Índice de masa corporal e índice de masa triponderal de 1.453 niños no obesos ni malnutridos de la generación del milenio. Estudio longitudinal de Barcelona / Body mass index and tri-ponderal mass index of 1,453 healthy non-obese, non-undernourished millennial children. The Barcelona longitudinal growth study

INTRODUCCIÓN: Hasta el momento no se han comunicado valores del índice de masa corporal (IMC) ni del índice de masa triponderal (IMT) de niños sanos sin malnutrición ni obesidad de la generación del milenio. Nuestro objetivo fue obtener estos valores. Sujetos y métodos: Estudio longitudinal de crecimiento (1995-2017) en 1.453 niños sanos sin malnutrición ni obesidad de la generación del milenio desde el nacimiento (n = 477) o los 4 años de edad (n = 976) hasta los 18 años en mujeres y los 19 años en varones (25.851 mediciones antropométricas). RESULTADOS: En ambos sexos, los valores medios del IMC según la edad aumentaron entre el nacimiento y el año de edad, luego decrecieron hasta los 5 años de edad y finalmente aumentaron a partir de dicha edad. Los valores del IMT según la edad descendieron abruptamente en los 6 primeros años de vida y lentamente a partir de esa edad en ambos sexos. Aunque a algunas edades los valores medios del IMC difirieron de manera significativa entre los sexos, esas diferencias fueron pequeñas y de escasa relevancia clínica. Lo mismo ocurrió con los valores del IMT según la edad. Los puntos de corte del IMC según la edad obtenidos para definir la malnutrición (-2 DE) fueron similares a los propuestos por Cole y la OMS en ambos sexos. En cambio, los puntos de corte del IMC según la edad obtenidos para definir la obesidad (+2 DE) fueron menores en ambos sexos (1,0-5,3) en comparación con los propuestos por Cole y similares a los propuestos por la OMS hasta los 12 años en niñas y los 14 en niños, e inferiores (1,0-4,8) a los de la OMS a partir de dichas edades. CONCLUSIONES: Presentamos valores del IMC y el IMT según la edad de niños sanos sin malnutrición ni obesidad de la generación del milenio. No se observaron diferencias significativas entre los 2 sexos. Estos valores podrían emplearse para evaluar la malnutrición y la obesidad en poblaciones pediátricas actuales y para estudiar la relación entre el IMC y el IMT (según la edad) en la práctica clínica

INTRODUCTION: Body mass index-for age (BMI) and tri-ponderal mass index-for-age (TMI) values of healthy non-underweight, non-obese millennial children have not been reported until now. We aimed to obtain these values. Subjects and methods: Longitudinal growth study (1995-2017) of 1,453 healthy non-underweight, non-obese millennial children, from birth (n = 477) or from 4 years of age (n = 976) to 18 years in girls and 19 years in boys (25,851 anthropometric measurements). RESULTS: In each sex, mean BMI-for-age values increased from birth to one year, declined until 5 and increased from then onwards. Mean TMI-for-age values decreased abruptly during the first 6 years of age and slowly thereafter, in both sexes. Although, at some ages, mean BMI-for age values differed statistically between sexes, differences were scant and of poor clinical significance. The same occurred for TMI-for-age values. BMI-for-age cut-off values to define underweight status (-2 SD) were similar to those proposed by Cole and the WHO for both sexes. However, BMI-for-age cut-off values to define obesity (+2 SD) were lower in both sexes (1.0-5.3) than those proposed by Cole and similar to those proposed by the WHO until 12 in girls and 14 in boys and lower (1.0-4.8) from these ages onwards. CONCLUSIONS: BMI-for-age and TMI-for-age values of healthy non-underweight, non-obese millennial children are provided. No clinically relevant differences were observed between sexes. These values may be used to measure underweight status and obesity in present pediatric populations and to evaluate the relationship between BMI-for-age and TMI-for-age in a clinical setting

Crecimiento puberal de 1.453 niños sanos según la edad de inicio de la pubertad. Estudio longitudinal de Barcelona / Pubertal growth of 1.453 healthy children according to age at pubertal growth spurt onset. The Barcelona longitudinal growth study

