWS) have abnormal body composition and impaired growth. Short-term GH treatment has beneficial effects. OBJECTIVES The aim of the study was to investigate effects of long-term continuous GH treatment on body composition, growth, bone maturation, and safety parameters. SETTING We conducted a multicenter prospective trial. DESIGN Fifty-five children with a mean +/- sd age of 5.9 +/- 3.2 yr were followed during 4 yr of continuous GH treatment (1 mg/m(2) . d). Data were annually obtained in one center: fat percentage (fat%) and lean body mass (LBM) by dual-energy x-ray absorptiometry, height, weight, head circumference, bone age, blood pressure, and fasting IGF-I, IGF binding protein-3, glucose, insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, and low-density lipoprotein. sd scores (SDS) were calculated according to Dutch and PWS reference values (SDS and SDS(PWS)). RESULTS Fat%SDS was significantly lower after 4 yr of GH treatment (P < 0.0001). LBMSDS significantly increased during the first year (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean +/- sd height normalized from -2.27 +/- 1.2 SDS to -0.24 +/- 1.2 SDS (P < 0.0001). Head circumference SDS increased from -0.79 +/- 1.0 at start to 0.07 +/- 1.1 SDS after 4 yr. BMISDS(PWS) significantly decreased. Mean +/- sd IGF-I and the IGF-I/IGF binding protein-3 ratio significantly increased to 2.08 +/- 1.1 and 2.32 +/- 0.9 SDS, respectively. GH treatment had no adverse effects on bone maturation, blood pressure, glucose homeostasis, and serum lipids. CONCLUSIONS Our study in children with PWS shows that 4 yr of continuous GH treatment (1 mg/m(2) . d) improves body composition by decreasing fat%SDS and stabilizing LBMSDS and head circumference SDS and normalizes heightSDS without adverse effects. Thus, long-term continuous GH treatment is an effective and safe therapy for children with PWS.

Patterns of growth and body proportions after total-body irradiation and hematopoietic stem cell transplantation during childhood.

Patterns of growth and body proportions were studied in 75 children receiving total-body irradiation (TBI) and hematopoietic stem cell transplantation (SCT) before onset of puberty. Of the 19 patients receiving GH, only data obtained before onset of GH were included. Thirty-two patients reached final height (FH). Median change in height SD score (SDS) between SCT and FH was –1.7 in boys and –1.1 in girls. Peak height velocity (PHV) was decreased in the majority of the patients (median PHV 5.7 cm/y in boys and 5.3 cm/y in girls), even though it occurred at appropriate ages. Changes in body proportions were analyzed by linear mixed-effects models. Decrease in sitting height SDS did not differ between boys and girls. In boys, decrease in leg length SDS was of comparable magnitude, whereas, in girls, decrease in leg length was less pronounced, leading to a significant decrease in SDS for sitting height/height ratio in girls only. The sex-specific effects of several variables on height SDS were analyzed by linear mixed-effects modeling, showing a slightly faster decrease in younger children and a more pronounced decrease during puberty in boys compared with girls. We conclude that 1) younger children are more susceptible to growth retardation after TBI and SCT, 2) pubertal growth is more compromised in boys, and 3) leg growth is relatively less affected in girls, possibly due to a high incidence of gonadal failure in girls.

The Jumping SHOX Gene—Crossover in the Pseudoautosomal Region Resulting in Unusual Inheritance of Leri-Weill Dyschondrosteosis

CONTEXT During meiosis I, the recombination frequency in the pseudoautosomal region on Xp and Yp (PAR1) in males is very high. As a result, mutated genes located within the PAR1 region can be transferred from the Y-chromosome to the X-chromosome and vice versa. PATIENTS Here we describe three families with SHOX abnormalities resulting in Leri-Weill dyschondrosteosis or Langer mesomelic dysplasia. RESULTS In about half of the segregations investigated, a transfer of the SHOX abnormality to the alternate sex chromosome was demonstrated. CONCLUSIONS Patients with an abnormality of the SHOX gene should receive genetic counseling as to the likelihood that they may transmit the mutation or deletion to a son as well as to a daughter.

A Girl With Beckwith-Wiedemann Syndrome and Pseudohypoparathyroidism Type 1B Due to Multiple Imprinting Defects

