Wit, J.M.

Inhibition of Gsk3β in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway (Article)

2011-11-01T00:00:00Z

Objective: In the past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3β (GSK3β) down-regulates transduction of the canonical Wnt signal by promoting degradation of β-catenin. In this study we wanted to further investigate the role of Gsk3β in cartilage maintenance. Design: Therefore, we have treated chondrocytes ex vivo and in vivo with GIN, a selective GSK3β inhibitor. Results: In E17.5 fetal mouse metatarsals, GIN treatment resulted in loss of expression of cartilage markers and decreased chondrocyte proliferation from day 1 onward. Late (3. days) effects of GIN included cartilage matrix degradation and increased apoptosis. Prolonged (7. days) GIN treatment resulted in resorption of the metatarsal. These changes were confirmed by microarray analysis showing a decrease in expression of typical chondrocyte markers and induction of expression of proteinases involved in cartilage matrix degradation. An intra-articular injection of GIN in rat knee joints induced nuclear accumulation of β-catenin in chondrocytes 72. h later. Three intra-articular GIN injections with a 2. days interval were associated with surface fibrillation, a decrease in glycosaminoglycan expression and chondrocyte hypocellularity 6. weeks later. Conclusions: These results suggest that, by down-regulating β-catenin, Gsk3β preserves the chondrocytic phenotype, and is involved in maintenance of the cartilage extracellular matrix. Short term β-catenin up-regulation in cartilage secondary to Gsk3β inhibition may be sufficient to induce osteoarthritis-like features in vivo.

How best to define the concept of minimal risk (Article)

2011-09-01T00:00:00Z

Regulating "higher risk, no direct benefit" studies in minors (Article)

2011-06-01T00:00:00Z

Effect of oxandrolone on glucose metabolism in growth hormone-treated girls with turner syndrome (Article)

2011-02-01T00:00:00Z

Background: The weak androgen oxandrolone (Ox) may increase height but may also affect glucose metabolism in girls with Turner syndrome (TS). Methods: In a randomized, placebo-controlled, double-blind study, we assessed the effect of Ox at a dosage of either 0.06 or 0.03 mg/kg/day on glucose metabolism in 133 growth hormone (GH)-treated girls with TS. Patients were treated with GH (1.33 mg/m2/day) from baseline, combined with placebo (Pl) or Ox from the age of 8, and estrogens from the age of 12. Oral glucose tolerance tests (OGTT) were performed, and HbA1c levels were measured before, during, and after discontinuing Ox/Pl therapy. Results: Insulin sensitivity, assessed by the whole-body insulin sensitivity index (WBISI) decreased during GH+Ox/Pl (p = 0.003) without significant differences between the dosage groups. Values returned to pre-treatment levels after discontinuing GH+Ox/Pl. On GH+Ox, fasting glucose was less frequently impaired (Ox 0.03, p = 0.001; Ox 0.06, p = 0.02) and HbA1c levels decreased more (p = 0.03 and p = 0.001, respectively) than on GH+Pl. Conclusions: We conclude that in GH-treated girls with TS, Ox at a dosage of 0.03 or 0.06 mg/kg/day does not significantly affect insulin sensitivity. Insulin sensitivity decreases during GH therapy, to return to a pre-treatment level after discontinuing therapy.

Comments on 'prospective study confirms oxandrolone-associated improvement in height in growth hormone-treated adolescent girls with turner syndrome' by Zeger et al., pp. 39-47, this issue (Article)

2011-01-01T00:00:00Z

Should blood gas analysis be part of the diagnostic workup of short children? Auxological data and blood gas analysis in children with renal tubular acidosis (Article)

2010-11-01T00:00:00Z

Background: Renal tubular acidosis (RTA) is a rare cause of growth failure, therefore it is uncertain whether routine screening with blood gas analysis of short infants and children is cost-effective. Objective: To investigate the clinical, growth and laboratory parameters in children with RTA to estimate the possible value of laboratory screening for this disorder in infants and children referred for short stature according to a recent guideline. Method: Retrospective chart analysis of 30 children diagnosed between 1978 and 2005 in The Netherlands and 3 centers in Belgium. Results: The current guideline for short stature detected 33% of children with RTA. Assuming a pre-test probability of RTA of 0.6 per 100,000 births, the likelihood ratio of poor growth was 58 and 17 below and above 3 years, respectively. Sensitivity was 17/30 and 12/24 for a -2.0 SDS cutoff for weight and body mass index, respectively. In infants and toddlers diagnosed before 3 years of age, the mean weight loss was 1.5 SD, and 0.8 SDS in older children. In short children >3 years RTA was extremely rare, always associated with clinical symptoms, and rarely detected by blood gas analysis. Conclusion: According to our data a decreasing weight SDS for age is a sufficient indication to perform blood gas analysis in children <3 years of age, particularly in the presence of additional clinical features, whereas it can be omitted in short children >3 years of age. Copyright

