Study of Ras/MAPK pathway gene variants in Chilean patients with Cryptorchidism.

Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty-nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high-resolution melting (HRM) analysis followed by sequencing. Restriction or allele-specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.

Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism.

Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty-nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs.

Pseudoautosomal abnormalities in terminal AZFb+c deletions are associated with isochromosomes Yp and may lead to abnormal growth and neuropsychiatric function.

STUDY QUESTION: Are copy number variations (CNVs) in the pseudoautosomal regions (PARs) frequent in subjects with Y-chromosome microdeletions and can they lead to abnormal stature and/or neuropsychiatric disorders? SUMMARY ANSWER: Only subjects diagnosed with azoospermia factor (AZF)b+c deletions spanning to the end of the Y chromosome (i.e. terminal deletions) harbor Y isochromosomes and/or cells 45,X that lead to pseudoautosomal gene CNVs, which were associated with abnormal stature and/or neuropsychiatric disorders. WHAT IS KNOWN ALREADY: The microdeletions in the long arm of the Y chromosome (Yq) that include the loss of one to three AZF regions, referred to as Yq microdeletions, constitute the most important known etiological factor for primary spermatogenic failure. Recently, controversy has arisen about whether Yq microdeletions are associated with gain or loss of PAR genes, which are implicated in skeletal development and neuropsychiatric function. STUDY DESIGN, SIZE, DURATION: We studied a cohort of 42 Chilean patients with complete AZF deletions (4 AZFa, 4 AZFb, 23 AZFc, 11 AZFb+c) from a university medical center, diagnosed over a period of 15 years. The subjects underwent complete medical examinations with special attention to their stature and neuropsychiatric function. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects were characterized for Yq breakpoints by PCR, and for CNVs in PARs by multiplex ligation-dependent probe amplification (MLPA), followed by qPCR analysis for genes in PAR1 (SHOX and ZBED1), PAR2 (IL9R) and two single copy genes (SRY and DDX3Y, respectively located in Yp11.3 and AZFa). In addition, karyotypes revision and fluorescence in situ hybridization (FISH) for SRY and centromeric probes for X (DXZ1) and Y (DYZ3) chromosomes were performed in males affected with CNVs. MAIN RESULTS AND THE ROLE OF CHANCE: We did not detect CNVs in any of the 35 AZF-deleted men with interstitial deletions (AZFa, AZFb, AZFc or AZFb+c). However, six of the seven patients with terminal AZFb+c deletions showed CNVs: two patients showed a loss and four patients showed a gain of PAR1 genes, with the expected loss of VAMP-7 in PAR2. In these patients, the Yq breakpoints localized to the palindromes P8, P5 or P4. In the four cases with gain of PAR1, qPCR analysis showed duplicated signals for SRY and DDX3Y and one copy of IL9R, indicating isodicentric Yp chromosomes [idic(Y)] with breakpoint in Yq11.22. The two patients who had loss of PAR1, as shown by MLPA, had an additional reduction for SRY and DDX3Y, as shown by qPCR, associated with a high proportion of 45,X cells, as determined by FISH and karyotype. In agreement with the karyotype analysis, we detected DYZ3++ and DYZ3+ cells by FISH in the six patients, confirming idic(Y) and revealing additional monocentric Y chromosome [i(Y)]. Five patients had a history of major depressive disorders or bipolar disorder, and three had language impairment, whereas two patients showed severe short stature (Z score: -2.75 and -2.62), while a man with bipolar disorder was very tall (Z score: +2.56). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The number of males studied with Y-chromosome microdeletions and normozoospermic controls with normal karyotypes may not be enough to rule out an association between AZF deletions and PAR abnormalities. The prevalence of Y isochromosomes and/or 45,X cells detected in peripheral blood does not necessarily reflect the variations of PAR genes in target tissues. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that CNVs in PARs were present exclusively in patients with terminal AZFb+c deletions associated with the presence of Y isochromosomes and 45,X cells, and may lead to neuropsychiatric and growth disorders. In contrast, we show that men with interstitial Yq microdeletions with normal karyotypes do not have an increased risk of PAR abnormalities and of phenotypical consequences. Moreover, our results highlight the importance of performing molecular studies, which are not considered in the usual screening for patients with Yq microdeletions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Fund for Scientific and Technological Development of Chile (FONDECYT), grant no. 1120176 (A.C.). The authors declare that no conflicting interests exist.

