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Background Children born small for gestational age (SGA) experience higher rates of morbidity and mortality than those born appropriate for gestational age. In Latin America, identification and optimal management of children born SGA is a critical issue. Leading experts in pediatric endocrinology throughout Latin America established working groups in order to discuss key challenges regarding the evaluation and management of children born SGA and ultimately develop a consensus statement. Discussion SGA is defined as a birth weight and/or birth length greater than 2 standard deviations (SD) below the population reference mean for gestational age. SGA refers to body size and implies length-weight reference data in a geographical population whose ethnicity is known and specific to this group. Ideally, each country/region within Latin America should establish its own standards and make relevant updates. SGA children should be evaluated with standardized measures by trained personnel every 3 months during year 1 and every 6 months during year 2. Those without catch-up growth within the first 6 months of life need further evaluation, as do children whose weight is ≤ -2 SD at age 2 years. Growth hormone treatment can begin in SGA children > 2 years with short stature (< -2.0 SD) and a growth velocity < 25th percentile for their age, and should continue until final height (a growth velocity below 2 cm/year or a bone age of > 14 years for girls and > 16 years for boys) is reached. Blood glucose, thyroid function, HbA1c, and insulin-like growth factor-1 (IGF-1) should be monitored once a year. Monitoring insulin changes from baseline and surrogates of insulin sensitivity is essential. Reduced fetal growth followed by excessive postnatal catch-up in height, and particularly in weight, should be closely monitored. In both sexes, gonadal function should be monitored especially during puberty. Summary Children born SGA should be carefully followed by a multidisciplinary group that includes perinatologists, pediatricians, nutritionists, and pediatric endocrinologists since 10% to 15% will continue to have weight and height deficiency through development and may benefit from growth hormone treatment. Standards/guidelines should be developed on a country/region basis throughout Latin America.

Objective To determine whether coronary artery calcification (CAC), elevated fasting lipids, and lipoproteins and peripheral inflammatory markers are present in insulin-dependent diabetic adolescents and young adults several years after diagnosis. Study design Hispanic insulin-dependent diabetics (n = 32) diagnosed a mean of 7.8 ± 4.5 years ago (range, 3 to 16 years), with a mean glycosylated hemoglobin concentration at the time of the study of 8.8% ± 2.3% and a mean chronological age of 16.1 ± 4.4 years, were evaluated. Healthy patients (n = 15) with a chronological age (CA) of 15.2 ± 2.2 years served as control subjects. CAC was assessed by multiple slice computed tomography, and total CAC score in Agatston units was calculated. Fasting lipids, C-reactive protein, apolipoprotein (Apo) A, Apo B, and metalloproteinase-9 (MMP-9) concentrations were measured in all subjects. Results Neither adolescents with type 1 diabetes nor healthy control subjects presented with evidence of CAC. Fasting lipids, Apo A, Apo B, CRP, and MMP-9 concentrations were similar between diabetic subjects and control subjects. However, 34.4% and 25.0% of our type 1 diabetic subjects had elevated total and LDL cholesterol levels (>200 and >130 mg/dL, respectively), whereas 15.6% and 28.1% had elevated triglyceride and Apo B concentrations (>150 mg/dL and >100 mg/dL, respectively). In addition, 28.1% and 34.4% presented with elevated CRP and MMP-9 levels (>2 mg/L and >80 ng/mL, respectively). Total, LDL and HDL cholesterol, triglycerides, Apo B, CRP, and MMP-9 concentrations correlated positively with duration of the disease and with glycosylated hemoglobin levels. Conclusions Although the study adolescents with type 1 diabetes did not present any radiologic evidence of CAC at this stage of the disease, they remain a high-risk group for the development of microvascular and macrovascular artery disease, as risk factors such as elevated lipoproteins and proinflammatory markers are already present in a significant percentage of patients studied.

Objective To examine the impact of adolescent growth hormone deficiency (GHD) on circulating adiponectin levels and the relation between adiponectin, fasting insulin, plasma lipid, and lipoprotein levels. Study design Twelve children with GHD on GH treatment with a chronological age (CA) of 14.4 2.0 years and 12 untreated adolescents with GHD with a CA of 14.9 2.3 years were studied. Adiponectin concentrations were measured in all patients, and the association of adiponectin with fasting insulin, total, LDL, and HDL cholesterol, triglycerides, apolipoprotein A-1, and apolipoprotein B was evaluated. Twelve healthy adolescents served as control subjects. Results Adiponectin levels were significantly lower in untreated GHD adolescents than in treated GHD subjects or in control subjects (P < .008). Total and LDL cholesterol, triglycerides, and Apo B concentrations were increased in untreated GHD adolescents, whereas HDL cholesterol levels were similar in all three groups. Insulin levels were significantly increased in treated GHD adolescents when compared with control subjects (P < .05) but similar to those with untreated GHD. Adiponectin was found to be negatively associated with body mass index, waist-to-hip ratio, and with Apo B, total cholesterol, triglycerides, and LDL cholesterol concentrations in untreated GHD adolescents, whereas a positive correlation between adiponectin and HDL cholesterol was noted in both untreated and treated GHD subjects. Adiponectin correlated inversely with fasting insulin levels in untreated and treated GHD adolescents. Conclusions GHD in adolescence is associated with low levels of adiponectin and with an unfavorable plasma lipid and lipoprotein profile. Our data suggest that treatment with GH may improve the abnormalities seen. (J Pediatr 2006;149:324-9)

Summary Objective We recently reported that children with idiopathic short stature (ISS) have decreased lumbar spine bone mineral density (BMD) that increases after 1 year of GH therapy. The aim of this study was to confirm these short-term results and to evaluate the effect of long-term GH therapy on the BMD of children with ISS. Patients and Design We treated a group of 16 short, slow-growing but otherwise healthy non-GH-deficient prepubertal children (8 girls and 8 boys) with a chronological age of 9·5 ± 0·9 years, a bone age of 8·1 ± 1·2 years and a height of 124·3 ± 6·3 cm (height-SDS of −2·1 ± 0·6) with GH at a dose of 0·1 IU/kg/day for 3 consecutive years. Measurements Height was determined at 3-month intervals and annual growth velocities were calculated. Bone ages and BMD were measured every 12 months by dual-energy X-ray absorptiometry, as were serum concentrations of the carboxy-terminal propeptide of type 1 collagen (PICP) and the carboxy-terminal cross-linked telopeptide of type 1 collagen (ICPT). Results Growth velocity increased from 4·0 ± 0·8 cm/year to 8·7 ± 1·5 and 8·0 ± 1·7 cm/year at 12 and 36 months of GH therapy, respectively, while height-SDS improved from −2·1 ± 0·6 to −1·6 ± 0·4 after 36 months of GH (P