The Effect of Oxandrolone on Voice Frequency in Growth Hormone-Treated Girls With Turner Syndrome (Article)

2010-10-25T00:00:00Z

Objectives/Hypothesis: Oxandrolone (Ox) increases height gain but may also cause voice deepening in growth hormone (GH)-treated girls with Turner syndrome (TS). We assessed the effect of Ox on objective and subjective speaking voice frequency in GH-treated girls with TS. Study Design: A multicenter, randomized, placebo (Pl)-controlled, double-blind study was conducted. Methods: One hundred thirty-three patients were included and treated with GH (1.33 mg/m2/d) from baseline, combined with Pl or Ox in a low (0.03 mg/kg/d) or conventional (0.06 mg/kg/d) dose from the age of 8 years and estrogens from the age of 12 years. Yearly from starting Ox/Pl until 6 months after discontinuing GH + Ox/Pl, voices were recorded and questionnaires were completed. Results: At start, mean (±standard deviation [SD]) voice frequency SD score (SDS) was high for age (1.0 ± 1.2, P < 0.001) but normal for height. Compared with GH + Pl, voices tended to lower on GH + Ox 0.03 (P = 0.09) and significantly lowered on GH + Ox 0.06 (P = 0.007). At the last measurement, voice frequency SDS was still relatively high in GH + Pl group (0.6 ± 0.7, P = 0.002) but similar to healthy girls in both GH + Ox groups. Voice frequency became lower than -2 SDS in one patient (3%) on GH + Ox 0.03 and three patients (11%) on GH + Ox 0.06. The percentage of patients reporting subjective voice deepening was similar between the dosage groups. Conclusions: Untreated girls with TS have relatively high-pitched voices. The addition of Ox to GH decreases voice frequency in a dose-dependent way. Although most voice frequencies remain within the normal range, they may occasionally become lower than -2 SDS, especially on GH + Ox 0.06 mg/kg/d.

Adult height in children with growth hormone deficiency: A randomized, controlled, growth hormone dose-response trial (Article)

2010-08-01T00:00:00Z

Aim: To investigate the effect of 2 growth hormone (GH) doses on adult height (AH) in GH deficiency (GHD). Methods: A multicenter, randomized, controlled dose-response trial compared attained AH minus target height (TH) between children receiving 0.7 mg/m2/day biosynthetic GH (approx. 0.025 mg/kg/day) or 1.4 mg/m2/day (approx. 0.050 mg/kg/day). The patients enrolled in the trial were 20 'naïve' GHD children (had not received GH before) and 15 'transfer' GHD children (already on GH for at least 1 year). Results: In the naïve group, the mean ± SD AH minus TH was -5.3 ± 6.1 and -2.2 ± 6.9 cm in patients on 0.7 and 1.4 mg/m 2/day, respectively (mean ± SE difference 3.1 ± 2.9; p = 0.3). In the transfer group, the mean ± SD AH minus TH was -4.4 ± 6.4 and +0.6 ± 7.0 cm in patients on 0.7 and 1.4 mg/m 2/day, respectively (mean ± SE difference 5.0 ± 3.5; p = 0.17). Spontaneous puberty started 1.1 years earlier in children on 1.4 compared to 0.7 mg/m2/day. Induction of puberty was more often delayed in transfer children on 0.7 than on 1.4 mg/m2/day. Conclusion: In our GHD patients, AH was 4-5 cm less than TH in patients on 0.7 mg/m2/day GH, while it was 0-2 cm less in patients on 1.4 mg/m 2/day GH, but this difference did not reach statistical significance, probably due to limited numbers of patients, considerable variability in the growth response and earlier spontaneous puberty and pubertal induction in the children on 1.4 mg/m2/day.