Oestrogen activity of the serum in adolescents with Type 1 diabetes.

AIMS: To assess serum oestrogen levels and oestrogenic activity in adolescents with Type 1 diabetes compared with a healthy control group. METHODS: We conducted a cross-sectional study that evaluated adolescents with Type 1 diabetes (n = 38) and healthy adolescents (control group; n = 32). Serum oestrogens, urinary oestrogen metabolites and serum oestrogenic activity were assessed. Oestrogenic activity was evaluated in an in vitro cell proliferation assay using a modified E-screen assay with MCF-7/BUS cells. RESULTS: Adolescents with Type 1 diabetes had lower oestrogenic activity levels in both phases of the menstrual cycle compared with the control group (follicular phase: 76 vs 94%; luteal phase: 97 vs 131%; P < 0.01), even after adjusting for BMI, oestradiol and oestrone levels. Postmenarcheal adolescents with Type 1 diabetes had lower oestradiol levels compared with control subjects in the follicular phase (63.3 pmol/l vs 89.4 pmol/l; P < 0.01) and higher oestrone levels compared with controls in the luteal phase (196 vs 151.9 pmol/l; P < 0.05). CONCLUSIONS: Adolescents with Type 1 diabetes had lower levels of serum oestrogenic activity, and these were lower than expected based on their serum oestradiol levels. We postulate that changes in the serum milieu of oestrogens in patients with Type 1 diabetes may explain their decreased oestrogenic activity and may play a role in their adverse metabolic profile.

C-Reactive protein and insulin growth factor 1 serum levels during the menstrual cycle in adolescents with Type 1 diabetes.

AIMS: To evaluate C-reactive protein, insulin growth factor 1 and lipid levels during the follicular and luteal phases in adolescents with Type 1 diabetes. METHODS: Adolescents with Type 1 diabetes (N = 40) and healthy controls (C; N = 43) were studied during the follicular and luteal phases of their menstrual cycles. C-Reactive protein, insulin growth factor 1 and lipid levels were measured. RESULTS: Adolescents with Type 1 diabetes exhibited higher C-reactive protein levels than the C group during the follicular (P < 0.0001) and luteal phases (P < 0.01). The elevation of C-reactive protein levels was more pronounced in overweight adolescents with Type 1 diabetes than in adolescents in the C group. More adolescents with Type 1 diabetes were classified as having an elevated risk of cardiovascular disease (C-reactive protein > 3 mg/l) in the luteal phase than in the follicular phase (37.5% and 17.5%, respectively); half of the overweight adolescents with Type 1 diabetes in the luteal phase reached this level. BMI was the only significant factor affecting follicular and luteal phase C-reactive protein levels in adolescents with Type 1 diabetes. Lower insulin growth factor 1 levels were observed during both phases of the menstrual cycle in adolescents with Type 1 diabetes compared with controls. An elevation in insulin growth factor 1 levels in the luteal phase relative to the follicular phase was observed in controls, but not in adolescents with Type 1 diabetes. Luteal insulin growth factor 1 and C-reactive protein exhibited an inverse correlation (r = -0.4, P = 0.01). CONCLUSIONS: Adolescents with Type 1 diabetes have higher C-reactive protein levels and lower insulin growth factor 1 levels relative to controls, especially during the luteal phase. Type 1 diabetes diminishes the natural elevation in insulin growth factor 1 levels observed during the luteal phase in controls. Excess weight exacerbates the subclinical inflammatory state observed during both phases of the menstrual cycle in adolescents with Type 1 diabetes.

