http://repub.eur.nl/res/aut/5516/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/25399/ 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. http://repub.eur.nl/res/pub/24927/ 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. http://repub.eur.nl/res/pub/36019/ 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. http://repub.eur.nl/res/pub/13491/ 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. http://repub.eur.nl/res/pub/9914/ 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.