The effect of oxandrolone on body proportions and body composition in growth hormone-treated girls with Turner syndrome (Article)

2010-08-01T00:00:00Z

Objective Untreated girls with Turner syndrome (TS) have short stature, relatively broad shoulders, a broad pelvis, short legs, a high fat mass and low muscle mass. Our objective was to assess the effect of the weak androgen oxandrolone (Ox) on body proportions and composition in growth hormone (GH)-treated girls with TS. DesignPatients 133 patients were included in a randomized, placebo-controlled, double-blind study. Methods Patients were treated with GH (1·33 mgm2per day) from baseline, combined with placebo (Pl) or Ox in a low (0·03 mgkg per day) or previously conventional (0·06 mgkg per day) dose from the age of eight, and oestrogens from the age of twelve. Sitting height, biacromial and biiliacal distances compared with height (i.e. shape values), BMI, waist circumference, sum of 4 skinfolds (sum4skin) and upper arm muscle area (UAMA) SD scores (SDS) were assessed half-yearly. Results Compared with GH + Pl, adult shape values on GH + Ox tended to be higher for sitting height (Ox 0·03, P = 0·2; Ox 0·06, P = 0·02) and biacromial distance (Ox 0·03, P = 0·2; Ox 0·06, P = 0·07) and lower for biiliacal distance (Ox 0·03, P = 0·004; Ox 0·06, P = 0·08). Sum4skin SDS tended to decrease more (Ox 0·03, P = 0·2; Ox 0·06, P = 0·005) while UAMA SDS increased more (Ox 0·03, P < 0·001; Ox 0·06, P < 0·001) than on GH + Pl. The increase in BMI and waist circumference SDS was comparable between the dosage groups. Conclusions In GH-treated girls with TS, Ox 0·06 increases sitting height and tends to increase biacromial distance and decrease biiliacal distance, while Ox 0·03 significantly decreases biiliacal distance compared with height. Furthermore, Ox 0·06 reduces subcutaneous fat mass, and both Ox dosages increase muscle mass.

Acceptable risks and burdens for children in research without direct benefit: a systematic analysis of the decisions made by the Dutch Central Committee (Article)

2010-07-01T00:00:00Z

Objectives To evaluate whether the requirement of "minimal risk and burden"for paediatric research without direct benefit to the subjects compromises the ability to obtain data necessary for improving paediatric care. To provide evidence-based reflections on the EU recommendation that allows for a higher level of risk. Design and setting Systematic analysis of the approval/ rejection decisions made by the Dutch Central Committee on Research involving Human Subjects (CCMO). Review methods The analysis included 165 proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. A separate, in-depth analysis of all drug studies included 18 early phase drug studies and nine other drug studies without direct benefit. Results 11 out of 165 studies were definitively rejected because the CCMO did not regard the risk and/or burden to be minimal. In three of these 11 cases (including two early phase drug studies) the requirement of minimal risk and burden was cited as the only reason for rejection. Four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal but were nevertheless approved. Conclusions The requirement of minimal risk and burden, aiming to protect research subjects, occasionally leads to rejection of protocols. Early phase drug studies relatively often do not comply with the requirement. Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution. The regulatory framework should be revised to make such occasional exceptions to the requirement legitimate and transparent.

High-dose GH treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height (Article)

2010-04-01T00:00:00Z

Objective: To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS). Design and methods: Forty children with no signs of puberty, age at start 4-8 years (girls) or 4-10 years (boys), height SDS <2-.0 SDS, and birth length >-2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m2per day (equivalent to 75 μg/kg per day at start and 64 μg/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (S.D.) age of 20.4 (2.3) years. Results: GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2-5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (-1.3 (0.8) SDS versus -2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3-12 years, AH was -2.1 (0.7) and -1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain. Conclusion: High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls.

Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome (Article)

2010-03-01T00:00:00Z

Context and Objective: GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. Design and Participants: A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m2· d) from baseline, combined with placebo (Pl) or Ox in low(0.03mg/kg · d) or conventional (0.06 mg/kg · d) dose from the age of 8yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. Results: Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean ± SD, 9.5 ± 4.7 vs. 7.2 ± 4.0 cm, P = 0.02) and per-protocol analysis (9.8 ± 4.9 vs. 6.8 ± 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH + Ox 0.06 was not significantly different from that on GH+Pl (8.3 ± 4.7 vs. 7.2 ± 4.0 cm, P=0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P = 0.001). Conclusions: In GH-treated girls with TS, we discourage the use of the conventional Oxdosage (0.06 mg/kg · d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg · d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development. Copyright

The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome (Article)

