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      Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

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          Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years’ height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, −2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was −1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was −1.51 (0.60) (154.90 [3.21] cm) in females and −1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ −2. Adverse drug reactions and GH-unrelated serious adverse events ( n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ –2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

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          Noonan syndrome.

          Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Short stature in Noonan syndrome: response to growth hormone therapy.

            Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. To assess the short and long term response to GH therapy in patients with Noonan syndrome. Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this post-marketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. Data on 66 patients (54 males) were available for study. At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from -2.9 pretreatment to -2.6 after one year and -2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range -1.1 to 6.5 cm). GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of effect; initial indications are that final height is not improved substantially in most patients.
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              The NordiNet® International Outcome Study and NovoNet® ANSWER Program®: rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hormone therapy (Norditropin®)

              Objective Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. Design The NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web Enabled Research (ANSWER Program®) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. Patients The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. Measurements The studies gather long-term data on the safety and effectiveness of reallife treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. Conclusion The NordiNet® IOS and ANSWER Program® studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                February 2021
                13 January 2021
                : 93
                : 6
                : 380-395
                aDepartment of Pediatric Endocrinology, University Children’s Hospital, Saarland University Medical Center, Homburg, Germany
                bDiabetes and Endocrine Center, Children’s Hospital & Clinics of Minnesota, Saint Paul, Minnesota, USA
                cCincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
                dEpidemiology, Novo Nordisk A/S, Søborg, Denmark
                eDepartment of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom
                fDepartment of Paediatrics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
                gDepartment of Paediatrics, Haukeland University Hospital, Bergen, Norway
                hDepartment of Health Registry Research and Development, National Institute of Public Health, Bergen, Norway
                iDepartment of Clinical Science, University of Bergen, Bergen, Norway
                jMedical Affairs, Novo Nordisk Inc., Princeton, New Jersey, USA
                kGlobal Medical Affairs, Novo Nordisk Health Care AG, Zurich, Switzerland
                lPaediatric Endocrinology, Diabetology and Gynaecology Department, Necker Children’s University Hospital, Imagine Institute, Paris, France
                mDepartment of Pediatrics, New York Medical College, Valhalla, New York, USA
                nNemours DuPont Hospital for Children and Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
                oPediatric Endocrinology, Karolinska University Hospital and Department of Women´s and Children´s Health, Karolinska Institutet, Solna, Sweden
                pPediatric Endocrinology, University of Minnesota Masonic Children’s Hospital, Minneapolis, Minnesota, USA
                Author notes
                *Tilman R. Rohrer, Department of Pediatric Endocrinology, University Children's Hospital, Saarland University Medical Centre, Kirrberger Strasse, DE–66421 Homburg/Saar (Germany), tilman.rohrer@uks.eu
                512429 Horm Res Paediatr 2020;93:380–395
                © 2021 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 2, Pages: 16
                Research Article


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