Hokken-Koelega, A.C.S.

Ovarian function and reproductive hormone levels in girls with prader-willi syndrome: A longitudinal study (Article)

2012-09-01T00:00:00Z

Context: The etiology of hypogonadism in girls with Prader-Willi syndrome (PWS) remains uncertain. Objectives:Theaimof the study was to evaluate gonadal function longitudinally in girls and female adolescents with PWS. Measurements: We performed a longitudinal assessment of anti-Müllerian hormone (AMH), gonadotropins, estradiol (E2), inhibin B and A, and pubertal development in girls and female adolescents with PWS. Patients and Methods: Sixty-one girls participating in the Dutch PWS Cohort study participated in the study. Serum AMH, gonadotropins, E2, and inhibin B and A levels were compared with reference values. Results: AMH levels in girls and female adolescents with PWS were comparable to reference levels between 6 months and 22 yr of age. From 10 yr of age, FSH and LH levels increased to above the 5th percentile compared to reference levels. E2and inhibin B levels were in the low normal range in the majority, and inhibin A levels were low but detectable in almost half the female adolescents with PWS. The median age at puberty onset was comparable, but the median ages at attaining Tanner M3 (P=0.05) and M4 (P<.0001) were significantly higher in girls with PWS than in healthy references. Conclusion: Our study shows that the primordial follicle pool and number of small antral follicles are conserved in girls and female adolescents with PWS. We found no classical hypogonadotropic hypogonadism. However, maturation of follicles and progression of pubertal development are impaired, which might be due to dysregulation of LH secretion. Because these impairments are not absolute, ovulation and thus conception cannot be ruled out in individual female adolescents with PWS. Copyright

Isolated GH deficiency: Mutation screening and copy number analysis of HMGA2 and CDK6 genes (Article)

2011-10-01T00:00:00Z

Objective: In most patients, the genetic cause of isolated GH deficiency (IGHD) is unknown. By identifying several genes associated with height variability within the normal population, three separate genome-wide association studies provided new candidate genes for human growth disorders. We selected two of them for genetic screening of our IGHD population. Aim:We aimed to determine whether high-mobility group A2 (HMGA2) and cyclin-dependent protein kinase 6 (CDK6) are involved in the pathogenicity of IGHD. Methods: We directly sequenced coding regions and exon-intron boundaries of the genes HMGA2 and CDK6 in 105 Caucasian IGHD patients from the Dutch HYPOPIT study. In addition, we developed a new probe set of multiplex ligation-dependent probe amplification for both genes in order to detect copy number variations. Results: In one patient with classical IGHD phenotype, we identified a new heterozygous 20 bp deletion in the intronic region of HMGA2 (c.250-29--9del), which was absent in the databases and healthy controls. Together, with recently published data concerning the 12q14 microdeletion syndrome, where patients with an HMGA2 haploinsufficiency had proportionate short stature, this study provides further support of the important role for HMGA2 in growth. In CDK6, we found only known polymorphisms. Conclusions: This study provides the first report of a deletion in the HMGA2 gene that might be related to IGHD. We suggest that this gene is investigated as a second screening in patients with a classical IGHD phenotype in which mutations in classical candidate genes have been excluded.

Diagnostic workup of the short child (Article)

2011-09-01T00:00:00Z

Documents detailing the diagnostic approach to identification of short stature in children have been generated following several consensus meetings. Besides assessment of medical history and a physical examination, specific tests are proposed based on clinical suspicion. In the absence of abnormal findings, patients are typically screened using laboratory tests and radiographs of the hand. However, there is limited evidence as to the choice of screening components; these decisions are based on clinical experience. To improve the diagnostic approach in children with short stature, diagnostic tools should be improved to allow better characterization of patient subpopulations and better measures of certain parameters. Copyright

Pubarche and serum dehydroepiandrosterone sulphate levels in children with Prader-Willi syndrome (Article)

2011-07-01T00:00:00Z

Context Premature pubarche (PP) is reported in children with Prader-Willi Syndrome (PWS). Pubarche is preceded by adrenarche - an increase in serum levels of adrenal androgens, most specifically dehydroepiandrosterone sulphate (DHEAS). Objectives To assess DHEAS levels, the age at and progression of pubarche and the prevalence of PP in children with PWS. Design/Patients In the Dutch PWS Cohort Study, 120 children (6 months-17 years) are prospectively followed. Their age at onset of pubarche and various pubic hair stages and prevalence of PP were determined. Serum DHEAS levels were assessed in 97 children. Results Median serum DHEAS levels were significantly higher in children with PWS than in healthy age-matched controls at ages 3-6 years (girls: P = 0·004 and boys: P = 0·010) and 6-10 years (girls: P = 0·045 and boys: P = 0·001). Age and gender significantly influenced DHEAS levels in children with PWS. The median [P10-P90] age at onset of pubarche in children with PWS was significantly younger than in healthy peers, 9·04[6·75-11·84] years in PWS girls (P < 0·0001) and 10·31 [8·65-12·29] years in PWS boys (P = 0·003). The prevalence of PP in children with PWS was 30·0% in girls and 16·1% in boys. Conclusions Compared to healthy children, children with PWS have significantly higher DHEAS levels from 3 to 10 years of age. They are younger at onset of pubarche and have a higher prevalence of premature pubarche. DHEAS levels in PWS are influenced by age and gender. Our findings indicate earlier maturation of the zona reticularis of the adrenal glands in children with PWS.

Maternal smoking during pregnancy and subcutaneous fat mass in early childhood. The Generation R Study (Article)

2011-04-01T00:00:00Z

Maternal smoking during pregnancy increases the risk of obesity in the offspring. Not much is known about the associations with other measures of body composition. We assessed the associations of maternal smoking during pregnancy with the development of subcutaneous fat mass measured as peripheral and central skinfold thickness measurements in early childhood, in a population-based prospective cohort study from early fetal life onward in the city of Rotterdam, The Netherlands. The study was performed in 907 mothers and their children at the ages of 1.5, 6 and 24 months. As compared to non-smoking mothers, mothers who continued smoking during pregnancy were more likely to have a younger age and a lower educational level. Their children had a lower birth weight, higher risk of small size for gestational age and were breastfed for a shorter duration (P-values <0.01). We did not observe differences in peripheral, central and total subcutaneous fat mass between the offspring of non-smoking mothers, mothers who smoked in first trimester only and mothers who continued smoking during pregnancy (P > 0.05). Also, the reported number of cigarettes smoked by mothers in both first and third trimester of pregnancy were not associated with peripheral, central and total subcutaneous fat mass in the offspring at the ages of 1.5, 6 and 24 months. Our findings suggest that fetal exposure to cigarette smoke during pregnancy does not influence subcutaneous fat mass in early childhood. Follow-up studies are needed in children at older ages and to identify associations of maternal smoking during pregnancy with other measures of body composition.

Anti-Müllerian hormone in short girls born small for gestational age and the effect of growth hormone treatment (Article)

2011-04-01T00:00:00Z

Background Fetal growth restriction is thought to negatively influence reproductive function in later life. Serum anti-Mllerian hormone (AMH) is a marker of the primordial follicle pool. The objectives of this study were to evaluate the effect of being born small for gestational age (SGA) on serum AMH levels and to investigate the effect of growth hormone (GH) treatment on serum AMH levels in short SGA girls.Methods Serum AMH levels were investigated in 246 prepubertal girls aged 310 years: 119 untreated short SGA and 127 healthy controls. Associations between AMH levels and clinical characteristics were analysed using multiple regression analyses. In addition, we investigated the effect of GH treatment on serum AMH levels in short SGA girls.Results Serum AMH levels were similar in short SGA and healthy control girls (P 0.95). In short SGA girls, AMH levels were not significantly influenced by birth weight standard deviation score (SDS), birth length SDS and gestational age, even after adjustment for age, height SDS and body mass index (BMI) SDS at sampling, socio-economic status and maternal smoking during gestation. Serum AMH levels did not change during 4 years of GH treatment in short SGA girls (P 0.43). Conclusions Serum AMH levels in prepubertal short SGA girls are similar to healthy controls, indicating that the follicle pool is not compromised due to SGA birth. GH treatment has no effect on AMH levels in short SGA girls.

Pathways leading to atherosclerosis: A structural equation modeling approach in young adults (Article)

2011-02-01T00:00:00Z

Several risk factors of cardiovascular diseases have been studied using direct association measures. Because the incidence of obesity and cardiovascular diseases is rising, it is important to correctly model these risk factors involved in development of cardiovascular diseases. Until now, statistical methods lacked to achieve this goal because of complex interrelationships involved. Structural Equation Modeling (SEM) is an advanced statistical technique that enables solving this issue. The aims of this study were to investigate whether SEM could unravel pathways involved in cardiovascular diseases and to visualize these pathways in a model. In 322 healthy participants of the PROGRAM (PROgramming factors for GRowth And Metabolism) study, 18 to 24 years of age, we explored pathways leading to atherosclerosis measured by carotid intima-media thickness. Using SEM, we were able to model these pathways for males and females using body fat percentage, serum lipid levels, and blood pressure. We are the first to present a model of complex direct and indirect effects of fat mass leading to atherosclerosis using SEM. Both male and female path-model had an excellent fit. Fat mass had a significant effect on carotid intima-media thickness through various pathways, with the largest effect size on carotid intima-media thickness via blood pressure. SEM showed that the pathways differed between males and females, with a larger effect of serum lipids on carotid intima-media thickness in males. In conclusion, SEM is suitable in identifying models to unravel potential causal pathways in complex origins of diseases. We present a model involving several pathways, showing that fat mass has an influence on risk factors for atherosclerosis, already at 21 years of age.

Foetal and postnatal growth and bone mass at 6 months: The Generation R Study (Article)

2011-02-01T00:00:00Z

Objective To examine whether parental, foetal and postnatal characteristics and growth patterns in foetal life and infancy are associated with bone mass at 6 months, as bone acquisition seems to be associated with genetic and environmental factors. Design This study was embedded in the Generation R Study, a prospective cohort from early foetal life onwards. Patients and measurements Bone mineral density (BMD) and bone mineral content (BMC) total body (TB) and BMD lumbar spine (LS) were measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, foetal and postnatal data were collected by physical and foetal ultrasound examinations and questionnaires. Results Maternal, foetal and postnatal anthropometrics were positively associated with BMDTBand BMCTBat 6 months, but only postnatal anthropometrics were associated with BMDLS. A gain in weight-SD-score during foetal life and prenatal catch-up in weight were positively associated with BMDTB. After birth, a gain in weight-SD-score was positively associated with BMDLSand bone mineral apparent density (BMADLS). The effect was strongest between 6 weeks and 6 months. Catch-up in weight was associated with a lower probability of low (lowest quartile of) BMDTBand BMDLS. Children remaining in the first tertile of weight from birth to 6 months had a much higher risk of low BMDTBat 6 months [OR (95% CI): 15 (2, 88)]. Conclusions Our findings suggest that growth patterns in foetal and postnatal life are associated with bone mass in infancy and may have consequences for bone mass in later life. Follow-up studies are needed to assess whether and to what extent maternal anthropometrics, foetal and postnatal growth patterns have an effect on bone status in adulthood.

Disturbance of glucose homeostasis after pediatric cardiac surgery (Article)

2011-02-01T00:00:00Z

This study aimed to evaluate the time course of perioperative blood glucose levels of children undergoing cardiac surgery for congenital heart disease in relation to endogenous stress hormones, inflammatory mediators, and exogenous factors such as caloric intake and glucocorticoid use. The study prospectively included 49 children undergoing cardiac surgery. Blood glucose levels, hormonal alterations, and inflammatory responses were investigated before and at the end of surgery, then 12 and 24 h afterward. In general, blood glucose levels were highest at the end of surgery. Hyperglycemia, defined as a glucose level higher than 8.3 mmol/l (>150 mg/dl) was present in 52% of the children at the end of surgery. Spontaneous normalization of blood glucose occurred in 94% of the children within 24 h. During surgery, glucocorticoids were administered to 65% of the children, and this was the main factor associated with hyperglycemia at the end of surgery (determined by univariate analysis of variance). Hyperglycemia disappeared spontaneously without insulin therapy after 12-24 h for the majority of the children. Postoperative morbidity was low in the study group, so the presumed positive effects of glucocorticoids seemed to outweigh the adverse effects of iatrogenic hyperglycemia.

Preterm birth does not affect bone mineral density in young adults (Article)

2011-01-01T00:00:00Z

Objective: Previous studies showed conflicting data on the effect of prematurity on bone mineral density (BMD) in infants and children. Only a few studies investigated the long-term effects of prematurity on BMD in early adulthood. The objective of our study was to assess the long-term effects of preterm birth on BMD of the total body (BMDTB), lumbar spine (BMDLS) and bone mineral apparent density of the LS (BMAD LS). Design: Cross-sectional study. Methods: It consists of two hundred and seventy-six healthy subjects without serious postnatal complications, aged 18-24 years. The contribution of gestational age to the variance in BMD in young adulthood and the differences in BMD between 151 subjects born preterm (median gestational age 32.2 weeks (interquartile range (IQR) 30.3-34.0)) and 125 subjects born at term (median gestational age 40.0 weeks (IQR 39.0-40.0)) were investigated. BMD was determined by dual-energy X-ray absorptiometry. Results: There were no significant linear correlations between gestational age and BMDTB (r = 0.063, P = 0.30), BMDLS (r = 0.062, P = 0.31) and BMADLS (r = 0.069, P = 0.26). Also after adjustment for possible confounders, gestational age was no significant contributor to the variance in BMDTB (P = 0.27), BMDLS (P = 0.91) and BMADLS (P = 0.87). No significant differences were found between preterm and term subjects with regard to BMDTB, BMD LS and BMADLS. Conclusion: In our cohort of 276 young adults, aged 18-24 years, gestational age was not a significant determinant in the variance of BMD. Preterm birth without serious postnatal complications is not associated with a lower BMD in young adulthood.

Socioeconomic Status is not Inversely Associated with Overweight in Preschool Children (Article)

2010-12-01T00:00:00Z

Objective: To assess whether socioeconomic inequalities were already present in preschool children. Study design: We used data from 2954 Dutch children participating in a longitudinal birth cohort study. Indicators of socioeconomic status were mother's educational level and household income. Body mass index (BMI)-for-age standard deviation scores were derived from a national reference. Overweight was defined at 24 and 36 months according to age- and sex-specific cut-off points for BMI. Multivariable regression analyses were performed. Results: Relative to children from mothers with the highest educational level, mean BMI standard deviation scores was lower at age 24 months in children from mothers with the low, mid-low, and mid-high educational level, and in the mid-low group at 36 months (P < .001). Prevalence of overweight was lower in children from mothers with the mid-low educational level at age 24 and 36 months (adjusted odds ratio at 24 months: 0.61; 95% confidence interval: 0.43-0.87 and at 36 months: 0.65; 95% confidence interval: 0.44-0.96) but was not significantly different for the other educational levels. There were no significant differences in childhood overweight by income level. Conclusions: The inverse association between socioeconomic status and childhood overweight presumably emerges after age 3 years. Before this age, the gradient may be the reverse.

Insulin resistance in children: Consensus, perspective, and future directions (Article)

2010-12-01T00:00:00Z

Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases. Copyright

Influence of preterm birth and small birth size on serum anti-Müllerian hormone levels in young adult women (Article)

2010-12-01T00:00:00Z

Background/objectives: Preterm birth has been associated with reduced reproduction rates, and controversies remain regarding the effect of being born small for gestational age (SGA) on ovarian function. Recent findings in young men showed no effect of preterm and SGA birth on testis function. We hypothesised that follicle pool size in young adult women is also not affected by preterm and SGA birth. Design/methods: In 279 young women of the PROGRAM/PREMS study, aged 18-24 years, the influence of gestational age, birth length and birth weight on serum levels of anti-Müllerian hormone (AMH) was analysed with multiple regression modelling. Additionally, AMH levels were analysed in preterm- versus term-born females and in three subgroups: females born SGA with either short stature or catch-up growth (SGA-CU), and females born term and appropriate for gestational age with normal stature (AGA controls). Results: Preterm and SGA birth did not affect AMH and other hormone levels. Older age at menarche and oral contraceptive pill use (OC-use) were related to lower AMH levels, and maternal smoking during gestation was related to higher AMH levels. After correction for maternal smoking, lower socioeconomic status (SES) was associated with lower AMH levels. In subgroup comparisons, SGA-CU women showed higher AMH levels than AGA controls, also after adjustment for several factors. Conclusion: Preterm and SGA birth did not affect AMH levels. Factors associated with serum AMH levels were OC-use, age at menarche, maternal smoking during gestation and SES. We conclude that preterm- and/or SGA-born females are not likely to have a reduced follicle pool size.

Glucocorticoid receptor gene haplotypes are not associated with birth anthropometry, blood pressure, glucose and insulin concentrations, and body composition in subjects born small for gestational age (Article)

2010-12-01T00:00:00Z

Objective: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programing of the hypothalamic - pituitary - adrenal axis has been suggested as a possible explanation. Fetal glucocorticoid (GC) overexposure has effects that suggest a role of GCs in this programing. The effects of GCs are mediated through the GC receptor (GR or NR3C1). Several functional polymorphisms have been described, which are associated with relative GC resistance or hypersensitivity. Our aim is to compare frequencies of GR haplotypes, characterized by the R23K, N363S, Bcl1, or 9β polymorphisms, in subjects born small for gestational age (SGA) and associate birth anthropometry data, response to GH treatment, blood pressure, glucose and insulin concentrations, and body composition with these haplotypes. Design: In total, 418 SGA subjects and 697 healthy controls were enrolled in this study. Methods: Anthropometry data were obtained, as well as blood samples to determine fasting glucose and insulin concentrations. Dual energy X-ray absorptiometry scans were used to measure the amount of fat and lean mass. Results: No differences were found between GR haplotype frequencies in SGA children compared with healthy controls. No associations were found between GR haplotypes and birth length and birth weight, growth response during GH treatment, blood pressure, glucose and insulin concentrations, and body composition. Conclusion: GR haplotypes and their effect on GC sensitivity do not seem to play a significant role in GH-induced catch-up growth and the risk factors of developing metabolic and cardiovascular disorders in adult life of SGA children.