Polymorphisms of MAMLD1 gene in hypospadias.

PURPOSE: Mastermind-like domain containing 1 (MAMLD1) is a causative gene for the fetal development of male external genitalia. Almost 10% of patients with both severe and non-severe hypospadias exhibit mutations of MAMLD1. The aim of this work was to determine whether polymorphisms of MAMLD1 are a genetic risk factor for hypospadias. MATERIAL AND METHODS: This study included 150 hypospadias with a range of severities and 150 controls. Direct sequencing of the MAMLD1 coding exons and their flanking splice sites was performed. In silico secondary and tertiary structure prediction and accessibility of changed amino acids were evaluated using JPred, Netsurf and PHYRE software. Functional studies of the transactivation of haplotypes on Hes3 promoter were performed in vitro using cDNAs of missense variants of MAMLD1. RESULTS: The p.P286S polymorphism was identified in 17/150 patients and 12/150 controls (11.3% vs. 8.0%, p = 0.32). The p.N589S polymorphism was identified in 22/150 patients and 12/150 controls (14.6% vs. 8.0%, p = 0.068). The double polymorphism (S-S haplotype) was present in 16/150 patients and 6/150 controls (10.6% vs. 4.0%, p = 0.044, OR = 2.87, CI from 1.09 to 7.55). The association of polymorphisms consistently revealed a modification in the structure prediction or amino acid accessibility in all three in silico models. The P286S, N589S and P286S + N589S proteins did not exhibit reduced transactivating activity on Hes3 promoter. CONCLUSION: Polymorphisms of MAMLD1 gene are frequent in patients with hypospadias. Although no change in transactivation was noted on Hes3 promoter, the in silico studies and the significantly increased incidence of the S-S haplotype in hypospadiac patients raise the hypothesis of a particular susceptibility conferred by these variants.

Expression and protein content of IGF-I and IGF-I receptor in placentas from small, adequate and large for gestational age newborns.

In humans, a direct relationship between IGF-I cord blood levels and birth weight has been demonstrated. To determine the placental IGF-I, IGF-II and IGF-IR mRNA and protein contents in full-term pregnancies from appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA) newborns, we studied the placentas from 35 AGA, 30 SGA and 28 LGA pregnancies. The IGF-I, IGF-II and IGF-I receptor (IGF-IR) placental mRNA and protein contents were determined in the basal and chorionic plates of the placenta. IGF1 and IGF1R mRNA was higher in SGA compared to AGA and LGA placentas and lower in LGA compared with AGA placentas. In addition, a higher protein content of IGF-I and IGF-IR was observed in SGA compared with AGA and LGA placentas and lower contents in LGA compared with AGA placentas. These results suggest that the higher IGF-I and IGF-IR contents observed in SGA placentas and the lower contents observed in LGA placentas compared with AGA placentas may be influencing human fetal growth.

Deficiencia somatotrófica en niños: características clínicas y bioquímicas según la etiología en 75 casos / Somatotrophic deficiency in children: report of 75 cases