The objective of our study was to evaluate whether cardiac mass and function, carotid artery intima-media thickness, and serum lipid and lipoprotein(a) levels are abnormal in adolescents with GH deficiency. Young adults with childhood-onset and adulthood-onset GH deficiency have been found to have a higher cardiovascular risk, as manifested among other factors by reduced left ventricular mass, impaired systolic function, significant increase in arterial intima-media thickness, and dyslipidemia. Twelve adolescents (seven males and five females) with GH deficiency (10 idiopathic and 2 organic), with an age of 14.2 +/- 2.8 yr and a height of 140.6 +/- 17.9 cm (height SD score, -2.6 +/- 0.3), were studied. Six children had received GH in the past but were off therapy for several years, whereas six patients had never been treated with GH. Fasting blood samples were obtained for serum lipids and lipoprotein(a) analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular mass, as well as left ventricular ejection fraction at rest and pulmonary venous flow velocities; carotid artery intima-media thickness was measured using high-resolution mode B ultrasound. Seven GH-deficient (GHD) adolescents on GH at the time of the study and 19 healthy adolescents, all comparable for age, pubertal status, height, weight, blood pressure, and pulse, participated in this study as controls. Interventricular septal thickness (6.5 +/- 1.3 vs. 7.0 +/- 1.5 mm), left ventricular posterior wall thickness (7.0 +/- 1.8 vs. 7.5 +/- 2.0 mm), and left ventricular mass after correction for body surface area (71.2 +/- 21.8 vs. 70.7 +/- 18.0 g/m(2)) were similar in untreated GHD patients and healthy controls. Similarly, the left ventricular ejection fraction at rest was similar in untreated GHD subjects and controls (70.0 +/- 0.7 vs. 70.0 +/- 0.6%), as were the pulmonary venous flow velocities (0.54 +/- 0.16 vs. 0.55 +/- 0.10 m/s for diastolic peak velocity; 0.51 +/- 0.16 vs. 0.50 +/- 0.09 m/s for systolic peak velocity; and 0.19 +/- 0.06 vs. 0.19 +/- 0.05 m/s for atrial reversal filling). Carotid artery intima-media thickness (0.60 +/- 0.02 mm and 0.59 +/- 0.02 mm for the right and left carotid arteries, respectively) was also normal in our untreated GHD patients when compared with healthy controls. In addition, all echocardiographic measurements were similar in GHD subjects on or off GH at the time of the study. Low-density lipoprotein cholesterol levels were increased in untreated GHD patients when compared with healthy controls (3.17 +/- 0.70 vs. 2.33 +/- 0.36 mmol/L; P < 0.01), whereas total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were similar to that of controls. Total cholesterol levels were increased in our untreated GHD adolescents when compared with GHD subjects receiving GH therapy at the time of the study, while low-density lipoprotein cholesterol and triglyceride levels were also elevated, although not significantly. Lipoprotein(a) levels were elevated in untreated GHD adolescents when compared with healthy controls, and untreated GHD subjects had higher lipoprotein(a) concentrations than GH-treated patients. GHD adolescents, regardless of whether or not they received GH therapy, do not seem to show alterations in cardiac mass and function or early atherosclerotic changes. They must, however, be followed carefully because they already present cardiovascular risk factors such as dyslipidemia, which may increase their cardiovascular morbidity over time.

Objective: To determine whether young women with Turner's syndrome who had normal bone mineral density (BMD) before the induction of puberty maintain normal BMD in young adulthood. Design: Controlled clinical study. Setting: A private hospital clinical research setting. Patients: Young women with Turner's syndrome in Tanner stage V of puberty with previously normal BMD. Interventions: Oral conjugated estrogens and progesterone acetate were administered continuously for a mean (±SD) of 4.1 ± 1.0 years. Bone mineral densities and blood samples were evaluated. Main Outcome Measure(s): The BMD of the lumbar spine and the femoral neck was determined during young adulthood. The change in BMD over the previous 6 years also was evaluated. Serum concentrations of the carboxy-terminal propeptide of type 1 collagen and of the carboxy-terminal cross-linked telopeptide of type 1 collagen were measured. Result(s): The BMD of the lumbar spine was reduced significantly in our patients. There was no change in the BMD of the femoral neck or lumbar spine over a period of 6.1 years. Concentrations of the carboxy-terminal propeptide of type 1 collagen were decreased, whereas concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen were increased. Conclusion(s): Young women with Turner's syndrome do not attain normal peak bone mass even when estrogen replacement therapy is begun in adolescence. Their low BMD seems to be due to decreased bone formation and increased bone resorption.

OBJECTIVE Combined gonadotrophin-releasing hormone analogue and recombinant human growth hormone therapy has been used in an attempt to improve the final height of short non-GH deficient adolescents with normally timed puberty; its use, however, is still controversial as only short-term studies in a very limited number of patients have been undertaken, with either improvement in height prognosis or no beneficial effect on predicted growth. We have treated a group of extremely short healthy children with very low predicted adult heights entering into normally timed puberty with combined therapy, in order to determine whether we could improve their final height above their pretreatment predicted adult height. PATIENTS We treated 10 healthy adolescent short children (7 girls and 3 boys) simultaneously for 30.0 +/- 5.2 months with the GnRH analogue leuprolide acetate (0.3 mg/kg im every 28 days) and with rhGH (0.1 U/kg/day, sc, 6 days a week). The mean chronological age of our patients was 11.8 +/- 1.3 years, with a mean bone age of 11.2 +/- 0.9 years, height of 128.9 +/- 7.5 cm (-2.4 +/- 0.4 SD below the mean) and a predicted adult height of 150.7 +/- 9.8 cm; they were all in Tanner stage II-III of puberty. Ten healthy short children (7 girls and 3 boys) in the early stages of puberty with a mean chronological age of 11.4 +/- 1.0 years, a mean bone age of 11.0 +/- 0.8 years, height of 128.9 +/- 7.8 cm (-2.3 +/- 0.4 SD below the mean) and a mean adult predicted height of 151.8 +/- 10.1 cm served as controls and were simultaneously followed without therapy for the same study period. MEASUREMENTS Height and pubertal status were followed every 3 months during combined therapy and until final height of our patients was reached; bone ages were obtained every 6 months. Growth hormone deficiency was ruled out in all our subjects prior to beginning of the study by a normal response to oral clonidine and normal IGF-1 levels. Basal serum testosterone and/or oestradiol levels, as well as LH and FSH following administration of LH-releasing hormone were obtained before treatment and after 6 weeks and 4 months of combined therapy and every 6 months thereafter. Routine biochemistry as well as thyroid function tests were obtained at each visit. RESULTS Combined treatment resulted in an interruption of pubertal development with a suppression of gonadal steroids and of the LH response to LH-releasing hormone. Growth velocity decreased from 6.5 +/- 1.6 cm/year before treatment to 5.5 +/- 1.5 cm/year and 3.9 +/- 1.3 cm/year during the first and second year of treatment (P < 0.02 and P < 0.05, respectively) resulting in a height Z score reduction, declining from -2.4 +/- 04 to -2.6 +/- 0.7 SD. Bone age maturation declined averaging 0.75 bone age year/year of treatment but height SDS for bone age declined from -1.7 +/- 0.7 to -2.2 +/- 0.5 at the end of the second year of therapy with no improvement in predicted adult height (150.7 +/- 9.8 cm before and 150.0 +/- 8.0 after 2 years of therapy). After discontinuing treatment growth velocity did not improve and bone maturation advanced more rapidly (averaging 2.0 +/- 0.4 year/year of follow up) and the mean final height of our patients was 151 +/- 2.4 cm (-2.6 +/- 0.6 SD below the mean) which was not greater than the mean pretreatment predicted adult height and well below their target height; these results were also similar to those of the control population in whom the predicted adult height at the beginning of the study and after 2 years of follow up, was not different from their final height and well below their target height. CONCLUSIONS We conclude that combined rhGH and GnRH analogue therapy in short adolescents with normally timed puberty does not contribute to increase their final height above their pretreatment predicted adult height; we can therefore not recommend this form of therapy for this group of patients given the poor results obtained, as well as the cost of these medications and the

