Increased height standard deviation scores in response to growth hormone therapy to near-adult height in older children with delayed skeletal maturation: results from the ANSWER Program

Abstract

BackgroundA primary goal of recombinant human growth hormone therapy (GHT) in children is attaining normal adult height. In this study, children with growth hormone deficiency (GHD) (including isolated idiopathic growth hormone deficiency [IGHD] and multiple pituitary hormone deficiency [MPHD]), idiopathic short stature (ISS), and Turner syndrome (TS) were evaluated for near-adult height (NAH) and percent achieving NAH within the normal range after approximately 4 years of GHT.MethodsData from the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program were analyzed for NAH from age at treatment start (ATS) (i.e., referral age as defined by age at enrollment in the study) to last clinic visit using one of the following two criteria: 1) age ≥18 years, or 2) if male: ≥16 years and height velocity (HV) <2 cm/year; if female: ≥15 years and HV <2 cm/year. All patients had a baseline height standard deviation score (HSDS) ≤ -2, and either GHD (n = 201), ISS (n = 19), or TS (n = 41). The main outcome measures included HSDS and corrected HSDS (HSDS-target HSDS) in response to GH treatment, and correlation of ATS with NAH HSDS.ResultsMean (± SD) chronological and bone ages at baseline were 14.0 ± 2.1 years and 11.7 ± 2.0 years, respectively, and mean GHT duration was 4.0 ± 1.6 years. Mean HSDS (baseline to NAH; GHD: -2.7 to -1.0; ISS: -2.8 to -1.4; TS: -3.0 to -1.8) and mean corrected HSDS (baseline to NAH; GHD: -2.1 to -0.3; ISS: -2.1 to -0.6; TS: -1.8 to -0.6) increased across diagnostic indications. Percentages of patients reaching near-adult HSDS > -2 were GHD: 87.6%; ISS: 78.9%; TS: 65.8%. Significant negative correlations were found between ATS and NAH HSDS when analyzed by sex.ConclusionsDespite a relatively advanced childhood age, the majority of GH-treated patients attained mean near-adult HSDS within the normal range (HSDS > -2). Negative correlations of ATS with near-adult HSDS indicate that an earlier age at treatment start would likely have resulted in greater adult height achieved in both male and female patients.

The Fitness Consequences of Aneuploidy Are Driven by Condition-Dependent Gene Effects

“…We identified appropriate segregants by genotyping and then used chemostat competition experiments to determine the independent fitness effects of each evolved mutation ( Fig 2 and S2 Table ). More than half of the mutations examined showed either neutral/near-neutral (<5%) fitness increase or negative effects on fitness, agreeing with previous reports that genetic hitchhiking is quite important for the spectrum of mutations observed in asexually evolving populations [ 33 , 34 ]. In particular, the supernumerary chromosome isolated from evolved clone S8c2, despite occupying 13% of the S8 population, actually decreased the fitness of clones carrying it by 10% ( Fig 2 ).…”

“…Second, we expected there to be fewer suppressor mutations, which are commonly selected for in a homozygous or haploid deletion background to ameliorate the effects of the deleted gene [ 41 , 42 ]. Importantly, we were only able to take advantage of the yeast heterozygous deletion collection in this way because our lab had previously determined a set of 2,254 strains from this collection that have neutral fitness, with a range of relative fitnesses from -0.05 to 0.04, under our standard chemostat growth conditions of sulfate-, glucose-, and phosphate-limitation ( S4 Table ) [ 34 ]. Thus, by restricting our method to these 2,254 deletion collection strains and the limitations under which they have neutral fitness, we can be reasonably confident that any fitness effects we do measure are due to the Tamp itself and not the underlying genetic background.…”

“…As expected, our results demonstrated that Tamps containing SUL1 increased fitness under sulfate-limiting conditions ( Fig 5A ). In addition to SUL1 , a second driver gene had previously been identified within this 60 kb region: BSD2 amplification increases fitness under sulfate-limiting conditions [ 34 ]. Data from this targeted Tamp screen identified both BSD2 and SUL1 as driver genes under sulfate-limiting conditions.…”

Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty

“…In a variety of prospective/retrospective, randomized/non-randomized, and controlled/ non-controlled trials, some researchers concluded that GH treatment improved ISS while others considered it ineffective. The efficacies in these studies varied dramatically [12][13][14][15][16][17][18]. Some meta-analyses showed that GHtreated ISS patients might gain more FAH than untreated children, but were still shorter than the normal populations.…”

“…Height standard deviation score (HtSDS) = (actual height − average height for children of the same sex and age) ÷ (SD of the heights for children of the same sex and age) [11]. TH (i.e., mid-parental target height) was as follows: FAH was defined as follows: age at the last follow-up was > 15 years, height velocity was below 1 cm/year, and the GH therapy had been discontinued [12].…”