2010-03-01T00:00:00Z

The weak androgen oxandrolone (Ox) increases height gain in growth-hormone (GH) treated girls with Turner syndrome (TS), but may also give rise to virilizing side effects. To assess the effect of Ox, at a conventional and low dosage, on behavior, aggression, romantic and sexual interest, mood, and gender role in GH-treated girls with TS, a randomized, placebo-controlled, double-blind study was conducted. 133 patients were treated with GH (1.33 mg/m2/d) from baseline, combined with placebo (Pl), Ox 0.03 mg/kg/d, or Ox 0.06 mg/kg/d from the age of eight, and with estrogens from the age of 12. The child behavior checklist (CBCL), Junior Dutch Personality Questionnaire (DPQ-J), State-subscale of the Spielberger's State-Trait Anger Scale, Romantic and Sexual Interest Questionnaire, Mood Questionnaire, and Gender Role Questionnaire were filled out before, during, and after discontinuing Ox/Pl. The changes during Ox/Pl therapy were not significantly different between the dosage groups. In untreated patients, the mean CBCL total (P = 0.002) and internalizing (P = 0.003) T scores, as well as the mean DPQ-J social inadequacy SD score (SDS) (P = 0.004) were higher than in reference girls, but decreased during GH + Ox/Pl therapy (P < 0.001, P = 0.05, P < 0.001, respectively). Whereas the mean total (P = 0.01) and internalizing (P < 0.001) T score remained relatively high, the mean social inadequacy SDS became comparable with reference values. We conclude that in GH-treated girls with TS, Ox 0.03 mg/kg/d or 0.06 mg/kg/d does not cause evident psychological virilizing side effects. Problem behavior, frequently present in untreated girls with TS, decreases during therapy, but total and internalizing problem behavior remain increased.

Drug development for children: How adequate is the current European ethical guidance? (Article)

2010-01-01T00:00:00Z

Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype (Article)

2009-12-01T00:00:00Z

Context: Small for gestational age (SGA)-born children comprise a heterogeneous group in which only few genetic causes have been identified. Objective: To determine copy number variations in 18 growth-related genes in 100 SGA children with persistent short stature. Methods: Copy number variations in 18 growth-related genes (SHOX, GH1, GHR, IGF1, IGF1R, IGF2, IGFBP1-6, NSD1, GRB10, STAT5B, ALS, SOCS2, and SOCS3) were determined by an "in house" multiplex ligation-dependent probe amplification kit. The deletions were further characterized by single-nucleotide polymorphism array analysis. Results: Two heterozygous de novo insulin-like growth factor 1 receptor (IGF1R) deletions were found: a deletion of the complete IGF1R gene (15q26.3, exons 1-21), including distally flanking sequences, and a deletion comprising exons 3-21, extending further into the telomeric region. In one case, serum IGF-I was low (-2.78 SD score), probably because of a coexisting growth hormone (GH) deficiency. Both children increased their height during GH treatment (1 mg/m2per day). Functional studies in skin fibroblast cultures demonstrated similar levels of IGF1R autophosphorylation and a reduced activation of protein kinase B/Akt upon a challenge with IGF-I in comparison with controls. Conclusions: IGF1R haploinsufficiency was present in 2 of 100 short SGA children. GH therapy resulted in moderate catch-up growth in our patients. A review of the literature shows that small birth size, short stature, small head size, relatively high IGF-I levels, developmental delay, and micrognathia are the main predictors for an IGF1R deletion. Copyright

Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi syndrome (Article)

2009-11-01T00:00:00Z

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 (1mg/m2·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 SDSPWS). 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. BMISDSPWSsignificantly 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 (1mg/m2·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. Copyright

Diagnostic approach in children with short stature (Article)

2009-10-13T00:00:00Z

For early detection of pathological causes of growth failure proper referral criteria are needed, as well as a thorough clinical, radiological and laboratory assessment. In this minireview we first discuss the two consensus-based and one evidence-based guidelines for referral that have been published. The evidence-based guidelines result in a sensitivity of approximately 80% at a false-positive rate of 2%. Then, relevant clues from the medical history and physical examination are reviewed, and specific investigations based on clinical suspicion listed. In the absence of abnormal clinical findings, an X-ray of the hand/wrist and a laboratory screen are usually performed. Scientific evidence for the various components of laboratory screening is scarce, but accumulated experience and theoretical considerations have led to a list of investigations that may be considered until more evidence is available.