Background It is possible that genes on the X chromosome are expressed differently depending of its parental origin. The objective of this study was to determine the influence of the parental origin of the X-chromosome on phenotypic variability, response to rhGH and on the biochemical profile of TS patients. Methods This was a cross-sectional multicenter correlational study carried out over three years in six Latin-American university hospitals. Unrelated 45,X TS patients (n = 93; 18.3 ± 8.5 years )) were evaluated. A subgroup (n = 34) of the patients were prospectively treated with rhGH over two years. DNA profiles of patients and their mothers were compared to determine the parental origin of the retained X-chromosome through 10 polymorphic X-chromosome-STRs. The association with clinical features, biochemical profiles and anthropometric data at the beginning and after two years of rhGH treatment was determined. Results Seventy two percent of patients retained the maternal X chromosome (Xm). A trend towards significance between maternal height and patients final height (p ≤ 0.07) in 45,Xm subjects was observed. There was no correlation between paternal height and patient height. No differences were detected between both groups in regard to dysmorphic features, classical malformations or increase in the height-SDS after rhGH. There were higher levels of triglycerides, total and LDL cholesterol in patients >20 years who retained the Xm. Conclusions The parental origin of the retained X chromosome may influence lipid metabolism in TS patients, but its effect on growth seems to be minimal. No parental-origin-effect on the phenotypic features, associated anomalies and on the growth response to rhGH was found in 45,X TS individuals.

Thirteen prepubertal children with a mean chronological age of 6.7 +/- 3.4 years and severe chronic renal failure (mean glomerular filtration rate of 20.8 +/- 17.7 ml/min/1.73 m2) were studied. Patients received recombinant human growth hormone (rhGH) at a dose of 1 IU/kg/week given subcutaneously on a daily basis for 12 months. Mean growth rates of our patients increased significantly from a baseline level of 4.3 +/- 2.1 to 9.1 +/- 2.0 cm/year at 12 months of rhGH therapy. Mean height SDS improved from -3.5 +/- 1.0 at initiation of therapy to -2.6 +/- 1.3 at 12 months. Mean serum creatinine and blood urea nitrogen levels remained stable during the study, while mean glomerular filtration rates decreased initially and then stabilized; however, 2 subjects had a significant deterioration of their renal function at 6 and 9 months of rhGH, requiring discontinuing treatment. Before rhGH treatment, total bone mineral content as well as bone mineral density in cortical and trabecular bone were significantly reduced in our patients when compared to healthy controls paired for chronological age and similar to those of a healthy control group paired for bone age and height. Both these parameters increased significantly during rhGH treatment so that at 12 months our patients had values similar to those seen in a healthy control population paired to our patients for chronological age. While trabecular bone mineral density did not change in a group of untreated uremic controls during 12 months of follow-up, the percent of bone mineral density change in trabecular bone in our uremic patients during 12 months of rhGH treatment was very significant (p0.001) and larger than that noted in a group of healthy controls paired for bone age and height during 12 months of follow-up. This study demonstrates how rhGH treatment in prepubertal uremic children increases their growth velocity and their bone mineral density significantly, with an improvement in height for age. Careful followup of the renal function of patients in needed as they improve their height and bone mineral status.

Bone mineral densities and growth velocities of young girls with Turner's syndrome treated with recombinant human growth hormone at an age before the decreased levels of estrogens secondary to their ovarian failure could contribute to osteopenia were studied. Twelve patients with a mean chronological age of 8.9 +/- 0.9 years and a mean bone age of 6.9 +/- 0.8 years received growth hormone therapy for over 2 years (0.5 IU/kg/week s.c.) Mean growth velocities increased significantly from a baseline level of 3.5 +/- 0.4 cm/year to 6.4 +/- 0.3 and 5.7 +/- 0.4 cm/year at 12 and 24 months of therapy, while height SDS improved from -3.1 +/- 0.4 at baseline to -2.7 +/- 0.3 and -2.4 +/- 0.3 at 12 and 24 months, respectively. Total bone calcium as well as cortical bone mineral density of our density of our patients while on recombinant human growth hormone were similar to that of a control group of prepubertal healthy growth children paired for bone age and height; bone density of trabecular bone was however increased in our patients when compared to healthy controls (0.791 +/- 0.04 vs. 0.669 +/- 0.02 g/cm2; p0.025). We conclude from our study that the bone mineral status of young girls with Turner's syndrome on growth hormone therapy seems to be normal.

HLA-DRB1, DQA1 and DQB1 alleles have been determined in 42 families with one IDDM proband and 64 healthy controls, by oligotyping (PCR-SSO) using primers and probes from the XI International Histocompatibility Workshop. A positive DRB1*03 and DRB1*04 association with the disease was observed, whereas DRB1*11 and DRB1*07 showed negative association but 19% of patients carried DRB1 alleles different to DRB1*03 or *04. When single alleles were considered, DQA1*03 showed the strongest association with susceptibility to the disease (RR = 8.2, Pc = 0.00001) but this association was outgrown by 2 and 3 allele combinations, with genotype DRB1*04-DQA1*03-DQB1*0302/DRB1*03- DQA1*0501- DQB1*0201 showing the strongest association (RR = 28, Pc = 0.002). Application of the relative predispositional effect (RPE) method to our data, revealed a further susceptibility risk provided by the DRB1*13-DQA1*0102-DQB1*0604 haplotype once DR3 and DR4 haplotypes were removed. When DQA1-DQB1 genotypes were analysed for presence of Arg 52 (DQ alpha) and absence of Asp 57 (DQ beta), genotypes SS/SS were found significantly increased in diabetics. Interestingly, one of the strongest associations with the disease was observed with the DQA1*03-DQB1*0201 combination encoded mainly by genes in trans (RR = 11.7 Pc = 0.00004). These observations and their comparison with DR-DQ haplotypes in more homogeneous ethnic groups support the stronger influence of the DQ molecule rather than the individual DR or DQ alleles in the susceptibility to IDDM. They also emphasize the need for detailed HLA haplotype studies in non-Caucasian and ethnically mixed populations to gain further insight into the nature of genetic and environmental factors contribution to autoimmunity.

We have prospectively assessed the influence of GHR and VDR gene polymorphisms on the response to rhGH therapy in Venezuelan children with growth hormone deficiency (GHD, n= 28) and Turner syndrome (TS, n= 25). Clinical data during rhGH treatment were compared in GH and TS patients with different genotypes. PCR amplifications were performed to obtain the genotype frequencies of the polymorphisms. Clinical data at the start of treatment and rhGH doses were indistinguishable among patients with GHD or TS with different GHR or VDR genotypes. After the first two years of rhGH treatment, clinical data in both GHD and TS patients were not different according GHR or VDR genotypes. In addition, there was no significant difference among the subjects when both these genotypes were combined. Gene polymorphisms in low penetrance genes do not contribute to the rhGH therapy response in patients with GHD and TS.