INTRODUCCIÓN: El patrón de crecimiento puberal varía según la edad de inicio del brote de crecimiento puberal, que ocurre dentro de un período de 5 años (mujeres: 8-13 años; varones: 10-15 años). Se ha propuesto la necesidad de utilizar más de un patrón de referencia puberal. Nuestro objetivo fue obtener 5 patrones puberales a intervalos de un año. Sujetos y métodos: Estudio longitudinal (6 años de edad-talla adulta) de crecimiento en 1.453 niños sanos con evaluación de valores de talla, velocidad de crecimiento y peso para la edad. Según la edad de inicio del brote de crecimiento puberal, las mujeres se consideraron: maduradoras muy tempranas (8-9 años, n = 119), maduradoras tempranas (9-10 años, n = 157), maduradoras intermedias (10-11 años, n = 238), maduradoras tardías (11-12 años, n = 127) y maduradoras muy tardías (12-13 años, n = 102); los varones se consideraron: maduradores muy tempranos (10-11 años, n = 110), maduradores tempranos (11-12 años, n = 139), maduradores intermedios (12-13 años, n = 225), maduradores tardíos (13-14 años, n = 133) y maduradores muy tardíos (14-15 años, n = 103). Se registró la edad de la menarquia y el crecimiento desde esta hasta alcanzar la talla adulta. RESULTADOS: En ambos sexos se observaron diferencias estadísticamente significativas (p < 0,0001) y clínicamente relevantes en el patrón de crecimiento puberal (valores medios de talla para la edad, velocidad de crecimiento para la edad y ganancia de talla puberal) entre los 5 grupos maduradores y entre cada uno de ellos y la población total, a pesar de que los valores de la talla adulta fueron similares en todos los grupos. Se observó la misma tendencia en relación con la edad de la menarquia y la ganancia de talla desde la menarquia hasta la talla adulta (p < 0,05). CONCLUSIONES: En ambos sexos, el inicio del brote de crecimiento puberal es un hito crítico que determina el crecimiento puberal y el desarrollo sexual. Nuestros datos contribuyen a una mejor evaluación clínica del crecimiento de acuerdo con el tempus madurativo de cada niño, obviando los errores que se cometen con el uso de un único patrón de referencia puberal

INTRODUCTION: Pubertal growth pattern differs according to age at pubertal growth spurt onset which occurs over a five years period (girls: 8-13 years, boys: 10-15 years). The need for more than one pubertal reference pattern has been proposed. We aimed to obtain five 1-year-age-interval pubertal patterns. Subjects and methods: Longitudinal (6 years of age-adult height) growth study of 1,453 healthy children to evaluate height-for-age, growth velocity-for-age and weight-for-age values. According to age at pubertal growth spurt onset girls were considered: very-early matures (8-9 years, n = 119), early matures (9-10 years, n = 157), intermediate matures (10-11 years, n = 238), late matures (11-12 years, n = 127) and very-late matures (12-13 years, n = 102), and boys: very-early matures (10-11 years, n = 110), early matures (11-12 years, n = 139), intermediate matures (12-13 years, n = 225), late matures (13-14 years, n = 133) and very-late matures (14-15 years, n = 103). Age at menarche and growth up to adult height were recorded. RESULTS: In both sexes, statistically-significant (P < .0001) and clinically-pertinent differences in pubertal growth pattern (mean height-for-age, mean growth velocity-for-age and mean pubertal height gain, values) were found among the five pubertal maturity groups and between each group and the whole population, despite similar adult height values. The same occurred for age at menarche and growth from menarche to adult height (P < .05). CONCLUSIONS: In both sexes, pubertal growth spurt onset is a critical milestone determining pubertal growth and sexual development. The contribution of our data to better clinical evaluation of growth according to the pubertal maturity tempo of each child will obviate the mistakes made when only one pubertal growth reference is used

[Body mass index and tri-ponderal mass index of 1,453 healthy non-obese, non-undernourished millennial children. The Barcelona longitudinal growth study]. / Índice de masa corporal e índice de masa triponderal de 1.453 niños no obesos ni malnutridos de la generación del milenio. Estudio longitudinal de Barcelona.

INTRODUCTION: Body mass index-for age (BMI) and tri-ponderal mass index-for-age (TMI) values of healthy non-underweight, non-obese millennial children have not been reported until now. We aimed to obtain these values. SUBJECTS AND METHODS: Longitudinal growth study (1995-2017) of 1,453 healthy non-underweight, non-obese millennial children, from birth (n = 477) or from 4 years of age (n = 976) to 18 years in girls and 19 years in boys (25,851 anthropometric measurements). RESULTS: In each sex, mean BMI-for-age values increased from birth to one year, declined until 5and increased from then onwards. Mean TMI-for-age values decreased abruptly during the first 6years of age and slowly thereafter, in both sexes. Although, at some ages, mean BMI-for age values differed statistically between sexes, differences were scant and of poor clinical significance. The same occurred for TMI-for-age values. BMI-for-age cut-off values to define underweight status (-2 SD) were similar to those proposed by Cole and the WHO for both sexes. However, BMI-for-age cut-off values to define obesity (+2 SD) were lower in both sexes (1.0-5.3) than those proposed by Cole and similar to those proposed by the WHO until 12 in girls and 14 in boys and lower (1.0-4.8) from these ages onwards. CONCLUSIONS: BMI-for-age and TMI-for-age values of healthy non-underweight, non-obese millennial children are provided. No clinically relevant differences were observed between sexes. These values may be used to measure underweight status and obesity in present pediatric populations and to evaluate the relationship between BMI-for-age and TMI-for-age in a clinical setting.