CONTEXT Several patients with Beckwith-Wiedemann Syndrome (BWS) with multiple imprinting defects found by genetic analysis have been described. However, only two cases have been described with both genetic and clinical signs and symptoms of multiple diseases caused by imprinting defects. CASE DESCRIPTION The girl in this case presented at the age of 6 months with morbid obesity (body mass index, +7.5 SDS) and a large umbilical hernia. Genetic analysis showed BWS (hypomethylation of the KCNQ1OT1 gene). Calcium homeostasis was normal, and she had no signs of Albright hereditary osteodystrophy. At the age of 10 years, she presented with fatigue, and laboratory analyses showed marked hypocalcemia with signs of PTH resistance, but without evidence for Albright hereditary osteodystrophy, thus suggesting pseudohypoparathyroidism type 1B. Consistent with this diagnosis, methylation analysis of the GNAS complex revealed hypomethylation (about 20%) of the GNAS exon 1A, NESPAS, and GNASXL loci and hypermethylation (100% methylation) of the NESP locus. CONCLUSIONS Imprinting defects at several different loci can occur in some patients, thus causing multiple different diseases. Symptoms of pseudohypoparathyroidism type 1B may be absent at diagnosis of BWS, yet prolonged subclinical hypocalcemia and/or hyperphosphatemia can have negative consequences (eg, intracerebral calcifications, myocardial dysfunction). We therefore suggest that patients with an imprinting disorder should be monitored for elevations in PTH, and epigenetic analysis of the GNAS complex locus should be considered.

EFFECTS OF TOTAL-BODY IRRADIATION ON GROWTH, THYROID AND PITUITARY GLAND IN RHESUS MONKEYS

PURPOSE To investigate the effect of total-body irradiation (TBI) on growth, thyroid and pituitary gland in primates. METHODS AND MATERIALS Thirty-seven rhesus monkeys (mean age 3.1+/-0.6 years) received either a low-dose (4-6 Gy) TBI (n = 26) or high-dose (7-12 Gy) TBI (n = 11) and were sacrificed together with 8 age-matched controls after a post-irradiation interval of 5.9+/-1.5 years. Anthropometric data were collected: thyroid and pituitary glands were examined; serum levels of thyroid stimulating hormone (TSH), free thyroxin (FT4), insulin-like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3) were measured. RESULTS Decrease in final height due to irradiation could not be demonstrated. There was a dose-dependent decrease in body weight, ponderal index, skinfold thickness and thyroid weight. The latter was not accompanied by elevation of TSH or decrease in FT4. Structural changes in the thyroid gland were found in 50% of the irradiated animals. Levels of IGF-I and IGFBP-3 did not differ between the dose groups, but the high-dose group had a lower IGF-1/IGFBP-3 ratio. CONCLUSION Total body irradiation had a negative effect on body fat. There was no evidence of (compensated) hypothyroidism, but dose-dependent decrease in thyroid weight and changes in follicular structure suggest some effect of TBI on the thyroid gland. The decreased IGF-I/IGFBP-3 ratio in the high-dose group can indicate that the somatotrophic axis was mildly affected by TBI. These results show that TBI can have an effect on the physical build and thyroid gland of primates even in the absence of cytostatic agents or immunosuppressive drugs.

Absence of clinically relevant growth acceleration in untreated children with non-classical congenital adrenal hyperplasia

Background/Aims: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. Methods: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS-THSDS). Bone maturation was expressed as bone age acceleration (BAc = bone age – calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. Results: In symptomatic patients (n = 17), HSDS-THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02–0.10). Mean BAc was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BAc was found. Conclusions: In untreated NC-CAH children, growth acceleration is small and generally not visible on their growth charts. BAc is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account.

Randomized GH trial with two different dosages in combination with a GnRH analogue in short small for gestational age children: effects on metabolic profile and serum GH, IGF1, and IGFBP3 levels

BACKGROUND GnRH analogue (GnRHa) combined with GH treatment has been proposed to increase adult height. Effect on metabolic profile and GH, IGF1, and IGFBP3 levels in short small for gestational age (SGA) children is unknown. OBJECTIVE To assess fat mass and lean body mass SDS, percentage trunk fat, blood pressure (BP), insulin sensitivity (Si), beta-cell function (disposition index, DI), lipid profile, and GH, IGF1, and IGFBP3 levels during 2 years of combined treatment. SUBJECTS Forty-one pubertal short SGA children with a mean (+/-S.D.) age of 12.1 (+/-1.0) years. DESIGN Children received 3.75 mg of leuprolide acetate depot subcutaneously every 4 weeks, and they were randomly assigned to receive 1 mg (group A) or 2 mg (group B) of GH/m(2) per day. RESULTS Percentage trunk fat increased in both groups, but to a lower extent in group B. Lean body mass SDS increased only in group B. Changes in BP, Si, DI, and lipids were similar in both groups. Si significantly decreased, but DI remained unchanged. Lipids remained normal. GH and IGF1 levels were significantly higher in group B. CONCLUSION Our study is the first to report that 2 years of combined treatment with a GnRHa and either 1 or 2 mg GH/m(2) per day does not adversely affect body composition and metabolic profile of short SGA children who come under medical attention at the onset of puberty. There was a dose-dependent effect on fat mass SDS(height), percentage trunk fat, lean body mass SDS(height), and GH and IGF1 levels in favor of treatment with GnRHa and the higher GH dose of 2 mg/m(2) per day.

Mutations in IRS4 are associated with central hypothyroidism

Background Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. Conclusions Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.