Inherited Disorders of the Thyroid System PDF
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Inherited Disorders of the Thyroid System Geraldo Medeiros-Neto and John Bruton Stanbury Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2019 by CRC Press © 1994 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: Publisher's Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-0-367-22529-2 (hbk) ISBN 13: 978-0-429-27538-8 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com PREFACE The history of this book extends back nearly four and a half decades when a family of goitrous cretins with a defect in the organification of iodine in the thyroid gland was first described. Since then several inborn defects of thyroid hormone synthesis, delivery, and action have been reported. Many of the more common disorders of the thyroid system have been suspected to have a strong genetic underpinning. Accordingly, we thought that it would be useful to record the old and the new information about the inherited disorders of the thyroid in a single volume for easy reference for the thyroid specialist, for endocrinologists, for geneticists, and for the medical profession in general. Most of the reports of dyshormonogenesis were described during the 20 years follow- ing the initial publication in 1950. A quiescent period of a decade or two followed. More recently the techniques of molecular biology have made it possible to determine in many of the affected families the mutations of the DNA that are responsible for some of these defects in thyroid hormone production. The polymerase chain reaction as a primary tool and other newly introduced techniques have permitted the disclosure of the molecular changes corresponding to these defects and identification of both the homozygote and the carriers of the traits. Importantly, they have made it possible to explore the extensive polymorphism of some of these genetic defects, and have permitted rational genetic counseling for affected kindreds. Much more complex and still largely unresolved prob- lems remain regarding the polygenic nature of the common thyroid disorders, such as the autoimmune thyroid diseases and simple sporadic goiter. It will doubtless be necessary to await future developments in the Human Genome Project in order to have a clear picture of the genetic processes involved in these disorders. This book could not have been written without the collaboration of many colleagues around the world, many of whom have contributed enormously to the knowledge of the inherited disorders of the thyroid gland. We have sought and gained the collaboration of Samuel Refetoff of Chicago, Hector Targovnik of Buenos Aires, and Gilbert Vassart of Brussels. We are most grateful to them. We owe special appreciation to Meyer Knobel who contributed to the chapter dealing with the iodide transport defect and to Ana Elisa C. Billerbeck who contributed to the chapter on defective organification of iodide, and to Humberto Cavalière who was most helpful in providing new information on Pendred's syndrome. Fredric Wondisford made several suggestions on central hypothyroidism and the mutant TSH gene, and Bernardo Leo Wajchenberg contributed a number of suggestions and participated in numerous discussions of the recent findings at the molecular level. We also wish to thank our collaborators and fellows at the Thyroid Laboratory at the Hospital das Clinicas in São Paulo, Helio Bisi, Patricia S. Mattos, Nicolau Lima, Filippo Pedrinola, Ana Carla Goldberg, Katia Rego, Jussara Vono, Fernanda Barca, and our devoted staff personnel, Jacyra M. Lima, Valeria Lando and Maria Sylvia Cardia. We also wish to express our appreciation for the assistance of our secretaries, Maria Suzette Pott, Margarida Lemos, and the professionals who helped with the illustrative material. We also gratefully thank the São Paulo State Research Foundation (FAPESP), the National Research Council (CNPq), Klabin Irmãos & Cia, and individual donors for their generous financial support. Finally, we wish to acknowledge the patience and collaboration of those families of patients with defective thyroid hormonogenesis that made it possible for the clinical investigators to seek new information on pathophysiology and to pursue their goal of unveiling the molecular details of those genetic defects. Geraldo Medeiros-Neto, M.D. John B. Stanbury, M.D. THE