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      Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models

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          The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.

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          Most cited references 60

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          A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone.

          Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this variation are entirely unknown. In two cohorts of short children treated with growth hormone, we found that an isoform of the growth hormone receptor gene that lacks exon 3 (d3-GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (P < 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001). One-half of Europeans are hetero- or homozygous with respect to the allele encoding the d3-GHR isoform, which is dominant over the full-length isoform. These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics.
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            Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables.

            Information about the expected growth response of children to GH therapy is currently inadequate. The aim of the study was to compare observed and expected growth in response to GH in prepubertal children and to propose how these parameters can be used to optimize GH therapy. Indices considered were observed growth, observed growth relative to reference data [height sd score (Ht SDS), change in (Delta) Ht SDS, height velocity (HV)], and observed growth relative to growth predicted from prediction models [Studentized residual (SR)]. Design/Setting/Patients/Intervention: Growth data from KIGS-Pfizer International Growth Database-on prepubertal children aged 1-13 yr with severe GH deficiency (GHD; maxGH <5 microg/liter; n = 2129), with less-severe GHD (maxGH of 5-10 microg/liter; n = 3075), and with Turner syndrome (n = 2350), and short children born small for gestational age (n = 993) were analyzed before and during 2 yr of GH treatment. For each patient group, growth responses during the first 2 yr of GH treatment were established. The relationships of HV and DeltaHt SDS with SR were determined. Reference data were generated for assessing adequate individual responses. Responses to GH in terms of HV and DeltaHt SDS were greatest in children with severe GHD. HV and DeltaHt SDS were highly correlated with SR during only the first year of GH treatment (R approximately 0.7; P < 0.001). Decisions on GH therapy regimens should be made using both traditional (HV or DeltaHt SDS) and prediction model-derived (SR) indices of growth response.
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              Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency.

              The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH). The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls. A randomized, controlled, long-term multicenter trial was conducted in Sweden. Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated. A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population. We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS. After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                June 2013
                27 May 2013
                : 79
                : 5
                : 257-270
                aDepartment of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; bPaediatric Endocrinology Section, Children's Hospital, University of Tübingen, Tübingen, Germany; cGöteborg Pediatric Growth Research Center (GP-GRC), Department of Pediatrics, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; dDepartments of Paediatrics and Paediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Autonomous University of Barcelona, CIBERER (Centre for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain; eDepartment of Pediatrics, Oregon Health and Science University, Portland, Oreg., USA; fTNO Quality of Life, Leiden, and gDepartment of Biostatistics, Utrecht University, Utrecht, The Netherlands; hDepartment of Pediatrics, Institute of Clinical Science, Umeå University, Umeå, Sweden; iDepartment of Pediatrics, University of Cologne, Cologne, Germany; jDepartment of Pediatric Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands; kDivision of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; lLilly Research Laboratories, Bad Homburg, Germany; mGoryeb Children's Hospital, Atlantic Health System, Morristown, N.J., nEthel Percy Andrus Gerontology Center, USC Davis School of Gerontology, University of Southern California, Los Angeles, Calif., USA; oMolecular Endocrinology Unit, ‘Bambino Gesù' Children's Hospital, Rome, Italy; pDepartment of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; qEndocrine Service, Hôpital Sainte-Justine, Université de Montréal, Montréal, Qué., Canada; rPaediatric Endocrinology, Royal Manchester Children's Hospital, and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK; sDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; tQuintiles Consulting, Hawthorne, N.Y., USA; uDepartment of Anthropogenetics, Vrije Universiteit Brussel, Brussels, Belgium
                Author notes
                *Dr. J.M. Wit, Department of Pediatrics, Leiden University Medical Center, NL-2300 Leiden (The Netherlands), E-Mail J.M.Wit@lumc.nl
                351025 Horm Res Paediatr 2013;79:257-270
                © 2013 S. Karger AG, Basel

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                Figures: 5, Tables: 3, Pages: 14
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