Somatotrophic deficiency (SDMT) can be due to a deficiency of growth hormone releasing hormone(GHRH), growth hormone (GH) or insulin like growth factor I (IGF-I). Although its clinical features have been thoroughly described, the diagnosis is still controversial. Now there is an effective treatment with GH or IGF-I for these patients. AIM: To analyze the main clinical, etiological and laboratory characteristics of 75 SD patients (44 males), aged 9.4 + 4.5 years, with severe growth retardation. The diagnosis was confirmed by the lack of response to two GH stimulation tests (Clonidine, Glugagon or Insulin) and low levels of IGF-I or insulin-like growth factor binding protein- 3 (IGFBP-3). RESULTS: In 34 patients (46 percent), the cause of DSMT was considered idiopathic (DSMT-I), in 31 (41 percent) there was an organic cause (DSMT-O), most commonly caused by malformations or pituitary tumors and in 10 (13 percent), it was genetic (DSMT-G) (three patients with Laron's Syndrome, five with mutations of GH gene and 2 with probable mutations of Prop-1 and Pit-1 genes). IGF-1 levels, were significantly lower in DSMT-O and DSMT-G thanin DSMT-I (21.2 +/- 46.1, 23.4 +/-30.3 ng/mL and 50.2 +/- 48.3 ng/mL, respectively). The lowest height score corresponded to DSMT-G, compared to DSMT-O and DSMT (­5.7 +/- 0.9, -4.0 +/- 1.6 and ­4.3 +/- 1.2 DS, respectively) CONCLUSIONS: The high percentage of organic and genetic etiologies in our patients can be due to the systematic search of these diseases. DSMT-G (Laron, mutations in GH and Pit-1 genes) had the most severe growth retardation.

Treatment of central precocious puberty with triptorelin 11.25 mg depot formulation.

A new triptorelin 11.25 mg long depot formulation is now available for the treatment of central precocious puberty (CPP). The aim of our study was to evaluate the efficacy of triptorelin 11.25 mg administered every 90 days to suppress gonadotropin and sex steroid secretion and pubertal signs in children with CPP during 2 years of treatment. Inclusion criteria were clinical pubertal development before the age of 8 years in girls or 9 years in boys, advanced bone age and a pubertal LH response (peak >5 mIU/ml) to GnRH. We studied 20 patients (19 girls and 1 boy), with a median age at entry into the study of 7.5 +/- 0.2 years for girls, and 9 years for the boy. The basal and GnRH-stimulated serum levels of LH and FSH decreased significantly from baseline to 3 months of therapy (p <0.0001). All patients had a GnRH-stimulated peak below 3 mIU/ml between 6 and 24 months of treatment. The pituitary-gonadal axis recovered adequately after discontinuation of therapy. These results suggest that 3-month depot triptorelin is a satisfactory alternative for the therapy of children with CPP. The longer interval between injections may increase acceptability and compliance with treatment.

Posibilidades terapéuticas en talla baja idiopática / No disponible

No disponible

Study of GH sensitivity in chilean patients with idiopathic short stature.

We hypothesized that some children with idiopathic short stature in Chile might bear heterozygous mutations of the GH receptor. We selected 26 patients (3 females, 23 males) from 112 patients who consulted for idiopathic short stature at the University of Chile. Their chronological age was 8.3 +/- 1.9, and bone age was 6.1 +/- 1.0 yr. Their height was -3.0 +/- 0.7 SDS; IGF-I, -1.2 +/- 1.1 SD; IGF binding protein 3, -0.7 +/- 2.0 SDS; and GH binding protein, 0.4 +/- 0.8 SDS. Patients were admitted, and blood samples were obtained every 20 min to determine GH concentrations overnight. Coding sequences and intron-exon boundaries of exons 2-10 of GH receptor gene were amplified by PCR and subsequently analyzed through single-strand conformational analysis. Mean serum GH concentration, over 12-h, was 0.20 +/- 0.08 nM; pulse amplitude, 0.40 +/- 0.15 nM; number of peaks, 5.8 +/-1.5 peaks/12 h; peak value of GH during the 12-h sampling, 1.03 +/- 0.53 nM; and area under the curve, 151.4 +/- 56.1 nM/12 h. There were positive correlations between mean GH vs. area under the curve (P < 0.001) and GH peak (P < 0.01). The single-strand conformational analysis of the GH receptor gene showed abnormal migration for exon 6 in 9 patients and for exon 10 in 9 patients, which (by sequence analysis) corresponded to 2 polymorphisms of the GH receptor gene: an A-to-G transition in third position of codon 168 in exon 6 and a C-to-A transversion in the first position of codon 526 in exon 10. We further sequenced all coding exons and intron-exon boundaries in the most affected patients (nos. 6, 9, 11, 14, 15, 16, and 23). This analysis revealed a C-to-T transition in codon 161 of exon 6 in patient 23, which results in an amino acid change (Arg to Cys) in an heterozygous form in the patient and his father. In conclusion, the results of our study suggest that, in Chilean patients with idiopathic short stature, GH receptor gene mutations are uncommon, although we cannot exclude mutations that were missed by single-strand conformational analysis or mutations within introns or in the promoter regions of the GH receptor gene.

Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children.

Ibutamoren mesylate (MK-0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH-releasing hormone receptor. We evaluated the safety and tolerability and the GH-insulin-like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 +/- 0.8 years (mean +/- SD), bone age of 7.4 +/- 0.7 years, growth velocity < 10th percentile for age, height < 10th percentile for age, and a maximum GH response of < or = 10 microg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1-7 or 8-14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8-14, group III). On day 15 all patients received an 0.8-mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day -1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 microg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 microg x h/L (range, 1.3 to 35.6) for the GH area under the concentration-time curve from time zero to 8 hours (AUC(0-8)) (P < .001), 12 microg/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 microg/L (range, -0.9 to 1.5) for serum IGF-binding protein 3 (IGFBP-3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24-hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short-term administration of ibutamoren mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.

[Reference values of growth hormone binding protein (GHBP) for a normal pediatric population]. / Valores de referencia para proteína transportadora de hormona de crecimiento en una población pediátrica normal.

UNLABELLED: Circulating concentrations of the high affinity growth hormone binding protein (GHBP) may be a marker of GH receptor density as well as GH sensitivity. GOAL: To determine values of GHBP for a normal Chilean pediatric population. METHODS: We determined GHBP levels in 73 males and 73 females between 4 to 15.5 years and 4 to 16.8 years respectively, divided in 7 groups according to age and puberal status. RESULTS: The population was normally distributed in weight, height and body mass index (BMI). GHBP activity increased up to Tanner IV in males and Tanner III in females, and decreased slightly thereafter in Tanner V and IV respectively. There was a significant difference between GHBP levels of preschool children and those found in Tanner II to V in both sexes (p < 0.05). In addition, we found a positive correlation between GHBP vs weight, height and BMI (p < 0.001) in males and females. CONCLUSION: The availability of this methodology allows us to establish the normative value of GHBP in our population and provides useful information to interpret GH circulating levels in children with growth disorders.

[Possible perinatal determinants of morbidity in adult age]. / Posibles determinantes perinatales de morbilidad en la edad adulta.

Recently, several groups have studied the influence of possible noxious elements present in the intrauterine environment which may favor the development of several diseases in the adult. There is evidence of an increased prevalence of some disorders in special risk groups of fetuses. In the small for gestational age patient, a form of "programming" may occur which produce metabolic changes in the fetus in response to malnutrition. There are several other associations described, but in most of them the precise pathogenic mechanisms involved have not been elucidated. In this article we present evidence of several disorders which develop in the adult and their relationship with conditions during fetal life. Finally, we offer some recommendations to diminish these risks.

[Clinical and molecular study of Chilean patients with McCune-Albright syndrome]. / Estudio clínico-molecular de pacientes chilenas con síndrome de McCune-Albright.

