Joost Rotteveel

A new leukoencephalopathy with vanishing white matter

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

Infant and Childhood Growth Patterns, Insulin Sensitivity, and Blood Pressure in Prematurely Born Young Adults

OBJECTIVE. Preterm infants are at increased risk to develop insulin resistance and high blood pressure. The influence of growth during childhood is not well established. METHODS. We investigated childhood growth patterns in relation to blood pressure and insulin sensitivity, measured by the hyperinsulinemic euglycemic clamp, in young adults. We compared 29 subjects born preterm appropriate for gestational age, 28 subjects born preterm small for gestational age, and 30 subjects born at term with a normal birth weight. RESULTS. Insulin sensitivity expressed as Mi value (glucose disposal mg/kg/min (insulin levels pmol/l) × 100) was lower in infants in the POPS-AGA (18.2) and POPS-SGA (15.2) groups than in the CON group (24.7). Systolic and diastolic blood pressure (mmHg) were higher in infants in the POPS-AGA (132/72) and POPS-SGA (127/71) groups than in the CON group (118/65). The preterm-born subjects, in lowest insulin sensitivity quartile had a higher height standard deviation score at ages 1, 2, and 5 years and a higher weight SD score at ages 2, 5, 10, 19, and 21 years than did those in the lowest insulin sensitivity quartile. The infants in the highest systolic blood pressure quartile had a higher height SD score at 3 months of age and at ages 2, 5, 10, 19, and 21 years and a higher weight SD score at ages 1, 2, 5, 10, 19, and 21 years than those in the lowest systolic blood pressure quartile. CONCLUSIONS. Young adults born preterm have lower insulin sensitivity and higher blood pressure than controls. Increments in height and weight during childhood are associated with lower insulin sensitivity and higher blood pressure in adulthood.

Beneficial Effects of Growth Hormone Treatment on Cognition in Children with Prader-Willi Syndrome: A Randomized Controlled Trial and Longitudinal Study

BACKGROUND Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited. METHODS Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores. RESULTS During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores. CONCLUSIONS Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment.

Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring.

CONTEXT Overt hypothyroidism in pregnant women is associated with poorer neurodevelopment in their children. Findings from studies investigating the effect of less severe impairments in the maternal thyroid function on cognitive functioning in offspring are difficult to interpret for a number of reasons, including lack of objective cognitive tests, preschool age at assessment, and small sample sizes. OBJECTIVE We aimed to assess the effect of the maternal thyroid status in early pregnancy on their offsprings cognitive performance at 5 to 6 years of age. DESIGN AND PARTICIPANTS This was a prospective study that included the data of 1765 healthy 5- to 6-year-old children from the Amsterdam Born Children and their Development study. Maternal serum free T4 and TSH were obtained at a median gestational age of 90 (interquartile range, 83 to 100) days. MAIN OUTCOME MEASURES Cognitive performance was tested using a computerized assessment program that measured response speed, response speed stability, visuomotor skills, response selection, and response inhibition. RESULTS Maternal hypothyroxinemia (ie, maternal free T4 in the lowest 10% of distribution) was associated with a 41.3 (95% confidence interval, 20.3-62.4) ms slower response speed in a simple reaction time task. In this test, it was also associated with a decreased stability in response speed. The relations found persisted after adjustment for family background and perinatal conditions. The effect of hypothyroxinemia on these outcomes was dependent on its interaction with TSH level. CONCLUSIONS Lower maternal free T4 concentration at the end of the first trimester predicted slower response speed and decreased stability in response speed in offspring at 5 to 6 years of age.

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.

The effect of interrupting prolonged sitting time with short, hourly, moderate-intensity cycling bouts on cardiometabolic risk factors in healthy, young adults

Although detrimental associations of sitting time and health indicators have been observed in young adults, evidence of pathophysiological mechanisms is lacking. Therefore, this study tested the hypothesis that the acute cardiometabolic effects of prolonged sitting can be compensated by hourly interruptions to sitting in healthy, young adults. Additionally, leg muscle activation during sitting and moderate-intensity physical activity interruptions was assessed. Eleven apparently healthy adults (18-24 yr; five men/six women) participated in this randomized, crossover study, involving two experimental conditions: 1) 8 h prolonged sitting and 2) 8 h of sitting, interrupted with hourly, 8-min, moderate-intensity cycling exercise bouts. In both conditions, participants consumed two standardized, high-fat mixed meals after 1 and 5 h. Capillary blood samples were collected hourly during each 8-h experimental condition. Muscle activity was measured using electromyography. Muscle activity during cycling was seven to eight times higher compared with rest. Postprandial levels of C-peptide were significantly lower (unstandardized regression coefficient = -0.19; confidence interval = [-0.35; -0.03]; P = 0.017) during interrupted sitting compared with prolonged sitting. Postprandial levels of other cardiometabolic biomarkers (e.g., glucose, triglycerides, cholesterol) were not significantly different between conditions. Hourly physical activity interruptions in sitting time, requiring a muscle activity of seven to eight times the resting value, led to an attenuation of postprandial C-peptide levels but not for other cardiometabolic biomarkers compared with prolonged sitting in healthy, young adults. Whether this acute effect transfers to chronic effects over time is unknown.