[Pubertal growth of 1,453 healthy children according to age at pubertal growth spurt onset. The Barcelona longitudinal growth study]. / Crecimiento puberal de 1.453 niños sanos según la edad de inicio de la pubertad. Estudio longitudinal de Barcelona.

INTRODUCTION: Pubertal growth pattern differs according to age at pubertal growth spurt onset which occurs over a five years period (girls: 8-13 years, boys: 10-15 years). The need for more than one pubertal reference pattern has been proposed. We aimed to obtain five 1-year-age-interval pubertal patterns. SUBJECTS AND METHODS: Longitudinal (6 years of age-adult height) growth study of 1,453 healthy children to evaluate height-for-age, growth velocity-for-age and weight-for-age values. According to age at pubertal growth spurt onset girls were considered: very-early matures (8-9 years, n=119), early matures (9-10 years, n=157), intermediate matures (10-11 years, n=238), late matures (11-12 years, n=127) and very-late matures (12-13 years, n=102), and boys: very-early matures (10-11 years, n=110), early matures (11-12 years, n=139), intermediate matures (12-13 years, n=225), late matures (13-14 years, n=133) and very-late matures (14-15 years, n=103). Age at menarche and growth up to adult height were recorded. RESULTS: In both sexes, statistically-significant (P<.0001) and clinically-pertinent differences in pubertal growth pattern (mean height-for-age, mean growth velocity-for-age and mean pubertal height gain, values) were found among the five pubertal maturity groups and between each group and the whole population, despite similar adult height values. The same occurred for age at menarche and growth from menarche to adult height (P<.05). CONCLUSIONS: In both sexes, pubertal growth spurt onset is a critical milestone determining pubertal growth and sexual development. The contribution of our data to better clinical evaluation of growth according to the pubertal maturity tempo of each child will obviate the mistakes made when only one pubertal growth reference is used.

Hiperinsulinisme en una unitat neonatal / Hiperinsulinismo en una unidad neonatal / Hyperinsulinism in a newborn unit

Introducció: lhiperinsulinisme (HI) és la causa més freqüent dhipoglucèmia neonatal mantinguda. Es pot dividir en transitori o secundari i persistent o congènit. Es presenta una revisió del tema, a partir de quatre casos diagnosticats a la nostra unitat durant set anys. Observació clínica: dels quatre casos, tres són transitoris o secundaris i un persistent. Els factors predisposants dels transitoris són la pèrdua del benestar fetal i la diabetis gestacional. El persistent, amb una ressonància magnètica (RM) cranial i un estudi genètic normals, no va respondre al tractament amb diazòxid (DI) i va millorar amb dextrinomaltosa i alimentació contínua. Cap cas va presentar seqüeles neurològiques. Comentaris: els nostres casos compleixen els criteris diag-nòstics dHI. La incidència dHI al nostre centre és d1/4.500 nascuts vius i la dHI persistent d1/20.000 nascuts vius en set anys. LHI transitori o secundari es relaciona amb lasfíxia neonatal, el retard del creixement intrauterí i la diabetis gestacional. Els casos descrits presen-ten pèrdua del benestar fetal i diabetis. El tractament inicial és laportació de glucosa. Després, el fàrmac de primera línia és el DI. LHI persistent acostuma a no respondre al tractament i pot ser focal o difús, el primer dels quals es pot beneficiar de cirurgia. El màxim objectiu és la prevenció de seqüeles neurològiques. És fonamental el maneig conjunt amb un especialista endocrinòleg

Introducción. El hiperinsulinismo (HI) es la causa más frecuente de hipoglucemia neonatal mantenida. Se puede dividir en transitorio o secundario y persistente o congénito. Se presenta una revisión del tema, a partir de cuatro casos diagnosticados en nuestra unidad durante siete años. Observación clínica. De los cuatro casos, tres son transitorios o secundarios y uno persistente. Los factores predisponentes de los transitorios son la pérdida del bienestar fetal y la diabetes gestacional. El persistente, con una resonancia magnética (RM) craneal y un estudio genético normales, no respondió al diazóxido (DI) y mejoró con dextrinomaltosa y alimentación continua. Ningún caso presentó secuelas neurológicas. Comentarios. Nuestros casos cumplen los criterios diagnósticos de HI. La incidencia de HI en nuestro centro es de 1/4.500 nacidos vivos y la de HI persistente de 1/20.000 nacidos vivos en siete años. El HI transitorio o secundario se relaciona con la asfixia neonatal, el retraso del crecimiento intrauterino y la diabetes gestacional. Los casos descritos presentan pérdida del bienestar fetal y diabetes. El tratamiento inicial es el aporte de glucosa. Después, el fármaco de primera linea es el DI. El HI persistente acostumbra a no responder al tratamiento y puede ser focal o difuso, el primero de los cuales puede beneficiarse de cirugía. El máximo objetivo es la prevención de secuelas neurológicas. Es fundamental el manejo conjunto con un especialista endocrinólogo (AU)