BACKGROUND: McCune-Albright Syndrome (MAS) is characterized by precocious puberty, "cafe au lait" skin lesions and polyostotic fibrous dysplasia. It is caused by 4 post-zygotic mutations of G alpha s protein with a mosaic distribution. AIM: To describe the clinical presentation and to investigate the presence of the Arg by his substitution (R201H) in 14 girls with MAS. PATIENTS AND METHODS: We performed a clinical analysis of the patients and specific allele PCR in DNA obtained from leukocytes. RESULTS: Twelve of 14 patients presented with precocious puberty, one with cyclical vaginal bleeding and one with pathological bone fractures. Eight girls had polyostotic fibrous dysplasia, one had hyperthyroidism, four had pathological fractures, ten had ovarian cysts, six had breast hyperpigmentation and ten had "cafe au lait" skin lesions. We detected the R2O1H mutation in 10 of 14 patients. We found no difference in the severity of symptoms or in the age of presentation between the patients with and without the mutation. CONCLUSIONS: The R201H mutation can be detected in white blood cells, in approximately 70% of cases. Patients exhibit wide clinical variability with the same molecular defect. This suggests that tissues have different proportions of mutant cells.

Relationship between serum growth hormone binding protein levels and height in young men.

The biochemical mediators responsible for variations in stature among normal subjects are largely unknown. To obtain some initial information about potential endocrine factors, we measured the serum concentrations of GH, IGF-1, IGFBP-3 and GHBP in healthy young men shorter than 159 cm and taller than 187 cm. We studied 14 volleyball and basketball players (tall group), and 14 jockey students from a horse racetrack (short group). A careful medical history was taken, including dietary intake, and physical examination with special attention to the possible presence of genetic stigmata was performed. Serum prealbumin was determined as an index of nutritional status. A buccal smear was performed to exclude Klinefelter's syndrome. The BMI and serum prealbumin levels were comparable in both groups of individuals. The nutritional survey, however, revealed that the tall subjects had a higher intake of calories (42.2+/-11.2 vs. 30.1+/-15.15 kcal/kg, p<0.05), and protein (1.5+/-0.6 vs. 0.8+/-0.4 mg/kg, p<0.01). Serum concentrations of GHBP did not differ in the two groups (0.95+/-0.37 nmol/l in the tall, and 0.95+/-0.53 nmol/l in the short group), and did not correlate with height, serum IGF-I levels, or BMI. We observed a significant difference in the serum concentrations of IGF-I in the two groups of individuals (42.02+/-9.37 nmol/l in the tall and 31.79+/-3.18 nmol/l in the short group, p<0.05), and this growth factor showed a positive correlation with height (r = 0.5, p<0.01). These preliminary findings suggest that final height differences in young men do not appear to be mediated by variations in GHBP concentrations.

Near final height in pubertal growth hormone (GH)-deficient patients treated with GH alone or in combination with luteinizing hormone-releasing hormone analog: results of a prospective, randomized trial.

To study the effects of delaying puberty in GH-deficient (GHD) children, we studied 21 GHD (9 boys, 14 girls), treatment-naive, pubertal patients in a prospective, randomized trial. Their chronological age was 14.3 +/- 1.6 yr, and their bone age was 11.3 +/- 1.1 yr (mean +/- SD) at the beginning of the study. Four patients who developed hypogonadotropic hypogonadism were subsequently excluded from the study. Patients were randomly assigned to receive GH + LH-releasing hormone analog (LHRH-A) (n = 7), or GH alone (n = 10). GH and LHRH-A treatment started simultaneously in each patient. GH (Nutropin) was administered at a dose of 0.1 U/kg x day sc, until patients reached a bone age (BA) of 14 yr in girls and 16 yr in boys, and LHRH-A (Lupron depot) was administered at a dose of 300 microg/ kg every 28 days in during 3 yr. We defined GH deficiency as patients with a growth velocity less than 4 cm/yr, BA delay more than 1 yr in relationship to chronological age, GH response to two stimulation tests less than 7 microg/L, associated with low serum insulin-like growth factor I and insulin-like growth factor binding protein 3 levels. Statistical analysis was performed by ANOVA or Kruskall Wallis when variances were not homogeneous. We observed a significant decrease in the rate of BA maturation in the group treated with GH+LHRH-A (1.5 +/- 0.2 yr) compared with the group treated with GH alone (4.2 +/-0.5 yr) during the 3 years of LHRH-A therapy (P < 0.05). This delay in BA maturation produced a significant gain in final height in the group treated with GH+LHRH-A, which reached - 1.3 +/- 0.5 SD score compared with -2.7 +/- 0.3 SD score (P < 0.05) in the group treated with GH alone. These results indicate that delaying puberty with LHRH-A in GHD children during treatment with GH increases final height.