AUTHORS Geraldo Medeiros-Neto, M.D., FACP, is Associate Professor of Endocrinology at the University of São Paulo Medical School and chief of the Thyroid Laboratory of the Hospital das Clinicas of the University of São Paulo Medical School, São Paulo, Brazil. Dr. Medeiros-Neto obtained his training at the University of São Paulo Medical School, São Paulo, Brazil, receiving the M.D. degree in 1959. After three years of internship and residence, he was granted the James Picker Foundation Clinical and Research Fellowship at the Thyroid Unit of the Massachusetts General Hospital, Harvard Medical School, under the guidance of John B. Stanbury. He stayed at this position for 2 years (1963-1964) returning to São Paulo in 1965 when he founded the Thyroid Laboratory at the Hospital das Clinicas. During his fellowship, he became interested in hereditary familial thyroid disorders and continued to work in this field in his own laboratory in São Paulo. For the past 30 years, an impressive number of families with dyshormonogenesis have been studied at the Thyroid Laboratory in São Paulo. Seven doctoral theses and many papers emerged from these studies. Dr. Medeiros-Neto is the author of more than 200 original papers in international medical journals and has been the editor, author, or co-author of eight books. He also authored 12 chapters in international and Brazilian textbooks. Dr. Medeiros-Neto is the founder of the Latin American Thyroid Society and served as its first president. He is a member of the Brazilian Endocrine Society, Endocrine Society (USA), American Thyroid Association, European Thyroid Association, Sociedade Medica de Chile and Société Française d' Endocrinologie. He was elected to the "Academia de Medicina" in São Paulo and is an honorary member of the "Academia de Medicina" in Santiago, Chile. He received many awards for his work including the international LATS award in 1980. Dr. Medeiros-Neto is on the Editorial Board of several national and international medical journals and is a member of the executive Committee of the International Council for Control of Iodine Deficiency Disorders (ICCIDD). His current major research inter- ests include the molecular pathogenesis of inherited disorders of the thyroid system, iodide deficiency disorders and their prevention, and clinical investigation of thyroid disease. John B. Stanbury, M.D., is Professor (emeritus) of Experimental Medicine, Massa- chusetts Institute of Technology and Honorary Physician at the Massachusetts General Hospital. He was director of the Thyroid Unit in the Department of Medicine, Massachu- setts General Hospital for many years. Dr. Stanbury graduated from Duke University and received his M.D. degree from Harvard in 1939. He received an honorary M.D. from the University of Leiden on the occasion of the 450th anniversary of the university in 1976, and was similarly cited at the University of Pisa on the 650th anniversary of that institution in 1994. He has received the medal of the Ministry of Health of Ecuador, the Fahrney medal of the Franklin Institute of Philadelphia, and is an honorary member of the faculty of the Central University of Ecuador, the University Cayatano Heredia of Peru, and of several others. He received the Prince Mahidol Award in January 1994 from the Government of Thailand. He is a member of the Endocrine Society, the American, Latin American, and European Thyroid Associations, the American Academy of Arts and Sciences, the Clinical and Climatological Society, and the American Association of Physicians, among others. He is chairman of the International Council for the Control of the Iodine Defi- ciency Disorders. Dr. Stanbury has traveled widely in pursuing his interest in diseases of the thyroid, including those arising from iodine deficiency, especially in Andean South America and Central Africa. He has published approximately 300 articles and books. He continues to be actively involved in the study of iodine deficiency and its prevention. CONTENTS Chapter 1 A Retrospective View of the Inherited Errors of the Thyroid System 1 References .5 Chapter 2 Familial Inherited TSH Deficiency ....7 Introduction ....7 Characterization of the Human Thyrotropin Subunit Gene ...7 Genetics 8 Clinical and Laboratory Findings 10 Molecular Biology 14 Analogy with Other Glycoprotein Mutations 15 Deficiency of Pituitary Transcription Factor-1 (PIT 1) 17 Summary ....20 References ........20 Chapter 3 Congenital Hypothyroidism Associated with Thyrotropin Unresponsiveness .....23 Introduction ..........23 The Thyrotropin Receptor ..................23 Animal Models 25 Human Studies .............28 Summary..... ..34 References ..34 Chapter 4 The Iodide Transport Defect ........37 Introduction .37 Clinical Aspects.... 