Growth monitoring to detect children with cystic fibrosis (Article)

2009-10-13T00:00:00Z

Background/Aims: Cystic fibrosis (CF) in infancy and childhood is often associated with failure to thrive (FTT). This would suggest that in countries without a newborn screening program for CF, FTT could be used as a clinical screening tool. The aim of this study is to assess the diagnostic performance of FTT for identifying children with CF. Methods: Longitudinal length and weight measurements up to 2.5 years of age were used from CF patients (n = 123) and a reference group (n = 2,151) in The Netherlands. Growth measurements after diagnosis were excluded. We developed five potential screening rules based upon length, weight and body mass index (BMI) standardized by age and gender (SDS). Outcome measures were sensitivity, specificity and positive predictive value (PPV). Results: BMI SDS had the highest sensitivity at low false-positive rates. An efficient scenario is a BMI SDS below -2.5 SD in combination with a decrease in BMI SDS of at least 0.5 SD. This scenario had a sensitivity of 32%, a specificity of 98.3% and a PPV of 0.75%. Conclusion: In the absence of a newborn screening program, young children with FTT for BMI are candidates to consider testing for CF.

Intelligence of very preterm or very low birthweight infants in young adulthood (Article)

2009-05-01T00:00:00Z

Objective: To examine the effect of intrauterine and neonatal growth, prematurity and personal and environmental risk factors on intelligence in adulthood in survivors of the early neonatal intensive care era. Methods: A large geographically based cohort comprised 94% of all babies born alive in the Netherlands in 1983 with a gestational age below 32 weeks and/or a birth weight >1500 g (POPS study). Intelligence was assessed in 596 participants at 19 years of age. Intrauterine and neonatal growth were assessed at birth and 3 months of corrected age. Environmental and personal risk factors were maternal age, education of the parent, sex and origin. Results: The mean (SD) IQ of the cohort was 97.8 (15.6). In multiple regression analysis, participants with highly educated parents had a 14.2-point higher IQ than those with less well-educated parents. A 1 SD increase in birth weight was associated with a 2.6-point higher IQ, and a 1-week increase in gestational age was associated with a 1.3-point higher IQ. Participants born to young mothers (<25 years) had a 2.7-point lower IQ, and men had a 2.1-point higher IQ than women. The effect on intelligence after early (symmetric) intrauterine growth retardation was more pronounced than after later (asymmetric) intrauterine or neonatal growth retardation. These differences in mean IQ remained when participants with overt handicaps were excluded. Conclusions: Prematurity as well as the timing of growth retardation are important for later intelligence. Parental education, however, best predicted later intelligence in very preterm or very low birthweight infants.

Antenatal glucocorticoid treatment is not associated with long-term metabolic risks in individuals born before 32 weeks of gestation (Article)

2008-11-01T00:00:00Z

Background: A single course of maternal glucocorticoid treatment is effective in reducing neonatal mortality after preterm birth. However, in animals, maternal glucocorticoid treatment is associated with lifelong hyperglycemia and hypertension, and impaired nephrogenesis in offspring. Findings from studies in humans on this topic are highly contradictory due to a number of methodological flaws, and renal function after glucocorticoid exposure has never been assessed. Objectives: To assess in individuals born <32 gestational weeks whether antenatal glucocorticoid treatment for preterm birth is associated with long-term metabolical risks, including renal function, in adulthood. Design: Birth cohort study. Setting: Multicentre study. Patients: 412 19 year olds born <32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort. Interventions: Maternal betamethasone 12 mg administered twice with a 24 h interval. Main outcome measures: Body composition, insulin resistance, the serum lipid profile, blood pressure and estimated renal function. Results: We did not find any long-term adverse effects of antenatal betamethasone, with the exception of an effect on glomerular filtration rate (GFR). In 19-year-old survivors, GFR was lower after betamethasone: -5.2 ml/min (95% CI -8.9 to -1.4) per 1.73 m2. Conclusions: The reduction in neonatal mortality associated with a single course of maternal betamethasone is not accompanied by long-term metabolical risks in survivors of preterm birth. The only adverse effect found was lower GFR. Although this difference was not clinically relevant at 19 years, it might predict an increased risk of chronic renal failure in prematurely born individuals who were exposed antenatally to betamethasone.

Screening rules for growth to detect celiac disease: A case-control simulation study (Article)

2008-09-11T00:00:00Z

Background: It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children. Methods: A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion. Results: Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group. Conclusion: For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease.