Objetivos. La deleción (GHRd3) o inserción (GHRfl) del exón 3 es un polimorfismo común en el gen del receptor de la hormona de crecimiento (GHR) en los seres humanos. La presencia del alelo GHRd3 se ha asociado con el grado de respuesta de terapia con Hormona de Crecimiento Recombinante Humana (rhGH). El objetivo de este estudio fue determinar las frecuencias alélicas y genotípicas de este polimorfismo en un grupo de 69 niños venezolanos con talla baja que estaban recibiendo rhGH. Métodos. Se extrajo DNA a través de la técnica del método combinado Fenol/Sevag e Inorgánica. Se determinó el genotipo del exón 3 del gen GHR usando tanto PCR- monoplex como PCR-multiplex. Resultados. Entre los pacientes con talla baja la frecuencia genotípica se distribuyó de la siguiente manera: GHRfl/GHRfl (55%) GHRfl/GHRd3 (35%) y GHRd3/GHRd3 (10%) y la frecuencia alélica fue de 0,27 para GHRd3 y 0,73 para GHRfl. Para el grupo testigo la frecuencia genotípica se distribuyo así: GHRfl/GHRfl (56%), GHRfl/ GHRd3 (30%) y GHRd3/GHRd3 (14%) y la frecuencia alélica era de 0,29 para GHRd3 y 0,71 para GHRfl. Las características clínicas basales de los pacientes con talla baja eran similares entre los diferentes genotipos encontrados en el grupo de estudio. Conclusiones. La proporción del genotipo y los alelos del gen GHR fueron similares entre el grupo testigo y los pacientes con talla baja, lo que traduce que la etiología de la talla baja no obedece a este polimorfismo. Objective. The deletion (GHRd3) or insertion (GHRfl) of exon 3 is a common polymorphism in the receptor growth hormone gene (GHR) in humans. The presence of the allele GHRd3 has been associated with the degree of responsiveness to therapy with recombinant human Growth Hormone (rhGH). The aim of this study was to determine the genotypic and allele frequencies of this polymorphism in a group of 69 Venezuelan children with short stature who were receiving rhGH. Methods. Genomic DNA was extracted from blood lymphocytes using combined method Fenol/SEVAG + Salting out. The GHR-exon 3 was genotyped using both PCR monoplex and multiplex assays. Results. Among patients with short stature, genotype frequency was distributed as follows: GHRfl/GHRfl (55%), GHRfl/GHRd3 (35%) and GHRd3/GHRd3 (10%) and allele frequency for GHRd3 and GHRfl was 0.27 and 0.73, respectively. For the control group, genotype frequency was distributed as follows: GHRfl/GHRfl (56%), GHRfl/GHRd3 (30%) and GHRd3/GHRd3 (14%) and allele frequency for GHRd3 and GHRfl was 0.29 and 0.71, respectively. The baseline clinical features of patients with short stature were similar among different genotypes found in the study group. Conclusions. The proportion of genotype and allele of the GHR gene were similar between the control group and patients with short stature, which translates that the etiology of short stature is not due to this polymorphism.

Background/Aims: Significant endothelial dysfunction as determined by lower flow-mediated vasodilation of the brachial artery was recently reported by us in growth hormone-deficient (GHD) adolescents. The circulating concentrations of markers of vascular endothelial cell and platelet activation and their relationship to inflammatory markers have not been previously evaluated in this group of patients. Objective: To assess the relationship between circulating levels of high-sensitivity C-reactive protein (CRP) and soluble markers of vascular endothelial cell activation in GHD adolescents. Design/Methods: Twenty-eight GHD children on GH treatment with a chronological age of 15.7 ± 2.6 years and 16 untreated GHD adolescents with a chronological age of 16.6 ± 3.3 years were studied. Concentrations of CRP, as an inflammatory marker, were measured in all patients and the association between CRP and the fasting soluble markers of vascular endothelial cell activation intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin levels was evaluated. Sixteen healthy adolescents with a mean chronological age of 15.1 ± 2.2 years served as controls. Results: CRP and P-selectin levels were significantly higher in untreated GHD adolescents than in treated GHD subjects or in healthy controls (p < 0.02), while VCAM-1 concentrations were increased in both untreated and treated GHD adolescents when compared to controls (p < 0.007). E-selectin and ICAM-1 levels were similar in all three groups. CRP was found to be associated with BMI (r: 0.62; p < 0.001), P-selectin (r: 0.43; p < 0.01), E-selectin (r: 0.27; p < 0.03), ICAM-1 (r: 0.23; p < 0.05) and VCAM-1 (r: 0.40; p < 0.001) concentrations in untreated GHD adolescents and with P-selectin (r: 0.88; p < 0.001) and E-selectin (r: 0.29; p < 0.01) in treated GHD subjects. A weak inverse association was observed in a subgroup of patients between brachial artery endothelium-dependent dilation and P-selectin (r: –0.56; p < 0.07). Conclusions: Low-grade inflammation as manifested by increased circulating levels of CRP seems to be associated with the early activation of vascular endothelial cells in GHD adolescents

Objectives To evaluate insulin sensitivity from data obtained from baseline values and from an oral glucose tolerance test (OGTT) in normal and obese children and adolescents. Study design We recruited 89 children 4-10 years old and 82 adolescents 11-18 years old divided into moderately obese (Mod OB), severely obese (Severe OB), and non-obese (Non-OB) controls. We evaluated the relationship between four simple measures of insulin sensitivity: homeostatic model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), fasting glucose to insulin ratio (FGIR), and fasting insulin resistance index (FIRI), with an insulin sensitivity measure derived from the standard 2-hour OGTT, the composite whole body insulin sensitivity index (ISI Comp). Results The strongest correlation was between QUICKI and ISI Comp and between FGIR and ISI Comp, (correlations [r] 0.81-0.85 in the Mod OB and 0.63-0.67 in the Severe OB). The relationship between HOMA-IR and ISI Comp and between FIRI and ISI Comp did not appear to be as strong (correlations [r] -0.36 and -0.53 in Mod OB and Severe OB, respectively). Moderately obese and severely obese children had fasting and 2-hour insulin levels 2-3 fold higher than the control group. Conclusions QUICKI and FGIR, are strongly correlated with OGTT measures of insulin sensitivity in children and adolescents with different degrees of obesity. These simple fasting-based indices may help the pediatrician identify patients at risk of developing insulin resistance.