Introduction. Hyperinsulinism (HI) is the most frequent cause of sustained neonatal hypoglycemia; it can be transient (secondary) or persistent (congenital). We describe four cases of neonatal HI seen in a neonatal unit over a seven-year period. Clinical observation. Three of the four cases were transient or secondary, and the other was persistent. Loss of fetal wellbeing and gestational diabetes were the predisposing factors in the three transient cases. The case of persistent HI had normal brain magnetic resonance imaging and genetics; it did not respond to treatment wth diazoxide (DI) but improved with continuous feeding and dextrinomaltose. All four cases recovered with no neurological sequelae. Comments. Our fours cases met the diagnosis criteria for HI. Over the seven-year period, the overall incidence of HI was 1 in 4,500 live births, while the incidence of persistent HI was 1 in 20,000 live births. Transient or secondary HI is related to birth asphyxia, intrauterine growth retardation, and gestational diabetes. The initial treatment of HI is with glucose and DI. Persistent or congenital HI seldom responds to treatment and it can be the result of focal or diffuse pancreatic disease, the first of which anomalies could benefit from surgery. Prevention of neurological sequelae is the main objective of the treatment. A multidisciplinary management with endocrinology is recommended (AU)

Contribution of human growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to isolated severe growth hormone deficiency (ISGHD) and normal adult height.

OBJECTIVE: Molecular causes of isolated severe growth hormone deficiency (ISGHD) in several genes have been established. The aim of this study was to analyse the contribution of growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to GH deficiency in a series of prepubertal ISGHD patients and to normal adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GHRHR gene sequence analysis was performed in 69 ISGHD patients and 60 normal adult height controls (NAHC). Four GHRHR single-nucleotide polymorphisms (SNPs) were genotyped in 248 additional NAHC. An analysis was performed on individual SNPs and combined genotype associations with diagnosis in ISGHD patients and with height-SDS in NAHC. RESULTS: Twenty-one SNPs were found. P3, P13, P15 and P20 had not been previously described. Patients and controls shared 12 SNPs (P1, P2, P4-P11, P16 and P21). Significantly different frequencies of the heterozygous genotype and alternate allele were detected in P9 (exon 4, rs4988498) and P12 (intron 6, rs35609199); P9 heterozygous genotype frequencies were similar in patients and the shortest control group (heights between -2 and -1 SDS) and significantly different in controls (heights between -1 and +2 SDS). GHRHR P9 together with 4 GH1 SNP genotypes contributed to 6·2% of height-SDS variation in the entire 308 NAHC. CONCLUSIONS: This study established the GHRHR gene sequence variation map in ISGHD patients and NAHC. No evidence of GHRHR mutation contribution to ISGHD was found in this population, although P9 and P12 SNP frequencies were significantly different between ISGHD and NAHC. Thus, the gene sequence may contribute to normal adult height, as demonstrated in NAHC.

Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia.

CONTEXT: Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH). OBJECTIVE: StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported. DESIGN: To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature. SETTING: Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain. PATIENTS: Two subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age. RESULTS: StAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol. CONCLUSIONS: StAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.

Longitudinal pubertal growth according to age at pubertal growth spurt onset: data from a Spanish study including 458 children (223 boys and 235 girls).

BACKGROUND: Age at pubertal growth spurt (PGS) onset varies and is sex-dependent. We present anthropometric pubertal growth data for five 1-year interval age maturity groups: very early, early, intermediate, late and very late. METHODS: Longitudinal growth study of 458 healthy children (223 boys, 235 girls). Ages at PGS onset and at adult height attainment, total pubertal growth (TPG), and peak height velocity (PHV) were evaluated. PGS begins between the ages of 10 and 15 in boys and 8 and 13 in girls; children were allocated to the corresponding 1-year interval age maturity group. RESULTS: For each sex, the earlier the start of PGS onset, the higher were PHV and TPG gain. However, adult heights were similar among the five pubertal maturity groups. Height SDS values for mean values of the very early, early, late and very late maturity groups calculated according to data from the five pubertal maturity groups taken together as a single group differed from zero in both sexes, mainly during the pubertal years for the very early (> +1) and very late (> -1) maturers. These differences disappeared at adult height. CONCLUSIONS: Our data might contribute to better clinical evaluation of pubertal growth according to individual pubertal maturity tempo.

Ezetimibe as monotherapy in the treatment of hypercholesterolemia in children and adolescents.

