Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment.

BACKGROUND/AIMS: The term idiopathic short stature (ISS) describes short stature of unknown, but likely polygenic, etiology. This study aimed to identify genetic polymorphisms associated with the ISS phenotype, and with growth response to supplemental GH. METHODS: Using a case-control analysis we compared the prevalence of "tall" versus "short" alleles at 52 polymorphic loci (17 in growth-related candidate genes, 35 identified in prior genome-wide association studies of adult height) in 94 children with ISS followed in the Genetics and Neuroendocrinology of Short Stature International Study, versus 143 controls from the Fels Longitudinal Study. RESULTS: Four variants were nominally associated with ISS using a genotypic model, confirmed by a simultaneous confident inference approach: compared with controls children with ISS had lower odds of "tall" alleles (odds ratio, 95% CI) for GHR (0.52, 0.29-0.96); rs2234693/ESR1 (0.50, 0.25-0.98); rs967417/BMP2 (0.39, 0.17-0.93), and rs4743034/ZNF462 (0.40, 0.18-0.89). Children with ISS also had lower odds of the "tall" allele (A) at the IGFBP3 -202 promoter polymorphism (rs2855744; 0.40, 0.20-0.80) in the simultaneous confident inference analysis. A significant association with 1st-year height SD score increase during GH treatment was observed with rs11205277, located near 4 known genes: MTMR11, SV2A, HIST2H2AA3, and SF3B4; the latter, in which heterozygous mutations occur in Nager acrofacial dysostosis, appears the most relevant gene. CONCLUSIONS: In children with ISS we identified associations with "short" alleles at a number of height-related loci. In addition, a polymorphic variant located near SF3B4 was associated with the GH treatment response in our cohort. The findings in our small study warrant further investigation.

Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program.

BACKGROUND: GH has an insulin antagonist effect, and GH treatment has therefore been suggested to impair glucose metabolism and increase risk of diabetes mellitus. SETTING: Data from 11,686 GH-treated patients in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS), a multinational observational study of children with growth disorders, were analyzed for diabetes incidence. Baseline diabetes prevalence was determined from a GH-naive subgroup. METHODS: Prevalence and incidence (by standardized incidence ratio) were compared with results from patients aged less than 20 yr in the U.S. SEARCH for Diabetes in Youth study. RESULTS: Baseline type 1 diabetes prevalence per 1000 persons was 4.92 (95% confidence interval = 1.91-12.58) in GeNeSIS and 1.03 (0.97-1.10) in SEARCH for 0- to 9-yr-olds, and 7.33 (4.20-12.77) and 2.99 (2.78-2.98), respectively, for 10- to 19-yr-olds; there were no GeNeSIS cases of type 2 diabetes before GH initiation. During a median 1.8 yr of GH treatment, diabetes standardized incidence ratios for U.S. patients were 1.4 (0.5-3.1) for type 1 and 8.5 (2.8-19.5) for type 2, and for all patients was 1.4 (0.7-2.4) for type 1 and 6.5 (3.3-11.7) for type 2. Among the 11 patients with incident type 2 diabetes, risk factors for diabetes were identified in 10 patients. Glucose concentrations normalized for seven of nine patients for whom glycemic status could be determined (three of whom continued GH therapy and four who discontinued). CONCLUSION: The incidence of type 2 diabetes was higher in GH-treated children than the general population. Monitoring of glucose, before and periodically during GH treatment, is recommended for those with preexisting type 2 diabetes risk factors.