The purpose of this study was to determine whether GH-deficient (GHD) adolescents have abnormalities of cardiac and vascular function detectable during the teenage years.Ten GHD children on GH treatment with a chronological age (CA) of 14.6 +/- 1.7 yr and 12 untreated GHD adolescents with a CA of 15.0 +/- 3.0 yr were studied. Cardiac mass and function, carotid artery intima-media thickness, flow-mediated endothelium-dependent vasodilation (percent change from baseline diameter during hyperemia), and hyperemia-induced blood flow increase of the brachial artery (percent change from baseline) and epicardial adipose tissue were evaluated by echocardiography. Fourteen healthy adolescents served as controls.Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P0.02). Interventricular septum thickness, posterior wall thickness, left ventricular ejection fraction, and carotid artery intima-media thickness were similar in all three groups. Hyperemia-induced blood flow increase was greater in treated GHD adolescents than both untreated subjects and controls (P0.001). Body mass index correlated positively with epicardial adipose tissue in all three groups and with carotid intima-media thickness in treated and untreated GHD adolescents.GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat, may contribute to an increased cardiovascular risk in the long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

We recently reported that children with idiopathic short stature (ISS) have decreased lumbar spine bone mineral density (BMD) that increases after 1 year of GH therapy. The aim of this study was to confirm these short-term results and to evaluate the effect of long-term GH therapy on the BMD of children with ISS.We treated a group of 16 short, slow-growing but otherwise healthy non-GH-deficient prepubertal children (8 girls and 8 boys) with a chronological age of 9.5 +/- 0.9 years, a bone age of 8.1 +/- 1.2 years and a height of 124.3 +/- 6.3 cm (height-SDS of -2.1 +/- 0.6) with GH at a dose of 0.1 IU/kg/day for 3 consecutive years.Height was determined at 3-month intervals and annual growth velocities were calculated. Bone ages and BMD were measured every 12 months by dual-energy X-ray absorptiometry, as were serum concentrations of the carboxy-terminal propeptide of type 1 collagen (PICP) and the carboxy-terminal cross-linked telopeptide of type 1 collagen (ICPT).Growth velocity increased from 4.0 +/- 0.8 cm/year to 8.7 +/- 1.5 and 8.0 +/- 1.7 cm/year at 12 and 36 months of GH therapy, respectively, while height-SDS improved from -2.1 +/- 0.6 to -1.6 +/- 0.4 after 36 months of GH (P0.0001). Baseline lumbar spine BMD was decreased when compared to that of a control group of healthy children paired for gender, bone age and height (0.640 +/- 0.08 g/cm2vs. 0.730 +/- 0.08 g/cm2; P0.003). Lumbar spine BMD increased after 1 year of GH from 0.640 +/- 0.08 to 0.749 +/- 0.08 g/cm2 (P0.05), reaching levels similar to that of controls followed for 1 year without therapy (0.749 +/- 0.04 g/cm2vs. 0.760 +/- 0.08 g/cm2). During this period lumbar spine BMD increased 14.5% in the ISS subjects and 3.9% in the controls. Over the following 2 years of GH therapy the lumbar spine BMD of our ISS patients increased at a rate similar to that of the control population, so that after 3 years of consecutive GH therapy the lumbar spine BMD of ISS children was comparable to that of the controls (0.784 +/- 0.12 g/cm2vs. 0.785 +/- 0.09 g/cm2). Femoral neck BMD of our patients was similar to that of the controls at baseline and at 36 months. Following 1 year of GH treatment serum concentrations of PICP increased from 229.6 +/- 63.5 to 358.6 +/- 87.9 micro g/l, while levels of ICTP increased from 9.6 +/- 5.9 to 13.7 +/- 2.1 micro g/l. After 36 months of GH therapy, PICP and ICTP values had decreased to 303.3 +/- 67.2 micro g/l and 11.3 +/- 3.3 micro g/l, respectively, and were no longer significantly different from baseline.Children with ISS have decreased lumbar spine BMD, which normalized after 1 year of GH. Over the next 2 years of therapy lumbar spine BMD increased at a normal rate, so that after 3 consecutive years of GH the lumbar spine BMD of children with ISS was similar to that of controls. Bone turnover increased with treatment as indicated by a rise in bone formation and bone resorption markers.

To evaluate cardiac mass and function, carotid intima-media thickness, and serum lipid and lipoprotein (a) (Lpa) levels in children and adolescents with type 1 diabetes mellitus (DM) of short duration.Diabetes mellitus has been found to be an important risk factor for macrovascular disease in adults. Increased serum lipids and Lpa levels have been reported in adolescents with type 1 DM; atherosclerotic vascular lesions involving a combination of fatty degeneration and vessel stiffening of the arterial wall and myocardial involvement impairing diastolic function may be present in adolescents and young adults with type 1 DM.Twenty children and adolescents (10 males, 10 females) diagnosed with type 1 DM before 3.4 +/- 3.3 years with a mean age of 11.9 +/- 3.6 years were studied; their HbA1c levels were 8.0 +/- 1.9%. Twenty healthy non-diabetic controls, 10 males and 10 females, aged 12.1 +/- 3.4 years, matched for height and weight, participated in the study. Fasting blood samples were obtained for lipid and Lpa analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of left atrial and ventricular dimensions and left ventricular (LV) wall thickness and mass. Stroke volume and cardiac output were measured using pulsed Doppler echocardiography; carotid intima-media thickness was measured using high-resolution mode B ultrasound.Interventricular septal thickness (7.1 +/- 1.8 vs 7.0 +/- 1.5 mm), LV posterior wall thickness (7.1 +/- 1.4 vs 7.5 +/- 2.0 mm) and LV mass after correction for body surface area (70.6 +/- 27.4 vs 70.7 +/- 18.0 g/m2) were similar in patients and controls. Similarly, the LV ejection fraction at rest was similar in patients and controls (69.9 +/- 2.3 vs 70.0 +/- 0.6%), as were pulmonary venous flow velocities (0.56 +/- 0.09 vs 0.55 +/- 0.10 m/s for diastolic peak velocity, 0.54 +/- 0.08 vs 0.50 +/- 0.09 m/s for systolic peak velocity and 0.17 +/- 0.07 vs 0.19 +/- 0.05 m/s for atrial reversal filling). Carotid intima-media thickness (0.60 +/- 0.02 and 0.59 +/- 0.02 mm for the right and left carotid artery) was similar to that of controls (0.60 +/- 0.03 and 0.61 +/- 0.02 mm for the right and left carotid artery). Low density lipoprotein cholesterol and Lpa levels were increased in patients compared to controls (113.2 +/- 26.0 mg/dl and 20.1 +/- 11.7 mg/dl in patients vs 90.4 +/- 14.3 mg/dl and 9.8 +/- 2.9 mg/dl in controls; p0.01), while total cholesterol, HDL cholesterol and serum triglyceride concentrations were similar to those in controls.Although children and adolescents with type 1 DM seem not to show alterations in cardiac mass and function or early atherosclerotic changes in the first few years after diagnosis, their cardiovascular risk is increased as they present with dyslipidemia at an early stage of the disease.