Randomized controlled GH trial: Effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome (Article)

2008-09-01T00:00:00Z

Background: Prader-Willi syndrome (PWS) children have impaired growth, and abnormal body composition. Previous 1-year controlled studies showed improvement of height and body composition during GH-treatment. Objective: To evaluate growth, body composition and body proportions during GH-treatment in a large group of PWS children. Design/patients: We performed a randomized controlled GH trial in 91 prepubertal PWS children (42 infants, 49 children, aged 3-14 years). After stratification for age, infants were randomized to GH-treatment (GH-group; 1 mg/m2/day; n = 20), or no treatment (control group; n = 22) for 1 year. In the second year all infants were treated with GH. After stratification for BMI, children > 3 years of age were randomized to GH-treatment (GH-group; 1 mg/m2/day; n = 27) or no treatment (control group; n = 22) for 2 years. Anthropometric parameters were assessed once in every 3 months. Body composition was measured by Dual Energy X-ray Absorptiometry. Results: Median (interquartile range, iqr) height SDS increased during 2 years of GH in infants from -2.3 (-2.8 to -0.7) to -0.4 (-1.1-0.0) and in prepubertal children from -2.0 (-3.1 to -1.7) to -0.6 (-1.1 to -0.1). In non-GH-treated children height SDS did not increase. Head circumference completely normalized during 1 and 2 years of GH in infants and children, respectively. Body fat percentage and body proportions improved in GH-treated children, but did not completely normalize. Lean body mass SDS improved compared to the control group. Serum IGF-I increased to levels above the normal range in most GH-treated children. Conclusions: Our randomized study shows that GH-treatment in PWS children significantly improves height, BMI, head circumference, body composition and body proportions. PWS children are highly sensitive to GH, suggesting that monitoring of serum IGF-I is indicated.

Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification (Article)

2008-06-01T00:00:00Z

Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition. Objective: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy. Patient: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr. Methods: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis. Results: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height. Conclusions: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height. Copyright

Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome (Article)

2008-06-01T00:00:00Z

Background: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited. Objective: To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls. Design/patients: Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group (n = 15) receiving 1 mg/m2/day GH or a non-GH-treated control group (n = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated. Results: Infants in the GH group had a median age of 2.3 years [interquartile range (IQR) 1.7-3.0] and in the control group of 1.5 years (IQR 1.2-2.7) (P = 0.17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9.3% (-5.3 to 13.3) vs. -2.9% (-8.1 to 4.9) (P < 0.05) in mental development and +11.2% (-4.9 to 22.5) vs. -18.5% (-27.9 to 1.8) (P < 0.05) in motor development, respectively. Conclusion: One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.

The diagnostic work up of growth failure in secondary health care; An evaluation of consensus guidelines (Article)

2008-05-13T00:00:00Z

Background: As abnormal growth might be the first manifestation of undetected diseases, it is important to have accurate referral criteria and a proper diagnostic work-up. In the present paper we evaluate the diagnostic work-up in secondary health care according to existing consensus guidelines and study the frequency of underlying medical disorders. Methods: Data on growth and additional diagnostic procedures were collected from medical records of new patients referred for short stature to the outpatient clinics of the general paediatric departments of two hospitals (Erasmus MC - Sophia Children's Hospital, Rotterdam and Spaarne Hospital, Haarlem) between January 1998 and December 2002. As the Dutch Consensus Guideline (DCG) is the only guideline addressing referral criteria as well as diagnostic work-up, the analyses were based on its seven auxological referral criteria to determine the characteristics of children who are incorrectly referred and the adequacy of workup of those who are referred. Results: Twenty four percent of children older than 3 years were inappropriately referred (NCR). Of the correctly referred children 74-88% were short corrected for parental height, 40-61% had a height SDS <-2.5 and 21% showed height deflection (Δ HSDS < -0.25/yr or Δ HSDS < -1). In none of the children a complete detailed routine diagnostic work up was performed and in more than 30% no routine laboratory examination was done at all. Pathologic causes of short stature were found in 27 children (5%). Conclusion: Existing guidelines for workup of children with suspected growth failure are poorly implemented. Although poorly implemented the DCG detects at least 5% pathologic causes of growth failure in children referred for short stature. New guidelines for referral are required with a better sensitivity and specificity, wherein distance to target height should get more attention. The general diagnostic work up for short stature should include testing for celiac disease in all children and for Turner syndrome in girls.

