Is the growth outcome of children with idiopathic short stature and isolated growth hormone deficiency following treatment with growth hormone and a luteinizing hormone-releasing hormone agonist superior to that obtained by GH alone?

AIM: The aim of this study was to evaluate the effect of combined therapy with growth hormone (GH) and luteinizing hormone-releasing hormone agonist (LHRHa) on the near-final height (NFH) of children with idiopathic short stature (ISS) and growth hormone deficiency (GHD) in early puberty. METHODS: A retrospective analysis of 20 patients with ISS and 9 patients with GHD treated with combined therapy was undertaken. Twelve children with ISS and ten with GHD, treated with GH alone, served as controls. Patients were matched at baseline for chronological age, bone age, height standard deviation score (SDS), and pubertal development. RESULTS: Patients with ISS or GHD treated with combined therapy improved both their predicted adult height (PAH) at 2 years of therapy (ISS, p < 0.001; GHD, p = 0.03) and their NFH (ISS, p < 0.05; GHD, p = 0.05). Treatment with combined therapy did not generate additional benefits on the PAH after 2 years of therapy (ISS children, an increase of 7.9 +/- 4.9 cm with combined therapy vs. 7.3 +/- 6.0 cm with GH; GHD children, an increase of 6.8 +/- 7.8 cm with combined therapy vs. 5 +/- 5.9 cm with GH). The total height gain SDS was higher in patients treated with GH alone compared with those with combined therapy, but the difference was not significant (ISS children, a gain of 2.4 SDS with GH vs. 0.8 SDS with combined therapy; GHD children, a gain of 1.8 SDS with GH vs. 0.6 SDS with combined therapy). CONCLUSIONS: Although 2 years of combined treatment with GH and LHRHa improved the PAH and the NFH of ISS and GHD patients in early puberty, this improvement was not significant compared with that observed in similar subjects treated with GH alone.

Latin American consensus: children born small for gestational age.

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.

GHR and VDR genes do not contribute to the growth hormone (GH) response in GH deficient and Turner syndrome patients.

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.

Circulating levels of high-sensitivity C-reactive protein and soluble markers of vascular endothelial cell activation in growth hormone-deficient adolescents.

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.

Relationship between different fasting-based insulin sensitivity indices in obese children and 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.

Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters.

OBJECTIVE: 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. DESIGN/METHODS: 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. RESULTS: Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P < 0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P < 0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P < 0.02). 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 (P < 0.001). 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. CONCLUSIONS: 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.

Cardiac mass and function, carotid artery intima-media thickness and lipoprotein (a) levels in children and adolescents with type 1 diabetes mellitus of short duration.

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 <0.01), while total cholesterol, HDL cholesterol and serum triglyceride concentrations were similar to those in controls. CONCLUSIONS: 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.

Higher prevalence of obesity and overweight without an adverse metabolic profile in girls with central precocious puberty compared to girls with early puberty, regardless of GnRH analogue treatment.

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.

Effect of the parental origin of the X-chromosome on the clinical features, associated complications, the two-year-response to growth hormone (rhGH) and the biochemical profile in patients with turner syndrome.

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.

Coronary artery calcification, serum lipids, lipoproteins, and peripheral inflammatory markers in adolescents and young adults with type 1 diabetes.

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.

Growth hormone deficiency, low levels of adiponectin, and unfavorable plasma lipid and lipoproteins.

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.

The effect of short- and long-term growth hormone treatment on bone mineral density and bone metabolism of prepubertal children with idiopathic short stature: a 3-year study.

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 < 0.0001). 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; P < 0.003). Lumbar spine BMD increased after 1 year of GH from 0.640 +/- 0.08 to 0.749 +/- 0.08 g/cm2 (P < 0.05), 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. CONCLUSIONS: 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.

Distribución de las frecuencias alélicas y genotípicas del polimorfismo GHRd3 en pacientes venezolanos con talla baja

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.