Should short children born small for gestational age with a distance to target height <1 standard deviation score be excluded from growth hormone treatment? (Article)

2010-09-01T00:00:00Z

Context The criteria for starting growth hormone (GH), an approved treatment for short children born small for gestational age (SGA), differ between Europe and the USA. One European requirement for starting GH, a distance to target height (DTH) of ≥1 standard deviation score (SDS), is controversial. Objective To investigate the influence of DTH on growth during GH treatment in short SGA children and to ascertain whether it is correct to exclude children with a DTH <1 SDS from GH. Patients A large group of short prepubertal SGA children (baseline n = 446; 4 years GH n = 215). Measurements We analysed the prepubertal growth response during 4 years of GH. We investigated the influence of the continuous variable DTH SDS on growth response and a possible DTH SDS cut-off level below which point the growth response is insufficient. Results Height gain SDS during 4 years of GH showed a wide variation at every DTH SDS level. Multiple regression analyses demonstrated that, after correction for other significant variables, an additional DTH of 1 SDS resulted in 0·13 SDS more height gain during 4 years of GH. We found no significant differences in height gain below and above certain DTH SDS cut-off levels. Conclusions DTH SDS had a weak positive effect on height gain during 4 years of GH, while several other determinants had much larger effects. We found no support for using any DTH cut-off level. Based on our data, excluding children with a DTH <1 SDS from GH treatment is not justified.

Phenotype-genotype correlation in a familial IGF1R microdeletion case (Article)

2010-07-01T00:00:00Z

Background: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype - phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. Methods and results: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. Conclusion: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

Growth patterns during childhood and the relationship with acylation-stimulating protein (Article)

2010-06-01T00:00:00Z

Background/Objectives Acylation-stimulating protein (ASP) is an adipose tissue-derived hormone, which stimulates glucose and free fatty acid (FFA) uptake into adipocytes. Changes in ASP metabolism are associated with alterations in lipid metabolism. As postnatal catch-up growth has been associated with dyslipidaemia in later life, we investigated the association between ASP and birth size, adult size and different growth patterns during childhood. Methods The associations were investigated by multiple regression analyses in 285 young adults, aged 18-24. Subsequently, differences in ASP were analysed in four clinically relevant subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age with idiopathic short stature (ISS) or with normal stature (controls). Results Weight gain during childhood, particularly fat accumulation, was positively related to ASP levels in early adulthood, independent of birth size, age and gender. Foetal growth, reflected by birth size, was not related to ASP levels. Between the subgroups, no differences in ASP were found, but SGA-CU and ISS subjects had significantly higher levels of FFA. Conclusion Exaggerated weight gain during childhood, but not foetal growth, contributes to alterations in ASP metabolism, which may be associated with impaired FFA uptake and delayed triglycerides clearance. Therefore, exaggerated weight gain during childhood should be prevented.

Adult height and health-related quality of life after growth hormone therapy in small for gestational age subjects (Article)

2010-06-01T00:00:00Z

Objective: To estimate health-related quality of life (HRQoL) in non-growth hormone deficient (GHD) small for gestational age (SGA) children before and after growth hormone (GH) treatment to adult height (AH). Methods: This was a multicentre, two-arm trial. Following an initial 2-year double-blind study period, patients entered a 2-year extension period followed by treatment to AH. At baseline patients were randomised to GH (0.033 or 0.067 mg/kg/day) and continued treatment at that dose until AH. Height was assessed at baseline and 3-monthly intervals to AH (height velocity <2 cm/year). Height standard deviation score (SDS) before and after GH therapy was mapped onto estimated HRQoL scores up to AH. Results: Of the 79 children randomised into the study 53 were non-GHD (defined as peak GH >20 mU/L [peak 24-h GH value and peak arginine tolerance test]). At baseline these children had a mean (mean [±SD]) height SDS of -3.2 (0.7), height velocity SDS -0.6 (1.2) and age, 8.1 (1.9) years. Estimated HRQoL scores were significantly (p < 0.001) increased from baseline at AH (HRQoL, 95 CI) (0.033 mg/kg/day, 0.112 [0.092, 0.132]; 0.067 mg/kg/day, 0.115 [0.094, 0.136]). HRQoL was not different between treatment groups. A significant gain in AH, relative to an SGA reference population, was reported in GH-treated patients. Mean (95 CI) AH SDS (0.033 mg/kg/day, 1.4 [1.1, 1.6]. 0.067 mg/kg/day, 1.7[1.4, 2.0]). Limitations: The analysis assumes HRQoL can be mapped onto height SDS. Conclusions: GH treatment in short children born SGA without signs of persistent catch-up growth was associated with significant improvement in HRQoL and normalisation of AH.

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 (Article)

2010-05-01T00:00:00Z

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), β-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/m2per 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/m2per 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 SDSheight, percentage trunk fat, lean body mass SDSheight, and GH and IGF1 levels in favor of treatment with GnRHa and the higher GH dose of 2 mg/m2per day.

PROP1, HESX1, POU1F1, LHX3 and LHX4 mutation and deletion screening and GH1 P89L and IVS3+1/+2 mutation screening in a dutch nationwide cohort of patients with combined pituitary hormone deficiency (Article)

2010-04-01T00:00:00Z

Background/Aims: Mutation frequencies of genes involved in combined pituitary hormone deficiency (CPHD) vary substantially between populations. The HYPOPIT study aims to obtain an overall picture of known and new genetic defects and variations in a nationwide cohort of Dutch (mostly) sporadic CPHD patients. Methods: We screened 79 CPHD patients from 78 families (regardless of MRI and hormonal phenotype) for mutations and deletions in PROP1, HESX1, POU1F1, LHX3 and LHX4, as well as the P89L and IVS3+1/+2 mutations in GH1, recently described to cause pituitary hormone impairment in addition to GH deficiency. Results: We did not find any mutation or deletion in PROP1, HESX1, LHX3 or LHX4, nor GH1 P89L and GH1 IVS3+1/+2 mutations. Among 12 patients with a typical 'POU1F1 phenotype', 1 patient was formerly known to have a POU1F1 mutation. This results in a POU1F1 mutation frequency in these patients of 8.3%. Conclusion: Thorough screening for mutations and deletions in PROP1, HESX1, POU1F1, LHX3, LHX4, as well as screening for GH1 P89L or GH1 IVS3+1/+2 mutations, did not reveal any genetic defect in our cohort of CPHD patients except for one formerly known POU1F1 mutation in 1 patient. Future research should focus on alternative explanations for CPHD, like other genes or environmental factors.

Cardiovascular and metabolic risk profile and acylation-stimulating protein levels in children with Prader-Willi syndrome and effects of growth hormone treatment (Article)

2010-04-01T00:00:00Z

Context: Reports on the cardiovascular and metabolic risk profile in children with Prader-Willi syndrome (PWS) and the effects of GH treatment are scarce. Acylation-stimulating protein (ASP) stimulates glucose uptake and triglyceride storage in adipose tissue. Objectives: The aim was to study the metabolic and cardiovascular risk profile and ASP levels and to investigate the effects of GH treatment. Design: We conducted a randomized controlled GH trial. Infants and prepubertal children were assigned to receive GH (1 mg/m2·d) or to serve as controls for 12 and 24 months, respectively. Patients: Eighty-five children with PWS (mean ± SD age of 4.9 ± 3.0 yr) participated in the study. Main Outcome Measures: We measured fat percentage (fat%) with dual-energy x-ray absorptiometry, blood pressure, fasting insulin and glucose levels, serum lipids, and ASP levels. Results: Mean ± SD fat% was 28.4 ± 6.2 in infants and 36.9 ± 8.5 in prepubertal children. Fat% SD score (SDS) was above 2 SDS in 95% of prepubertal children. In addition, 63% of infants and 73% of prepubertal children demonstrated at least one cardiovascular risk factor, defined as hypertension or dyslipidemia. The metabolic syndrome was demonstrated in 5% of all children. Mean ± SD baseline ASP was 107 ± 45 nmol/liter (normal < 58 nmol/liter) and correlated with fat mass and TG levels. GH improved fat%SDS and the HDLc/LDLc ratio (P < 0.0001 and P = 0.04). GH had no effect on mean ASP levels in this population. Conclusions: Many children with PWS had dyslipidemia and high ASP levels. GH improved fat% and high-density lipoprotein cholesterol/low-density lipoprotein cholesterol, but not ASP. High ASP levels may prevent complete normalization of fat%SDS during GH treatment but may contribute in keeping glucose and insulin levels within normal range. Copyright

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

Serum insulin-like growth factor-binding protein-2 levels and metabolic and cardiovascular risk factors in young adults and children born small for gestational age (Article)

2010-02-01T00:00:00Z

Background: IGF binding protein (IGFBP)-2 might protect against cardiovascular disease. Small for gestational age (SGA) birth could be associated with a higher risk for type 2 diabetes mellitus and cardiovascular disease in later life. No data are available on the relationship between serum IGFBP-2 levels and cardiovascular risk factors in young adults and children born SGA. Objective: The aim of the study was to determine circulating IGFBP-2 levels in subjects born SGA and to investigate the association with cardiovascular risk factors. Methods: IGFBP-2 levels were measured in sera from 151 young adults born SGA and 147 short SGA children. Age-andgender-adjusted SD scores (SDS) were calculated. We determined blood pressure, serum lipids, body composition by dual-energy x-ray absorptiometry, and glucose homeostasis by homeostasis model of assessment for insulin resistance or frequently sampled iv glucose tolerance test. Results: Serum IGFBP-2 SDS was significantly reduced in SGA young adults (with normal or short stature). Fat mass SDS was relatively high in SGA young adults and was reduced in short SGA children. Serum IGFBP-2 SDS in SGA young adults correlated positively with insulin sensitivity and negatively with fat mass SDS, insulin secretion (acute insulin response), fasting insulin, homeostasis model of assessment for insulin resistance, total cholesterol, triglycerides, and blood pressure SDS. The association between serum IGFBP-2 SDS and insulin sensitivity, blood pressure, total cholesterol, and triglyceride levels persisted after adjustment for known covariates including fat mass SDS. In short SGA children, IGFBP-2 SDS did not correlate with any of the cardiovascular risk factors. Conclusion: In young adultswhowere born SGA, serum IGFBP-2 levels associate with cardiovascular risk markers. Copyright

Insulin VNTR and IGF-1 promoter region polymorphisms are not associated with body composition in early childhood: The generation R study (Article)

2010-02-01T00:00:00Z

Objective: The objective of this study was to examine the associations between insulin gene variable number of tandem repeats (INS VNTR) and insulin-like growth factor 1 (IGF1) gene promoter region polymorphisms with body composition in early childhood. Methods: This study was embedded in an ongoing prospective cohort study. Growth in early childhood (body mass index, total subcutaneous fat mass and waist-hip ratio) was assessed at birth and at the ages of 6 weeks and 24 months. DNA for genotyping was available in 738 children. Results: The genotype distribution of the INS VNTR gene was I/I 50.4%, I/III 40.4%, and III/III 9.2%. IGF1 genotypes were categorized in the following categories based on their 192-bp allele: homozygous (wild-type) 43.1%, heterozygous 45.8%, and noncarrier 11.2%. No differences were found in body mass index, total subcutaneous fat mass and waist-hip ratio in early childhood between the three groups for both the INS VNTR and IGF1 genotypes. We also did not find interactions between these genotypes and gender or birth weight on the effects of body composition measures. Conclusions: Our results do not support previous studies showing associations between INS VNTR and IGF1 promoter region polymorphisms with body composition in early childhood. Copyright

Interactions between TCF7L2 genotype and growth hormone-induced changes in glucose homeostasis in small for gestational age children (Article)

2010-01-01T00:00:00Z

Context The Transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism has been associated with risk of developing type 2 diabetes mellitus (DM), possibly by decreasing insulin secretion. Small for gestational age (SGA) birth has been associated with type 2 DM in later life. Growth hormone (GH) treatment reduces insulin sensitivity and increases insulin secretion. Therefore, GH-treated SGA children are an ideal group to investigate whether the TCF7L2 rs7903146 genotype is associated with changes in glucose homeostasis. Objective To determine the impact of the TCF7L2 rs7903146 polymorphism on changes in insulin secretion and insulin sensitivity during 4 years of GH treatment in children born SGA. Subjects A total of 246 Caucasian short children born SGA, with a median age of 7·8 years. Outcome measures Insulin sensitivity and insulin secretion were measured by the frequently sampled intravenous glucose tolerance test (FSIGT) (n = 68) and homeostasis model assessment (HOMA) calculations (all). Results There was no association between rs7903146 genotype and insulin sensitivity or insulin secretion at baseline but after adjustment for possible confounders, insulin secretion was higher in the CT/TT group than in the CC group. During GH treatment, carriers of the rs7903146 T allele had an increase in insulin secretion similar to that of carriers of the CC genotype. The decrease in insulin sensitivity was only significant in the CT/TT group, but the difference in decrease between genotype groups did not reach significance (P = 0·06). The disposition index (insulin secretion × insulin sensitivity), which is an estimate of beta cell function, was not associated with genotype and did not change during GH treatment. Conclusion The TCF7L2 rs7903146 polymorphism is not associated with the change in insulin secretion during GH treatment in short SGA children.

The PPAR-γ Pro12Ala polymorphism associates with weight gain during GH-treatment in short children born small for gestational age (Article)

2010-01-01T00:00:00Z

Context: Short children born small for gestational age (SGA) have a lean phenotype with lower insulin sensitivity and higher blood pressure. GH treatment results in weight gain, and a decrease in blood pressure and insulin sensitivity. However, not all children respond in the same way. The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR-gγ) gene is inversely associated with body mass index (BMI), changes in BMI and the risk to develop type 2 diabetes mellitus. Objective: To analyze the contribution of the PPAR-γ Pro12Ala polymorphism to GH induced changes in determinants of metabolic and cardiovascular disease in short SGA children. Methods: PPAR-γ was genotyped in 238 Caucasian short SGA children (mean age 7.5 years). Height, weight, blood pressure, and serum lipids were measured before start and during 4 years of GH treatment. In addition, glucose homeostasis by homeostasis model assessment insulin resistance ratio (HOMA-IR) (n=148) and by frequently sampled i.v. glucose tolerance test (n=51), and body composition by dual energy X-ray absorptiometry (n=79) were measured. Results: At baseline, the Ala12 allele was not associated with any determinant of metabolic and cardiovascular disease. After 4 years of GH treatment, the increase in weight for height SDS and BMI SDS was significantly greater in carriers of an Ala12 allele than in noncarriers. The change in all other parameters was not associated with Pro12Ala genotype. Conclusion: The Ala12 variant of the PPAR-γ gene is associated with higher weight gain during GH treatment but not with changes in determinants of metabolic and cardiovascular diseases in Caucasian subjects born SGA.

Genetic polymorphisms in the locus control region and promoter of GH1 are related to serum IGF-I levels and height in patients with isolated growth hormone deficiency and healthy controls (Article)

2010-01-01T00:00:00Z

Background/Aims: Expression of the human growth hormone (GH) gene (GH1) is regulated by a locus control region (LCR) and the highly polymorphic GH1 promoter. We analyzed GH1 LCR/promoter single nucleotide polymorphisms (SNPs) in patients with isolated growth hormone deficiency (IGHD) in relation to clinical data. Methods: We directly sequenced the GH1 LCR/promoter of 62 Dutch IGHD patients without mutations or deletions in GH1 or GHRHR and of 72 controls with normal height. We related GH1 LCR/promoter SNPs to height, serum insulin-like growth factor 1 (IGF-I) levels and response to GH treatment. Results: In IGHD patients, promoter SNPs 6, 8 and 9 were associated with height and IGF-1 levels. In controls, SNPs 6 and 11 were associated with height. Homozygosity for the minor allele of SNP 9, associated with lower IGF-I levels in patients, was significantly more frequent among patients than among controls. Genotypes based on SNPs 6, 8, 9 and 11 explained 10.8% of IGF-I SDS variation in IGHD patients and 15.9% of height SDS variation in controls. Conclusion:GH1 Promoter SNPs 6, 8 and 9 were associated with height and IGF-1 levels among patients, and SNPs 6 and 11 with height in controls. Copyright

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

Influence of preterm birth and birth size on gonadal function in young men (Article)

2009-11-01T00:00:00Z

Background/Objectives: Preterm birth has been associated with reduced reproduction rates and being born small for gestational age (SGA) with reduced gonadal function. We hypothesized that alterations concerning gonadal function in young men are not due to preterm birth or being born SGA, but are due to other (environmental) factors. Methods: In 207 young men of the PROGRAM/PREMS cohort study, aged 18-24 yr, the influence of preterm birth, birth length, and birth weight on serum levels of anti-Mullerian hormone, inhibin B, testosterone, SHBG, non-SHBG-bound testosterone, LH, and FSH was analyzed with multiple regression modeling. In addition, markers of male gonadal function were analyzed in four subgroups: men born SGA with either short stature or catch-up growth, or men born appropriate for gestational age with idiopathic short stature or with normal stature (control). Results: Preterm birth and SGA did not affect gonadal function. After adjustment for age, birth size, adult height, fat mass, and socioeconomic status (SES), preterm birth even showed a positive relation with inhibin B. Higher SES was associated with higher inhibin B levels. Higher fat mass was associated with decreased testosterone and SHBG levels and maternal smoking with increased LH and non-SHBG-bound testosterone levels. After adjustment for confounders, there were no significant differences in gonadal function between the subgroups. Conclusion: Preterm birth and SGA did not affect gonadal function in young men. Factors that affected gonadal function were: lower SES, a higher fat mass, and maternal smoking during pregnancy. Copyright

Bone mineral density and effects of growth hormone treatment in prepubertal children with Prader-Willi syndrome: A randomized controlled trial (Article)

2009-10-19T00:00:00Z

Background: Bone mineral density (BMD) is unknown in children with Prader-Willi syndrome (PWS), but is decreased in adults with PWS. In patients with GH deficiency, BMD increases during GH treatment. Objectives: The aim of the study was to evaluateBMDin children with PWS and to study the effects of GH treatment. Design: We conducted a randomized controlled GH trial. Forty-six prepubertal children were randomized into either a GH-treated group (1.0 mg/m2· d) or a control group for 2 yr. At start, 6, 12, and 24 months of study, total body and lumbar spine BMD were measured by dual-energy x-ray absorptiometry, and lumbar spine bone mineral apparent density (BMAD) was calculated. Results: Base line total body and lumbar spine BMDSD score (SDS) were normal [mean(SD),-0.2SDS(1.1) and -0.4 SDS (1.2), respectively]. BMADSDS, which corrects for short stature, was also normal [mean (SD), 0.40 SDS (1.1)]. Total body BMDSDS decreased during the first 6 months of GH (P < 0.0001), but increased during the second year of treatment. After 24 months of study, total body and lumbar spine BMDSDS, and the BMADSDS did not significantly differ between GH-treated children and randomized controls (P = 0.30, P = 0.44, and P = 0.47, respectively). Results were similar when corrected for body mass index SDS. Repeated measurements analysis showed a significant positive association between IGF-I SDS and total body and lumbar spine BMDSDS, but not with BMADSDS. Conclusions: Our results show that prepubertal children with PWS have a normal BMD. GH treatment had no effect on BMD, except for a temporary decrease of total body BMDSDS in the first 6 months. Copyright

The -G1245A IGF1 polymorphism is related with small head size and less brain sparing in small for gestational age born children (Article)

2009-09-08T00:00:00Z

Context: Small for gestational age (SGA) subjects experience pre- and postnatal growth restriction, which might be influenced by polymorphisms in the IGF1 gene. The well-known -841(CA)n/192 bp polymorphism has been associated with birth size, cardiovascular disease, and IGF-1 levels, and is in linkage disequilibrium with the KG1245A single nucleotide polymorphism (SNP; rs35767). Objective: To associate the -G1245A SNP with head circumference (HC) and brain sparing (a greater head compared with height SDS) in short SGA and SGA catch-up subjects. Design: Gene association study. Patients: We studied 635 SGA subjects out of which 439 remained short and 196 had a postnatal height >-2.00 SDS. Measurements: The -G1245A SNP IGF1 gene polymorphism and head size. Results: All SGA subjects had a postnatal head size below the population mean (-1.01 SDS, P<0.001). Whereas SGA catch-up subjects had a head size that was in proportion with their height, short SGA subjects displayed extensive brain sparing (HC - height: SGA CU: 0.01 versus short SGA: 1.75 SDS, P<0.001). The most severely SGA born subjects had a 0.4 SDS smaller postnatal head size and 0.6 SDS less brain sparing when carrying the -1245 A-allele in contrast to G-allele carriers (P=0.03). The association between the -G1245A SNP and head size remained significant after correction for birth weight and postnatal height SDS (P=0.03). Birth weight, birth length and postnatal height SDS were not related with the - G1245A SNP. Conclusions: The -1245 A-allele of the IGF1 promoter SNP is associated with a small head size and less brain sparing in SGA born subjects and particularly those with the lowest birth weight.

