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J M Wit,
M B Ranke,
K Albertsson-Wikland,
A Carrascosa,
R G Rosenfeld,
S Van Buuren,
B Kristrom,
E Schoenau,
L Audi, A C S Hokken-Koelega, [......],
W F Blum,
L A Silverman,
P Cohen,
S Cianfarani,
C Deal,
P E Clayton,
L de Graaff,
J Dahlgren,
J Kleintjens,
M Roelants
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ABSTRACT: The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.
Hormone Research in Paediatrics 05/2013;
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ABSTRACT: To investigate the effect of birth size and weight gain during childhood on blood pressure and carotid intima-media thickness (cIMT) in young adulthood.
The relationship of birth size with systolic blood pressure (SBP), diastolic blood pressure (DBP), and cIMT was investigated in 243 adults, aged 18–24 years. SBP, DBP, and cIMT were also analyzed in 4 subgroups: subjects 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 or with normal stature (controls).
Adult weight SDS and fat mass were positively related to SBP and DBP, adjusted for birthweight SDS which was not related to SBP and DBP. Birth size was also not related to cIMT. Subgroup analyses showed no differences in blood pressure between subgroups, but cIMT was significantly greater in SGA-CU subjects than in controls after correction for age, gender and artery diameter. This difference became borderline significant after additional correction for smoking and SBP.
Not birth size but childhood weight gain, especially fat mass, determines young adult blood pressure. Postnatal catch-up growth appears to have a greater influence on cardiovascular disease markers than birth size.
Hormone Research in Paediatrics 07/2012; 77(6):394-401.
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ABSTRACT: Risicofactoren voor hart- en vaatziekten, type−2-diabetes en obesitas ontwikkelen zich al vanaf de vroege kinderleeftijd.
Aangetoond is dat een laag geboortegewicht en een snelle postnatale inhaalgroei het risico op het ontwikkelen van deze risicofactoren
verhogen. Zowel vroege voedingsfactoren als genetische factoren zouden hierbij belangrijk kunnen zijn als causale mechanismen.
Deze causale mechanismen dienen geïdentificeerd te worden om preventieve strategieën te ontwikkelen gericht op de vroegste
fase van het leven. Een prospectief cohortonderzoek lijkt de meest geschikte epidemiologische onderzoeksopzet om deze causale
mechanismen te identificeren.
Risk factors for cardiovascular disease, type 2 diabetes and obesity develop from early childhood. It has been demonstrated
that low birth weight and early postnatal catch-up growth increase the risk of developing these risk factors. Both nutritional
factors and genetic factors could be important as causal mechanisms. These causal mechanisms should be identified to develop
preventive strategies focused on the earliest phase of life. A prospective cohort study seems to be the most optimal epidemiological
study design to identify these causal mechanisms.
Tijdschrift voor kindergeneeskunde 04/2012; 73(2):187-191.
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ABSTRACT: Associations between small size at birth and abnormal cardiovascular parameters in later life have been reported. It is, however, unknown whether the effect of a small size at birth on cardiovascular risk factors in later life is due to a small size for gestational age or due to prematurity. Due to advances in neonatal care, survival of preterm infants has significantly improved, and nowadays an increasing number of these children reach adulthood. It is, therefore, of increasing importance to assess the long-term effect of prematurity on determinants for cardiovascular disease.
The aim of the study was to assess the long-term effects of gestational age and particularly preterm birth on lipid levels and fat mass in early adulthood.
A cross-sectional study was conducted with 455 healthy subjects, aged 18 to 24 yr; 167 preterm subjects were compared with 288 full-term subjects.
Total fat mass, trunk fat mass, and limb fat mass were determined by dual-energy x-ray absorptiometry. Furthermore, fasting lipid levels (total cholesterol, low-density lipoprotein, triglyceride, apolipoprotein B, lipoprotein a, high-density lipoprotein, and apolipoprotein A-I) were measured.
Preterm subjects had a significantly higher percentage of total fat mass, trunk fat mass, and limb fat mass than subjects born term. Furthermore, preterm subjects had significantly lower serum lipoprotein a levels and higher apolipoprotein A-I levels than term subjects. Multiple linear regression analyses to assess the association between gestational age and fat mass and lipid levels showed similar results.