Transtorno del crecimiento en el niño y adolescente con diabetes mellitus tipo I

Los efectos de la diabetes mellitus tipo 1 sobre el crecimiento y desarrollo de niños y adolescentes son aún controversiales. Algunos grupos de investigadores afirman que la diabetes en la edad pediátrica va a alterar el crecimiento de los niños, independiente del grupo de control metabólico y otros, incluyendo nuestro grupo, hemos demostrado que el paciente con un llamado "mal control" metabólico con hiperglicemia crónica reflejadas por niveles de hemoglobina glicosilada (HbA1C) elevados, van a presentar una disminución de la velocidad de crecimiento y por tanto terminan con una talla final más baja que su potencial genético. El objetivo de este trabajo es realizar un análisis del efecto que tiene la diabetes sobre la fisiopatología de los factores de crecimiento y como repercuten los mismos sobre las anormalidades que se presentan en la clínica y la auxología del niño y adolescente con diabetes mellitus tipo 1

The effect of type 1 diabetes mellitus on the growth and development of children and adolescents remains controversial. Some groups of investigators have reported that diabetes during the pediatric age will alter the growth of children, independently of the degree of metabolic control, while others, including our group, have demonstrated, that what is called a “poor metabolic bolic”control, with chronic hyperglycemia reflected by elevated HbA1C, will produce a decrease in growth velocity that will end in subjects with short stature for their genetic potential. The aim of this study is to analyze the effect that diabetes has on the physiopathology of growth factors and the role they play on the clinical and auxiological abnormalities that are seen in children with type 1 diabetes mellitus

Síndrome de resistencia a la insulina en niños y adolescentes / Insulin resistance syndrome in children and adolescents

El propósito de este estudio es evaluar la presencia del síndrome de resistencia a la insulina en niños y adolescentes, sobre todo considerando que hasta hace poco tiempo este síndrome era considerado, como una entidad rara en la edad pediátrica, la cual estaba limitada a la práctica de medicina del adulto. En las últimas décadas se ha presenciado un aumento importante de la aparición de diabetes tipo 2 en el niño y adolescente, que ha llegado a niveles epidémicos, lo cual es un reflejo directo del incremento de obesidad en este grupo etario y en consecuencia el desarrollo de resistencia a la insulina (síndrome metabólico, síndrome X, o síndrome de resistencia a la insulina). En este trabajo analizamos la fisiopatología y las características clínicas de este síndrome, al igual que los parámetros bioquímicos para definirlo, así como estudios diagnósticos realizados en nuestra Unidad de Endocrinología Pediátrica, en niños de la población venezolana. Se ha analizado la relación glicemia/insulina en condiciones basales en pacientes con diferentes grados de obesidad, desarrollando índices matemáticos que ayudan a definir el cuadro de resistencia a la insulina. Por último se hacen consideraciones sobre prevención y tratamientos recientes para evitar la aparición de diabetes, dislipidemia y complicaciones cardiovasculares

Tratamiento de la pubertad precoz verdadera con analógos de GnRH: efectos sobre variables antropométricas y niveles hormonales / Precocious puberty treatment with GnRH analogous: effects on anthopometric variables and hormonal level