OBJECTIVE To evaluate cardiac mass and function, carotid intima-media thickness, and serum lipid and lipoprotein (a) (Lpa) levels in children and adolescents with type 1 diabetes mellitus (DM) of short duration. BACKGROUND Diabetes mellitus has been found to be an important risk factor for macrovascular disease in adults. Increased serum lipids and Lpa levels have been reported in adolescents with type 1 DM; atherosclerotic vascular lesions involving a combination of fatty degeneration and vessel stiffening of the arterial wall and myocardial involvement impairing diastolic function may be present in adolescents and young adults with type 1 DM. DESIGN/METHODS Twenty children and adolescents (10 males, 10 females) diagnosed with type 1 DM before 3.4 +/- 3.3 years with a mean age of 11.9 +/- 3.6 years were studied; their HbA1c levels were 8.0 +/- 1.9%. Twenty healthy non-diabetic controls, 10 males and 10 females, aged 12.1 +/- 3.4 years, matched for height and weight, participated in the study. Fasting blood samples were obtained for lipid and Lpa analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of left atrial and ventricular dimensions and left ventricular (LV) wall thickness and mass. Stroke volume and cardiac output were measured using pulsed Doppler echocardiography; carotid intima-media thickness was measured using high-resolution mode B ultrasound. RESULTS Interventricular septal thickness (7.1 +/- 1.8 vs 7.0 +/- 1.5 mm), LV posterior wall thickness (7.1 +/- 1.4 vs 7.5 +/- 2.0 mm) and LV mass after correction for body surface area (70.6 +/- 27.4 vs 70.7 +/- 18.0 g/m2) were similar in patients and controls. Similarly, the LV ejection fraction at rest was similar in patients and controls (69.9 +/- 2.3 vs 70.0 +/- 0.6%), as were pulmonary venous flow velocities (0.56 +/- 0.09 vs 0.55 +/- 0.10 m/s for diastolic peak velocity, 0.54 +/- 0.08 vs 0.50 +/- 0.09 m/s for systolic peak velocity and 0.17 +/- 0.07 vs 0.19 +/- 0.05 m/s for atrial reversal filling). Carotid intima-media thickness (0.60 +/- 0.02 and 0.59 +/- 0.02 mm for the right and left carotid artery) was similar to that of controls (0.60 +/- 0.03 and 0.61 +/- 0.02 mm for the right and left carotid artery). Low density lipoprotein cholesterol and Lpa levels were increased in patients compared to controls (113.2 +/- 26.0 mg/dl and 20.1 +/- 11.7 mg/dl in patients vs 90.4 +/- 14.3 mg/dl and 9.8 +/- 2.9 mg/dl in controls; p

We recently demonstrated that children with type 1 diabetes mellitus (DM) have decreased lumbar spine bone mineral density (BMD) as early as four years after clinical diagnosis of the disease. In order to determine whether osteopenia is already present in patients very early on after diagnosis of clinical DM, we evaluated the bone mineral status of a group of newly diagnosed children (5.8 +/- 1.5 mo after diagnosis). We studied 23 prepubertal children (7 M, 16 F) with a mean chronological age of 9.5 +/- 2.2 yr and a mean glycosylated hemoglobin of 8.9 +/- 2.4%. Lumbar spine and femoral neck BMD were measured by dual X-ray absorptiometry, while bone turnover was assessed by the determination of the serum concentration of the carboxy-terminal propeptide of type I collagen (PICP) and the carboxy-terminal cross-linked telopeptide of type I collagen (N-telopeptide). Results were compared to those of age, height, and pubertal status matched controls. Lumbar spine BMD Z-scores were decreased in patients compared to controls (Z-scores of -0.89 +/- 1.2, with 10 of 22 patients showing values1 SD below the mean). When lumbar spine Z-scores were analyzed in those patients with3 months oror =3 months since diagnosis of DM a significant difference was noticed between groups (-0.648 +/- 1.12 vs -1.267 +/- 1.17; p0.02). No significant differences were noted in femoral neck BMD and total BMD between groups. Serum PICP levels were decreased when compared to controls (233.6 +/- 39.3 vs 375.9 +/- 50.7 microg/l; p0.002), while serum N-telopeptide concentrations, although increased, were not significantly different (9.3 +/- 1.3 vs 5.7 +/- 1.5 microg/l). In summary, early on after the diagnosis of type 1 DM, children present with decreased lumbar spine BMD and decreased bone formation markers.

Recent studies in adult volunteers have demonstrated that the free fatty acid reduction induced by acipimox, a nicotinic acid analog, stimulated GH secretion per se and enhanced in an additive manner the GH secretion elicited by such different stimuli as pyridostigmine, GHRH and GHRP-6. In order to evaluate whether acipimox administration stimulates GH secretion in prepubertal children, we administered a single oral dose of acipimox (100 mg for children weighing30 kg and 200 mg for those30 kg) to 14 healthy prepubertal children with a mean age of 8.2 +/- 1.9 years, a mean bone age of 6.2 +/- 3.0 years, growing along the 5-10th percentiles, and with normal thyroid function and IGF-I levels. Acipimox administration elicited a sustained increase in GH from a mean baseline level of 0.6 +/- 0.4 to 6.7 +/- 2.4 microg/l at the end of the test (p0.05), with a mean GH peak of 10.5 +/- 3.5 microg/l. GH release was delayed so that peak GH levels were achieved 180 minutes after acipimox administration. In order to determine whether acipimox was capable of enhancing the GH secretion elicited by levodopa (L-Dopa), we administered either oral L-Dopa (250 mg for children weighing30 kg and 500 mg for those30 kg) or oral acipimox plus L-Dopa to the same children on different days. GH concentrations increased in a similar fashion following either of these tests (from a baseline level of 1.2 +/- 0.4 and 0.7 +/- 0.4 microg/l to 8.4 +/- 2.7 and 9.3 +/- 2.9 microg/l at the end of the test (p0.001), with peak GH concentrations of 13.1 +/- 4.1 and 11.8 +/- 3.3 microg/l after L-Dopa or acipimox plus L-Dopa, respectively). Although the peak GH concentrations obtained after the combined administration of acipimox plus L-Dopa were similar to those obtained after either acipimox or L-Dopa administration, a larger number of our patients reached a GH cut-off point of7 microg/l following combined therapy than with either stimulus alone (13/14 patients with combined therapy and 10/14 with acipimox alone). No side effects other than mild facial flushing were noted after acipimox administration. These results indicate that: 1) following the administration of a single oral dose of acipimox, significant GH secretion was elicited in healthy short prepubertal children; 2) the combined administration of acipimox plus L-Dopa did not, however, enhance the GH secretion of this group of children; 3) acipimox was well tolerated with minimal side effects; and 4) further studies in both GH sufficient and GH deficient children are necessary to evaluate acipimox's usefulness in assessing GH reserve.

Patients with growth hormone (GH) deficiency have impaired bone mineral metabolism; treatment with GH leads to an improvement in their bone mineral density (BMD). The effect of GH on the BMD of children with idiopathic short stature is unknown. We studied 14 short, slowly growing, otherwise healthy, prepubertal children without GH deficiency (7 girls and 7 boys) with a chronological age of 10.9 +/- 1.4 years, bone age of 8.8 +/- 1.5 years, and height of 127.8 +/- 8.5 cm (height SD score of -2.2 +/- 0.5). Growth velocity increased from 3.9 +/- 1.1 cm/y to 8.0 +/- 1.9 cm/y, and height SD score improved from -2.2 +/- 0.5 to -1.8 +/- 0.5 after 12 months of GH treatment (P.007 and P.001, respectively). Baseline lumbar spine BMD was decreased when compared with that of a control group of children matched for bone age and height (0.645 +/- 0.09 g/cm(2) vs 0.730 +/- 0.08 g/cm(2); P.003). Lumbar spine BMD increased in subjects with ISS after 1 year of GH treatment from 0.645 +/- 0.09 g/cm(2) to 0.808 +/- 0.04 g/cm(2) (P.05), reaching levels similar to those of control subjects, followed up without therapy (0.808 +/- 0.04 g/cm(2) vs 0.760 +/- 0.08 g/cm(2)); lumbar spine BMD increased 25.3% in the subjects with ISS and 4.1% in the control subjects. Femoral neck BMD did not change during treatment. Serum concentrations of the carboxy-terminal propeptide of type 1 collagen increased from 231.6 +/- 65.5 microg/L to 351.6 +/- 87.2 microg/L, and levels of the carboxy-terminal cross-linked telopeptide of type 1 collagen increased from 9.9 +/- 5.9 microg/L to 13.9 +/- 2.4 microg/L. Children with ISS have decreased lumbar spine BMD, which increases with GH therapy, reaching levels similar to those of control subjects. Bone turnover increased as indicated by a rise in bone formation and bone resorption markers.