In our cohort of 455 young adults, preterm birth was associated with more total fat mass, trunk fat, and limb fat mass but a relatively favorable lipid profile.
The Journal of clinical endocrinology and metabolism 03/2012; 97(4):1294-302. · 6.50 Impact Factor
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ABSTRACT: Breastfeeding has a protective effect on childhood obesity, but the influences on body composition in early childhood are not known. The objective of this study is to assess whether the duration and exclusiveness of breastfeeding, and the timing of introduction of solid foods are associated with the subcutaneous fat mass in early childhood.
This study was embedded in a population-based prospective cohort study among 779 children. Peripheral (biceps, triceps) and central (suprailiacal and subscapular) subcutaneous fat mass was measured as skinfold thickness at the ages of 1.5, 6 and 24 months.
Breastfeeding duration was not associated with subcutaneous fat mass at the age of 1.5 months. Shorter breastfeeding was associated with higher peripheral and total subcutaneous fat mass at the age of 6 months (P-value for trend <0.05), but not at the age of 24 months. As compared to children who were exclusively breast fed for 4 months, those who were non-exclusively breast fed had a higher central fat mass at the age of 24 months (P-value for trend <0.01). Timing of introduction of solid foods was not associated with subcutaneous fat mass.
Our results suggest that a shorter duration and non-exclusive breastfeeding affect early body composition during the first 2 years of life. Follow-up studies at older ages are needed to explore the long-term consequences.
European journal of clinical nutrition 02/2012; 66(2):253-60. · 3.07 Impact Factor
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ABSTRACT: GH treatment of short children born small for gestational age (SGA) results in a decline in fat mass (FM) and an increase in lean body mass (LBM). It is, however, unknown whether these changes persist into adulthood.
Our objective was to assess the long-term impact of GH treatment during childhood on body composition and fat distribution.
A total of 377 young adults participated in this cross-sectional study: 59 previously GH-treated young SGA adults compared to 52 untreated SGA adults with short stature (SGA-S), 161 SGA adults with spontaneous catch-up growth (SGA-CU), and 105 healthy normal-statured controls born appropriate for gestational age (AGA).
Body composition and fat distribution were determined by dual-energy x-ray absorptiometry.
Mean (SD) duration of GH treatment was 7.7 (2.4) yr and period after discontinuation 6.8 (1.8) yr. FM, fat distribution, and LBM of GH-treated SGA adults were not significantly different from that of untreated SGA-S adults. GH-treated SGA adults also had a similar FM and fat distribution as SGA-CU adults but a lower LBM. All SGA subgroups had a lower LBM and tended to have a higher FM than healthy AGA controls.
Body composition and fat distribution of previously GH-treated SGA adults was similar to that of untreated SGA-S adults. GH-induced catch-up growth has no unfavorable effect on FM and fat distribution compared with spontaneous catch-up growth. However, our study shows that SGA adults in general may have a different body composition than healthy AGA controls.
The Journal of clinical endocrinology and metabolism 09/2011; 96(12):3710-6. · 6.50 Impact Factor
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ABSTRACT: The aim of the study was to validate dual-energy X-ray absorptiometry (DXA) as a method to assess bone age in children.
Paired dual-energy X-ray absorptiometry (DXA) scans and X-rays of the left hand were performed in 95 children who attended the paediatric endocrinology outpatient clinic of University Hospital Rotterdam, the Netherlands. We compared bone age assessments by DXA scan with those performed by X-ray. Bone age assessment was performed by two blinded observers according to the reference method of Greulich and Pyle. Intra-observer and interobserver reproducibility were investigated using the intraclass correlation coefficient (ICC), and agreement was tested using Bland and Altman plots.
The intra-observer ICCs for both observers were 0.997 and 0.991 for X-ray and 0.993 and 0.987 for DXA assessments. The interobserver ICC was 0.993 and 0.991 for X-ray and DXA assessments, respectively. The mean difference between bone age assessed by X-ray and DXA was 0.11 years. The limits of agreement ranged from -0.82 to 1.05 years, which means that 95% of all differences between the methods were covered by this range.