Con el objeto de evaluar la respuesta al tratamiento con acetato de leuprolide en niños con pubertad precoz verdadera (PPV) idiopática, se estudiaron 10 pacientes (7 hembras y 3 varones) con edad cronológica de 8,05 ñ 0,59 años de edad ósea de 10,48 ñ 0,47 años, quienes iniciaron pubertad a los 6,38 ñ 0,59 años. La dosis inicial del análogo fué de 30 ug/kg/día de la preparación subcutánea (4 pacientes) y de 165 ug/kg/mes de la de depósito (6 pacientes); la dosis se ajustó a las 6-8 semanas luego cada 3 meses hasta obtener una buena respuesta clínica (velocidad de crecimiento en rango prepuberal y avance de edad ósea paralelo a la edad cronológica) y una supresión adecuada de hormonaluteinizante (LH) postestimulación con hormona liberadora de gonadotropinas (GnRH), pico<4mU/ml. Con el tratamiento se observó una adecuada supresión de los niveles de gonadotropinas en la prueba de estimulación con GnRH (pico de LH de 35,17 ñ 11,99 mU/ml antes del tratamiento, 4,46 ñ 0,54 a los 12 meses; p<0,025), detención en la progresión del desarrollo puberal, normalización de la velocidad de crecimiento (10,78 ñ 1,44 cm/año antes del tratamiento, 7,38 ñ 0,73 a los 6 meses (p<0,005) y 5,97 ñ 0,50 a los 12 meses (p<0,0025), reducción de la relación EdadOsea/Edad Cronológica (1,39 ñ 0,08 pre-tratamiento, 1,34 ñ 0,06 a los 6 meses y 1,30ñ 0,06 a los 12 meses), y en consecuencia, mejoría de la predicción de la talla adulta (162,76 ñ 3,61 cm antes del tratamiento, 164,57 ñ 3,15 a los 6 meses, y 167,37 ñ 4,31 a los dose meses). Se concluye que el tratamiento con acetato de leuprolide en niños con PPV idiopática es efectivo, tanto para detener la progresión en los caracteres sexuales secundarios, como para mejorar la predicción de talla final. Es importante una minuciosa evaluación de estos pacientes para definir si necesitan o no del tratamiento, y en caso afirmativo, se recomienda un seguimiento estrecho del mismo, mediante el ajuste de la dosis, basados en criterios clínicos y de laboratorio para lograr el beneficio esperado

Detección de hipotiroidismo congénito en Venezuela / Detection of congenital hypothyroidism in Venezuela

El hipotiroidismo congénito, es una enfermedad metabólica cuya incidencia mundial es de aproximadamente 1/3.800 a 1/4.000 de recién nacidos vivos. En Venezuela, aún no se ha implantado en forma generalizada, el método de detección neonatal de hipotiroidismo, por lo cual no conocemos nuestros datos estadísticos. Sin embargo, nosotros vemos un número relativamente alto de niños con hipotiroidismo, lamentablemente de diagnóstico tardío. En el Hospital de Niños "J.M. de los Ríos-, encontramos que el 72,9% de los niños diagnosticados con hipotiroidismo congénito, fueron referidos a nuestro Servicio de Endocrinología, después de los 2 años. Además, el 12,5% entre 1 y 2 años, y ninguno de ellos antes de los 3 meses. Hoy en día, se ha determinado, que mientras más temprano se diagnostique, y se inicie el tratamiento, se evita el retardo mental, que en nuestros casos es de un 75%. Dado la severidad de este problema, en nuestro país, hemos iniciado un proyecto piloto de despistaje neonatal de hipotiroidismo congénito, utilizando para ellos, el método de papel de filtro en sangre capilar, del recién nacido, tomado antes de ser dado de alta de la Maternidad. Analizamos 462 recién nacidos del Hospital "Carlos J. Bello", Cruz Roja Venezolana, en 10 meses de estudio. Las muestras, junto con un protocolo elaborado para el proyecto, eran enviadas al Servicio de Endocrinología, del Hospital de Niños "J.M. de los Ríos", y procesadas en el Laboratorio Central. Se determinaron 462 test de T4 y 382 test de TSH, según el método de RIA, y consideramos que debido a que en nuestras maternidades, los recién nacidos son dados de alta antes de las 48 horas, no es suficiente realizar sólo el TSH, por lo que debe complementarse con T4. Se concluye que técnicamente es posible realizar el método, y que analizando la relación costo/beneficio, es necesario implementar lo antes posible, en forma generalizada, centralizada, y con carácter de obligatoriedad, la detección de hipotiroidismo congénito, que es una de las causas prevenibles de retardo mental