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      Idiopathic Growth Hormone Deficiency: A Vanishing Diagnosis?

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          Abstract

          Some non-organic causes for growth hormone (GH) deficiency (GHD) can be attributed to genetic defects within the hypothalamo-pituitary axis. Using modern molecular biology techniques micromutations within the GH and GH-releasing hormone receptor genes have been detected as a rare cause of isolated GHD. Combined pituitary hormone deficiencies (CPHD), on the other hand, are associated with defects that manifest during the organogenesis of the anterior pituitary gland. In recent years an increasing number of patients with CPHD has been reported, showing mutations within pituitary transcription factors Pit-1, Prop-1 and HesX1. Such defects can be observed with different frequencies in patients. Some disorders, such as CPHD due to Pit-1 mutations, display a hormonal phenotype that seems more or less invariable. In most other forms of genetic CPHD both the combination and severity of anterior pituitary hormone deficiencies vary considerably. Ongoing research concentrates on factors involved in the differentiation and proliferation of cells that belong to the hypothalamo-pituitary growth axis. As not every possible candidate turns out to be a frequent cause of GHD or CPHD in humans, it will be many more years before the term ‘idiopathic’ becomes a vanishing attribute to the clinical diagnosis of pituitary insufficiency.

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          Most cited references 10

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          Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1.

          Mutations at the mouse dwarf locus (dw) interrupt the normal development of the anterior pituitary gland, resulting in the loss of expression of growth hormone, prolactin and thyroid-stimulating hormone, and hypoplasia of their respective cell types. Disruptions in the gene encoding the POU-domain transcription factor, Pit-1, occur in both characterized alleles of the dwarf locus. The data indicate that Pit-1 is necessary for the specification of the phenotype of three cell types in the anterior pituitary, and directly link a transcription factor to commitment and progression events in mammalian organogenesis.
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            Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.

            The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.
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              Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.

              During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.
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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
                978-3-8055-7155-5
                978-3-318-00645-2
                1663-2818
                1663-2826
                2000
                August 2000
                17 November 2004
                : 53
                : Suppl 3
                : 1-8
                Affiliations
                Department of Paediatrics, RWTH Aachen School of Medicine, Aachen, Germany
                Article
                23524 Horm Res 2000;53(suppl 3):1–8
                10.1159/000023524
                10971095
                © 2000 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: 2, Tables: 1, References: 53, Pages: 8
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