Developing evidence-based guidelines for referral for short stature (Article)

2008-03-01T00:00:00Z

Objective: To establish evidence based guidelines for growth monitoring on a population basis. Study design: Several auxological referral criteria were formulated and applied to longitudinal growth data from four different patient groups, as well as three samples from the general population. Results: Almost 30% of pathology can be detected by height standard deviation score (HSDS) below -3 or at least two observations of HSDS below -2.5 at a low false-positive rate (<1%) in 0-3-year-old infants. For 3-10-year olds, a rule concerning distance to target height of >2 SD in combination with HSDS <-2.0 has the best predictive value. In combination with a rule on severe short stature (<-2.5 SDS) and a minor contribution from a rule on "height deflection", 85.7% of children with Turner syndrome and 76.5% of children who are short because of various disorders are detected at a false-positive rate of 1.5-2%.Conclusions: The proposed guidelines for growth monitoring show high sensitivity at an acceptably low false-positive rate in 3-10-year-old children. Distance to target height is the most important criterion. Below the age of 3 years, the sensitivity is considerably lower. The resulting algorithm appears to be suitable for industrialised countries, but requires further testing in other populations.

Functional outcomes and participation in young adulthood for very preterm and very low birth weight infants: The Dutch project on preterm and small for gestational age infants at 19 years of age (Article)

2007-09-01T00:00:00Z

OBJECTIVE. Young adults who were born very preterm or with a very low birth weight remain at risk for physical and neurodevelopmental problems and lower academic achievement scores. Data, however, are scarce, hospital based, mostly done in small populations, and need additional confirmation. METHODS. Infants who were born at <32 weeks of gestation and/or with a birth weight of <1500 g in the Netherlands in 1983 (Project on Preterm and Small for Gestational Age Infants) were reexamined at age 19. Outcomes were adjusted for nonrespondents using multiple imputation and categorized into none, mild, moderate, or severe problems. RESULTS. Of 959 surviving young adults, 74% were assessed and/or completed the questionnaires. Moderate or severe problems were present in 4.3% for cognition, 1.8% for hearing, 1.9% for vision, and 8.1% for neuromotor functioning. Using the Health Utility Index and the London Handicap Scale, we found 2.0% and 4.5%, respectively, of the young adults to have ≥3 affected areas in activities and participation. Special education or lesser level was completed by 24%, and 7.6% neither had a paid job nor followed any education. Overall, 31.7% had ≥1 moderate or severe problems in the assessed areas. CONCLUSIONS. A total of 12.6% of young adults who were born very preterm and/or with a very low birth weight had moderate or severe problems in cognitive or neurosensory functioning. Compared with the general Dutch population, twice as many young adults who were born very preterm and/or with a very low birth weight were poorly educated, and 3 times as many were neither employed nor in school at age 19. Copyright

Psychomotor development in infants with Prader-Willi syndrome and associations with sleep-related breathing disorders (Article)

2007-08-01T00:00:00Z

Prader-Willi syndrome (PWS) is a neurogenetic disorder with hypotonia, psychomotor delay, obesity, short stature, and sleep-related breathing disorders. The aim of this study was to evaluate the association between psychomotor development and sleep-related breathing disorders in PWS infants. Bayley Scales of Infant Development were performed in 22 PWS infants, with a median (interquartile range, IQR) age of 1.8 (1.1-3.4) y, and a body mass index SD score (BMISDS) of -0.5 (-1.3 to 1.6). We evaluated psychomotor development in relation to results of polysomnography. Median (IQR) mental and motor development was 73.1% (64.3-79.6%) and 55.2% (46.5-63.1%) of normal children, respectively. All infants had sleep-related breathing disorders, mostly of central origin. The apnea hypopnea index was not associated with psychomotor development. Only four infants had obstructive sleep apnea syndrome (OSAS). They had a significantly delayed mental development of 65.5% (60.0-70.3%) of normal. They had a median BMISDS of 1.4 (0.1-1.6), which tended to be higher than in those without OSAS. Our data indicate that psychomotor development in PWS infants is not related to central sleep-related breathing disorders, but infants with OSAS have more severely delayed mental development, suggesting that PWS infants should be screened for OSAS.

Referral patterns of children with poor growth in primary health care (Article)

2007-06-07T00:00:00Z

Background. To promote early diagnosis and treatment of short stature, consensus meetings were held in the mid nineteen nineties in the Netherlands and the UK. This resulted in guidelines for referral. In this study we evaluate the referral pattern of short stature in primary health care using these guidelines, comparing it with cut-off values mentioned by the WHO. Methods. Three sets of referral rules were tested on the growth data of a random sample (n = 400) of all children born between 01-01-1985 and 31-12-1988, attending school doctors between 1998 and 2000 in Leiden and Alphen aan den Rijn (the Netherlands): the screening criteria mentioned in the Dutch Consensus Guideline (DCG), those of the UK Consensus Guideline (UKCG) and the cut-off values mentioned in the WHO Global Database on Child growth and Malnutrition. Results. Application of the DCG would lead to the referral of too many children (almost 80%). The largest part of the referrals is due to the deflection of height, followed by distance to target height and takes primarily place during the first 3 years. The deflection away from the parental height would also lead to too many referrals. In contrast, the UKCG only leads to 0.3% referrals and the WHO-criteria to approximately 10%. Conclusion. The current Dutch consensus guideline leads to too many referrals, mainly due to the deflection of length during the first 3 years of life. The UKCG leads to far less referrals, but may be relatively insensitive to detect clinically relevant growth disorders like Turner syndrome. New guidelines for growth monitoring are needed, which combine a low percentage of false positive results with a good sensitivity.

Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty (Article)

2007-04-01T00:00:00Z

Objective: Our objective was to assess final height (FH) and adverse effects of combined GH and GnRH agonist (GnRHa) treatment in short adolescents born small for gestational age or with normal birth size (idiopathic short stature). Design and Patients: Thirty-two adolescents with Tanner stage 2-3, age and bone age (BA) less than 12 yr for girls or less than 13 yr for boys, height SD score (SDS) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height (PAH0) less than -2.0 SDS were randomly allocated to receive GH plus GnRHa (n = 17) or no treatment (n = 15) for 3 yr. FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys. Results: FH was not different between treatment and control groups. Treated children had a larger height gain (FH - PAH0) than controls: 4.4 (4.9) and -0.5 (6.4) cm, respectively (P < 0.05). FH was higher than PAH0in 76 and 60% of treated and control subjects, respectively. During follow-up, 50% of the predicted height gain at treatment withdrawal was lost, resulting in a mean gain of 4.9 cm (range, -4.0 to 12.3 cm) compared with controls. Treatment did not affect body mass index or hip bone mineral density. Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys, albeit statistically not significant. Conclusion: Given the expensive and intensive treatment regimen, its modest height gain results, and the possible adverse effect on peak bone mineralization in males, GH plus GnRHa cannot be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age. Copyright

Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in The Netherlands. (Article)

2005-09-01T00:00:00Z

OBJECTIVE: To determine whether intrauterine growth restriction (IUGR) is a predisposing factor for high blood pressure (BP) in 19-year-olds who were born (very) preterm. METHODS: A prospective follow-up study was conducted at age 19 in individuals who born preterm in the Netherlands in 1983. Systolic, diastolic, and mean BP values and plasma renin activity concentration were obtained in 422 young adults who were born with a gestational age (GA) <32 weeks. BP values were also measured in 174 individuals who born with a GA of > or =32 weeks and a birth weight of <1500 g. RESULTS: An increased prevalence of hypertension and probably also of prehypertensive stage was found. IUGR, birth weight, GA, and plasma renin activity were not associated with BP. Current weight and BMI were the best predicting factors for systolic BP at the age of 19 years. CONCLUSIONS: The prevalence of hypertension is high in individuals who were born preterm when compared with the general population. In the individuals who were born very preterm, no support to the hypothesis that low birth weight is associated with increased BP at young adult age can be given.

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation (Article)

2001-01-01T00:00:00Z

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.

Pubertal development in The Netherlands 1965-1997 (Article)

2001-01-01T00:00:00Z

We investigated pubertal development of 4019 boys and 3562 girls >8 y of age participating in a cross-sectional survey in The Netherlands and compared the results with those of two previous surveys. Reference curves for all pubertal stages were constructed. The 50th percentile of Tanner breast stage 2 was 10.7 y, and 50% of the boys had reached a testicular volume of 4 mL at 11.5 y of age. Median age at menarche was 13.15 y. The median age at which the various stages of pubertal development were observed has stabilized since 1980. The increase of the age at stage G2 between 1965 and 1997 is probably owing to different interpretations of its definition. The current age limits for the definition of precocious are close to the third percentile of these references. A high agreement was found between the pubic hair stages and stages of pubertal (genital and breast) development, but slightly more in boys than in girls. Menarcheal age was dependent on height, weight, and body mass index. At a given age tall or heavy girls have a higher probability of having menarche compared with short or thin girls. A body weight exceeding 60 kg (+1 SDS), or a body mass index of >20 (+1 SDS), has no or little effect on the chance of having menarche, whereas for height such a ceiling effect was not observed. In conclusion, in The Netherlands the age at onset of puberty or menarche has stabilized since 1980. Height, weight, and body mass index have a strong influence on the chance of menarche.

The effect of pubertal delay by GnRH agonist in GH-deficient children on final height (Article)

2001-01-01T00:00:00Z