BACKGROUND: A prospective study was conducted to evaluate low-density lipoprotein-cholesterol (LDL-C) lowering efficacy and tolerability of ezetimibe as monotherapy in children and adolescents with polygenic hypercholesterolemia (PH) or familial hypercholesterolemia (FH). METHODS AND RESULTS: Children with PH (n=6) or FH (n=11) aged 5-15 years were consecutively enrolled to receive ezetimibe as monotherapy at 10 mg/day for 11.3 +/- 7.3 and 15.9 +/- 10.1 months, respectively. Plasma biochemical and lipid profiles were assessed before and after treatment. Ezetimibe significantly lowered total cholesterol (TC) and LDL-C in patients with PH and FH: TC from 260.5 +/- 12.4 to 180.0 +/- 21.6 mg/dl (p = 0.02) and from 315.3 +/- 41.8 to 233.3 +/- 36.8 mg/dl (p = 0.003), respectively, and LDL-C from 177.1 +/- 17.7 to 102.6 +/- 16.7 mg/dl (p = 0.02) and from 243.0 +/- 41.8 to 170.0 +/- 29.8 mg/dl (p = 0.003), respectively. However, high-density lipoprotein-cholesterol (HDL-C) only decreased significantly (from 58.1 +/- 10.0 to 49.3 +/- 9.1 mg/dl) (p < 0.01) in patients with FH and remained unaltered in patients with PH. Triglyceride levels remained unchanged in both groups. Biochemical profile (hemogram, transaminases, creatinine, calcium, phosphorus and liposoluble vitamins A and E) remained unchanged; no adverse effects were observed. CONCLUSIONS: Our data show that ezetimibe as monotherapy significantly lowered TC and LDL-C in children with PH and FH.

Growth hormone (GH) dose, but not exon 3-deleted/full-length GH receptor polymorphism genotypes, influences growth response to two-year GH Therapy in Short Small-for-Gestational-Age Children.

CONTEXT: In short small-for-gestational-age (SGA) patients, the exon 3-deleted(d3)/full-length (fl)-GHR polymorphism was associated with responsiveness to GH therapy (30-48 microg/kg.d); however, these results were not confirmed for higher GH doses (56-66 microg/kg.d). We hypothesized that higher doses would mask the lower dose differences. OBJECTIVE: Our objective was to evaluate, in short SGA patients, 2-yr growth response to GH therapy (32.1 +/- 3.8 microg/kg.d) according to exon d3/fl-GHR genotypes. SETTING: This was a 2-yr follow-up study. PATIENTS: There was a total of 60 short SGA children (d3/d3 n = 8, d3/fl n = 23, and fl/fl n = 29). There were 11 children that entered puberty during the second follow-up year. Results were evaluated for all patients (group A1, n = 60, 7.7 +/- 2.7 yr) and for patients who remained prepubertal (group A2, n = 49, 6.9 +/- 2.2 yr). MAIN OUTCOME MEASURES: Patients were followed by a single clinical team, and exon d3/fl-GHR genotypes were determined and analyzed in the same hospital. RESULTS: In groups A1 and A2, growth velocity significantly (P < 0.0001) increased during the first and second years of therapy, as did height sd score (SDS). These increases were similar in each exon d3/fl-GHR genotype. Total 2-yr height gain (cm, SDS) did not differ statistically among genotypes: group A1, 15.0 +/- 2.0 cm and 1.15 +/- 0.45 SDS in d3/d3, 16.0 +/- 2.4 cm and 1.17 +/- 0.51 SDS in d3/fl, 16.1 +/- 2.4 cm and 1.15 +/- 0.53 SDS in fl/fl; and group A2, 15.4 +/- 2.0 cm and 1.03 +/- 0.42 SDS in d3/d3, 15.6 +/- 2.1 cm and 1.22 +/- 0.51 in d3/fl, and 16.2 +/- 2.6 cm and 1.21 +/- 0.56 SDS in fl/fl. CONCLUSIONS: These results did not confirm our hypothesis and show that, in short SGA children, 2-yr growth response to GH therapy 32.1 +/- 3.8 microg/kg.d was similar for each exon d3/fl-GHR genotype carried, as occurred in our previous study using 66 microkg.d.

Human growth hormone (GH1) gene polymorphism map in a normal-statured adult population.

OBJECTIVE: GH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: -2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height. RESULTS: Twenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5'UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6.2% of the variation in adult height (P = 0.0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (-0.063 +/- 0.031, -0.693 +/- 0.350 and -0.489 +/- 0.265, Mean +/- SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1.094 +/- 0.456 and +1.184 +/- 0.432). CONCLUSIONS: This study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them.

Hypoglycaemia-insulin test: discordant growth hormone and cortisol response in paediatric patients regarding recovery from hypoglycaemia with or without oral glucose solution.

BACKGROUND: Hypoglycaemia-insulin test (HIT) is the 'gold standard' for the diagnosis of adrenal-pituitary-hypothalamic axis disorders. Controversy exists on the convenience of recovery from an insulin-induced hypoglycaemia since this test is not risk-free. OBJECTIVE: To ascertain whether recovery from insulin-induced hypoglycaemia with an oral glucose solution produces a different response of growth hormone (GH) and cortisol at different times of the study compared with spontaneous recovery from hypoglycaemia. PATIENTS AND METHODS: Prospective study of 100 children and adolescents with growth delay who underwent an HIT. Patients were consecutively assigned to two groups of 50. In one group recovery from hypoglycaemia occurred spontaneously and in the other recovery was achieved with an oral glucose solution (20 g of glucose) when glycaemia was under 30 mg/dl. The two groups did not differ in age, sex, pubertal status, weight, height and IGF-I levels. RESULTS: The response of GH at 30, 60, 90 and 120 min and cortisol at 10, 60, 90 and 120 min was lower and statistically significant in patients with recovery from hypoglycaemia with oral glucose solution. GH deficiency was diagnosed more frequently in patients recovered with glucose solutions (94%) compared to those with spontaneous recovery (68%). CONCLUSIONS: Oral glucose solution administration when glycaemia was under 30 mg/dl in HIT produced a lower GH and cortisol response to insulin stimulus and a greater frequency of GH deficit diagnosis.

