Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency.

CONTEXT: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). OBJECTIVE: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores. METHODS: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies. RESULTS: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores. CONCLUSION: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points.

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

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 x 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.

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

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 > or =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.

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

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.

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

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.

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

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 (>or= 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.

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

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 (> or =36 wk) children, was included in the study. OUTCOME MEASURE: Insulin sensitivity, beta-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.

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

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.

Infliximab in a child with therapy-resistant systemic vasculitis.

Treatment of systemic vasculitides is usually based on the use of corticosteroids and other immunosuppressive drugs. We describe a 10-year-old girl with systemic vasculitis resistant to immunosuppressive treatment who had a rapid and impressive response to treatment with infliximab.

Preterm birth does not affect bone mineral density in young adults.

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 (BMD(TB)), lumbar spine (BMD(LS)) 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 BMD(TB) (r=0.063, P=0.30), BMD(LS) (r=0.062, P=0.31) and BMAD(LS) (r=0.069, P=0.26). Also after adjustment for possible confounders, gestational age was no significant contributor to the variance in BMD(TB) (P=0.27), BMD(LS) (P=0.91) and BMAD(LS) (P=0.87). No significant differences were found between preterm and term subjects with regard to BMD(TB), BMD(LS) and BMAD(LS). 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.

[Myocardial infarction in a 16-year old following inhalation of butane gas]. / Myocardinfarct bij een 16-jarige na inhalatie van butaangas.

BACKGROUND: Butane gas is inhaled by young people with the aim of getting 'high'. This can cause coronary spasm with myocardial infarction and ventricular fibrillation as a result. CASE DESCRIPTION: We report on a 16-year-old male who collapsed at home after sniffing butane. His father, together with a paramedical emergency team that had found ventricular fibrillation, started basic and advanced life support. ECG showed exaggerated ST-elevations and an echocardiography showed a hypokinetic anterior ventricular wall and ventricular septum. After treatment with dobutamine, nitroglycerine, acetylsalicylic acid and dalteparine, the ECG and left ventricular function improved. He was admitted to a pediatric intensive care unit where he was artificially ventilated for 4 days and treated for cardiogenic shock. In the following days his cardiovascular condition improved. Magnetic resonance imaging showed no ischaemic damage of the brain. At 6 weeks his general condition was not as before, but ECG and cardiac function had almost recovered. CONCLUSION: Young people who experiment with inhalation of volatile substances generally do not know how dangerous this is. Provision of information about the possible consequences will have a preventive effect.

The PPAR-gamma Pro12Ala polymorphism associates with weight gain during GH-treatment in short children born small for gestational age.

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-gamma) 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-gamma Pro12Ala polymorphism to GH induced changes in determinants of metabolic and cardiovascular disease in short SGA children. METHODS: PPAR-gamma 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-gamma 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.

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.

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- and gender-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 adults who were born SGA, serum IGFBP-2 levels associate with cardiovascular risk markers.

Cardiovascular risk factors in parents of short children born small for gestational age.

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.