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies (Article)

2009-07-17T00:00:00Z

Background: An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy. Methods: This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort. Results: Minor allele frequency did not differ significantly (p = 0.47)between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort. Conclusion: We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis (Article)

2009-07-01T00:00:00Z

Objective: Corticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis. Patients and design: Twenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-α (determining most of the cortisol effect), GR-P (increasing GR-α effect) and GR-β (inhibitor of GR-α) were measured quantitatively. Main results: Neutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-α and GR-P splice variants on day 0 compared to after recovery. GR-α and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-β mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = -0.60, P = 0.009). Conclusions: Children with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock.

The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children (Article)

2009-07-01T00:00:00Z

Context We previously reported that short, small for gestational age (SGA) children who were born preterm have a lower body fat percentage and a higher blood pressure, insulin secretion and disposition index than short SGA children born at term. Whether preterm birth also influences these parameters during GH treatment is unknown. Objective To compare blood pressure, insulin sensitivity, beta-cell function and body composition during 4 years of GH treatment, between preterm and term short SGA children. Patients A total of 404 prepubertal non-GH-deficient short SGA children were divided into 143 preterm (< 36 weeks) and 261 term children. Outcome measures Height, blood pressure (n = 404), body composition measured by dual energy X-ray absorptiometry (DXA) (n = 138) and insulin sensitivity and beta-cell function calculated from a frequent sampling intravenous glucose tolerance test (FSIGT) with tolbutamide (n = 74) or from the homeostasis model assessment of insulin resistance (HOMA-IR) (n = 204). Results In preterm and term children, GH treatment resulted in a similar decrease in systolic and diastolic blood pressure, body fat percentage, limb fat/total fat ratio and insulin sensitivity, and a similar increase in insulin secretion and disposition index. Lean body mass (LBM) corrected for gender and height increased in term children and did not change in preterm children. Multiple regression analysis revealed that this difference in GH effect on LBM was not associated with gestational age. Conclusion The effect of GH treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, SGA children.

The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi syndrome (Article)

2009-07-01T00:00:00Z

Background: The annual death rate of patients with Prader-Willi syndrome (PWS) is high (3%). Many deaths of children are sudden and unexplained. Sleep apneas have been suggested to play a role in sudden deaths. Recently, we discovered that 60% of patients with PWS suffer from central adrenal insufficiency (CAI) during stress. Objective: The aim was to study the relationship between CAI and sleep-related breathing disorders. Design: In 20 children with PWS who underwent a metyrapone test (30 mg/kg at 2330 h), sleep-related breathing was evaluated by polysomnography before the metyrapone test. In addition,we recorded sleep-related breathing in 10 children with PWS during their metyrapone test. CAI was diagnosed when ACTH levels during the metyrapone test were below 33 pmol/liter at 0730 h. All tests were performed during healthy condition. Setting: The study was conducted in a pediatric intensive care unit and specialized sleep center. Results: Median (interquartile range) age was 8.4 yr (6.5-10.2). After metyrapone administration, median (interquartile range) central apnea index (number/hour) increased significantly from 2.2 (0.4-4.7) to 5.2 (1.5-7.9) (P = 0.007). The increase tended to be higher in children with CAI [2.8 (2.0-3.9) vs. 1.0 (-0.2 to 2.6); P = 0.09]. During polysomnography before the metyrapone test, sleep-related breathing was worse in children with CAI, who had a significantly higher central apnea index and tended to have a lower minimum oxygen saturation compared to those without CAI (P = 0.03 and P = 0.07). Conclusions: In children with PWS, the central apnea index increased significantly after metyrapone administration, particularly in those with CAI during stress. In addition, children with CAI had a higher central apnea index compared to those without several months before the metyrapone test. Copyright

Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood (Article)

2009-06-03T00:00:00Z

Context: Growth during infancy appears to be an important determinant of cardiovascular disease and type 2 diabetes later in life. Objectives: To specify which period in the first year of life is related to determinants of cardiovascular disease and type 2 diabetes in early adulthood and to investigate the association between tempo of first-year weight gain (>0.67 SDs) and these determinants. Design, Setting, and Participants: Observational study using longitudinal data collected in the Programming Factors for Growth and Metabolism (PROGRAM) study of 217 healthy participants, aged 18 to 24 years, including a relatively large sample of participants born small for gestational age and participants with short stature, performed at a medical center in the Netherlands between August 2004 and September 2007. The association of cardiovascular disease and type 2 diabetes with tempo of weight gain was assessed in a subgroup of 87 participants. Main Outcome Measures: Associations between periods of first-year growth and tempo of weight gain and determinants of cardiovascular disease and type 2 diabetes in early adulthood. Results: Weight gain in the first 3 months of life was inversely associated with insulin sensitivity (β, -0.223; 95% confidence interval [CI], -0.386 to -0.060) and serum high-density lipoprotein cholesterol level (β, -0.053; 95% CI, -0.090 to -0.016) and positively associated with waist circumference (β, 1.437; 95% CI, 0.066 to 2.808), acute insulin response (β, 0.210; 95% CI, 0.024 to 0.395), ratio of total cholesterol to high-density lipoprotein cholesterol (β, 0.052; 95% CI, 0.010 to 0.094), and level of triglycerides (β, 0.066; 95% CI, 0.003 to 0.129) in early adulthood. Rapid weight gain during the first 3 months of life resulted in a higher percentage of body fat, more central adiposity, and reduced insulin sensitivity in early adulthood than when slower weight gain occurred during the entire first year. Conclusion: Rapid weight gain in the first 3 months of life is associated with several determinants of cardiovascular disease and type 2 diabetes in early adulthood.

Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): Correlation with serum IGFBP-3 levels and growth in short children born small for gestational age (Article)

2009-06-01T00:00:00Z

Context: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. Objective: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. Patients: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. Intervention: Short prepubertal SGA children received GH 1 mg/m2/day. Outcome measures: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. Results: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P < 0.001). Children with C-202/C-185haplotype, compared to children with A-202/C-185haplotype, had lower IGFBP-3 levels (P = 0.003) and were shorter (P = 0.03). During GH treatment, children with C-202/C-185haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A-202/C-185haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. Conclusion: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.

Reduced levels of GH during GnRH analogue treatment in pubertal short girls born small for gestational age (SGA) (Article)

2009-06-01T00:00:00Z

Context Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls. Objective To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls. Patients Twenty-four pubertal and 16 prepubertal short SGA girls. Intervention After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3·75 mg subcutaneously every 4 weeks. Outcome measures GH, IGF-I and IGFBP-3 levels. Results At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC0(P = 0·02), mean (P = 0·02) and maximum GH levels (P = 0·008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls (P = 0·03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment. Conclusion Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.

Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. the generation R study (Article)

2009-06-01T00:00:00Z

Objective We aimed to examine the associations of maternal anthropometrics with fetal weight measured in different periods of pregnancy and with birth outcomes. Design Population-based birth cohort study. Setting Data of pregnant women and their children in Rotterdam, the Netherlands. Population In 8541 mothers, height, prepregnancy body mass index (BMI) and gestational weight gain were available. Methods Fetal growth was measured by ultrasound in mid- and late pregnancy. Regression analyses were used to assess the impact of maternal anthropometrics on fetal weight and birth outcomes. Main outcome measures Fetal weight and birth outcomes: weight (grams) and the risks of small (<5th percentile) and large (>95th percentile) size for gestational age at birth. Results Maternal BMI in pregnancy was positively associated with estimated fetal weight during pregnancy. The effect estimates increased with advancing gestational age. All maternal anthropometrics were positively associated with fetal size (P-values for trend <0.01). Mothers with both their prepregnancy BMI and gestational weight gain quartile in the lowest and highest quartiles showed the highest risks of having a small and large size for gestational age child at birth, respectively. The effect of prepregnancy BMI was strongly modified by gestational weight gain. Conclusions Fetal growth is positively affected by maternal BMI during pregnancy. Maternal height, prepregnancy BMI and gestational weight gain are all associated with increased risks of small and large size for gestational age at birth in the offspring, with an increased effect when combined.

Birth Size, Postnatal Growth and Growth during Growth Hormone Treatment in Small-for-Gestational-Age Children: Associations with IGF1 Gene Polymorphisms and Haplotypes? (Article)

2009-06-01T00:00:00Z

Background: Short small-for-gestational-age (SGA) children experience pre- and postnatal growth restriction, which might be influenced by polymorphisms in the IGF1 gene. The well-known-841(CA)n/192 bp polymorphism has been associated with birth size and cardiovascular disease. Aims: To determine whether birth size, postnatal growth and growth during growth hormone (GH) treatment, were associated with IGF1 gene polymorphisms and haplotypes. Methods: 201 short SGA children were investigated for four IGF1 gene polymorphisms in the promoter (-G1245A,-841(CA)n), intron 2 (+3703(CT)n) and 3UTR (+A1830G). Spontaneous growth and growth during GH treatment were studied. Results: The-1245 A allele was identified as a marker-allele for the well-known-841(CA)n/non-192 bp allele, both part of haplotype 2. The-1245 A allele was not associated with head circumference at birth, but was associated with a postnatal 0.3 SDS smaller head circumference at age 1-3. The-1245 A allele was also associated with a 1-week shorter gestational age which explained the association with a smaller absolute birth size. No associations were found with gestational age-adjusted birth size, height and weight SDS during postnatal life and with growth during GH treatment. Conclusions: The-G1245A SNP appeared to be a marker for the well-known-841(CA)n/192 bp polymorphism. Haplotype 2, of which the-1245 A allele was the marker, was associated with a smaller head circumference SDS during spontaneous postnatal growth, but not during GH treatment.

Fetal and postnatal growth and body composition at 6 months of age (Article)

2009-06-01T00:00:00Z

Objectives: The objectives of the study was to examine which parental, fetal, and postnatal characteristics are associated with fat and lean mass at the age of 6 months and examine the effect of growth (catch-down, catch-up) in fetal life and early infancy on fat and lean mass. Design: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Body composition was measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, fetal, and postnatal data were collected by physical and fetal ultrasound examinations and questionnaires. Results: Children with fetal catch-up in weight (gain in weight SD score >0.67) in the second trimester tended to have a higher fat mass percentage [FM(%)] at 6 months of age, whereas children with fetal catch-down in weight had a lower FM(%) compared with nonchangers. In the third trimester, both catch-up and catch-down in weight were associated with an increase in FM(%) at 6 months. Children with catch-down in the third trimester had a greater risk for postnatal catch-up in weight greater than 0.67 SD score. Birth weight and weight at 6 wk were positively associated with fat mass at 6 months. Postnatal catch-up in weight within 6 wk after birth had the highest association with total and truncal FM(%) at 6 months. Total and truncal FM were higher in girls. Conclusion: Catch-down in weight in the third trimester was strongly associated with postnatal catch-up within 6 wk after birth, and both were associated with an increase in fat mass at the age of 6 months. Our study shows that fetal as well as postnatal growth patterns are associated with body composition in early childhood. Copyright

About the benefits of growth hormone treatment in children with Prader-Willi syndrome (Article)

2009-05-01T00:00:00Z

Genetic screening of a Dutch population with isolated GH deficiency (IGHD) (Article)

2009-05-01T00:00:00Z

Objective Five per cent to 30% of cases of idiopathic isolated GH deficiency (IGHD) have first-degree relatives with short stature, which is suggestive of a genetic aetiology. The HYPOPIT study aimed to obtain an overall picture of gene encoding pituitary GH (GH1) and gene encoding GH releasing hormone-receptor (GHRHR) defects in a Dutch IGHD cohort and to relate them with clinical parameters. Design, patients and measurements Genetic analysis was performed of exons and exon-intron boundaries of GH1 and GHRHR in 89 Caucasian IGHD patients from 81 families, using denaturing high-performance liquid chromatography (dHPLC), DNA sequencing and multiplex ligation-dependent probe amplification. In addition, we performed functional studies on novel identified GH1 exonic variants. Results Five different heterozygous GH1 mutations were present in 5 out of 81 participating families (6·1%), whereas no mutations in GHRHR were found. Patients with IGF-I SDS < -4·0 and peak GH levels < 5·7 mU/l had a mutation frequency of 40%, in contrast to 6·8% in patients with only one criterion, and 0·0% in patients with none of these criteria (P = 0·00007). Five new GH1 and two GHRHR variants were also identified; two of them (GH1 F92L and D153H) caused a marked reduction of GH secretion in vitro. Conclusion GH1 and GHRHR mutations are rare in Caucasian Dutch IGHD patients, which suggests the involvement of other genetic determinants in the aetiology of IGHD. IGF-I < -4·0 and peak GH levels < 5·7 mU/l are strong predictors of GH1 mutations in the studied population.

Effect of birth weight and postnatal weight gain on body composition in early infancy. The Generation R Study (Article)

2009-05-01T00:00:00Z

Background: Rapid postnatal weight gain is associated with obesity and type 2 diabetes in later life. The influence of rapid weight gain on body composition in early infancy is still unknown and the critical periods of weight gain for later disease are debated. Aims: To investigate the effect of birth weight and rapid weight gain on body composition in the first 6 months of life. Study design: The Generation R Study, a population-based prospective cohort study from fetal life onwards. Subjects and outcome measures: We measured body fat and fat distribution by skinfold thickness at the age of 6 weeks and 6 months in 909 Dutch term infants. Analyses were adjusted for current body mass index, sex and maternal socioeconomic status, pre-pregnancy body mass index, height and duration of breastfeeding. Results: Upward postnatal weight percentile change was associated with increased skinfold thickness, percentage body fat at 6 weeks and 6 months and a larger truncal/peripheral fat ratio at 6 months (p < 0.01 for all). Birth weight was inversely associated with truncal/peripheral fat ratio (p < 0.01) but not with relative body fat at 6 months. Conclusion: During early postnatal rapid weight gain infants do not grow in all body tissues in equal measure. Instead, they acquire relatively large amounts of fat, which is preferentially distributed to the truncal region. Long term observational studies have to assess if such changes in body composition persist into adulthood.

Overnight levels of luteinizing hormone, follicle-stimulating hormone and growth hormone before and during gonadotropin-releasing hormone analogue treatment in short boys born small for gestational age (Article)

2009-05-01T00:00:00Z

Aims: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone (GH) profiles and fasting insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels after 3 months of GnRHa treatment with those at baseline. Methods: After measurement of baseline overnight profiles and IGF-I and IGFBP-3 levels, 14 short pubertal SGA boys received leuprorelide acetate depots of 3.75 mg subcutaneously, every 4 weeks. Results: At baseline, mean GH levels were comparable with those of controls, whereas IGF-I and IGFBP-3 standard deviation scores (SDS) were significantly lower than zero SDS. After 3 months of GnRHa treatment, all boys showed clinical arrest of puberty. The area under the curve above zero, mean and maximum LH and FSH had significantly decreased to prepubertal levels. Peak LH during the GnRH agonist test, however, indicated insufficient pubertal suppression in 43% of boys. Overnight GH profile characteristics and IGF-I and IGFBP-3 levels did not significantly change. Conclusions: Puberty was sufficiently suppressed by GnRHa treatment, as shown by the prepubertal LH and FSH profiles. After 3 months of GnRHa treatment, overnight GH profile characteristics had not significantly changed, reflecting that GH levels are comparable for prepubertal and early pubertal boys.