39 Heredity ......46 Therapy 46 Concluding Remarks .....49 Summary.......... 49 References .........49 Chapter 5 Defective Organification of Iodide 53 Introduction 53 Incidence........ 53 Organification of Iodide and the Coupling Reaction 53 Molecular Cloning of TPO .........55 Assays of TPO Activity 57 Defective Organification of Iodide 58 Classification ..58 Clinical Findings .68 Laboratory Data.................. ........69 Biochemical Studies 71 Microscopic Examination 71 Molecular Genetics 71 Summary 74 References 75 Chapter 6 Pendred's Syndrome: Association of Congenital Deafness with Sporadic Goiter 81 Introduction 81 Clinical Studies 82 Laboratory Findings 83 Radioisotope Studies 83 Serum Thyroid Hormones 91 Ultrasonographic Studies 92 Sensitivity to Potassium Perchlorate 92 Genetics . 92 Thyroid Pathology 93 The Cochlear Defect 94 Decreased TPO Activity and Defective TG Structure 97 Molecular Biology..... 101 Summary 101 References 103 Chapter 7 Defects in Tg Gene Expression and Tg Secretion 107 Introduction 107 The Structure of Thyroglobulin and Synthesis of Thyroid Hormone 107 The Tg Gene: Structure, Expression, and Regulation 109 Animal Models of Defective Tg Synthesis 112 Hereditary Congenital Goiter in South Australian Merino Sheep 112 Hereditary Goiter of the Afrikander Cattle 112 Hereditary Goiter in Other Bovine Species 113 Hereditary Goiter of the Dutch Goats 113 Hereditary Goiter of the cog/cog Mice 116 Human Congenital Goiter with Defective Tg Synthesis 117 Clinical Features 117 Genetics 117 Prevalence 117 Laboratory Investigation and Diagnosis 117 Microscopic Examination 124 Biochemical Studies on Tissues with Defective Tg Synthesis 124 Molecular Biological Studies 128 Summary 131 References 131 Chapter 8 The Iodotyrosine Deiodinase Defect 139 Metabolism of the Iodotyrosines 139 Diiodotyrosine Deiodinase 140 The Iodotyrosine Deiodinase Defect: Case Reports 142 Additional Observations on Dehalogenase Deficiency 146 Genetics 149 Homozygotes .....149 Hétérozygotes 149 The Mechanism of the Deiodinase Defect 150 Molecular Biology ...151 Diagnosis of the Iodotyrosine Deiodinase Defect 151 Treatment .... 152 Summary 153 References 153 Chapter 9 The Syndromes of Reduced Responsiveness to Thyroid Hormone 161 Classification and the Clinical Findings .163 Generalized Resistance to Thyroid Hormone (GRTH) .....163 Diagnosis of GRTH 167 Diagnosis in the Fetal or Neonatal Period 168 Pituitary Resistance to Thyroid Hormone (PRTH) 168 Peripheral (Excluding Pituitary) Resistance to Thyroid Hormone 169 Treatment and Prognosis .................170 The Thyroid Hormone Receptor and the Molecular Basis for Thyroid Hormone Resistance 170 Mutations in the Genes for Thyroid Hormone Resistance 172 Summary ..174 References 175 Chapter 10 Inherited Abnormalities in Thyroid Hormone Transport Proteins .................... 179 Introduction .......179 Biosynthesis, Metabolism, and Molecular Genetics of Thyroid Hormone Transport Proteins 179 Thyroxine-Binding Protein .179 Transthyretin (TTR) 180 Inherited Abnormalities of Thyroxine-Binding Globulin (TBG) ....180 Complete TBG Deficiency (TBG-CD) 181 Partial TBG Deficiency 184 TBG Excess . ..186 Other TBG Variants 187 Genetic Defects Affecting Transthyretin (TTR) and Albumin..... 187 Familial Dysalbuminemic Hyperthyroxinemia (FDH) 188 Summary . 188 References 189 Chapter 11 Other Inherited Disorders of the Thyroid System 193 Introduction 193 The Autoimmune Thyroid Diseases 193 Familial Predisposition of AITD 194 Immunogenetics 195 Graves' Disease and Hashimoto's Thyroiditis 195 Animal Models ....197 Graves' Ophthalmopathy 199 Postpartum Thyroiditis 199 Simple Goiter (Sporadic) , 199 Medullary Thyroid Carcinoma ..200 Thyroid Carcinoma 200 Summary 202 References 202 Chapter 12 Thyroid Malignancy and Dyshormonogenetic Goiter 207 Introduction 207 The Pathology of Dyshormonogenetic Goiter 207 Thyroid Malignancy and Dyshormonogenetic Goiter 210 Summary 215 References 217 Index 219
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