The effects of insulin dependent diabetes mellitus (IDDM) on bone metabolism are still not well defined. We evaluated total bone mineral content (TBMC) and bone mineral density (BMD) at the lumbar spine and femoral neck using dual X-ray absorptiometry in 26 IDDM children (15 M, 11 F) with a mean chronological age of 12.1+/-3.1 yr (range 7.1-14.2 yr). Duration of diabetes was 4.3+/-2.9 yr, with a mean glycosylated hemoglobin of 9.2+/-0.4%. BMD and TBMC standard deviation scores (Z-scores) were determined by comparing our results to controls matched for age, sex and pubertal status. BMD and bone formation and resorption markers were determined at the beginning of the study and after one year of follow up. Mean lumbar spine Z-score was -1.06+/-0.2, with negative values in 24 of 26 children (92.6%); 14/26 patients (53.8%) had a lumbar spine Z-score >1.0 SD below the mean. Mean lumbar spine Z-score remained unchanged after one year of follow up (-1.02+/-0.3). No significant differences were obtained in femoral neck BMD or TBMC between groups. No correlation was observed between lumbar spine BMD Z-scores and duration of IDDM or degree of diabetes control, as assessed by the mean glycosylated hemoglobin. Daily urinary calcium excretion was elevated in our patients initially and after one year of follow up; however, no correlation was obtained between lumbar spine BMD and 24 h urinary calcium excretion. Carboxy-terminal propeptide of type 1 collagen values and levels of urinary cross-linked N-telopeptides of type 1 collagen in the diabetic children were significantly lower than those of the matched controls. Osteoblastic activity as assessed by serum osteocalcin and by the carboxy-terminal propeptide of type I collagen and bone resorption as measured by cross-linked N-telopeptides of type 1 collagen did not correlate with the lumbar spine Z-scores. When IDDM patients were subdivided into males and females and into children with more than or less than 2 yr duration of diabetes since diagnosis, no differences between groups were found. These results suggest that insulin dependent diabetes in children is associated with low bone turnover resulting in a deficit in bone mass which may be manifested as osteopenia in the growing bone. This defect is already present in trabecular bone early on in the disease and seems not to be related to glycemic control.

Objective: To evaluate whether girls with Turner's syndrome have an increased risk for cardiovascular disease due to alterations in their lipoprotein metabolism. Design: Controlled clinical study. Setting: Private academic hospital. Patient(s): Fifteen untreated girls with Turner's syndrome were studied initially; 11 of these patients were evaluated further while on therapy. Intervention(s): Serum lipids, lipoprotein lp(a), and plasminogen activator (PA) inhibitor-1 were measured before and during 6 months of either GH or estrogen (E) treatment. Main Outcome Measure(s): Serum lipids, lipoprotein lp(a), and PA inhibitor-1 (PAI-1). Result(s): Total and low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein lp(a), and PA inhibitor-1 levels were normal in Turner's syndrome patients compared with age matched controls; HDL cholesterol was increased. During GH treatment, a significant decrease in total and LDL cholesterol was noted, whereas lipids, lipoprotein(a), and PA inhibitor-1 levels did not change with E therapy. Conclusion(s): The normal lipoproteins of untreated adolescents with Turner's syndrome, as well as the further decrease of total and LDL cholesterol during GH treatment, would seem to indicate that lipoproteins do not increase the cardiovascular risk of these girls.

In order to evaluate the effectiveness of the gonadotropin-releasing hormone agonist leuprolide acetate in distinguishing gonadotropin deficiency from delayed puberty, a single subcutaneous dose of 20 micrograms/kg of leuprolide acetate was administered at 07.00 h to 14 patients with constitutionally delayed puberty and to 8 gonadotropin-deficient subjects, and serum gonadotropin and testosterone levels were determined at baseline and 1,2,3,6,12, and 24 h thereafter. The increase in gonadotropin and testosterone levels was significant in patients with delayed puberty, so that the mean peak luteinizing hormone and to a lesser degree the mean peak testosterone levels clearly differentiated normally delayed from gonadotropin-deficient puberty. However, when the peak gonadotropin and testosterone concentrations were analyzed individually, there was a considerable overlap between the two groups of males, limiting the usefulness of this test.

To determine the effect of glycemic control on the growth velocity and several metabolic parameters of children with insulin-dependent diabetes mellitus (IDDM), 79 patients with IDDM, 45 females and 34 males with a mean chronological age of 8.4 +/- 3.0 years were followed over a 5-year period starting at the onset of diabetes. Glycemic control was assessed by measuring total glycosylated hemoglobin; children were divided into better controlled, GHb9%, 30 children (Group A) and worse controlled, GHbor = 9%, 49 patients (Group B). Growth velocity was significantly lower, in the five years of follow up, in the worse controlled patients when compared to the better controlled subjects (4.8 +/- 1.6 vs 6.7 +/- 2.2 cm/yr after the first year and 5.0 +/- 2.0 vs 6.5 +/- 1.8 cm/yr after the fifth year, in group B and group A, respectively). Higher cholesterol (185.3 +/- 33.7 vs 158.8 +/- 39.5 mg/dl) and triglyceride levels (85.9 +/- 43.5 vs 71.0 +/- 37.4 mg/dl) were apparent in the worse controlled patients, when compared to the better controlled children. Insulin dose was not significantly different in the two groups (0.76 +/- 0.3 vs 0.84 +/- 0.4 U/kg/day in the 1st year and 0.9 +/- 0.3 vs 0.92 +/- 0.4 U/kg/day in the 5th year, in group B and A respectively). Although both groups received the same initial and long term training by our pediatric diabetes team, more frequent blood glucose monitoring, better record keeping and rotation of injection sites and more clinic visits were clearly noted in the better controlled group. Ketoacidotic episodes were more common in the worse controlled patients, while better controlled children had a higher number of hypoglycemic episodes. In conclusion, we have found poor glycemic control, as reflected by higher glycosylated hemoglobin levels, to affect the growth velocity and several metabolic parameters of children with diabetes followed for a five-year period. Other factors besides insulin dose and initial and subsequent diabetic education seem to play a role in their glycemic control.

Decreased Trabecular Bone Mineral Density in Children with Idiopathic Short Stature. Normalization of Bone Density and Increased Bone Turnover after One Year of Growth Hormone Treatment

We have recently demonstrated that children and adolescents with IDDM present with decreased lumbar spine BMD as early as 5 years after diagnosis. The purpose of this study was to evaluate the bone mineral status in a group of newly diagnosed children (9.0±1.9 months after diagnosis). We studied 10 children (5 males and 5 females) with a mean chronological age of 9.9±1.7 years and a mean glycosilated hemoglobin of 8.6±0.8%. Lumbar spine and femoral neck BMD were measured by dual X-Ray absorptiometry, while bone turnover was asssessed by the determination of the serum concentrations of the carboxy-terminal propeptide of type 1 procollagen (PICP) and the carboxy-terminal cross-linked telopeptide of type 1 collagen (ICTP). Results were compared to those of age, height, weight and pubertal status matched controls. Lumbar spine BMD Z-scores were decreased in our patients when compared to controls (Z-scores were -1.5±0.3, with eight out of ten patients showing values >1SD below the mean). No significant differences were noted in femoral neck BMD and total bone mineral content between groups. Serum PICP levels were decreased when compared to controls(233.6±39.3 vs 375.9±50.7 ug/L; p< 0.002), while serum ICTP concentrations, although increased, were not significantly different(9.3±1.3 vs 5.7±1.5 ug/L). However, PICP and ICTP did not correlate with the lumbar spine Z-score. In summary, early after diagnosis IDDM children present with decreased lumbar spine BMD and decreased bone formation markers.