Prematurity is not associated with reduced insulin sensitivity in adulthood (Article)

2009-05-01T00:00:00Z

Background: In 2005, 12.7% of all babies were born preterm, and the incidence is rising. Nowadays, due to improved survival, an increasing number of children born preterm reach young adulthood. A recent report suggested lower insulin sensitivity in children born preterm, which may put them at risk for the development of type 2 diabetes. It is, however, still unknown whether this reduced insulin sensitivity persists into adulthood. Methods: We determined insulin sensitivity and β-cell function with frequently sampled iv glucose tolerance tests in 305 young adults (aged 18-24 yr; 169 preterm and 136 term). Adult body composition was measured by dual energy x-ray absorptiometry. We investigated the effect of gestational age, size at birth, and adult body composition on insulin sensitivity. Results: In contrast to previous reports, we found no evidence that preterm birth has a deleterious effect on insulin sensitivity in young adulthood. Adult trunk fat and the use of oral contraceptives in women were the most important determinants of insulin insensitivity, independently of size at birth and duration of pregnancy. Conclusion: Contrary to our hypothesis, preterm birth was not associated with reduced insulin sensitivity in young adulthood. Copyright

Randomized controlled trial to investigate the effects of growth hormone treatment on scoliosis in children with prader-willi syndrome (Article)

2009-04-01T00:00:00Z

Context: The prevalence of scoliosis in children with Prader-Willi syndrome (PWS) is 30-80%, depending on age. Although reports about effects of GH treatment on scoliosis in children with PWS are limited, scoliosis is generally considered a contraindication for GH treatment. Objective: The aim was to study the effects of GH treatment on the onset of scoliosis and curve progression in children with PWS. Design: We conducted a multicenter, randomized, controlled GH study in infants and prepubertal and pubertal children. Infants and prepubertal children were randomized into a GH-treated group (1.0 mg/m2 · d) and a control group for 1 and 2 yr, respectively. Pubertal children were randomized to receive somatropin 1.0 or 1.5 mg/m2 · d. Yearly, x-rays of the spine were taken, and height, weight, truncal lean body mass (with dual energy x-ray absorptiometry), and IGF-I were measured. Patients: A total of 91 children with PWS (median age, 4.7 yr; interquartile range, 2.1-7.4) participated in the study. Main Outcome Measures: We measured the onset of scoliosis (Cobb <10°) and scoliotic curve progression. Results: GH-treated children had similar onset of scoliosis and curve progression as randomized controls (P = 0.27-0.79 and P = 0.18-0.98, respectively). GH treatment, IGF-I sd score (SDS), and catch-up growth had no adverse effect on the onset of scoliosis or curve progression, even after adjustment for confounders. Height SDS, truncal lean body mass, and IGF-I SDS were significantly higher in GH-treated children than in randomized controls. At baseline, a higher IGF-I SDS was associated with a lower severity of scoliosis. Conclusions: Scoliosis should no longer be considered a contraindication for GH treatment in children with PWS.

Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children? (Article)

2009-04-01T00:00:00Z

Objective To investigate whether prematurity has an independent influence on the response to GH treatment in short, small for gestational age (SGA) children. Design A longitudinal 3-year GH study. Patients A total of 392 prepubertal non-GH-deficient, short SGA children, comprising 138 preterm (< 36 weeks) and 254 term (≥ 36 weeks) children. Measurements Height, weight, head circumference, skinfolds and serum IGF-I and IGFBP-3 levels were measured before start of GH treatment and after 6 months, 1, 2 and 3 years of treatment. Results Preterm short SGA children were significantly lighter and shorter at birth after correction for gestational age than term short SGA children (P < 0·001). At start of GH treatment, preterm children were significantly shorter than term children when height was corrected for target height (TH). Preterm children were also significantly leaner as shown by a lower body mass index (BMI) standard deviation score (SDS) and a lower sum of four skinfolds SDS. Prematurity had no influence on childhood IGF-I and IGFBP-3 levels. The response to GH treatment was similar for preterm and term SGA children. Conclusions Within a population of short SGA children, prematurity is associated with a smaller size for gestational age and a shorter height corrected for TH and leaner phenotype in childhood. The response to GH treatment is similar for preterm and term short SGA children.

Insulin-like growth factor-binding protein-1: Serum levels, promoter polymorphism, and associations with components of the metabolic syndrome in short subjects born small for gestational age (Article)

2009-04-01T00:00:00Z

Context: IGF binding protein (IGFBP)-I is the only acute regulator of IGF-I bioavailability. Its production is suppressed by insulin, and low levels are associated with hyperinsulinemiaand cardiovascular disease risk in adults. Data on IGFBP-1 levels in short, small for gestational age (SGA) subjects are scarce, and associations with IGFBP1 promoter single nucleotide polymorphisms have not been established. Objective: The aim of the study was to determine IGFBP-1 levels in short SGA subjects compared with those in controls, to assess genotype frequency of the -575 G/A single nucleotide polymorphism, and to determine its impact on IGFBP-1 levels. Subjects: A total of 272 short subjects born SGA and 330 subjects with normal stature (245 children, 85 young adults) participated in the study. Outcome Measures: We measured fasting levels of IGFBP-1, IGF-I, insulin and lipid parameters, and body composition. Results: IGFBP-1 sd score (SDS) was comparable to controls in lean, short, SGA children but significantly lower in short SGA adults with normal fat mass (P <0.001). IGFBP-1 SDS correlated significantly with insulin levels, systolic blood pressure SDS, and various lipid parameters. Baseline IGFBP-1 SDS was lowest in SGA children with-575 GG genotype and significantly higher in SGA children with one or two copies of the A allele. In response to a given insulin level, children with the AA genotype had a significantly higher IGFBP-1 SDS compared to children with the GG genotype. Conclusion: Normal IGFBP-1 levels in lean, short, SGA children may reflect a normal metabolic state, despite reported hyperinsulinemia. IGFBP-1 is modulated by polymorphic variability and seems to be an additional player in the complex interaction between the IGF-IGFBP axis, glucose homeostasis, and lipid metabolism. Copyright

Network of European studies of genes in growth (NESTEGG) (Article)

2009-04-01T00:00:00Z

The network of European studies of genes in growth (NESTEGG) is an international growth genomics project, focusing on the birth size phenotypes of small for gestational age (SGA) and idiopathic short stature. Seven hundred controls and 1,275 cases with their parents have been recruited. Detailed clinical histories and auxological measurements are recorded in a clinical database. Candidate gene studies are being undertaken with the study DNA samples. These genetic data will be used to explore associations with the clinical phenotypes of short stature and SGA birth size, and, in a subset, response to growth hormone (GH) therapy. This article describes the study methodology and reviews the association of the exon 3-deleted genotype of the GH receptor with GH responsiveness in GH-treated children born SGA.

Influence of birth size on body composition in early adulthood: The programming factors for growth and metabolism (PROGRAM)-study (Article)

2009-02-01T00:00:00Z

Background/Objectives: Several studies have investigated the relationship of birth size with fat mass and lean body mass (LBM), but the findings differed greatly due to different ways of measuring FM and LBM, different study populations and age groups. We hypothesized that birth size has no influence on adult body composition, whereas weight gain during childhood has. Methods: In the programming factors for growth and metabolism (PROGRAM)-study, a cohort of 312 young adults, aged 18-24 years, FM and LBM were determined by dual energy X-ray absorptiometry (DXA). Subsequently, differences in FM and LBM were analysed in four subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age (AGA) with idiopathic short stature (ISS) or with normal stature (controls). Results: Age, gender, adult height SDS and adult weight SDS were significant positive determinants of FM and LBM, whereas weight gain during childhood was positively significant for FM and negatively for LBM. Birth weight SDS tended to be significant and birth length SDS was not. Weight gain during childhood was positively correlated with waist : hip ratio and trunk fat : total fat ratio. SGA-CU subjects had significantly higher FM and significantly lower LBM than controls. Conclusion: Weight gain during childhood is an important determinant of body composition in young adulthood, whereas birth size is less important. In clinical practice, too much weight gain in childhood should be prevented as it results in a relatively high fat mass, especially in children with catch-up growth in weight, like SGA-CU subjects.

Glucocorticoid receptor gene polymorphism is less frequent in children born small for gestational age without catch-up growth (Article)

2009-02-01T00:00:00Z

Background/Aims: Glucocorticoids are important regulators of many processes involved in embryonal growth and development and fat and glucose metabolism. Glucocorticoids exert their effect through the glucocorticoid receptor (GR). The aim of this study was to investigate possible associations between 4 well-known GR gene haplotypes and size at birth. Methods: We investigated associations between GR haplotypes and size at birth in a Dutch reference cohort. This reference cohort consisted of 222 young healthy Caucasian subjects. Associations between size at birth and glucocorticoid receptor gene haplotypes were tested. Furthermore, we investigated a group of 119 children born small for gestational age (SGA), without catch-up growth. Prevalence of the different GR haplotypes was compared between the SGA group and the reference cohort. Results: No associations were found between any of the GR haplotypes and birth weight or birth length in the reference group. The prevalence of GR haplotype 2 (Bcl1) was significantly lower in the SGA group compared to controls. Conclusion: Genetic variance in the GR seems not to be associated with intrauterine growth in the general population. However, GR haplotype might play a role in growth of children born SGA, reflected by the decreased prevalence of GR haplotype 2 (Bcl1) in this group. Copyright

Antipituitary antibodies in Dutch patients with idiopathic hypopituitarism (Article)

2009-01-01T00:00:00Z

Background: Despite extensive research, in the majority of patients with isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD), the cause of their clinical picture remains unknown. Recent articles suggest that some cases of idiopathic growth hormone deficiency might be explained by a silent form of autoimmune hypophysitis based on the presence of antipituitary antibodies (APA) at high titers (>1:8). Methods: We collected clinical data and serum from 71 patients participating in the Dutch HYPOPIT study. APA screening in 40 IGHD patients and 31 MPHD patients was performed by an indirect immunofluorescence method. APA, when present, were related to clinical and morphological pituitary findings. Results: APA were present at high titers in 7 of 31 MPHD patients (23%) and 1 of 40 IGHD patients (2.5%). Among APA-positive MPHD patients, apart from growth hormone deficiency, all patients of pubertal age had gonadotroph defi- ciency, all had thyroid hormone deficiency and 50% had ACTH deficiency. Conclusion: The high frequency of APA in our idiopathic MPHD population indicates that, in 23% of the patients diagnosed with idiopathic MPHD, the hormone deficiencies might actually be caused by a silent form of autoimmune hypophysitis. Screening for APA should therefore be considered in all patients with 'idiopathic' MPHD. Copyright

Testis function in prepubertal boys and young men born small for gestational age (Article)

2008-12-01T00:00:00Z

Background/Aims: Some studies reported an impaired gonadal function in males born small for gestational age (SGA). We investigated Sertoli cell function by measuring serum inhibin B and antimullerian hormone (AMH) levels in prepubertal boys and young men born SGA in comparison with age-matched controls born appropriate for gestational age (AGA). Methods: Inhibin B and AMH levels were determined in 73 prepubertal short SGA boys and in 72 age-matched AGA boys. In addition, 25 SGA boys were re-examined after 2 years of growth hormone (GH) treatment. Furthermore, inhibin B, AMH, testosterone, LH and FSH were studied in three groups of young men: 21 SGA men treated with GH, 15 SGA men with spontaneous catch-up growth and 25 young men born AGA. Results: Prepubertal short SGA boys and AGA boys had similar inhibin B (87.3 and 78.2 ng/ml) and AMH levels (75.6 and 63.6 μg/l, respectively). GH treatment did not result in different inhibin B and AMH levels. In young SGA men, inhibin B, testosterone, LH and FSH levels were similar compared to young AGA men. AMH levels were higher in the young SGA men (p = 0.03). Conclusions: Being born SGA does not impair Sertoli cell function. Young men born SGA have a normal hypothalamic-pituitary- testis axis.

Cognition and behavior in pre-pubertal children with Prader-Willi syndrome and associations with sleep-related breathing disorders (Article)

2008-12-01T00:00:00Z

Prader-Willi syndrome (PWS) is characterized by hypotonia, hypogonadism, obesity, and short stature. Neurobehavioral abnormalities, cognitive impairment, and sleep-related breathing disorders (SRBD) are common. In the general population associations between neurobehavioral and cognitive abnormalities and SRBD have been found. We investigated cognition, behavior, and SRBD in children with PWS. Thirty-one pre-pubertal PWS children were evaluated (5 with paternal deletion, 14 with maternal disomy, 4 with imprinting-center mutation, and in 8 the defect was not specified). Cognition was assessed by Wechsler scale subtests, and behavior by parent-questionnaires. Polysomnography was performed. Cognition, behavior, and associations with SRBD were evaluated. All cognitive subtests were significantly below O SDS, with the lowest median (interquartile range) scores for the Block design subtest (-2.7 SDS (-3.0 to -0.3)). In 60%, verbal subtests were less affected than performance subtests. Parents reported problem behavior related to "emotions/behavior not adapted to the social situation" and "insensitivity to social information." All children had SRBD, with an Apnea Hypopnea Index of 4.1/hr (2.6-7.9). One performance subtest score was significantly higher in children with better sleep efficiency, and daytime sleepiness was associated with more autistic-like social impairment. In contrast to our expectations, behavior was worse in children with better sleep-related breathing. In pre-pubertal PWS children, cognition is impaired. Neurobehavioral abnormalities are common, particularly autistic-like social impairment. Sleep efficiency was associated with better performance on one of the performance subtests, and neurobehavioral abnormalities were associated with daytime sleepiness. In contrast, we could not confirm a positive association of neurobehavioral abnormalities with SRBD in PWS.

Fat mass and apolipoprotein E genotype influence serum lipoprotein levels in early adulthood, whereas birth size does not (Article)

2008-11-01T00:00:00Z

Background/Objectives: An association between an unfavorable lipid profile and low birth weight has been reported, although this association remains controversial. We hypothesized that birth size does not have any influence on serum lipid levels but fat accumulation during childhood has. Methods: In the PROgramming factors for GRowth And Metabolism study, a cohort of 297 young adults, aged 18-24 yr, the influence of clinical parameters on total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, lipoprotein a, and apolipoprotein (apo) A-1 and apoB was analyzed with multiple regression modeling. In addition, differences in these lipid levels and ApoE genotype prevalence were analyzed in four subgroups: young adults either born small for gestational age with short stature or with catch-up growth, or born appropriate for gestational age with idiopathic short stature or with normal stature (controls). Results: Birth length SD score (SDS) and birth weight SDS were no significant determinants of the serum lipid levels, whereas gender, ApoE genotype, adult height SDS, adult weight SDS, and fat mass were. Comparison of the subgroups showed that small for gestational age with short stature subjects had a significantly higher apoB than controls. There were no other significant differences in lipid levels or ApoE genotype prevalence among the four subgroups. Conclusions: ApoE genotype is an important genetic determinant of lipid levels in young adulthood. Furthermore, fat accumulation during childhood significantly determines serum lipid levels, whereas birth size has no significant contribution. For public health practice, this means that parents and their children need to be informed about the risks of fat accumulation during childhood. Copyright

Recommendations for the diagnosis and management of Prader-Willi syndrome (Article)

2008-11-01T00:00:00Z

Objective: The objective of the study was to provide recommendations for the diagnosis and management of Prader-Willi syndrome throughout the life span to guide clinical practice. Participants: An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer. Evidence: Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. Consensus Process: This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments). Conclusions: The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness. Copyright

Small for gestational age children without early catch-up growth: Spontaneous growth and prediction of height at 8 years (Article)

2008-10-01T00:00:00Z

Background/Aim: About 10-15% of children born small for gestational age (SGA) have at the age of 2 years a height standard deviation score (HSDS 2y) still below -2. There is no model to predict which children will catch up in height after 2 years of age. The aim of this study was to determine the percentage of children with catch-up growth to a normal height after the age of 2 years and to develop a prediction model for growth after that age. Methods: In a cohort of 724 SGA children, the percentage of children with HSDS above -2 at 8 years of age was determined. In data of 97 children with HSDS 2y below -2, a prediction model was developed for growth between 2 and 8 years. Results: Thirty-nine percent of children with HSDS2y below -2 reached an HSDSabove -2 between 2 and 8 years (6% of the total group). Determinants of growth after age 2 years, all with a positive influence, were the difference between target height SDS and HSDS2y, change in height SDS during first 2 years of life, female gender and multiple birth. Conclusions: Catch-up growth to a normal height occurred in 91% of SGA children, in 6% between 2 and 8 years of age. The difference between target height SDS and HSDS2y was the most important determinant. The presented prediction model can identify children with low or high probability of catch-up growth after the age of 2 years. This may assist to determine which children require medical follow-up.

Longitudinal changes in insulin sensitivity and body composition of small-for-gestational-age adolescents after cessation of growth hormone treatment (Article)

2008-09-01T00:00:00Z

Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stopping GH treatment. Objective: Our objective was to investigate longitudinal changes in Si, β-cell function, and body composition after cessation of long-term GH treatment. Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. Outcome Measure: We took paired measurements of Si and β-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dualenergy x-ray absorptiometry. Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and β-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution. Copyright

Influence of birth size and body composition on bone mineral density in early adulthood: The PROGRAM study (Article)

2008-09-01T00:00:00Z

Background/objectives: Low bone mineral density (BMD) may lead to osteoporosis and is associated with increased fracture risk. Associations between BMD and various factors have been reported. Our objective was to investigate whether birth size, lean body mass (LBM) and fat mass (FM) are determinants of BMD of the total body (BMDTB) and the lumbar spine (BMDLS). Methods: In the PROgramming factors for GRowth And Metabolism (PROGRAM) study of a cohort of 312 young adults aged 18-24 years, BMDTBand BMDLSwere determined by dual-energy X-ray absorptiometry (DXA). Subsequently, differences in BMDTBand BMDLSwere analysed in four subgroups: young adults born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age (AGA) with idiopathic short stature (ISS) or with normal stature (controls). Results: Adult weight, LBM, FM and weight gain during childhood were the main positive determinants for BMDTBin early adulthood, whereas birth size had no influence (adjusted R2= 0.50). Gender, adult weight, LBM, FM and weight gain were the significant determinants of BMDLS. In the subgroups, after correction for age, gender and adult body size, the ISS group had a significantly lower BMDTBthan controls but there was no difference in BMDLSbetween the subgroups. Conclusions: Prenatal growth has no significant influence on BMDTBand BMDLSin early adulthood. Gender and postnatal growth, particularly weight gain, are the main positive determinants. To achieve a normal BMD in adulthood, healthcare workers should aim for a normal weight gain in children.

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.