[Glucose intolerance in obese children and adolescents]. / Intolerancia a la glucosa en niños y adolescentes obesos.

BACKGROUND AND OBJECTIVE: The rise in the prevalence of glucose intolerance and type 2 diabetes mellitus in childhood and adolescence in recent decades appears to be closely related to the increase in the incidence of obesity in developed countries. We decided to establish the frequency of glucose intolerance and type 2 diabetes mellitus in a population of obese children and adolescents evaluated at our hospital. PATIENTS AND METHOD: Prospective study of 145 obese patients (60 boys: BMI 29.5 (4.9), BMI z score 4.4 (1.7); and 85 girls: BMI 28.8 (4.6), BMI z score 3.8 (1.4); age range: (4-18 years) who underwent an oral glucose tolerance test (OGTT) between 1998 and 2003. OGTT results were evaluated according to WHO criteria. Insulin secretion and sensitivity parameters (HOMA, QUICKI, area under the curve for glycemia, area under the curve for insulin and insulinogenic index) were also calculated. RESULTS: The frequency of glucose intolerance in the whole population was 19.2%. However, this prevalence varied with age and maturation stage (prepuberty 7.0%, puberty 28.2% and postpuberty 26.5%), and with the obesity degree (BMI z-score between +2 and +3: 8.9%; between +3 and +4: 21.9% and higher than +4: 25%). No type 2 diabetes mellitus cases were observed. CONCLUSIONS: Obese children and adolescents display an elevated incidence of glucose intolerance which seems to be related to the degree of adiposity.

Intolerancia a la glucosa en niños y adolescentes obesos / Glucose intolerance in obese children and adolescents

Fundamento y objetivo: El incremento de la prevalencia de la intolerancia a la glucosa y de la diabetes mellitus tipo 2 en la infancia y adolescencia en las últimas décadas parece estar asociado al aumento de la incidencia de obesidad en las sociedades desarrolladas. El objetivo del estudio fue conocer la frecuencia de la intolerancia a la glucosa y de la diabetes tipo 2 en una población de niños y adolescentes obesos evaluados en un hospital. Pacientes y método: Estudio prospectivo de 145 pacientes obesos (60 varones con un índice de masa corporal [IMC] medio [desviación estándar] de 29,5 [4,9] kg/m2 y una puntuación z del IMC de 4,4 [1,7]; y 85 mujeres con IMC medio de 28,8 [4,6] kg/m2 y una puntuación z del IMC 3,8 [1,4] de edades comprendidas entre los 4 y 18 años, a quienes se les practicó un test de tolerancia oral a la glucosa (TTOG) entre 1998 y 2003. Los resultados del TTOG se evaluaron según los criterios de la Organización Mundial de la Salud y se calcularon parámetros de secreción y sensibilidad a la insulina (Homeostasis Model Assessment [HOMA], Quantitative Insuline Sensitivity Check Index [QUICKI]), área bajo la curva de glucemia, área bajo la curva de insulina e índice insulinogénico). Resultados: La frecuencia de la intolerancia a la glucosa fue del 19,2%. Sin embargo, ésta varió con la edad y el estadio puberal (prepuberal: 7,0%; puberal: 28,2%; pospuberal: 26,5%) y con el IMC (puntuación z del IMC entre +2 y +3: 8,9%; entre +3 y +4: 21,9%; mayor de +4: 25%). Ninguno de los pacientes cumplía criterios de diabetes tipo 2. Conclusiones: Los niños y adolescentes obesos de nuestro medio presentan una elevada incidencia de estados de intolerancia a la glucosa que parecen estar muy directamente relacionados con el grado de adiposidad

