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      Metabolic Control and Growth during Exclusive Growth Hormone Treatment in X-Linked Hypophosphatemic Rickets

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          Abstract

          Background: GH may improve phosphate balance and height in X-linked hypophosphatemic rickets (XLH). This study evaluated the impact of exclusive rhGH therapy on phosphate homeostasis and growth. Methods: Ten children (median age 12.2 years) with XLH were included in a 12-month trial with GH. Conventional treatment was discontinued 1 month prior GH (0.033 mg/kg/day); 1α-hydroxyvitamin D was added at 6 months and oral phosphate at 12 months, when GH was discontinued. Patients were followed 1–3 monthly until 18 months for clinical, biochemical and radiographic parameters. Results: Serum phosphate Z-score increased significantly from baseline at 6 months (p = 0.005) and 9 months (p = 0.009) but returned to baseline by 12 months. Serum 1,25-dihydroxyvitamin D also increased significantly. Parathyroid function normalized. The median height Z-score was –2.2 (–2.7 to +0.4) at GH onset and –1.7 (–2.3 to +0.3) at 12 months. One patient showed a significant increase in radiographic rickets activity and 3 patients aggravation of lower limb deformity; the others showed no changes or improvement in these parameters. Conclusions: GH treatment improved serum phosphate and 1,25-dihydroxyvitamin D, normalized parathyroid function and improved longitudinal growth in XLH. It may however aggravate pre-existing skeletal deformities.

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          Most cited references23

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          A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium.

          X-linked hypophosphatemic rickets (HYP) is a dominant disorder characterised by impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules. By positional cloning, we have isolated a candidate gene from the HYP region in Xp22.1. This gene exhibits homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones. This gene (which we have called PEX) is composed of multiple exons which span at least five cosmids. Intragenic non-overlapping deletions from four different families and three mutations (two splice sites and one frameshift) have been detected in HYP patients, which suggest that the PEX gene is involved in the HYP disorder.
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            Effects of therapy in X-linked hypophosphatemic rickets.

            Patients with X-linked hypophosphatemic rickets, which is clinically manifested by growth failure and bowing of the legs, are usually treated with phosphate and a vitamin D preparation. However, the efficacy of this treatment has been disputed, and nephrocalcinosis is a recognized complication of therapy. We studied 24 patients with X-linked hypophosphatemic rickets (9 boys and 15 girls) ranging in age from 1 to 16 years (median, 5.3). The duration of combination therapy ranged from 0.3 to 11.8 years (median, 3.0). We measured height as a standard-deviation (SD) score (the number of SDs from the mean height for chronologic age). Measurements made before the age of two years or after the onset of puberty were excluded. We compared the results with those reported in 1971 for 16 untreated prepubertal Australian patients. We also determined the severity of nephrocalcinosis (on a scale of 0 to 4, with 0 indicating no abnormalities and 4 stone formation) with renal ultrasonography and whether it could be related to the dosage of phosphate or vitamin D or to other factors. Patients treated for at least two years before the onset of puberty (n = 19) had a mean height SD score of -1.08, as compared with -2.05 in the untreated historical controls. The 13 patients who had been treated with calcitriol and phosphate for at least two years had an increase in the mean height SD score of 0.33, from -1.58 to -1.25 (95 percent confidence interval, 0 to 0.67; P = 0.05). Nineteen of the 24 patients (79 percent) had nephrocalcinosis detected on renal ultrasonography. The grade of nephrocalcinosis was significantly correlated with the mean phosphate dose (r = 0.60, P = 0.002), but not with the dose of vitamin D or the duration of therapy. All patients had normal serum creatinine concentrations. Therapy with calcitriol and phosphate may increase the growth of children with X-linked hypophosphatemic rickets. Nephrocalcinosis in these children represents a complication of therapy and is associated with the dose of phosphate received.
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              The roles of specific genes implicated as circulating factors involved in normal and disordered phosphate homeostasis: frizzled related protein-4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 23.

              Normal serum phosphate (Pi) concentrations are relatively tightly controlled by endocrine mediators of Pi balance. Recent data involving several disorders of Pi homeostasis have shed new light on the regulation of serum Pi balance. It has been hypothesized that circulating phosphaturic factors, or phosphatonins, exist that, when present at high serum concentrations, directly act on the kidney to induce renal Pi wasting. This review will focus upon recently discovered factors that are overexpressed in tumors associated with tumor-induced osteomalacia and have reported activity consistent with effecting Pi balance in vivo. Currently, the best-characterized group of phosphatonin-like polypeptides includes secreted frizzled related protein-4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor-23. Our understanding of these factors will, in the short term, aid us in understanding normal Pi balance and, in the future, help to design novel therapeutic strategies for disorders of Pi handling.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2008
                April 2008
                21 January 2008
                : 69
                : 4
                : 212-220
                Affiliations
                aHospital for Children and Adolescents, Pediatric Endocrinology and Metabolic Bone Clinic; Departments of bClinical Radiology, and cClinical Genetics, Helsinki University Hospital, Helsinki, Finland, and dHospital for Sick Children, Division of Endocrinology, University of Toronto, Toronto, Ont., Canada
                Article
                113021 Horm Res 2008;69:212–220
                10.1159/000113021
                18204268
                7415a301-bac1-4644-990e-e8ea2d8c5ceb
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. 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.

                History
                : 06 February 2007
                : 17 May 2007
                Page count
                Figures: 2, Tables: 3, References: 36, Pages: 9
                Categories
                Original Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Metabolic control,Growth hormone,IGF-I,Rickets,Hypophosphatemia

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