A variant of the IGF-I gene is associated with blood pressure but not with left heart dimensions at the age of 2 years: The Generation R Study (Article)

2008-09-01T00:00:00Z

Background and objective: A common variant of the IGF-I gene has been shown to be associated with cardiovascular disease in adulthood. The objective of this study was to examine whether this variant of the IGF-I gene is associated with blood pressure and left heart dimensions in early childhood. Research design and methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life onwards. IGF-I promoter region was genotyped in DNA obtained from cord blood. Blood pressure (systolic and diastolic) and echocardiography (left ventricular mass, left atrial diameter and aortic root diameter) measurements were performed at the age of 2 years. Analyses were performed in 538 subjects. Results: Eight alleles of the IGF-I promoter region were identified. In total, 43% of the subjects were homozygous for the 192 bp allele (wild type), 46% were heterozygous and 11% were non-carriers. Significantly lower systolic and diastolic blood pressures were found in non-carrier subjects (difference compared with homozygous subjects: - 4.4 (95% confidence interval (CI) - 7.8 to - 1.1) mmHg and - 3.5 (95% CI: - 6.9 to - 0.1) mm respectively). No significant differences were found for left heart dimensions at the age of 2 years. No association was found when we used a previously proposed alternative classification of the IGF-I gene. Conclusion: The variant type of the IGF-I promoter region is associated with lower blood pressure but not with left heart dimensions at the age of 2 years. Follow-up studies are needed to examine whether these differences persist in later life.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment (Article)

2008-08-01T00:00:00Z

Context: Disturbances in thyroid function have been described in small-for-gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children. Objectives: To determine whether short SGA children have higher TSH levels compared to age-matched controls and evaluate the influence of gestational age. To investigate whether GH treatment alters thyroid function. Patients: A total of 264 short SGA children (116 preterm), prepubertal and non-GH deficient. Measurements: Serum FT4 and TSH at baseline and after 6, 12 and 24 months of GH treatment. Results: Baseline mean TSH was higher in preterm short SGA children than in age-matched controls (P < 0.05). Mean FT4 was not significantly different between short SGA children and controls. Baseline FT4 or TSH did not correlate with gestational age, or SDS for birth weight, birth length, height, body mass index, IGF-I or IGFBP-3. Mean FT4 decreased significantly during the first 6 months of GH treatment, but remained within the normal range. TSH did not change during treatment. The change in FT4 did not correlate with the change in height SDS during 24 months of GH treatment. Conclusion: Preterm short SGA children have higher, although within the normal range, TSH levels than controls. The level of TSH does not correlate with gestational age, birth weight SDS or birth length SDS. FT4 decreases during GH treatment, but is neither associated with an increase in TSH nor does it affect the response to GH treatment. As these mild alterations in thyroid function do not appear clinically relevant, frequent monitoring of thyroid function during GH therapy is not warranted in short SGA children.

Plasma matrix metalloproteinase-9 levels and blood pressure in short children born small for gestational age and effects of growth hormone treatment (Article)

2008-08-01T00:00:00Z

Context: Short small-for-gestational-age (SGA) children have an increased systolic blood pressure (BP) that decreases during long-term GH treatment. The underlying mechanism is still unknown. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteinases that are involved in the remodelling of the extracellular matrix (ECM) and are thought to play a role in atherosclerosis. High MMP-9 levels are found in hypertensive patients and predict cardiovascular mortality. Objectives: To investigate whether GH treatment affects plasma MMP-9 levels in short SGA children and whether these are related to BP. Design: Case-control study. Intervention: GH treatment vs. no treatment during 36 months. Patients: Thirty-eight short SGA children receiving GH treatment vs. 17 sex- and age-matched untreated short SGA controls. Outcome measure: Plasma MMP-9 levels and BP were measured at baseline, and after 6, 12 and 36 months of study. Results: MMP-9 decreased significantly during 3 years of GH treatment but remained similar in untreated SGA controls. After 3 years of GH treatment, MMP-9 levels were significantly lower in the GH group than in the untreated SGA controls. Systolic BP SDS significantly decreased in the GH group but remained unaltered in the untreated SGA controls. MMP-9 levels did not correlate with systolic or diastolic BP. Conclusions: Plasma MMP-9 levels and systolic BP SDS decreased to almost 50% of baseline values in the GH group but remained unchanged in untreated SGA controls. Our data indicate that GH has a positive effect on both MMP-9 levels and systolic BP SDS.

Cardiovascular risk factors in parents of short children born small for gestational age (Article)

2008-07-01T00:00:00Z

Small for gestational age (SGA) children have a higher prevalence of cardiovascular risk factors at a young age. It is not known whether this increased risk is caused by their size at birth, a familial predisposition for cardiovascular disease or smallness at birth or a combination of these factors. The cardiovascular risk profile of parents of SGA children is unknown. We compared anthropometry, blood pressure, fasting serum lipid, glucose, and insulin levels of 482 parents (mean age 41 y) and 286 short SGA children with age- and sex-matched references. We also investigated whether these parameters correlated between parents and their offspring. Mothers had higher systolic blood pressure, fathers had a higher body mass index and parents had more frequently high fasting glucose levels than age- and sex-matched references. Children had significantly higher systolic and diastolic blood pressure than sex- and height-matched references. Twenty-four percent (mothers) and 10% (fathers) were born SGA but they did not have more cardiovascular risk factors than those born appropriate for gestational age. Cardiovascular risk factors did not correlate between parents and children. In conclusion, parents of short SGA children have a modest increase in some cardiovascular risk factors but risk factors did not correlate between parents and children. Copyright

Facial and pituitary morphology are related in Dutch patients with GH deficiency (Article)

2008-07-01T00:00:00Z

Objective: Classical GH deficiency (GHD) is associated with typical phenotypic features. We have analysed standardized photographs of 137 Caucasian patients with GHD, in order to examine the relations between auxological, biochemical, pituitary and facial morphometric features. Patients and measurements: We analysed pictures of 137 patients: 73 (55 Males/18 Females) with Isolated GHD and 64 (48 M/16 F) with multiple pituitary hormone deficiency (MPHD). Of each patient, standardized frontal and lateral digital pictures were taken and analysed using Adobe Photoshop 5.0. Results: Canthal index (CI), the relative distance between the eyes, was related to pituitary morphology. Patients with an ectopic posterior pituitary (EPP) had significantly higher CI values than patients without EPP. We found CI > 39 to be a good cut-off value to select children with highest probability of having EPP. The combination of CI > 39 with the presence of hormonal deficiencies additional to GHD strongly predicted EPP: 93% of the patients with a CI > 39 and additional hormonal deficiencies had EPP, in contrast to 77% of the patients with additional hormonal deficiencies but a CI < 39, and 29% of the patients with none of these criteria (P = 0.0001). Conclusion: CI, measured on digital pictures, is associated with ectopia of the posterior pituitary and this might be caused by an altered midline development, affecting both the pituitary and the facial structures of GHD patients.

Tracking and determinants of subcutaneous fat mass in early childhood: The Generation R Study (Article)

2008-07-01T00:00:00Z

Objectives: To examine the development and tracking of subcutaneous fat mass in the first 2 years of life and to examine which parental, fetal and postnatal characteristics are associated with subcutaneous fat mass. Design: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Subcutaneous fat mass was measured by skinfold thickness (biceps, triceps, suprailiacal, subscapular) at the ages of 1.5, 6 and 24 months in 1012 children. Information about parental, fetal and postnatal growth characteristics was collected by physical and fetal ultrasound examinations and questionnaires. Results: Normal values of subcutaneous fat mass are presented. Total subcutaneous fat mass was higher in girls than in boys at the age of 24 months (P=0.01). Subjects in the lowest and highest quartiles at the age of 6 months tended to keep their position in the same quartile at the age of 24 months (odds ratios 1.86 (95% confidence interval (CI) 1.3, 2.7)) and 1.84 (95% CI: 1.3, 2.6), respectively). Maternal height and weight, paternal weight, fetal weight at 30 weeks, birth weight and weight at the age of 6 weeks were each inversely associated with subcutaneous fat mass at the age of 24 months after adjustment for current weight at 24 months. Conclusion: This study shows for the first time that subcutaneous fat mass tends to track in the first 2 years of life. Furthermore, the results suggest that an adverse fetal environment and growth are associated with increased subcutaneous fat mass at the age of 24 months. Further studies are needed to examine whether these associations persist in later life.

GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age (Article)

2008-06-01T00:00:00Z

Objective: GH acts through the GH receptor (GHR). The GHR gene contains a genetic polymorphism caused by a deletion of exon 3 (d3), with high frequency in the normal population. There is a continuing controversy whether the presence or absence of the exon 3 deletion (d3+ vs. d3-) affects the effect of GH in human growth. Design, patients and measurements: For 144 patients with idiopathic isolated GH deficiency (IGHD, n = 72) or multiple pituitary hormone deficiency (MPHD, n = 72), amplification of the region around exon 3 of the GHR gene was performed. Clinical data and response to GH treatment were compared between GHR d3+ and d3- IGHD and MPHD patients born either small for gestational age (SGA) or appropriate for gestational age (AGA). Results: IGHD patients born SGA had a significantly higher d3+ frequency (82%) than IGHD patients born AGA (35%, P = 0.006). Within the group of IGHD patients born SGA, d3- patients showed a slightly better spontaneous catch up growth before start of GH treatment than d3+ patients (1.1 ± 1.1 SD vs. 0.6 ± 1.1 SDS, P = 0.040) There was no difference in patients first year's response to GH treatment between GHR d3+ and d3- patients. Conclusions: In IGHD and MPHD patients, response to GH treatment was independent of GHR genotype. GHR-d3 was significantly more frequent among IGHD patients born SGA. As we are the third to report an association between birth size and GHR d3 status, it is conceivable that the GHR-d3 might affect prenatal growth in IGHD patients by a yet unknown mechanism.

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.

Polymorphisms in the IGF1 and IGF1R genes and children born small for gestational age: results of large population studies (Article)

2008-06-01T00:00:00Z

Small for gestational age (SGA) is the term used to describe a group of children born with a birth weight and/or birth length below the normal range of a reference population, corrected for their gestational age. Although animal models have shown that insulin-like growth factor 1 (IGF1) and insulin-like growth factor 1 receptor (IGF1R) genes are important candidates for reduced pre- and postnatal growth, only limited case reports have been published describing mutations. This might suggest that IGF1 and IGF1R are such crucial growth factors that only common genetic polymorphisms are allowed to survive. Common IGF1 and IGF1R gene polymorphisms, such as single nucleotide polymorphisms and variable number of tandem repeats, have been investigated with conflicting results with respect to SGA-related outcomes. The exact contribution of these polymorphisms to clinical practice remains to be elucidated.

High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome (Article)

2008-05-01T00:00:00Z

Context: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. Objective: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Design: Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessedona different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. Setting: The study was conducted in a pediatric intensive care unit. Patients: Patients included 25 randomly selected PWS patients. Main Outcome Measure: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. Results: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions. Conclusions: Strikingly, 60% of our PWS patients had CAI. The high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test. Copyright

Ficoll-separated mononuclear cells from sepsis patients are contaminated with granulocytes (Article)

2008-05-01T00:00:00Z

Objective: To determine the cell content and purity of Ficoll-separated peripheral blood mononuclear cells and granulocyte isolates in sepsis patients compared to healthy controls. Design and setting: Prospective study in the adult and pediatric intensive care departments of the Erasmus University Medical Center in the Netherlands. Patients: Three sepsis patients (two adults, one child) and four healthy controls. Measurements and results: Blood leukocytes were separated by Ficoll into an interface and a bottom fraction. The cell content and purity was analyzed by cytospin and flow-cytometric immunofluorescence. In sepsis patients, the interface consisted of 11-52% mononuclear cells only, due to high contamination with granulocytes (48-89%). This was in contrast to a high proportion of mononuclear cells (88-100%) in healthy controls. The bottom fraction showed a cell purity of ≥92% polymorphonuclear granulocytes in sepsis patients as well as in healthy controls. Conclusions: Ficoll-separated leukocytes of sepsis patients are not suitable for studying mononuclear cells but can be used for studying granulocytes with high purity. The mononuclear cell fraction is highly contaminated with granulocytes. Additional separation techniques are necessary to obtain a pure cell fraction.

Variation in the IGF1 gene and growth in foetal life and infancy. The Generation R Study (Article)

2008-03-01T00:00:00Z

Objective: The objective of this study was to examine whether variants of the IGF1 gene are associated with growth patterns from foetal life until infancy. Study design and measurements: This study was embedded in the Generation R Study, a population-based prospective cohort study of foetal life. Foetal growth (head circumference, abdominal circumference, femur length, estimated foetal weight) was assessed by ultrasound in early, mid- and late pregnancy. Growth in infancy was assessed at birth (weight) and at the ages of 6 weeks, 6 months and 14 months (head circumference, length, weight). The IGF1 promoter region genotype was determined in 738 children. Results: Eight alleles of the IGF1 promoter region were identified. In total, 43% of the subjects were homozygous for the most common 192-bp allele (wild-type), 45% were heterozygous, and 12% were noncarriers of the 192-bp allele. No differences were found in birthweight between the three groups. However, noncarriers had a lower estimated foetal weight in mid-pregnancy (P = 0.040), followed by an increased growth rate until 6 months (P < 0.005) in comparison to the 192-bp homozygotes. A similar difference in growth rate was found for length (P < 0.001). Conclusions: Variants of the IGF1 promoter region are not associated with birthweight. However, noncarriers of the 192-bp allele tend to have a smaller foetal size, followed by an increased growth rate from mid-pregnancy to early infancy. Studies in larger cohorts are necessary to replicate our findings and to examine whether these effects persist throughout childhood.

Scoliosis in Prader-Willi syndrome: prevalence, effects of age, gender, body mass index, lean body mass and genotype (Article)

2008-02-08T00:00:00Z

BACKGROUND: The reported prevalence of scoliosis in children with Prader-Willi syndrome varies from 15% to 86%. OBJECTIVE: To study the prevalence of scoliosis and the effects of age, gender, body mass index (BMI), total lean body mass (LBM), LBM of the trunk (trunkLBM) and genotype. DESIGN: Radiographs were taken, length and weight were measured (BMI standard deviation scores (BMI SDS) and body surface area (BSA)), and dual energy x-ray absorptiometry was performed, measuring LBM and trunkLBM. PATIENTS: 96 children, median (interquartile range) age 4.8 years (2.1 to 7.5), were included in a multicentre study. None received growth hormone treatment. MAIN OUTCOME MEASURES: Two types of scoliosis were identified: (1) long C-curve type scoliosis (LCS) and (2) idiopathic scoliosis (IS). Children were divided into age categories (infants, 0-3 years; juveniles, 3-10 years; adolescents, 10-16 years). RESULTS: The prevalence of scoliosis was 37.5% and increased with age (infants and juveniles, approximately 30%; adolescents, 80%); 44% of children with scoliosis had a Cobb angle above 20 degrees . Children with scoliosis were significantly older than those without. Children with LCS were younger and more hypotonic than those with IS: median (interquartile range) age 4.4 years (1.7-5.9) vs 11.1 years (6.5-12.1) (p = 0.002) and trunkLBM/BSA ratio 7080 (6745-7571) vs 7830 (6932-8157) (p = 0.043). CONCLUSIONS: The prevalence of scoliosis in children with Prader-Willi syndrome is high (37.5%). Many children with scoliosis (13%) had undergone brace treatment or surgery. The type of scoliosis is affected by age and trunkLBM/BSA ratio.

Fat mass accumulation during childhood determines insulin sensitivity in early adulthood (Article)

2008-02-01T00:00:00Z

Background/Objectives: Low birth weight and postnatal catch-up growth have been associated with an increased risk for diabetes mellitus type II (DMII). We evaluated the contribution of birth and adult size, body composition, and waist-to-hip ratio to DMII risk factors in young adulthood. Methods: In a group of 136 young adults, aged 18-24 yr, insulin sensitivity and disposition index were determined by frequent sampling iv glucose tolerance test. The association of clinical parameters with these variables was analyzed with multiple regression modeling. In addition, differences in insulin sensitivity and disposition index, a measure for β-cell function, were analyzed in four subgroups, young adults either born small for gestational age SGA with short stature (n = 25) or SGA with catch-up growth (n = 23) or born appropriate for gestational age with idiopathic short stature (n = 23) or with normal stature (controls) (n = 26). Results: Fat mass was the only significant predictor of insulin sensitivity, whereas birth length and birth weight were not significant. After correction for age, gender, and adult body size, insulin sensitivity was significantly lower in subjects born SGA with catch-up growth compared with controls. None of the variables had a significant influence on disposition index, and there was no significant difference in disposition index between the subgroups. Conclusions: Our data show that a higher body fat mass at 21 yr is associated with reduced insulin sensitivity, independent of birth size. These findings have important implications for public health practice. Copyright

Prediction model for adult height of small for gestational age children at the start of growth hormone treatment (Article)

2008-02-01T00:00:00Z

Context: GH treatment is approved for short children born small for gestational age (SGA). The optimal dose is not yet established. Objective: Our objective was to develop a model for prediction of height at the onset of puberty and of adult height (AH). Design and Setting: Two GH studies were performed in short SGA children. Patients/Intervention: A total of 150 SGA children with height SD scores (SDS) less than -2, age 3 yr or older, no signs of catch-up growth, available height at the onset of puberty, and at least 1 yr of GH treatment before the onset of puberty were studied. In one study, patients were randomly assigned to either 0.033 or 0.067 mg/kg·d; in the other study all received 0.033 mg/kg·d. In 71 children, AH was reached. Main Outcome Measures: Height SDS at the onset of puberty and AH SDS were calculated. Results: Determinants positively related to height SDS at the onset of puberty were: height SDS at the start; target height SDS; and GH dose, whereas age at the start and female gender were negatively related. Positively related to AHSDS were: height SDS and chronological age - bone age at the start; target height SDS; and GH dose, whereas serum IGF binding protein (IGFBP)-3 SDS at the start was negatively related. There was a significant interaction between GH dose and IGFBP-3 SDS, indicating a smaller GH dose effect for higher levels of IGFBP-3. The final model explained 57% of the variance in height SDS at the onset of puberty and 41% of AH SDS. Conclusions: The prediction model for height SDS at the onset of puberty and AH SDS of short SGA children treated with GH provides useful information about the expected long-term growth. Because GH dosage is one of the determinants, the model aids in determining the optimal GH dose for each child. Copyright

Independent effects of prematurity on metabolic and cardiovascular risk factors in short small-for-gestational-age children (Article)