Results of bone age assessment by DXA scan are similar to those obtained by X-ray. The DXA method seems to be an alternative for assessing bone age in a paediatric hospital-based population.
The British journal of radiology 05/2011; 85(1010):114-20. · 2.11 Impact Factor
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ABSTRACT: Genome-wide association studies on body mass index (BMI) have identified an FTO polymorphism (rs9939609) as having the strongest effect.
We examined the effect of FTO genotype on body composition at the age of 6 months using skinfold thickness measurements and dual energy X-ray absorptiometry (DXA).
This study was embedded in a population-based prospective cohort study from early fetal life onwards. FTO genotype was related to anthropometric measurements (weight and height), subcutaneous fat mass measured by skinfold thickness, and total, truncal, and peripheral fat mass and lean mass measured by DXA. Analyses for skinfold thickness and DXA were performed in 695 and 216 children, respectively.
Genotype frequency was TT 40.3%, TA 45.5%, and AA 14.2%. No significant differences between FTO genotypes were found in weight, height or BMI. Furthermore, FTO genotype was not associated with any skinfold thickness. Finally, no associations between FTO genotype and body composition measures (fat and lean mass) assessed by DXA were found.
We observed no association between this FTO polymorphism and body composition at the age of 6 months. Longer follow-up studies are necessary to examine at which age and by which mechanisms FTO genotype starts to influence fat mass and body composition.
Journal of endocrinological investigation 01/2011; 34(1):16-20. · 1.57 Impact Factor
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ABSTRACT: Background Fetal growth restriction is thought to negatively influence reproductive function in later life. Serum anti-Müllerian 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 3-10 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.
Human Reproduction 01/2011; 26(4):898-903. · 4.47 Impact Factor
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ABSTRACT: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programming 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 programming. 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.
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.
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.
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.
European Journal of Endocrinology 12/2010; 163(6):911-8. · 3.42 Impact Factor
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ABSTRACT: 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.
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).
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.
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.
Clinical Endocrinology 06/2010; 72(6):775-80. · 3.17 Impact Factor
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ABSTRACT: 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.
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.
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.
Journal of Medical Genetics 12/2009; 47(7):492-8. · 6.36 Impact Factor
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ABSTRACT: We aimed to examine the associations of maternal anthropometrics with fetal weight measured in different periods of pregnancy and with birth outcomes.
Population-based birth cohort study.
Data of pregnant women and their children in Rotterdam, the Netherlands.
In 8541 mothers, height, prepregnancy body mass index (BMI) and gestational weight gain were available.
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.
Fetal weight and birth outcomes: weight (grams) and the risks of small (<5th percentile) and large (>95th percentile) size for gestational age at birth.
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.
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.
BJOG An International Journal of Obstetrics & Gynaecology 07/2009; 116(7):953-63. · 3.41 Impact Factor
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ABSTRACT: 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).
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.
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.
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.
Hormone Research 12/2008; 71(1):22-7. · 2.48 Impact Factor
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ABSTRACT: 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).
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.
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 microg/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).
Being born SGA does not impair Sertoli cell function. Young men born SGA have a normal hypothalamic-pituitary-testis axis.
Hormone Research 11/2008; 70(6):357-63. · 2.48 Impact Factor
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ABSTRACT: 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.
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.
292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature.
Short prepubertal SGA children received GH 1mg/m(2)/day.
Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS.
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(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, 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.
Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 10/2008; 19(3):198-205. · 2.35 Impact Factor
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ABSTRACT: 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.
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).
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.
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.
Journal of Clinical Endocrinology & Metabolism 09/2008; 93(11):4307-14. · 6.50 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
International journal of obesity (2005) 08/2008; 32(7):1050-9. · 4.34 Impact Factor
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ABSTRACT: 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.
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).
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.
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.
Clinical Endocrinology 07/2008; 68(6):930-4. · 3.17 Impact Factor
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ABSTRACT: 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.
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.
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).
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.
Clinical Endocrinology 07/2008; 69(1):112-6. · 3.17 Impact Factor