Background and objective: The rise in the prevalence of glucose intolerance and type 2 diabetes mellitus in childhood and adolescence in recent decades appears to be closely related to the increase in the incidence of obesity in developed countries. We decided to establish the frequency of glucose intolerance and type 2 diabetes mellitus in a population of obese children and adolescents evaluated at our hospital. Patients and method: Prospective study of 145 obese patients (60 boys: BMI 29.5 (4.9), BMI z score 4.4 (1.7); and 85 girls: BMI 28.8 (4.6), BMI z score 3.8 (1.4); age range: (4 - 18 years) who underwent an oral glucose tolerance test (OGTT) between 1998 and 2003. OGTT results were evaluated according to WHO criteria. Insulin secretion and sensitivity parameters (HOMA, QUICKI, area under the curve for glycemia, area under the curve for insulin and insulinogenic index) were also calculated. Results: The frequency of glucose intolerance in the whole population was 19.2%. However, this prevalence varied with age and maturation stage (prepuberty 7.0%, puberty 28.2% and postpuberty 26.5%), and with the obesity degree (BMI z-score between +2 and +3: 8.9%; between +3 and +4: 21.9% and higher than +4: 25%). No type 2 diabetes mellitus cases were observed. Conclusions: Obese children and adolescents display an elevated incidence of glucose intolerance which seems to be related to the degree of adiposity

[Secular growth changes. Weight, height and body mass index values in infant, children, adolescent and young adults from Barcelona population]. / Aceleración secular del crecimiento. Valores de peso, talla e índice de masa corporal en niños, adolescentes y adultos jóvenes de la población de Barcelona.

BACKGROUND AND OBJECTIVE: A secular trend in growth has been reported in developed countries. Our aim was to evaluate weight, height and body mass index values in a middle class sample of people from Barcelona and compare these values with those obtained before 1987. SUBJECTS AND METHOD: Height, weight and body mass index were evaluated in a) 268 male and 243 female newborns from normal gestations of 40 weeks, born in 2001 and 2002; b) 158 boys and 146 girls born during 1998-2000 and evaluated every 0.25-0.50 years from 0.25 to 3 years of age; c) 2,781 boys and 2,476 girls, aged 3-18 years, evaluated in 2002 and 2003, and distributed in 0.5 year intervals, and d) 394 males and 364 females, aged 18-24 years, evaluated in 2002 and 2003. RESULTS: Mean, standard deviation and percentiles values with 0.25-0.5 year-period intervals from birth to adulthood are reported. In comparison with data obtained before 1987 in Spanish populations, an increase of 3.5 cm was observed in adult height in both sexes as well as an increase of 7-8.3 kg in percentiles 3, 50 and 97 values in male adult weight with no significant differences in female adult weight. Moreover, pubertal growth spurt begins one year earlier in both boys and girls. Age of menarche (12.78 [1.30] years) was similar in our adult female population and in the female population evaluated before 1987. CONCLUSIONS: A secular trend in growth was observed in our population. There is a need to update periodically the growth data used in the evaluation of children and adolescents.

Aceleración secular del crecimiento. Valores de peso, talla e índice de masa corporal en niños, adolescentes y adultos jóvenes de la población de Barcelona / Secular growth changes. Weight, height and body mass index values in infant, children, adolescent and young adults from Barcelona population

FUNDAMENTO Y OBJETIVO: En las sociedades desarrolladas existe una aceleración secular del crecimiento. Nuestro objetivo ha sido valorar el crecimiento en una muestra de individuos de clase media de Barcelona y comparar los datos obtenidos con los de estudios realizados antes de 1987. SUJETOS Y MÉTODO: Valoración del peso, longitud e índice masa corporal en: a) 268 niños y 243 niñas recién nacidos a término de madres sanas, de gestaciones únicas de 40 semanas, medidos entre 2001 y 2002; b) 158 niños y 146 niñas de 3 meses de edad medidos durante 1998 y 2003 con intervalos de 3 a 6 meses durante los primeros 3 años de edad; c) 5.257 niños y adolescentes de 3 a 18 años de edad medidos durante 2002 y 2003, agrupados en intervalos de 6 meses de edad (2.781 varones y 2.476 mujeres), y d) 758 adultos jóvenes de 18 a 24 años de edad (394 varones y 364 mujeres) medidos durante 2002 y 2003. Se realizaron 8.649 valoraciones (4.571 en varones y 4.078 en mujeres). Todos estaban sanos, eran de raza caucásica y sus padres eran de origen español. RESULTADOS: Presentamos los valores de la media, la desviación estándar y los percentiles 3, 25, 50, 75 y 97 desde el nacimiento a la edad adulta, en intervalos de 3-6 meses, para el peso, la talla y el índice de masa corporal en cada sexo. En comparación con estudios anteriores a 1987 existe un incremento de 3,5 cm en los valores de los percentiles 3, 50 y 97 de la talla adulta en ambos sexos, y de 7-8,3 kg en los valores de los percentiles 3, 50 y 97 del peso de la población adulta masculina, sin diferencias importantes en los valores del peso de la población adulta femenina. El brote de crecimiento puberal se inicia en las poblaciones masculina y femenina actuales un año antes que en las valoradas antes de 1987. La edad media (desviación estándar) de la menarquia en nuestras adultas jóvenes a los 12,78 (1,30) años (n = 328) fue similar a la de la población evaluada antes de 1987. CONCLUSIONES: Con relación a estudios realizados antes de 1987, existe un incremento de la talla en ambos sexos y únicamente del peso en el sexo masculino. Nuestro estudio muestra la necesidad de actualizar periódicamente los datos de referencia utilizados en la valoración del crecimiento durante la infancia y adolescencia (AU)

[Association of vitamin D receptor gene polymorphism with type 1 diabetes mellitus in two Spanish populations]. / Asociación de los polimorfismos del gen del receptor de la vitamina D con la diabetes mellitus tipo 1 en dos poblaciones españolas.