2008-02-01T00:00:00Z

Context: Both small-for-gestational-age (SGA) and preterm birth have been associated with an increased incidence of adult cardiovascular disease and diabetes mellitus type 2. However, it is unclear whether preterm birth has an additional effect on cardiovascular risk factors in short children born SGA. Objective: Our objective was to investigate whether prematurity has an independent influence on several cardiovascular risk factors within a population of short SGA children. Design: A cross-sectional observational study was performed. Patients: A total of 479 short SGA children (mean age 6.8 yr), divided into preterm (<36 wk) and term (≥36 wk) children, was included in the study. Outcome Measure: Insulin sensitivity, β-cell function, body composition, and lipid levels were studied in subgroups, and blood pressure (BP), anthropometry at birth and during childhood in the total group. Results: Preterm SGA children were significantly lighter and shorter at birth after correction for gestational age than term SGA children (P < 0.001) but had a comparable head circumference. In preterm SGA children, we found a significantly higher systolic (P = 0.003) and diastolic BP SD score (P = 0.026), lower percent body fat SD score (P = 0.011), and higher insulin secretion (P = 0.033) and disposition index (P = 0.021), independently of the degree of SGA. Insulin sensitivity, serum lipid levels, muscle mass, and body fat distribution were comparable for preterm and term SGA children. Conclusions: Within a population of short SGA children, preterm birth has divergent effects on several cardiovascular risk factors. Whereas preterm SGA children had a higher systolic and diastolic BP, they also had a lower percent body fat and a higher insulin secretion and disposition index than term SGA children. Copyright

Long-term GH treatment is not associated with disadvantageous changes of inflammatory markers and adipocytokines in children born small for gestational age (Article)

2008-02-01T00:00:00Z

Context: Low birth weight is associated with increased risks for adult cardiovascular disease (CVD) and diabetes mellitus type 2 (DM2). Adiponectin and resistin are hormones, considered, respectively, protective and disadvantageous regarding these risks. No data exist on the effect of long-term GH treatment on these hormones and inflammatory markers in children born small for gestational age (SGA). Objective: To describe longitudinal changes in inflammatory markers and adipocytokines during and after a long-term dose-response GH study. Design: Longitudinal dose-response study [group A: 1 mg/m2body surface area (BSA) (approximately 0.033 mg/kg/day) vs. group B: 2 mg/m2BSA (approximately 0.067 mg/kg/day)] and comparison with age-related controls. Patients: One hundred and three SGA children. Measurements: We measured adiponectin, resistin, interleukin-6 (IL-6) and C-reactive protein (CRP) levels at baseline, after 1 and 7 years of GH treatment and 6 months after discontinuation of GH. Results: Adiponectin levels decreased over time, but remained comparable with controls. Resistin levels increased and remained lower or comparable with controls. There were no significant differences between the GH dosage groups. After the GH treatment was stopped, adiponectin was decreased in group B and resistin increased in group A. GH therapy did not affect IL-6 and CRP levels at any time point. An increase in body mass index (BMI) standard deviation score (SDS) over time was associated with a decrease in adiponectin levels. None of the markers were associated with insulin sensitivity. Conclusions: Long-term GH treatment is not associated with disadvantageous changes in adiponectin, resistin, IL-6 and CRP levels, neither during nor after GH treatment.

Subclassification of small for gestational age children with persistent short stature: Growth patterns and response to GH treatment (Article)

2008-01-01T00:00:00Z

Aim: We determined whether subclassification of short small for gestational age (SGA) children according to birth anthropometrics could delineate different patterns in gestation, delivery, postnatal growth, response to growth hormone (GH) treatment and parental height. Methods: 201 short SGA children were divided into three groups, SGAL, SGAL+Wand SGAL+W+HC, according to birth length (L), weight (W) and head circumference (HC) ≤-2.00 standard deviation score (SDS). Results: SGAL+W+HCchildren were born after the shortest gestational age and more often by caesarean section than SGALchildren (36.3 vs. 38.1 weeks, 68.4 vs. 24.4%). SGAL+Wchildren had an intermediate pattern and experienced most gestational hypertension (p = 0.01). At birth, SGAL+W+HCchildren were shorter than SGALor SGAL+W(-4.12 vs. -2.67 and -3.72 SDS, p ≤ 0.001). During the first 3 years of life, SGAL+W+HCchildren exhibited an increased growth in height (0.98 SDS) and HC (1.28 SDS) than SGAL(height, -0.06 SDS; HC, -0.30 SDS) and SGAL+W(height, 0.62 SDS; HC, -0.31 SDS). However, HC SDS remained smaller for SGAL+W+HCthan the other groups at age 3. The groups did not differ in growth response during GH treatment. SGALchildren tended to have shorter parents and target height than SGAL+W+HCchildren. Conclusions: Our study shows that subclassification of short SGA children might be a useful method for investigating SGA children as the subgroups revealed a different gestation, delivery and postnatal growth pattern. Response to GH treatment was not different between the groups. Copyright

One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis (Article)

2008-01-01T00:00:00Z

Objective: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Design: Retrospective study conducted between 1997 and 2004. Setting: University-affiliated paediatric intensive care unit (PICU). Patients and participants: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Interventions: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12 h and 24 h. To assess disease severity, PRISM score and selected laboratory parameters were determined. Measurements and main results: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24 h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24 h after admission. Conclusions: Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24 h. It might therefore increase risk of death.

Insulin gene variable number of tandem repeats is not associated with weight from fetal life until infancy: The Generation R Study (Article)

2007-12-01T00:00:00Z

Objective: The aim of this study was to examine whether the insulin gene variable number of tandem repeats (INS VNTR) is associated with growth patterns in fetal life and infancy. Design and methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life until young adulthood. Fetal growth was assessed by ultrasounds in early, mid-, and late pregnancy. Anthropometry in infancy was assessed at birth and at the ages of 6 weeks, 6 months, and 14 months. DNA for genotyping of the INS VNTR promoter region was available in 859 children. Results: The genotype distribution was I/1 50.8%, I/III40.0%, and III/ III9.2%. III/III individuals had a shorter gestational age (P<0.005 versus I/I) and a lower birth weight (P<0.05 versus I/I). There were no differences in birth weight after adjusting for gestational age. Class III homozygotes had a smaller abdominal circumference/head circumference (HC) ratio (P<0.005 versus I/I) in mid-pregnancy, but not in late pregnancy. Also, III/III subjects had a relative decrease in HC (SDS) from mid-pregnancy to the age of 14 months (P<0.05 versus I/I). No other differences in pre- and postnatal growth characteristics and patterns were found. Conclusions: Class III homozygotes were born at an earlier gestational age. No association was found between INS VNTR and birth weight adjusted for gestational age. Our data suggest that the III/III genotype may be associated with asymmetrical growth in mid-pregnancy, but not in late pregnancy.

Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: Six-year follow-up of a randomized controlled GH trial (Article)

2007-10-01T00:00:00Z

Context: Alterations in the GH-IGF-I axis in short small-for-gestational- age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long-term effects of GH treatment are very scarce. Objective: To investigate effects of long-term GH treatment on body composition and BMD by dual energy X-ray absorptiometry (DXA) in short SGA children. Design: Longitudinal 6-year GH study with a randomized controlled part for 3 years. Results: At baseline, fat percentage standard deviation score (SDS) and lumbar spine BMD SDS corrected for height (BMADLSSDS) were significantly lower than zero. Lean body mass (LBM) SDS adjusted for age was also reduced, but LBM adjusted for height (LBM SDSheight) was not decreased. GH treatment induced a decrease in fat percentage SDS and an increase in BMADLSSDS. LBM SDSheightremained similar in GH-treated children, but deteriorated in untreated controls. When these untreated controls subsequently started GH treatment, their LBM SDSheightrapidly normalized to values comparable with zero. Conclusion: During long-term GH treatment in short SGA children, fat percentage SDS decreased and BMADLSSDS increased. These effects of GH treatment were most prominent in children who started treatment at a younger age and in those with greater height gain during GH treatment. LBM SDSheightremained around 0 SDS in GH-treated children, but declined to low normal values in untreated controls.

GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism (Article)

2007-09-01T00:00:00Z

Objective: The polymorphic deletion of exon 3 of the GH receptor (d3-GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA). Design: The study included short prepubertal SGA children treated with rhGH for 1 or 2 years. Population: Two hundred and forty white Caucasian SGA children (138 male, 102 female) aged 6.6 ± 2.3 years with a height at -3.0 ± 0.7 SDS at start of rhGH treatment; 193 ethnically matched controls. Methods: The GHR polymorphism (fl/fl, fl/d3 or d3/d3) was genotyped by polymerase chain reaction (PCR) multiplex assay. Growth velocity (G/V) in cm/year and changes in GV during the first and second year of rhGH treatment were evaluated. Results: The change in GV was significantly greater in SGA children carrying one or two copies of the d3-GHR allele (P = 0.038 for the first year and P = 0.041 for the second year of GH treatment), but the change in height was not significantly different. Birthweight was significantly lower in SGA children with the d3/d3 genotype than in SGA children with the fl/fl genotype (P = 0.034) and in those with the fl/d3 genotype (P = 0.016). Conclusion: Our data, based on a large cohort, showed that the exon 3 GHR polymorphism is associated with responsiveness to rhGH treatment in SGA children with short stature.

Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment (Article)

2007-09-01T00:00:00Z

Background: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, obesity and short stature. Several endocrine abnormalities have been described, including GH deficiency and hypogonadotrophic hypogonadism. Published data on thyroid hormone levels in PWS children are very limited. Objective: To evaluate thyroid function in children with PWS, before and during GH treatment. Design/patients: At baseline, serum levels of T4, free T4 (fT4), T3, reverse T3 (rT3) and TSH were assessed in 75 PWS children. After 1 year, assessments were repeated in 57 of the them. These children participated in a randomized study with two groups: group A (n = 34) treated with 1 mg GH/m2/day and group B (n = 23) as controls. Results: Median age (interquartile range, IQR) of the total group at baseline was 4.7 (2.7-7.6) years. Median (IQR) TSH level was -0.1 SDS (-0.5 to 0.5), T4 level -0.6 SDS (-1.7 to 0.0) and fT4 level -0.8 SDS (-1.3 to -0.3), the latter two being significantly lower than 0 SDS. T3 level, at 0.3 SDS (-0.3 to 0.9), was significantly higher than 0 SDS. After 1 year of GH treatment, fT4 decreased significantly from -0.8 SDS (-1.5 to -0.2) to -1.4 SDS (-1.6 to -0.7), compared to no change in untreated PWS children. However, T3 did not change, at 0.3 SDS (-0.1 to 0.8). Conclusions: We found normal fT4 levels in most PWS children. During GH treatment, fT4 decreased significantly to low-normal levels. TSH levels remained normal. T3 levels were relatively high or normal, both before and during GH treatment, indicating that PWS children have increased T4 to T3 conversion.

Free/dissociable insulin-like growth factor (IGF)-I, not total IGF-I, correlates with growth response during growth hormone treatment in children born small for gestational age (Article)

2007-08-01T00:00:00Z

Context: IGF-I plays an important role in pre- and postnatal growth. Its serum levels are regulated by metabolic and genetic factors. Mean total IGF-I in short, small for gestational age (SGA) children is reduced, but within the normal range. Free/dissociable IGF-I is the bioactive form of IGF-I. Objectives: The aim of the study was to investigate changes in free IGF-I during GH treatment in short SGA children and to evaluate whether free IGF-I levels contribute to predicting first-year growth response and/or adult height. Design, Setting, and Intervention: We conducted a randomized, double-blind GH dose-response study with a GH dose of either 1 mg/m2·d (group A) or 2 mg/m2·d (group B). Free IGF-I, total IGF-I, and IGF binding protein (IGFBP)-3 were determined at baseline, after 1 and 5 yr, at stop, and 6 months after GH discontinuation. Patients: We studied 73 (46 male) short SGA children (36 group A) with a baseline mean age of 7.7 (2.2) yr and a mean GH duration of 8.2 (2.1) yr. Main Outcome Measures: Untreated SGA children had a mean free IGF-I SD score (SDS) of -0.2 (1.2), not related to total IGF-I. During GH therapy, free IGF-I significantly increased to 1.6 (0.7) SDS, as did total IGF-I and IGFBP-3 [2.0 (0.8) and 1.3 (0.9), respectively]. Multiple regression analysis showed that baseline free IGF-I and IGFBP-3 were negatively correlated with adult height SDS, whereas baseline bone age delay, target height SDS, baseline height SDS, and GH dose were positively correlated. Free IGF-I was also negatively correlated with first-year growth response. Conclusions: Circulating baseline free IGF-I and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in short SGA children. 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.

Breathing disorders in Prader-Willi syndrome: The role of obesity, growth hormone treatment and upper respiratory tract infections (Article)

2007-07-01T00:00:00Z

Prader-Willi syndrome is a neurogenetic disorder characterized by a number of signs and symptoms, including muscular hypotonia in infancy, hypogonadism, obesity and short stature. Neurobehavioral abnormalities and cognitive impairment are common. In addition, breathing abnormalities have been described, including sleep-related breathing disorders, abnormal chemoreceptor sensitivity and pulmonary function abnormalities. Growth hormone treatment is now widely used in children with Prader-Willi syndrome to improve growth and body composition. Over the last 4 years, case reports have been published concerning unexpected death, many of which were related to respiratory abnormalities. This review focuses on breathing abnormalities in Prader-Willi syndrome individuals and the influence of obesity, growth hormone treatment and upper respiratory tract infections.

Adiponectin levels in prepubertal children with Prader-Willi syndrome before and during growth hormone therapy (Article)

2007-04-01T00:00:00Z

Context: Children with Prader-Willi syndrome (PWS) may have obesity and an abnormal body composition with a high body fat percentage, even if they have a normal body weight. Adiponectin has been inversely related to obesity and insulin resistance. Objective: The objective of the study was to evaluate in prepubertal PWS children the following: 1) adiponectin levels, body composition, carbohydrate metabolism, and triglyceride levels; 2) associations between adiponectin and body composition, carbohydrate metabolism, and triglycerides; and 3) effects of GH treatment on these outcome measures. Patients: Twenty prepubertal PWS children participated in the study. Intervention: The subjects were randomized into a GH treatment group (n = 10, 1 mg/m2·d) and a non-GH-treated control group (n = 10). Main Outcome Measures: At baseline, after 1 and 2 yr of GH treatment, fasting levels of adiponectin, glucose, insulin, and triglycerides were assessed. Body composition and fat distribution were measured by dual energy x-ray absorptiometry. Results: PWS children had significantly higher median (interquartile range) adiponectin levels [17.1 mg/liter (13.9 -23.2)] than healthy sex- and age-matched controls [11.8 mg/liter (9.7-12.5), P < 0.005]. Body fat percentage was significantly higher than 0 SD score [1.8 SD score (1.5-2.1), P < 0.001]. Adiponectin levels were inversely related to triglyceride levels (r = -0.52, P < 0.03). There was a tendency to an inverse relation with body fat percentage and body mass index, but no correlation with fasting insulin or glucose levels, the insulin to glucose ratio, or homeostasis model assessment index. During GH treatment, adiponectin levels increased significantly and did not change in randomized controls. Conclusion: Adiponectin levels were increased, and inversely associated with triglyceride levels, in prepubertal, not overweight PWS children, although they had a relatively high body fat percentage. During GH treatment, adiponectin levels further increased, whereas no change was found in the controls, which is reassuring with respect to the development of insulin resistance during GH treatment. Copyright

A new method to determine mean adult height from incomplete follow-up data (Article)

2007-03-01T00:00:00Z

Background/Aim: In long-term growth studies with adult height (AH) as outcome, reporting is often required while data are incomplete because some participants have not yet reached AH whereas others might be lost to follow-up. Current practice is to analyze only participants who did reach AH, which can easily give biased results. We introduce a new method into the area of growth research. Methods: We used the data of patients from a registration database and a growth study. The new method uses growth data in time intervals. The percentage of children still growing and the mean growth at each interval are used to determine mean AH. Results: With the new method, estimated mean AHs had smaller bias and standard error than with commonly used methods. The method is not hampered by a correlation between AH and age at reaching AH, unlike methods merely using patients who have reached AH. Conclusion: In contrast to commonly used methods, the new method provides valid results on mean AH when complete actual measurements of AH are not (yet) available, provided that drop-out, if any, is not related to (disappointing) growth. As it also uses observed data of children with incomplete follow-up, the method employs the data more effectively. Copyright

Prediction of adult height in growth-hormone-treated children with growth hormone deficiency (Article)

2007-03-01T00:00:00Z

Context: Several studies have searched for factors that significantly influence adult height (AH) of children with GH deficiency (GHD) who have been treated with biosynthetic GH, but a prediction model for AH has not yet been presented. Objective: Our objective was to develop models for prediction of AH, using information available at the start of GH treatment or after 1 yr of treatment. Design and Setting: For this retrospective study, data were collected from the National Registry of Growth Hormone Treatment in Children, which contained data of Dutch children treated with GH. Patients/Intervention: Patients included males born before 1985 and females born before 1987 with either diagnosis of GHD (syndromes, tumors, and other diseases were excluded) or a maximal GH response during provocation tests of less than 11 ng/ml, treated with biosynthetic GH for at least 1 yr. To be able to use the complete group of 342 children for the development of the models, multiple imputation was used for missing values. Main Outcome Measure: We assessed AH SD scores (SDS). Results: Each prediction model contained both target height SDS and current height SDS. The change in height SDS during the first year proved an important predictor for AH. In all models, addition of GH dose was not significant. The percent explained variance, after correction for overfitting, ranged from 37% (prepubertal children, prediction at start) to 60% (pubertal children, prediction after 1 yr). Conclusion: The presented prediction models give accurate predictions of AH for children with GHD at start and after 1 yr of GH treatment. They are useful tools in the treatment of these children. Copyright

Effect of growth hormone therapy on serum adiponectin and resistin levels in short, small-for-gestational-age children and associations with cardiovascular risk parameters. (Article)

2007-01-01T00:00:00Z

BACKGROUND: Adiponectin and resistin are fat cell-derived hormones, which are thought to be respectively protective and disadvantageous with regard to the development of cardiovascular disease and diabetes mellitus type 2. Low birth weight has been associated with increased risks for the development of these diseases. In short, small-for-gestational-age (SGA) children, GH therapy has several positive effects regarding cardiovascular risk factors. On the other hand, concern has been expressed about the effects of GH therapy on insulin sensitivity. METHODS: We measured adiponectin and resistin levels in 136 short prepubertal children born SGA and their association with cardiovascular risk parameters and growth factors. Also, we compared the levels with normal-statured controls. The effect of GH treatment was evaluated in 50 short SGA children vs. baseline and vs. an untreated sex- and age-matched SGA control group. RESULTS: Short SGA children had similar adiponectin and lower resistin levels, compared with normal-statured controls. In GH-treated SGA children, neither adiponectin nor resistin levels changed significantly during 2 yr of GH treatment. Compared with untreated sex- and age-matched SGA controls, GH-treated SGA children had similar adiponectin and lower resistin levels. Adiponectin correlated inversely with age but not any cardiovascular risk parameter or growth factor. Higher IGF-I levels in GH-treated children were associated with lower resistin levels. CONCLUSIONS: Compared with normal-statured controls, short prepubertal SGA children had similar adiponectin and lower resistin levels. Two years of GH treatment had no effect on their adiponectin and resistin levels.

Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls. (Article)

2007-01-01T00:00:00Z

CONTEXT: Low birth weight might increase risk of diabetes mellitus type 2 and metabolic syndrome (MS). GH has insulin-antagonistic properties. Therefore, long-term follow-up of GH-treated children born small for gestational age (SGA) is important. OBJECTIVE AND PATIENTS: The objective of the study was to evaluate insulin sensitivity (Si) and disposition index (DI), all components of the MS and IGF-I and IGF binding protein (IGFBP)-3 levels in 37 previously GH-treated young SGA adults in comparison with 25 untreated short SGA controls. RESULTS: GH-treated subjects were 22.3 (1.7) yr old. Mean duration of GH treatment had been 7.3 (1.3) yr. Mean period after discontinuation was 6.5 (1.4) yr. Si and DI were comparable for GH-treated and untreated SGA subjects. Fasting glucose and insulin levels increased during GH treatment but recovered after discontinuation. Body mass index, waist circumference, high-density lipoprotein cholesterol levels, and triglycerides were equivalent. Systolic and diastolic blood pressure and cholesterol were significantly lower in GH-treated subjects. Thirty-two percent of untreated controls vs. none of the GH-treated subjects had an increased blood pressure. GH-induced rises in IGF-I and IGFBP-3 levels had completely recovered after GH stop. CONCLUSION: At 6.5 yr after discontinuation of long-term GH treatment, Si, DI, fasting levels of glucose and insulin, body mass index, waist circumference, and IGF-I and IGFBP-3 levels were equivalent for GH-treated and untreated young SGA adults. Systolic and diastolic blood pressure and serum cholesterol were even lower in GH-treated subjects. These data are reassuring because they suggest that long-term GH treatment does not increase the risk for diabetes mellitus type 2 and MS in young adults.

Sleep-related breathing disorders in prepubertal children with Prader- Willi syndrome and effects of growth hormone treatment. (Article)

2006-12-01T00:00:00Z

CONTEXT: Recently, several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome (PWS), patients were reported. GH treatment in PWS results in a remarkable growth response and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however, limited. OBJECTIVE: The objective of the study was to evaluate effects of GH on respiratory parameters in prepubertal PWS children. DESIGN: Polysomnography was performed before GH in 53 children and repeated after 6 months of GH treatment in 35 of them. PATIENTS: Fifty-three prepubertal PWS children (30 boys), with median (interquartile range) age of 5.4 (2.1-7.2) yr and body mass index of +1.0 sd score (-0.1-1.7). INTERVENTION: Intervention included treatment with GH 1 mg/m2.d. RESULTS: Apnea hypopnea index (AHI) was 5.1 per hour (2.8-8.7) (normal 0-1 per hour). Of these, 2.8 per hour (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and body mass index, but central apneas decreased with age (r = -0.34, P = 0.01). During 6 months of GH treatment, AHI did not significantly change from 4.8 (2.6-7.9) at baseline to 4.0 (2.7-6.2; P = 0.36). One patient died unexpectedly during a mild upper respiratory tract infection, although he had a nearly normal polysomnography. CONCLUSIONS: PWS children have a high AHI, mainly due to central apneas. Six months of GH treatment does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during upper respiratory tract infection in PWS children should be considered.

Euthyroid sick syndrome in meningococcal sepsis: the impact of peripheral thyroid hormone metabolism and binding proteins. (Article)

2005-10-01T00:00:00Z

CONTEXT AND OBJECTIVES: The objective of this study was to elucidate the influence of disease severity, deiodination, sulfation, thyroid hormone binding, and dopamine use on thyroid function in euthyroid sick syndrome. SETTING: The study was performed at a university-affiliated pediatric intensive care unit (PICU). DESIGN: This was an observational cohort study. PATIENTS: Sixty-nine children with meningococcal sepsis were studied. MAIN OUTCOME MEASURES: Differences in thyroid function among nonsurvivors, shock survivors, and sepsis survivors on PICU admission were the main outcome measures. RESULTS: The main study group consisted of 45 non-dopamine-treated children. All children had decreased total T3 (TT3)/rT3 ratios without elevated TSH. T4 sulfate levels were decreased in 88%. Nonsurvivors had paradoxically higher TT3/rT3 ratios than shock survivors (0.71 vs. 0.30); this ratio also correlated with shorter duration of disease (r = -0.43). TT4 and T4-binding globulin (TBG) levels declined with increasing disease severity. TBG levels correlated inversely with elastase levels (r = -0.46). Only TSH levels were significantly lower in 24 dopamine-treated children compared with non-dopamine-treated children (0.65 vs. 0.84), whereas other thyroid hormones did not significantly differ. Both higher TT3/rT3 ratios and lower TT4 levels were predictive for mortality, but this disappeared when IL-6 was entered into the regression model. CONCLUSIONS: All children with meningococcal sepsis showed signs of euthyroid sick syndrome. Alterations in peripheral thyroid hormone metabolism related inversely to the duration of disease and seemed to be enacted by profound induction of type 3 deiodinase rather than by down-regulation of type 1. Lower TT4 levels were related to increased turnover of TBG by elastase. Dopamine was found to suppress only TSH secretion, not other thyroid hormone levels, on PICU admission. Both the TT3/rT3 ratio and TT4 levels were predictive for mortality, but were not superior to IL-6.

A randomized, placebo-controlled GH trial in very preterm infants who were at risk for bronchopulmonary dysplasia and were treated with dexamethasone. (Article)

2005-10-01T00:00:00Z

Very preterm infants who develop bronchopulmonary dysplasia are often treated with dexamethasone (DEXA) to wean them from the ventilator. As DEXA has growth-suppressive and catabolic effects, which might have long-term consequences on growth and organ development, we investigated whether high-dose GH treatment could overcome these effects. In a randomized, double-blind, placebo-controlled trial, 30 ventilated very low birth weight infants were assigned to receive either GH or placebo treatment after start of DEXA. DEXA was given for 24 d (starting dose 0.5 mg . kg(-1) . d(-1), tapering off every third day). Simultaneously, high-dose GH (0.3 mg . kg(-1) . d(-1)) or placebo was administered during 6 wk. During high-dose DEXA treatment (dose 0.5-0.3 mg . kg(-1) . d(-1)), no gain in head circumference, weight, crown-heel length, and knee-heel length occurred in the GH and placebo groups. Growth during the 6-wk study period was not different between the GH and the placebo groups. Two patients in the placebo group died, but the number and the severity of adverse effects was not statistically different between the GH and placebo groups. In conclusion, high-dose GH treatment did not improve growth in DEXA-treated very preterm infants and thus cannot be recommended to prevent growth failure in these infants. During high-dose DEXA, a complete growth arrest occurred, including stunting of head growth. Growth in head circumference and weight with lower dose DEXA was comparable to growth after discontinuation of DEXA.

Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. (Article)

2005-09-01T00:00:00Z

CONTEXT: Adequate adrenal function is pivotal to survive meningococcal sepsis. OBJECTIVES: The objective of the study was to evaluate adrenocortical function in meningococcal disease. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a university-affiliated pediatric intensive care unit. PATIENTS: Sixty children with meningococcal sepsis or septic shock participated in the study. MAIN OUTCOME MEASURES: The differences in adrenal function between nonsurvivors (n = 8), shock survivors (n = 43), and sepsis survivors (n = 9) on pediatric intensive care unit admission were measured. RESULTS: Nonsurvivors had significantly lower median cortisol to ACTH ratio than shock survivors and sepsis survivors. Because cortisol binding globulin and albumin levels did not significantly differ among the groups, bioavailable cortisol levels were also significantly lower in nonsurvivors than sepsis survivors. Nonsurvivors had significantly lower cortisol to 11-deoxycortisol ratios but not lower 11-deoxycortisol to 17-hydroxyprogesterone ratios than survivors. Using multiple regression analysis, decreased cortisol to ACTH ratio was significantly related to higher IL-6 levels and intubation with etomidate (one single bolus), whereas decreased cortisol to 11-deoxycortisol ratio was significantly related only to intubation with etomidate. Aldosterone levels tended to be higher in nonsurvivors than shock survivors, whereas plasma renin activity did not significantly differ. CONCLUSIONS: Our study shows that the most severely ill children with septic shock had signs of adrenal insufficiency. Bioavailable cortisol levels were not more informative on adrenal function than total cortisol levels. Besides disease severity, one single bolus of etomidate during intubation was related to decreased adrenal function and 11beta-hydroxylase activity. Decreased adrenal function was not related to decreased 21-hydroxylase activity. Based on our results, it seems of vital importance to take considerable caution using etomidate and consider combining its administration with glucocorticoids during intubation of children with septic shock.

Intelligence and psychosocial functioning during long-term growth hormone therapy in children born small for gestational age. (Article)

2004-11-01T00:00:00Z

Short stature is not the only problem faced by small for gestational age (SGA) children. Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence, and behavioral problems. Although GH treatment in short children born SGA can result in a normalization of height during childhood, the effect of GH treatment on intelligence and psychosocial functioning remains to be investigated. We show the longitudinal results of a randomized, double-blind, GH-dose response study initiated in 1991 to follow growth, intelligence quotient (IQ), and psychosocial functioning in SGA children during long-term GH treatment. Patients were assigned to one of two treatment groups (1 or 2 mg GH/m(2) body surface.d, or approximately 0.035 or 0.07 mg/kg.d). Intelligence and psychosocial functioning were evaluated at start of GH treatment (n = 74), after 2 yr of GH treatment (n = 76), and in 2001 (n = 53). IQ was assessed by a short-form Wechsler Intelligence Scale for Children-Revised or Wechsler Adult Intelligence Scale (Block-design and Vocabulary subtests). Behavioral problems were measured by the Achenbach Child Behavior Checklist or Young Adult Behavior Checklist, and self-perception was measured by the Harter Self-Perception Profile. Mean (sem) birth length sd score was -3.6 (0.2), mean age and height at start was 7.4 (0.2) yr and -3.0 (0.1) sd score, respectively, mean duration of GH treatment was 8.0 (0.2) yr, and mean age in 2001 was 16.5 (0.3) yr. After 2 yr of GH treatment, 96% of both GH groups showed a height gain sd score of 1 sd from the start of treatment or more, resulting in a normal height (i.e. height >/= -2.0 sd for age and sex) in 70% of the children. In 2001, 48 (91%) of the 53 children participating in this study had reached a normal height. Block-design s-score and the estimated total IQ significantly increased (P < 0.001 and P < 0.001, respectively) from scores significantly lower than Dutch peers at start (P < 0.001 and P < 0.001, respectively) to comparable scores in 2001. The increase over time for the Vocabulary s-score was not significant. Internalizing Behavior sd scores remained comparable to Dutch peers, whereas Externalizing Behavior sd scores and Total Problem Behavior sd scores improved significantly during GH therapy (P < 0.01 and P < 0.05, respectively) to scores comparable to Dutch peers. Self-perception sd scores improved from start of GH treatment until 2001 (P < 0.001) to scores significantly higher than Dutch peers (P < 0.05). No significant differences between the two GH dosage groups were found. Improvement in Externalizing and Total Problem Behavior sd scores over time was significantly related to change in height sd score (P < 0.05 and P < 0.01, respectively), whereas scores over time for Vocabulary, Block-design, Internalizing, or total Harter Self-Perception score were not related to change in height sd scores.In conclusion, parallel to a GH-induced catch-up growth in adolescents born SGA, IQ, behavior, and self-perception showed a significant improvement over time from scores below average to scores comparable to Dutch peers. In addition, children whose height over time became closer to that of their peers showed less problem behavior.

Head circumference and body proportions before and during growth hormone treatment in short children who were born small for gestational age. (Article)

2004-09-01T00:00:00Z

OBJECTIVE: Although short children who were born small for gestational age (SGA) seem to have normal body proportions, objective data both before and during growth hormone (GH) treatment are very limited. Therefore, we investigated in a large group of short children who were born SGA the effects of GH treatment versus no treatment on head circumference (HC) and body proportions. Furthermore, we studied differences in linear growth and HC between SGA children who were born with a low birth length and birth weight (SGA(L+W)) and SGA children who were born with a low birth length only (SGA(L)). METHODS: An open-labeled, GH-controlled, multicenter study was conducted for 3 years. Non-GH-deficient short SGA children (n = 87), with a mean age (standard deviation) of 5.9 (1.5) years, were randomized to either a GH group (n = 61), receiving GH in a dose of 33 microg/kg/day, or an untreated control group (n = 26). Height; weight; HC; sitting height; armspan; and hand, tibial, and foot size were measured and expressed as standard deviation score (SDS) adjusting for gender and age. RESULTS: At baseline, all anthropometric measurements, except HC SDS, were significantly lower compared with -2 SDS. During GH treatment, all anthropometric measurements normalized in accordance to the normalization of height SDS. At the start of the study, mean HC SDS was significantly lower in SGA(L+W) children compared with SGA(L) children. It is interesting that most (14 of 16) children with an HC SDS less than -2.00 had been born SGA(L+W). During GH treatment, the 3-year increase in height, HC, and other anthropometric measurements was comparable between SGA(L+W) and SGA(L) children. In both SGA(L+W) and SGA(L) control subjects, no changes in SDSs of height, HC, and other anthropometric measurements were found during the 3-year follow-up period. CONCLUSIONS: Untreated short SGA children have normal body proportions with the exception of HC, which is relatively large in many of these children. SGA(L+W) children still had a smaller HC at the age of 5.9 years compared with SGA(L) children. Three years of GH treatment induced a proportionate growth resulting in a normalization of height and other anthropometric measurements, including HC, in contrast to untreated SGA control subjects.

Serum dehydroepiandrosterone sulfate levels and pubarche in short children born small for gestational age before and during growth hormone treatment (Article)

2004-01-01T00:00:00Z

It has been suggested that the programming of the endocrine axes occurs during critical phases of fetal development and will be affected by intrauterine growth retardation. As a result, children born small for gestational age (SGA) might have several hormonal disturbances. In later life, one of the questions that might arise is: Do short children born SGA have higher serum dehydroepiandrosterone sulfate (DHEAS) levels than their peers? Therefore, we compared serum DHEAS levels of 181 short prepubertal children aged 3-9 yr born SGA [birth length (SD score) below -2 for gestational age] with a control group of 170 prepubertal age-matched, normal-statured children born appropriate for gestational age (birth length between -2 and +2 SD score). Because relatively high serum DHEAS levels at a young age might result in a premature pubarche, we investigated the incidence of premature pubarche. We also investigated the association between serum DHEAS levels and bone maturation. In addition, we analyzed whether 1 yr of GH treatment with 1 and 2 mg/m(2).d ( approximately 0.035 and 0.070 mg/kg.d, respectively) had an effect on serum DHEAS levels of prepubertal short SGA children. Serum DHEAS levels of the SGA group were comparable with those of age-matched appropriate for gestational age controls. The incidence of premature pubarche was comparable with that of the normal population. There was a weak negative correlation between serum DHEAS levels and bone maturation after the age of 7 yr. After 1 yr of GH treatment, the increase of serum DHEAS levels was the same for both GH dosage groups and the untreated group. In conclusion, this study shows that small size at birth, which might be a feature of fetal growth restriction, has no effect on serum DHEAS levels before the age of 9 yr. The incidence of premature pubarche is comparable with the normal population. Finally, 1 yr of GH treatment has no effect on serum DHEAS levels.

Effect of dexamethasone treatment on serum GH, IGF-I, and the binding proteins IGFBP-1 and -3 in ventilated very preterm infants. (Article)

2003-07-01T00:00:00Z

Very preterm infants developing bronchopulmonary dysplasia frequently show a compromised growth in the neonatal period especially when steroids are given to facilitate weaning from the ventilator. The aim of this study was to evaluate the short-term effect of dexamethasone (DEXA) on the GH-IGF axis in ventilated very preterm infants developing bronchopulmonary dysplasia. We studied 10 very preterm artificially ventilated infants with bronchopulmonary dysplasia [median (range) gestational age 27.5 wk (25.9-32.0 wk), median (range) birth weight 970 g (610-2150 g)] immediately before and 2 d after the start of DEXA treatment. On both days of study, serum GH profiles were obtained, and serum IGF-I and IGF binding protein (IGFBP) -1 and -3 levels were measured. The ventilation score and the nutritional intake were calculated. Before the start of DEXA treatment, the median serum mean GH level was 12.0 microg/L (6-28.4 microg/L), whereas 2 d after the start of DEXA treatment the median serum mean GH level declined significantly to a value of 4.4 microg/L (1.7-11.9 microg/L). During DEXA treatment, mean, baseline, and maximal GH levels (Pulsar analysis) were significantly lower compared with pretreatment levels (p < 0.01, p < 0.01, and p < 0.05, respectively). Serum IGF-I and IGFBP-3 levels did not decline during DEXA. Serum IGFBP-1 levels were significantly lower compared with pretreatment levels (p < 0.01). Serum GH levels during DEXA treatment were correlated with neither the time interval between the administration of DEXA and the second GH profile nor the cumulative DEXA dose administered. Ventilation score and nutritional intake did not significantly correlate with serum GH, IGF-I, or IGFBP-1 or -3 levels, either before or after the start of DEXA. Two days of DEXA treatment in very preterm ventilated infants has a suppressive effect on serum GH levels, without an acute decline in serum IGF-I levels. A concomitant decrease in serum IGFBP-1 levels was found.

