Table Of ContentInherited
Disorders
of the
Thyroid
System
Geraldo Medeiros-Neto
and
John Bruton Stanbury
Boca Raton London New York
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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
