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      Clinical and Endocrine Characteristics in Atypical and Classical Growth Hormone Insensitivity Syndrome

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          Abstract

          Objective: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder ‘atypical’ GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. Methods: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. ‘classical’ required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), ‘atypical’ required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. Results: Fifty patients [24 males, 26 females, aged 8.6 ± 4.6 years (mean ± SD)] had ‘classical GHIS’, 9 patients (7 males, 2 females, aged 7.8 ± 4.1 years) had ‘atypical GHIS’, 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS –4.0 ± 1.4) compared to classical GHIS (–6.7 ± 1.4), less reduction in IGFBP-3 SDS (atypical –5.5 ± 3.3; classical –8.6 ± 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). Conclusions: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.

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          Most cited references 3

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          Insulin-Like Growth Factor-Binding Proteins in Serum and Other Biological Fluids: Regulation and Functions

           S. Rajaram (1997)
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            Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group.

            Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein. We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene. Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor. Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.
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              A dominant-negative mutation of the growth hormone receptor causes familial short stature.

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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
                2001
                2001
                03 September 2001
                : 55
                : 3
                : 125-130
                Affiliations
                Paediatric Section, St. Bartholomew’s Hospital, London, UK; Paediatric Endocrinology Centres contributing to European GHIS series (Birmingham, UK, Manchester, UK, Toulouse, France, Heidelberg, Germany, Stuttgart, Germany, Newcastle, Australia, Tehran, Iran, Riyadh, Saudia Arabia, Ankara, Turkey), and Growth Hormone Insensitivity Working Group (Tübingen, Germany, Lyon, France, London, UK, Portland, USA)
                Article
                49983 Horm Res 2001;55:125–130
                10.1159/000049983
                11549873
                © 2001 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.

                Page count
                Figures: 3, Tables: 3, References: 25, Pages: 6
                Categories
                Original Paper

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