Effect of discontinuation of growth hormone treatment on risk factors for cardiovascular disease in adolescents born small for gestational age (Article)

2003-01-01T00:00:00Z

Hyperlipidemia, diabetes mellitus type 2, and coronary heart disease have been associated with being born small for gestational age (SGA). It has been reported that GH treatment induced higher insulin levels, which has led to concern regarding the long-term effect of GH treatment in predisposed individuals such as children born SGA. In this study, we assessed the effect of discontinuation of long-term GH treatment in 47 adolescents born SGA on oral glucose tolerance tests, blood pressure (BP), and serum lipid levels for two GH dosage groups (3 vs. 6 IU/m2 x d). At 6 months after discontinuation of GH treatment mean (SD) age was 16.0 (2.1) yr. Mean duration of GH treatment had been 6.9 (1.5) yr. Fasting glucose levels and 120-min area under the curve for glucose 6 months after discontinuation of GH treatment showed no difference from pretreatment levels for both GH dosage groups. After discontinuation of GH treatment, fasting insulin levels returned to pretreatment levels (8.4 mU/liter), whereas the 120-min area under the curve for insulin decreased, compared with 6-yr levels (P < 0.01), regardless of GH dosage group. No significant difference was found when levels were compared with a control group. In addition, for both GH dosage groups, no significant changes in systolic and diastolic BP SD score, total cholesterol, and atherogenic index (total cholesterol/high-density lipoprotein cholesterol) were seen from 6 yr of GH until 6 months after discontinuation of GH treatment. In conclusion, in children born SGA, the GH-induced insulin insensitivity disappeared after discontinuation of GH, even after long-term GH treatment. Furthermore, the beneficial effect of GH on BP was not changed after discontinuation of GH, and most children had normal lipid levels.

Validation and calibration of the Kabi Pharmacia International Growth Study prediction model for children with idiopathic growth hormone deficiency (Article)

2003-01-01T00:00:00Z

In 1999 a model was published for prediction of growth in children with idiopathic GH deficiency (IGHD) during GH therapy, derived using data from the Kabi Pharmacia International Growth Study (KIGS) database (Pharmacia \\|[amp ]\\| Upjohn, Inc., International Growth Database). We validated and calibrated this KIGS model for growth in the first year of GH therapy using data from 136 Dutch children with IGHD. Observed vs. predicted outcomes were plotted, and the fitted regression line was significantly different from the line of identity (P = 0.03). It appeared that the predictions were too extreme: relatively low predictions were too low, relatively high predictions were too high. This is a well known phenomenon in the context of prediction models, called overoptimism. For valid application to other data the KIGS predictions should be calibrated. Calibrated predictions are obtained using Y(cal) = Y(orig) + (2.153 - 0.192 x Y(orig)), where Y(cal) is the calibrated prediction, and Y(orig) is the KIGS prediction. The calibrated prediction will be higher than the original KIGS prediction when the original prediction is less than 11.2 cm/yr and will be lower otherwise. The variability of the prediction errors of the calibrated predictions was positively related to the value of the prediction (P < 0.001), described by the equation SD(pred err) = -1.017 + 0.286 x Y(cal). Our calibrated model will give better predictions for children with IGHD fulfilling the same criteria.

Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial (Article)

2003-01-01T00:00:00Z

The GH dose-response effect of long-term continuous GH treatment on adult height (AH) was evaluated in 54 short children born small for gestational age (SGA) who were participating in a randomized, double-blind, dose-response trial. Patients were randomly and blindly assigned to treatment with either 3 IU (group A) or 6 IU (group B) GH/m(2).d ( approximately 0.033 or 0.067 mg/kg.d, respectively). The mean (+/-SD) birth length was -3.6 (1.4), the age at the start of the study was 8.1 (1.9) yr, and the height SD score (SDS) at the start of the study -3.0 (0.7). Seventeen of the 54 children were partially GH deficient (stimulated GH peak, 10-20 mU/liter). Fifteen non-GH-treated, non-GH-deficient, short children born SGA, with similar inclusion criteria, served as controls [mean (+/-SD) birth length, -3.3 (1.2); age at start, 7.8 (1.7) yr; height SDS at start, -2.6 (0.5)]. GH treatment resulted in an AH above -2 SDS in 85% of the children after a mean (+/-SD) GH treatment period of 7.8 (1.7) yr. The mean (SD) AH SDS was -1.1 (0.7) for group A and -0.9 (0.8) for group B, resulting from a mean (+/-SD) gain in height SDS of 1.8 (0.7) for group A and 2.1 (0.8) for group B. No significant differences between groups A and B were found for AH SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.2, 0.6; P > 0.2) and gain in height SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.1, 0.7; P > 0.1). When corrected for target height, the mean corrected AH SDS was -0.2 (0.8) for group A and -0.4 (0.9) for group B. The mean (+/-SD) AH SDS of the control group [-2.3 (0.7)] was significantly lower than that of the GH-treated group (P < 0.001). Multiple regression analysis indicated the following predictive variables for AH SDS: target height SDS, height SDS, and chronological age minus bone age (years) at the start of the study. GH dose had no significant effect. In conclusion, long-term continuous GH treatment in short children born SGA without signs of persistent catch-up growth leads to a normalization of AH, even with a GH dose of 3 IU/m(2).d ( approximately 0.033 mg/kg.d).

Puberty in growth hormone-treated children born small for gestational age (SGA) (Article)

2003-01-01T00:00:00Z

Seventy-five small for gestational age (SGA) children were studied in a randomized, double-blind, dose-response GH trial with either 1 or 2 mg GH/m(2).d. Mean (SD) age at the start of GH therapy was 7.3 (2.2) yr. Data were compared with Dutch reference data. In SGA boys, mean (SD) age at onset of puberty was 12.0 (1.0) and 11.6 (0.7) yr, and in SGA girls it was 10.9 (1.1) and 10.6 (1.2) yr when treated with 1 and 2 mg GH/m(2).d, respectively. SGA boys treated with the lower GH dose started puberty later than the appropriate for gestational age (AGA) controls; for the other GH-dosage groups there was no significant difference in age at onset of puberty compared to AGA controls. The age at menarche and the interval between breast stage M2 and menarche were not significantly different for GH-treated SGA girls compared to their peers. The duration of puberty and pubertal height gain of GH-treated SGA boys and girls were not significantly different between the two GH-dosage groups and were comparable with untreated short children born SGA. In conclusion, long-term GH therapy in short SGA children has no influence on the age at onset and progression of puberty compared to AGA controls, regardless of treatment with a dose of 1 or 2 mg GH/m(2).d. Duration of puberty and pubertal height gain were not significantly different between the GH-dosage groups.

Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA) (Article)

2002-01-01T00:00:00Z

Low birth weight is associated with an increased risk in adult life of type 2 diabetes, hypertension and cardiovascular disease (CVD). The fetal insulin hypothesis postulates that genes involving insulin resistance could effect birth weight and disease in later life (Hattersley, 1999). Besides insulin, there is extensive evidence that insulin-like growth factor-I and -II (IGF-I, IGF-II) play an important role in fetal growth. We hypothesized that minor genetic variation in the IGF-I gene could influence pre- and postnatal growth. Three microsatellite markers located in the IGF-I gene in 124 short children (height < -1.88 SDS) who were born small for gestational age (SGA) and their parents were studied. SGA was defined as both a birth weight and birth length below -1.88 SDS for gestational age. Two polymorphic markers showed transmission disequilibrium. Allele 191 of the IGF1.PCR1 marker was transmitted more frequently from parent to child (chi(2) = 4.8 and p = 0.02) and allele 198 of the 737/738 marker was transmitted less frequently from parent to child (chi(2)= 4.5 and p = 0.03). Children carrying the 191-allele had significantly lower IGF-1 levels than children not carrying this allele (-1.1 SDS vs. -0.05 SDS; p = 0.03). Also, head circumference SDS remained smaller in children with allele 191 compared to children without allele 191 (-2.1 SDS vs. -0.9 SDS; p = 0.003). Our results show that genetically determined low IGF-I levels may lead to a reduction in birth weight, length and head circumference and to persistent short stature and small head circumference in later life (proportionate small). Since low IGF-I levels are associated with type 2 diabetes and CVD, we propose that the IGF-I gene may provide a link between low birth weight and such diseases in later life.

Acute stress response in children with meningococcal sepsis: important differences in the growth hormone/insulin-like growth factor I axis between nonsurvivors and survivors (Article)

2002-01-01T00:00:00Z

Septic shock is the most severe clinical manifestation of meningococcal disease and is predominantly seen in children under 5 yr of age. Very limited research has been performed to elucidate the alterations of the GH/IGF-I axis in critically ill children. We evaluated the GH/IGF-I axis and the levels of IGF-binding proteins (IGFBPs), IGFBP-3 protease, glucose, insulin, and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 d after admission. The median age was 22 months (range, 4-185 months). Eight patients died. Nonsurvivors had extremely high GH levels that were significant different compared with mean GH levels in survivors during a 6-h GH profile (131 vs. 7 mU/liter; P < 0.01). Significant differences were found between nonsurvivors and survivors for the levels of total IGF-I (2.6 vs. 5.6 nmol/liter), free IGF-I (0.003 vs. 0.012 nmol/liter), IGFBP-1 (44.3 vs. 8.9 nmol/liter), IGFBP-3 protease activity (61 vs. 32%), IL-6 (1200 vs. 50 ng/ml), and TNFalpha (34 vs. 5.3 pg/ml; P < 0.01). The pediatric risk of mortality score correlated significantly with levels of IGFBP-1, IGFBP-3 protease activity, IL-6, and TNFalpha (r = +0.45 to +0.69) and with levels of total IGF-I and free IGF-I (r = -0.44 and -0.55, respectively). Follow-up after 48 h in survivors showed an increased number of GH peaks, increased free IGF-I and IGFBP-3 levels, and lower IGFBP-1 levels compared with admission values. GH levels and IGFBP-1 levels were extremely elevated in nonsurvivors, whereas total and free IGF-I levels were markedly decreased and were accompanied by high levels of the cytokines IL-6 and TNFalpha. These values were different from those for the survivors. Based on these findings and literature data a hypothetical model was constructed summarizing our current knowledge and understanding of the various mechanisms.

Adrenal function in sick very preterm infants (Article)

2000-01-01T00:00:00Z

Some very preterm neonates admitted to the neonatal intensive care unit show circulatory and respiratory problems that improve after administration of steroids. It is unclear whether these symptoms could be caused by adrenal insufficiency. The objective of our study was to investigate the cortisol levels and the cortisol release from the adrenals after ACTH in very preterm infants with and without severe illness and to find whether a relation exists between adrenal function and outcome. An ACTH test (0.5 microg) was performed on d 4 in 21 very preterm infants (gestational age, 25.6-29.6 wk; birth weight, 485-1265 g). Baseline cortisol and 17-hydroxyprogesterone (17OHP) levels and the cortisol levels 30, 60, and 120 min after ACTH administration were measured. The Score for Neonatal Acute Physiology was used to measure illness severity. All infants showed an increase in cortisol levels after ACTH, but the cortisol levels were significantly lower in the ventilated more severely ill infants. After adjusting for birth weight and gestational age, the mean baseline cortisol levels and cortisol/17OHP ratios were significantly lower and the 17OHP levels significantly higher in the ventilated infants compared with the nonventilated infants. Patients with an adverse outcome had significantly lower baseline cortisol/17OHP ratios and 60-min cortisol levels during ACTH testing (p = 0.002 and p = 0.03, respectively). These data suggest an insufficient adrenal response to stress in sick ventilated very preterm infants with gestational ages younger than 30 wk compared with nonventilated less sick preterm infants. Further studies are required to investigate whether supplementation with physiologic doses of hydrocortisone may benefit the outcome.

Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors (Article)

2000-01-01T00:00:00Z

To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission. On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18). Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs. 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs. 231 ng/L). Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs. 17), TSH (0.97 vs. 0.29 mE/L), T3 (0.53 vs. 0.38 nmol/L), reverse T3 (rT3) (0.75 vs. 1.44 nmol/L), C-reactive protein (34 vs. 78 mg/L), nonesterified fatty acids (0.32 vs. 0.95 mmol/L), and lactate (7.3 vs. 3.2 mmol/L). In those who survived, the most important changes within 48 h were seen in a normalization of cortisol and ACTH levels, but without a circadian rhythm; a decrease of rT3 and an increase in the T3/rT3 ratio; and a decrease in the levels of the nonesterified free fatty acids and an unaltered high urinary nitrogen excretion. At this moment, it is yet unknown whether the hormonal abnormalities are determining factors in the outcome of acute meningococcal sepsis or merely represent secondary effects. Understanding the metabolic and endocrine alterations is required to design possible therapeutic approaches. The striking difference between nonsurvivors and survivors calls for reconsideration of corticosteroid treatment in children with meningococcal sepsis.

Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency (Article)

2000-01-01T00:00:00Z

To assess the effects of long-term continuous GH treatment on body composition, blood pressure (BP), and lipid metabolism in children with short stature born small for gestational age (SGA), body mass index (BMI), skinfold thickness measurements, systemic BP measurements, and levels of blood lipids were evaluated in 79 children with a baseline age of 3-11 yr with short stature (height SD-score, < -1.88) born SGA (birth length SD-score, < -1.88). Twenty-two of the 79 children were GH deficient (GHD). All children participated in a randomized, double-blind, dose-response multicenter GH trial. Four- and 6-yr data were compared between two GH dosage groups (3 vs. 6 IU/m2 body surface/day). Untreated children with short stature born SGA are lean (mean BMI SD-score, -1.3; mean SD-score skinfolds, -0.8), have a higher systolic BP (SD-score, 0.7) but normal diastolic BP (SD-score, -0.1), and normal lipids (total cholesterol, 4.7 mmol/L; low-density lipoprotein, 2.9 mmol/L; high-density lipoprotein, 1.3 mmol/L) compared with healthy peers. During long-term continuous GH treatment, the BMI normalized without overall changes in sc fat compared with age-matched references, whereas the BP SD-score and the atherogenic index decreased significantly. Although the mean 6-yr increase in height SD-score was significantly higher in the children receiving GH treatment with 6 IU/m2 x day (2.7) than in those receiving treatment with 3 IU/m2 day (2.2), no differences in the changes in BMI, skinfold measurements, BP, and lipids were found between the GH dosage groups. The pretreatment SD-scores for BMI, skinfold, and BP, as well as the lipid levels, were not significantly different between GHD and non-GHD children, but after 6 yr of GH treatment the skinfold SD-score and BP SD-score had decreased significantly more in the GHD than in the non-GHD children. Our data indicate that GH treatment has at least up to 6 yr positive instead of negative effects on body composition, BP, and lipid metabolism. In view of the reported higher risk of cardiovascular diseases in later life in children born SGA, further research into adulthood remains warranted.

Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone (Article)

1999-01-01T00:00:00Z

OBJECTIVES: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol. DESIGN: Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years). PATIENTS: Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years). MEASUREMENTS: To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS). RESULTS: The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment. CONCLUSIONS: Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.

Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial (Article)

1999-01-01T00:00:00Z

The growth-promoting effect of continuous GH treatment was evaluated over 5 yr in 79 children with short stature (height SD score, less than -1.88) born small for gestational age (SGA; birth length SD score, less than -1.88). Patients were randomly and blindly assigned to 1 of 2 GH dosage groups (3 vs. 6 IU/m2 body surface-day). GH deficiency was not an exclusion criterium. After 5 yr of GH treatment almost every child had reached a height well within the normal range for healthy Dutch children and in the range of their target height SD score. Only in children who remained prepubertal during the study period was the 5-yr increase in height SD score (HSDS) for chronological age significantly higher in the study group receiving 6 compared to 3 IU GH/m2 x day. Remarkably, the 5-yr increment in HSDS for chronological age was not related to spontaneous GH secretion, maximum GH levels after provocation, or baseline insulin-like growth factor I levels. GH treatment was associated with an acceleration of bone maturation regardless of the GH dose given. The HSDS for bone age and predicted adult height increased significantly. GH treatment was well tolerated. In conclusion, our 5-yr data show that long term continuous GH treatment at a dose of 3 or 6 IU/m2 x day in short children born SGA results in a normalization of height during childhood followed by growth along the target height percentile.

Fatness and muscularity as risk indicators of child mortality in rural Congo (Article)

1998-01-01T00:00:00Z

OBJECTIVES: To examine the relationship of anthropometrical indicators of fatness and muscularity with mortality in children in a rural African community. BACKGROUND: A prospective cohort study was carried out in the rural health zone of Bwamanda, Northern Congo using a random cluster sample of 5167 children, aged 0-5 years. MAIN OUTCOME MEASURES: Short- and long-term mortality rates, being deaths within 3 months and deaths in 3-month periods observed 3-30 months after enrolment. Rates of all cause mortality and of mortality from kwashiorkor or marasmus, by level of baseline fatness and muscularity. Indicators of fatness and muscularity were obtained by correcting anthropometric arm fat and arm muscle areas for age, sex, weight and height. RESULTS: The relationship of both the fatness and muscularity scores with short-term mortality was marked by a clear threshold (-0.5 SDS) below which there was a significant rise in mortality from all causes as well as from kwashiorkor and marasmus. These excess mortalities were also found in normal weight children. Fatness and muscularity scores remained significant determining factors of short-term mortality in a multiple logistic regression analysis with sex, age, season and weight-for-age. A ROC curve analysis showed that fat and muscularity scores had better predictive abilities than weight-for-age. Low fat status had a bad prognosis on the long-term in underweight children. CONCLUSIONS: Measures of current nutritional status should not be based on weight indices alone. Objective and/or clinical evaluation of fat and muscle status (also in normal weight children) should be added in order to detect a higher proportion of malnourished children and to more accurately evaluate mortality risk.

Growth failure in children with renal disease : incidence, pathophysiology, new perspectives with growth hormone therapy (Doctoral Thesis)

1994-06-15T00:00:00Z

Stunted growth is a serious problem for children with chronic renal insufficiency (CRI). Advances in the treatment of renal insufficiency, including dialysis and renal transplantation, have greatly improved the survival rate for these patients. Consequently the failure to grow has become a major issue. Unfortunately. despite intensive medical care, optimized nutrition. vitamin D and mineral supplements, and dialysis, it has proved impossible to improve height velocity.' Growth retardation tends to occur when the glomerular filtration rate drops below 20-30 ml/min/L73m'. Infants with CRI secondary to congenital renal abnonnalities are particularly prone to growth failure during the first years of life. When CRI is first diagnosed in a child, the child's height will often lie below the third height percentile for age. It has been reported that nearly 40% of children that enter dialysis have a height below the third height percentile.