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      Compound Heterozygous and Homozygous Mutations of the TSHβ Gene as a Cause of Congenital Central Hypothyroidism in Europe

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          Abstract

          Background: Thyroid hormones are crucial for normal growth and central nervous system development. In recent years, germline variants of the TSHβ subunit gene have been identified as a cause of congenital TSH deficiency. Methods: We performed a genetic and clinical study in children from four European countries diagnosed with congenital isolated central hypothyroidism. Results: TSHβ gene analysis revealed compound heterozygosity for 145C→T (Q49X) and 313delT (C105Vfs114X) in 1 infant and homozygous mutation 313delT (C105Vfs114X) in 5 patients. Although all presented with typical symptoms of hypothyroidism, diagnosis and treatment was delayed until 3–5 months in 5 of 6 patients. In a longitudinal sibpair analysis, thyroxine substitution initiated immediately after birth was effective to prevent developmental delay and growth retardation. Conclusion: Clinical awareness is required to detect hypothyroidism due to TSHβ mutations, which is not identified by TSH-based newborn screening. TSHβ variants C105Vfs114X and Q49X are the most frequent cause of this severe disorder in Europe, now for the first time observed in compound heterozygous state.

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          Most cited references 15

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          Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.

          Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.
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            Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program.

            We examined the results of the Northwest Regional Screening Program (NWRSP) over its first 10 years to determine whether the detection of hypopituitary hypothyroidism is a justified advantage of the primary thyroxine (T4)-supplemental thyroid-stimulating hormone (TSH) screening strategy, and to determine whether all such infants will be detected by this screening approach. Between May 1975 and May 1985, the NWRSP screened 850,431 infants, detecting 192 infants with primary hypothyroidism (1:4429) and eight with hypopituitary hypothyroidism (1:106,304). In 11 additional infants, TSH deficiency, not detected by the screening program, was diagnosed on recognition of clinical features over the same period. Thyroid hormone treatment was begun in seven of the 11 infants prior to obtaining the screening sample results because of clinical symptoms of hypopituitarism, including hypoglycemia, persistent jaundice, microgenitalia, diabetes insipidus, midface hypoplasia, cleft lip or palate, or abnormalities of vision. The other four infants were not detected despite clinical features of hypopituitarism (in retrospect) and low serum T4 with TSH concentration below assay sensitivity on at least one screening sample. The most accurate assessment of total cases comes from Oregon, where all cases of congenital hypopituitarism are referred to our center; we estimate a frequency of 1:29,000. In our experience, a combination of newborn T4-supplemental TSH screening measurements and recognition of clinical features of hypopituitarism is the optimal strategy for detecting infants with congenital hypopituitary hypothyroidism.
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              A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene

               R Collu (1997)
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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
                2004
                September 2004
                10 September 2004
                : 62
                : 3
                : 149-155
                Affiliations
                aUniversity Children’s Hospital, University of Ulm, Ulm, Germany; bChildren’s Hospital Brabois, University of Nancy, Vandoeuvre, France; cUniversity Children’s Hospital, University of Zürich, Zürich, Switzerland; dChildren′s Hospital de San Joao, University of Porto, Porto, Portugal; eUniversity Children’s Hospital, University of Leipzig, Leipzig, fVestische Kinderklinik, University of Witten-Herdecke, Datteln, and gDepartment of Internal Medicine 1, University of Ulm, Ulm, Germany
                Article
                80071 Horm Res 2004;62:149–155
                10.1159/000080071
                15297803
                © 2004 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: 1, References: 25, Pages: 7
                Categories
                Original Paper

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