BACKGROUND AND OBJECTIVE: In order to assess whether vitamin D receptor gene polymorphisms are involved in the genetic regulation of type 1 diabetes susceptibility, a case-control study was conducted in two Spanish populations with different genetic backgrounds. PATIENTS AND METHOD: 155 patients with childhood-onset type 1 diabetes and 280 healthy controls from Barcelona, and 89 patients and 116 controls from Navarre were studied for vitamin D receptor gene polymorphisms in peripheral blood DNA. Intron 8 (BsmI) and exon 2 (FokI) segments were amplified by PCR and sequenced to determine each corresponding genotype. Differences for allele, genotype and combined haplotype and genotype distribution between patients and controls within each population and between the two populations were analyzed. RESULTS: BsmI genotype and allele frequencies showed a tendency towards increased bb genotype and b allele frequencies in Barcelona patients and the tendency was inverse in Navarre. FokI polymorphism distribution analysis showed a significant decrease in ff genotype (p = 0.016) in patients versus controls from Navarre. Combined genotypes showed homozygous bb/FF genotype to be increased in Barcelona patients (p = 0.04) whereas homozygous bb/ff genotype was decreased in Navarre patients (p = 0.02) versus their corresponding controls. BF haplotype frequency distribution between patients and controls was inverse and significantly different between Barcelona and Navarre (p = 0.04). CONCLUSIONS: Combined genotypes for vitamin D receptor gene polymorphisms at intron 8 and exon 2 suggest that the more active form of vitamin D receptor gene (FF genotype) can be increased in Mediterranean diabetic patients whereas the less active form (ff genotype) can be decreased in those from Navarre. Our results suggest that, in both groups, the F allele of exon 2 VDR gene polymorphism may increase type 1 diabetes susceptibility.

Clinical and biochemical determinants of bone metabolism and bone mass in adolescent female patients with anorexia nervosa.

Among pathologies prevalent in western societies, anorexia nervosa has increased over the last decade. Its effects on bone mass need to be defined, and prognostic factors, either clinical or biochemical, could aid clinicians in individual patient management. To determine which clinical and/or biochemical parameters could be related to bone mass status in adolescent female anorexia nervosa patients, 73 female patients were classified according to different stages of their illness and studied in terms of clinical and biochemical parameters and bone densitometric mineral content at lumbar spine. Patients (age 17.2 +/- 1.7 y, mean +/- SD) with Tanner pubertal stage 5, regular menstruation for more than 3 mo before the onset of secondary amenorrhea, and diagnosed with anorexia nervosa were consecutively studied and classified in three clinical situations: I) active phase (34 patients): undernourished and amenorrheic; II) weight recovered but still amenorrheic (20 patients); III) fully recovered (19 patients). Clinical data were recorded at the time of bone density measurement, concomitant with blood sample extraction for study of IGF-I, IGF-binding protein 3 (IGFBP-3), IGFBP-1, estradiol, sex hormone-binding globulin, dehydroepiandrosterone sulfate, prealbumin, amino-terminal propeptide of procollagen III, osteocalcin, bone alkaline phosphatase, carboxy-terminal propeptide of procollagen I, amino-terminal propeptide of procollagen I, carboxy-terminal telopeptide of collagen I, 25-OH-vitamin D, 1,25(OH)(2)-vitamin D, and parathormone. In addition, a 24-h urine collection was made for cortisol, GH, deoxypyridinoline, amino-terminal telopeptide of collagen I, and calcium and creatinine content analysis. IGF-I, estradiol, and biochemical bone formation markers were higher and IGFBP-1, sex hormone-binding globulin, and biochemical bone resorption markers were lower in the weight-recovered stages (stages II and III) compared with the active phase (stage I). Bone formation markers correlated positively with body mass index SD score and IGF-I, whereas bone resorption markers correlated negatively with body mass index SD score and estradiol. Although no statistically significant differences regarding lumbar spine bone mineral density SD score values were recorded among the three stages of the illness, the proportion of osteopenic patients was clearly lower among stage III patients. The actual bone mineral density was inversely related to the duration of amenorrhea and directly related to duration of postmenarcheal menses before amenorrhea. In addition, a subset of osteopenic patients (five of 19) in the fully clinically recovered group with accelerated bone turnover was identified. Normal circulating estrogen level exposure time predicts actual bone mineral density at lumbar spine in young adolescent anorexia nervosa patients. In addition to psychiatric and nutritional interventions, estrogen-deprivation periods must be shortened to less than 20 mo. Patients remaining osteopenic at full clinical recovery require additional follow-up studies.