Eight Years of Growth Hormone Treatment in Children With Prader-Willi Syndrome : Maintaining the Positive Effects

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 = .06, P = .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.

Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria.

CONTEXT Sex steroids are important for bone mass accrual. Adolescents with gender dysphoria (GD) treated with gonadotropin-releasing hormone analog (GnRHa) therapy are temporarily sex-steroid deprived until the addition of cross-sex hormones (CSH). The effect of this treatment on bone mineral density (BMD) in later life is not known. OBJECTIVE This study aimed to assess BMD development during GnRHa therapy and at age 22 years in young adults with GD who started sex reassignment (SR) during adolescence. DESIGN AND SETTING This was a longitudinal observational study at a tertiary referral center. PATIENTS Young adults diagnosed with gender identity disorder of adolescence (DSM IV-TR) who started SR in puberty and had undergone gonadectomy between June 1998 and August 2012 were included. In 34 subjects BMD development until the age of 22 years was analyzed. INTERVENTION GnRHa monotherapy (median duration in natal boys with GD [transwomen] and natal girls with GD [transmen] 1.3 and 1.5 y, respectively) followed by CSH (median duration in transwomen and transmen, 5.8 and 5.4 y, respectively) with discontinuation of GnRHa after gonadectomy. MAJOR OUTCOME MEASURES How BMD develops during SR until the age of 22 years. RESULTS AND CONCLUSION Between the start of GnRHa and age 22 years the lumbar areal BMD z score (for natal sex) in transwomen decreased significantly from -0.8 to -1.4 and in transmen there was a trend for decrease from 0.2 to -0.3. This suggests that the BMD was below their pretreatment potential and either attainment of peak bone mass has been delayed or peak bone mass itself is attenuated.

Abnormal lipid profile and hyperinsulinaemia after a mixed meal: additional cardiovascular risk factors in young adults born preterm

Aims/hypothesisLow birthweight in infants born at term is related to the presence of the metabolic syndrome as an adult. Individuals born preterm invariably have low birthweights and may develop the metabolic syndrome as well. Although high BP, glucose intolerance and insulin resistance have been documented, dyslipidaemia has never been reported in individuals born preterm.MethodsIn three groups of young adults [29 participants from the POPS (Project On Premature and Small for Gestational Age Infants) cohort born preterm appropriate for gestational age (POPS-AGA), 28 participants from the POPS cohort born preterm small for gestational age (POPS-SGA) and 30 individuals born at term with normal birthweight (CON)] we investigated fasting lipids as well as postprandial responses during a mixed meal test. The relationship between fasting and postprandial measurements and insulin sensitivity, measured by the hyperinsulinaemic clamp, was investigated.ResultsPreterm participants had higher BP than CON individuals. Postprandial triacylglycerol levels were increased in POPS-SGA men. POPS-SGA individuals were hyperinsulinaemic during the mixed meal test.Conclusions/interpretationThe mixed meal test provides additional information on cardiovascular risk factors. Postprandial triacylglycerol levels are increased in POPS-SGA men. Postprandial hyperinsulinaemia is found in POPS-SGA individuals.

Type 2 diabetes in children in the Netherlands: The need for diagnostic protocols

OBJECTIVE The worldwide trend towards obesity in childhood is also observed in the Netherlands and one of the consequences may be type 2 diabetes. In this study, we assessed the number of children with type 2 diabetes, diagnosed by paediatricians, in the Netherlands. METHODS In 2003 and 2004 the Dutch Paediatric Surveillance Unit, a nationwide paediatric register, was used to assess new cases of diabetes mellitus. Data on socio-demographic and clinical characteristics were collected by means of a questionnaire. A second questionnaire was sent to the reporting paediatrician if the diagnosis was inconclusive or if the diagnosis was type 1 diabetes in combination with overweight or obesity, according to international criteria. RESULTS During the 24 months of registration, the paediatricians reported 1142 new cases of diabetes, 943 of which were eligible for analysis. Initially, 14 patients (1.5%) were reported with type 2 diabetes. Only seven of these patients were classified as type 2 diabetes according to the ADA criteria, as information on C-peptides or antibodies was often missing. Based on clinical characteristics, the other seven patients were very likely to have type 2 diabetes. After the second questionnaire, six more patients met the ADA criteria and two were very likely to have type 2 diabetes. Most of the patients were female (95%), 14% were of Turkish and 18% of Moroccan origin. CONCLUSION This study shows a discrepancy between the number of patients with type 2 diabetes diagnosed by paediatricians in daily practice and diagnosed according to the ADA criteria. Moreover, a considerable amount of reported patients were misclassified. Finally, 2.4% patients were classified as (very likely) type 2 diabetes. The development of programmes and protocols for prevention, diagnosis and classification applicable in daily practice is warranted.