[Usefulness of the measurement of insulin-like growth factor (IGF-I) and IGF-1 binding protein-3 (IGFBP-3) for the diagnosis of growth hormone (GH) deficiency in children]. / Utilidad de la determinación del factor de crecimiento insulino-simil tipo I (IGF-I) y de su proteína ligante tipo 3 (IGFBP-3) en el diagnóstico de la deficiencia de hormona de crecimiento en niños.

BACKGROUND: The diagnosis of GH deficiency (GHD) is based upon the results of GH stimulation tests, which have several drawbacks. AIM: To evaluate the usefulness of IGF-1 and IGFBP-3 for the diagnosis of GHD in prepuberal children. MATERIAL AND METHODS: We measured IGF-I and IGFBP-3 in three group of subjects: I. GHD (n: 24), height < -2SD for age (Z score, average +/- SD: -4.2 +/- 1.2), growth velocity < p10 (3.4 +/- 1.0 cm/year) and peak GH level on two GH stimulation tests < 7 ng/ml (1.2 +/- 0.6 ng/ml); II. Short non-GHD (NGHD, n: 32), height of -2.7 +/- 0.9 SD for age, growth velocity < p 25 (3.9 +/- 1.2 cm/year), and peak GH level on two GH stimulation tests > 7 ng/ml (15.3 +/- 6.9 ng/ml), y III. Normal school children (n: 35) with normal heights (-0.17 +/- 0.12 SD) were studied as controls. RESULTS: IGF-1 and IGFBP-3 were significantly lower in GHD than in NGHD and controls (p < 0.001), and in NGHD than in C (p < 0.001). We defined the normal range of both proteins as +/- 2 SD of the mean of the control group. Using this criteria, IGF-I was low in 21/24 GHD, and in 12/32 NGHD. IGFBP-3 was low in 22/24 GHD, and in 6/32 NGHD. Only 1 GHD patient had both exams in the normal range, suggesting that he is probably NGHD. 4/32 of the NGHD and both exams below normal range, suggesting that they are probably GHD. CONCLUSIONS: IGF-1 and IGFBP-3 are important tools for the diagnosis of GHD.

Trace minerals in human growth and development.

Trace mineral deficiencies may affect several biological functions in humans, including physical growth, psychomotor development and immunity. We have reviewed the mechanisms whereby several trace mineral deficiencies may affect these biological functions at different ages (fetal life, infancy, childhood and adolescence), as well as the evidence supporting this association. We describe the effects of zinc deficiency on the hormonal regulation of growth and sexual development in both humans and animal models. We provide data regarding the effects of iron deficiency on growth and psychomotor development. We mention the effects of copper, manganese, selenium and iodine deficiencies on growth and development. We conclude that iron deficiency may affect psychomotor development, but does not appear to affect growth. Zinc deficiency may cause growth retardation and psychomotor delay.

Trace minerals in human growth and development.

Trace mineral deficiencies may affect several biological functions in humans, including physical growth, psychomotor development and immunity. We have reviewed the mechanisms whereby several trace mineral deficiencies may affect these biological functions at different ages (fetal life, infancy, childhood and adolescence), as well as the evidence supporting this association. We describe the effects of zinc deficiency on the hormonal regulation of growth and sexual development in both humans and animal models. We provide data regarding the effects of iron deficiency on growth and psychomotor development. We mention the effects of copper, manganese, selenium and iodine deficiencies on growth and development. We conclude that iron deficiency may affect psychomotor development, but does not appear to affect growth. Zinc deficiency may cause growth retardation and psychomotor delay.