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.

Mutations in the GH receptor gene have been identified as the cause of growth hormone insensitivity syndrome (GHIS), a rare autosomal recessive disorder. We studied the clinical and biochemical characteristics and the coding sequence and intron-exon boundaries of the GH receptor gene in a consanguineous family with severe short stature which consisted of two patients, their parents and five siblings. The two adolescents had heights of -4.7 and -5.5 SDS, respectively, with elevated growth hormone associated with low IGF-I, IGFBP-3 and GHBP concentrations. Molecular analysis of the GH receptor gene revealed a mutation in exon 6, present in both patients This mutation, Ε180 splice, has been previously described in an Ecuadorian cohort, and in one Israeli and six Brazilian patients. We determined the GH receptor haplotypes based on six polymorphic sites in intron 9. Co-segregation of the E180splice mutation with haplotype Ϊ was found in this family, compatible with a common Mediterranean ancestor, as shown for previous cases with the E180splice mutation described to date.

Background. In recent years worldwide, there has been an increase in childhood obesity together with an advance in the age at which puberty begins in girls; however, in boys the evidence has been controversial (i.e. Crocker MK JCEM 2014, Lee JM pediatrics 2016). Objective. To determine whether total and central body obesity in pre-pubertal children evaluated since age 4 is associated with precocious puberty through the measurement of testicular volume. Methods. We included 527 boys for the Growth and Obesity Cohort Study longitudinal cohort. The anthropometric measures (weight, height, waist circumference) were registered and Body Mass index SDS calculated. Trained personnel valuated the onset of puberty through a Prader Orchidometer and precocious puberty was defined as reaching a testicular volume greater than 3 cc before 9 years of age in any of the testicles. The association between obesity (total body adiposity and central body adiposity) and precocious puberty, were analyzed through logistic regression models and the Odds Ratio (OR) and 95% confidence interval (CI) were estimated. Results. There was an increase in BMI SDS and prevalence of total obesity and central obesity through the years :at 6 - 7 yr, 0.99±1.32 SDS and 22.0% & 11.8 % respectively, and at Tanner 2 ,age 11.4±1.4 yr (n = 494) , 1.15±1.22 SDS and 28.6 % & 17.4% respectively. Forty ive boys initiated puberty before 9 yrs (9.1%). A positive and statistically significant association was found between total body obesity and precocious puberty from 4 to 7 years of age (i.e. between 5 and 6 years of age, OR: 2.68 95% CI: 1.09 - 6.57) and at the time of pubertal onset OR: 3.59 95% CI: 1.92 - 6.70. When analyzing BMI SDS as a continuous variable, the association remained positive and significant at birth and from 4 to 8 years of age and at the time of pubertal onset. Likewise, a positive and significant association was found between central obesity and precocious puberty from 4 to 7 years of age (example between 5 and 6 years, OR: 6.36 95% CI: 2.03-19.92). Conclusions. Total and central body obesity in boys aged 4 to 7 years is associated with earlier puberty. Our observation supports the association of adiposity and earlier pubertal events in Chilean boys. Early puberty might increase the risk of behavior problems. In addition, it has been postulated that precocious puberty in boys, could be related to higher incidence of testicular cancer in adulthood. Our results suggest that controlling the obesity epidemic could be useful in decreasing these risks. Additional studies are needed to understand the possible relationships among race/ethnicity, gender, BMI, and the timing of pubertal development

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Some, but not all, women develop hypothalamic amenorrhea (HA) in association with exercise and/or food restriction. We hypothesized that variants in genes associated with the more severe hypogonadotropic disorder, idiopathic hypogonadotropic hypogonadism (IHH), may contribute to a given woman’s susceptibility to HA when she is faced with a physiologic stressor. Indeed, rare sequence variants (RSVs) in IHH-associated genes were previously identified in women with HA that were absent in controls 1 . This study, however, used a variant-level, as opposed to the now preferred gene-level, approach and only examined 7 genes. To build upon these earlier findings and provide more definitive support for our hypothesis, we screened 106 women with HA and 477 controls for RSVs in a much larger IHH-gene panel (n=54 genes) using exome sequencing. Healthy controls were a convenience sample drawn from the ClinSeq Project 2 who had originally been selected for a range of atherosclerosis risk phenotypes, but were unselected for reproductive phenotypes. We compared the frequency of RSVs (moderate- to high-impact, minor allele frequency [MAF] < 1%) across all 54 genes in HA compared with controls using a rare variant burden test (Fisher’s exact test. We identified 54 heterozygous RSVs (51 missense, 1 nonsense, 2 frameshift; 27.4% of alleles) in 46 HA women (1-3 RSVs/woman, 58 total RSVs, 12 subjects with >1 RSV) and 149 heterozygous RSVs (141 missense, 1 nonsense, 4 frameshift, 3 inframe indels; 18.8%) in 146 control women (1-4 RSVs/woman, 179 total RSVs, 28 subjects with >1 RSV) which represents a significantly increased burden of RSVs in HA ( P = 0.006). A slightly greater proportion of RSVs in the HA group were considered damaging/deleterious by both Polyphen2 and SIFT vs controls (41.1% vs 36.0%), but this was not statistically significant. Thus, women with HA are significantly enriched for RSVs in genes that cause IHH as compared with controls. These results indicate that the risk of developing HA with exposure to physiologic stressors may indeed be increased in the presence of heterozygous protein-altering variants in genes related to the regulation of GnRH neuronal development and function. 1 Caronia LM, et al . N Engl J Med. 2011;364:215-25. 2 Biesecker LG, et al . Genome Res. 2009;19:1665-74. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.