We have previously shown that prepubertal girls with TS on growth hormone have normal BMD. The present study reevaluates the BMD, as assessed by dual X ray absorptiometry, of the original 8 girls; they are now 18.25±1.06 years of age, in Tanner stage V of puberty and have reached a final height of 149.5±6.2 cm. They have been off growth hormone for 3.8±0.9 years and on conjugated estrogens (0.625 mg daily) continuously for 4.1±1.0 years. The results were compared to our own reference data of age and gender related controls and to literature reference data which allow for comparison with girls of similar weight and pubertal status. Lumbar spine BMD was significantly reduced in our patients when compared to age and gender controls (mean Z score of -3.26±0.43, with 7 out of 8 patients with Z-scores >2 SD below the mean). When the lumbar spine BMD was compared to controls of similar weight and pubertal status it was still reduced, but to a lesser degree (mean Z-score of -1.06±0.53 with only 2 patients showing Z-scores >2 SD below the mean). When we compared the femoral neck and lumbar spine BMD of our subjects, as adults on estrogen replacement, to that obtained 6 years ago while they were prepubertal and on growth hormone, no significant change was found despite a mean increase in their height during this period of 18.4±3.5 cm (BMD of 0.758±0.04 and 0.779±0.05 g/cm2 in femoral neck and lumbar spine, respectively, while prepubertal and on growth hormone vs 0.754±0.03 and 0.816±0.03 g/cm2 as adults on estrogen replacement). The serum concentrations of the carboxyterminal propeptide of type 1 procollagen are decreased (p< 0.05), while the serum levels of the carboxyterminal cross-linked telopeptide of type 1 collagen are increased in our patients when compared to controls (p

We evaluated 91 newly diagnosed IDDM children mean age 7.8 ± 4.5 yrs; 56.7% had had an upper respiratory infection prior to diagnosis and 12.7% had had either mumps or varicella. Peak incidence of disease was found in February and March and August to October. Eighty seven percent had HLA-DR3 and/or DR4 vs 37% of the Venezuelan general population; 81.6% were HLA-DQW2 and/or HLA-DQW8. Studies of oligonucieotid hybridization showed the presence of arginine in position 52 of the DQ alpha chain and absence of aspartic acid in position 57 of the DQ beta chain, with an increased prevalence of DR2 and especially with DQB1 0602 which has been associated with protection. We found 55.9% to have positive islet cell antibodies (ICA) with 4 of these having a positive complement fixation test. Three patients (7.9%) were found to have positive insulin autoantibodies. No positive serotypes for enterovirus (Coxsackie-B) were found in our patients, but we detected 11 cases with elevated titers for cytomegalovirus antibodies. Positive antibodies for measles, mumps, herpes and varicella were found in some children. This study contributes to a better understanding of the epidemiology and immunogenetics of insulin dependent diabetes mellitus in Latin-American children.

Studies in four children with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency provide evidence for two separate 11β-hydroxylating systems in the adrenal zona fasciculata and zona glomerulosa. In addition, these studies support the proposal that the adrenal 11β- and 18-hydroxylating activities are related and may involve the same enzyme protein and catalytic site. In the untreated or poorly treated state, despite elevation of deoxycorticosterone (DOC) and tetrahydrodeoxycorticosterone, urinary free 18-hydroxy-DOC was in the low normal range and did not increase normally with ACTH. PRA and urinary free 18-hydroxycorticosterone (18-OHB), tetrahydroaldosterone (TH Aldo), and pH 1 aldosterone were suppressed in the untreated and ACTH periods. Glucocorticoid administration suppressed plasma ACTH, and urinary tetrahydro-DOC and free DOC excretion decreased to the normal range. Concomitantly, there was a rise in PRA accompanied by parallel increase in urinary 18-OHB, urinary TH Aldo, and pH 1 ald...

A syndrome is described whose features, suggestive of primary mineralcorticoid excess, included hypertension, hypokalemia, low PRA, and responsiveness to spironolactone. Aldosterone levels were subnormal but as yet there has been no evidence of overproduction of other mineralocorticoids by chemical analysis or by bioassay of plasma and urinary extracts. The steroidal abnormalities that were observed involved peripheral matabolism rather than secretion. One patient exhibited a transient delay in reduction of the 3-keto group in the A ring, and both patients exhibited a decrease in the metabolism of cortisol to biologically inactive cortisone. This was shown by the marked decrease in the excretion of urinary metabolites bearing an 11-keto group and a decrease in the oxidation of 11 alpha-[3H]cortisol to tritiated water. The defect appeared not to be a deficiency of the 11 beta-oxidoreductase system itself, since the reverse reaction of conversion of cortisone to cortisol proceeded normally, but, rater, an alteration in the equilibrium position of 11 beta-oxidoreduction in favor of the reduced form. This was also expressed by a prolongation of the half-time of disappearance of cortisol. The decrease in the MCR permitted the maintenance of normal cortisol plasma levels and normal glucocorticoid function at a diminished rate of secretion. The decreased rate of conversion of cortisol to cortisone serves as a biochemical marker of this hypertensive syndrome.

Objectives 1. To determine BMI, obesity/overweight rates, glucose and lipids at baseline, during GnRHa treatment and shortly after therapy discontinuation in female children with CPP and EP. 2. To compare this response to that seen in a similar group of untreated patients. Methods A retrospective analysis of 71 children with either CPP (n = 37) or EP (n = 34) was undertaken. Forty three were treated with a GnRHa for at least 2 years, while 28 were followed without treatment. Results At the time of diagnosis, a higher BMI (z-score of 1.1 ± 0.8 vs. 0.6 ± 0.7, p = 0.004) and a higher prevalence of obesity/overweight (72.9 vs. 35.3%, p = 0.001) was observed in subjects with CPP when compared to those with EP. Children with EP had higher fasting glucose and total cholesterol than those with CPP. BMI z-score, obesity/overweight rates, fasting glucose and lipids did not change significantly in girls with CPP or EP during 3 yrs of follow up, regardless of treatment. Weight z-scores were higher at 3 years in treated than in untreated girls with CPP (p = 0.02), while it was higher in untreated than in GnRHa-treated patients with EP at baseline, 1, 2 and 3 years (p = 0.007, p = 0.002, p = 0.02 and p = 0.04, respectively) and remained so shortly after stopping therapy (p = 0.03). Conclusions There is a high prevalence of obesity/overweight in girls with CPP and EP at diagnosis. However, this risk is greater in CPP than in EP girls. BMI, Obesity/overweight rates, fasting glucose and lipids remained stable in CPP and EP girls regardless of therapy. Weight z-scores were found to be higher in treated CPP girls and in untreated girls with EP.