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Sandra W K de Kort and Anita C S Hokken-Koelega

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-γ) 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.

Free access

Darya Gorbenko Del Blanco, Laura C G de Graaff, Dirk Posthouwer, Theo J Visser, and Anita C S Hokken-Koelega

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.

Free access

Petra E Breukhoven, Ralph W J Leunissen, Sandra W K de Kort, Ruben H Willemsen, and Anita C S Hokken-Koelega

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 (BMADLS).

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, BMDLS 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.

Free access

Darya Gorbenko Del Blanco, Christopher J Romero, Daniel Diaczok, Laura C G de Graaff, Sally Radovick, and Anita C S Hokken-Koelega

Orthodenticle homolog 2 (OTX2) is a homeobox family transcription factor required for brain and eye formation. Various genetic alterations in OTX2 have been described, mostly in patients with severe ocular malformations. In order to expand the knowledge of the spectrum of OTX2 mutation, we performed OTX2 mutation screening in 92 patients with combined pituitary hormone deficiency (CPHD). We directly sequenced the coding regions and exon–intron boundaries of OTX2 in 92 CPHD patients from the Dutch HYPOPIT study in whom mutations in the classical CPHD genes PROP1, POU1F1, HESX1, LHX3, and LHX4 had been ruled out. Among 92 CPHD patients, we identified a novel heterozygous missense mutation c.401C>G (p.Pro134Arg) in a patient with CPHD, pituitary malformation, and an underdeveloped left optic nerve. Binding of both the wild-type and mutant OTX2 proteins to bicoid binding sites was equivalent; however, the mutant OTX2 exhibited decreased transactivation. We describe a novel missense heterozygous OTX2 mutation that acts as a dominant negative inhibitor of target gene expression in a patient with CPHD, pituitary malformation, and optic nerve hypoplasia. We provide an overview of all OTX2 mutations described till date, which show that OTX2 is a promising candidate gene for genetic screening of patients with CPHD or isolated GH deficiency (IGHD). As the majority of the OTX2 mutations found in patients with CPHD, IGHD, or short stature have been found in exon 5, we recommend starting mutational screening in those patients in exon 5 of the gene.

Free access

Dennis O Mook-Kanamori, J J Miranda Geelhoed, Eric A P Steegers, Jacqueline C M Witteman, Albert Hofman, Henriëtte A Moll, Cornelia M van Duijn, Anita C S Hokken-Koelega, and Vincent W V Jaddoe

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/I 50.8%, I/III 40.0%, and III/III 9.2%. 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.

Free access

Vera A A van Houten, Dennis O Mook-Kanamori, Lennie van Osch-Gevers, Eric A P Steegers, Albert Hofman, Henriëtte A Moll, Cornelia M van Duijn, Willem A Helbing, Anita C S Hokken-Koelega, and Vincent W V Jaddoe

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.

Restricted access

Layla Damen, Lionne N Grootjen, Stephany H Donze, Laura C G de Graaff, Janielle A E M van der Velden, and Anita C S Hokken-Koelega

Objective

In children with Prader–Willi syndrome (PWS), growth hormone (GH) treatment has positive effects on bone mineral density (BMD). Two 1-year studies did not show a difference between GH or placebo on BMD in young adults with PWS. However, there are no studies investigating BMD during longer-term GH treatment in young adults with PWS.

Design

Open-label, a prospective study in 43 young adults with PWS.

Methods

BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA.

Results

In the total group, estimated mean (95% CI) of BMDTB remained similar during 3 years of GH, being −0.76 (−1.11 to −0.41) SDS at start and −0.90 (−1.27 to −0.54) SDS after 3 years (P = 0.11), as did BMADLS, being −0.36 (−0.72 to 0.01) SDS and −0.46 (−0.77 to −0.16) SDS, respectively (P = 0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMADLSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT).

Conclusions

During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMDTBSDS, probably due to insufficient SSRT. We recommended to continue GH treatment in young adults with PWS and to start SSRT during adolescence unless puberty progresses normally.

Restricted access

Lionne N Grootjen, Joost P H J Rutges, Layla Damen, Stephany H Donze, Alicia F Juriaans, Gerthe F Kerkhof, and Anita C S Hokken-Koelega

Objective

Scoliosis is frequently seen in children with Prader–Willi syndrome (PWS). There is still concern that growth hormone (GH) treatment might increase the risk of onset or progression of scoliosis. Short-term data suggested no adverse effects of GH on scoliosis, but long-term effects of GH treatment on development of scoliosis in PWS are unknown. This study investigated the effects of 8 years of GH treatment on scoliosis in children with PWS.

Design

Open-label, prospective cohort study in 103 children with PWS receiving GH for 8 years was analyzed. Prevalence and severity of scoliosis were compared to a group of 23 age-matched GH-untreated children with PWS.

Methods

Spine X-rays and DEXA-scans were performed, and Cobb angel was measured by two independent observers.

Results

After 8 years of GH treatment, at median age of 10.8 years, prevalence of scoliosis was 77.7%. No difference in prevalence or severity of scoliosis was found between GH-treated and age-matched untreated children with PWS (P = 0.409 and P = 0.709, respectively). Height SDS and trunkLBM were significantly higher in GH-treated children. Higher bone mineral density of the lumbar spine was found in children without scoliosis after 8 years of GH. Bone mineral apparent density of lumbar spine (BMADLS) SDS was associated with lower Cobb angle (r = −0.270, P = 0.008).

Conclusions

Eight years of GH treatment has no adverse effects on the prevalence and severity of scoliosis in children with PWS until 11 years of age. As BMADLS SDS is inversely associated with Cobb angle, it is pivotal to optimize the BMD status in children with PWS.