Genetic Defects in Thyroid Hormone Supply

Immacolata Cristina Nettore; Gianfranco Fenzi; Paolo E Macchia

Genetic Defects in Thyroid Hormone Supply

Review

In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

2018 Jan 12.

Authors

Immacolata Cristina Nettore¹, Gianfranco Fenzi², Paolo E Macchia²

Book Editors

Kenneth R Feingold¹, Bradley Anawalt², Marc R Blackman³, Alison Boyce⁴, George Chrousos⁵, Emiliano Corpas⁶, Wouter W de Herder⁷, Ketan Dhatariya⁸, Kathleen Dungan⁹, Johannes Hofland¹⁰, Sanjay Kalra¹¹, Gregory Kaltsas¹², Nitin Kapoor¹³, Christian Koch¹⁴, Peter Kopp¹⁵, Márta Korbonits¹⁶, Christopher S Kovacs¹⁷, Wendy Kuohung¹⁸, Blandine Laferrère¹⁹, Miles Levy²⁰, Elizabeth A McGee²¹, Robert McLachlan²², Maria New²³, Jonathan Purnell²⁴, Rakesh Sahay²⁵, Amy S Shah²⁶, Frederick Singer²⁷, Mark A Sperling²⁸, Constantine A Stratakis²⁹, Dace L Trence³⁰, Don P Wilson³¹

Affiliations

¹ Università degli Studi di Napoli “Federico II”, Dipartimento di Medicina Cinica e Chirurgia, Via S. Pansini, 5. 80131 Napoli – ITALY
² Professor of Medicine Universit

Book Affiliations

¹ Professor of Medicine Emeritus, University of California, San Francisco, CA
² Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
³ Sr. Physician Scientist, Washington DC VA Medical Center; Professor of Medicine & Rehabilitation Medicine, Georgetown University; Clinical Professor of Medicine, Biochemistry and Molecular Medicine, George Washington University; and Professor of Medicine (Part-time), Johns Hopkins University
⁴ Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
⁵ Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
⁶ M.D. Ph.D in Gerontology. Honorary Professor of Medicine, Universidad de Alcalá, Madrid. Consultant in Endocrinology, Hospital HLA Guadalajara (Spain).
⁷ Professor of Endocrine Oncology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
⁸ Consultant in Diabetes, Endocrinology and General Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.
⁹ Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
¹⁰ Consultant Endocrinologist, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
¹¹ Consultant Endocrinologist, Department of Endocrinology, Bharti Hospital, Karnal, India
¹² Professor of General Medicine-Endocrinology, 1st Department of Propaedeutic Medicine, National and Kapodistrian University of Athens, Athens, Greece
¹³ Professor of Endocrinology, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College & Hospital, Vellore, Tamil Nadu, India, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Australia.
¹⁴ Professor, The University of Tennessee Health Science Center, Memphis, Tennessee
¹⁵ Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
¹⁶ Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
¹⁷ University Research Professor and Professor of Medicine (Endocrinology and Metabolism), Obstetrics & Gynecology, and BioMedical Sciences, at Memorial University of Newfoundland in St. John’s, Newfoundland, Canada.
¹⁸ Director of the Division of Reproductive Endocrinology at Boston Medical Center and an Associate Professor of Obstetrics and Gynecology at the Boston University School of Medicine
¹⁹ Professor of Medicine, New York Nutrition Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Consultant endocrinologist at University Hospitals of Leicester and Honorary Associate Professor at Leicester University
²¹ Professor of Obstetrics and Gynecology at the University of Vermont and Director of the Division of Reproductive Endocrinology and Infertility. Burlington, Vermont
²² Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
²³ Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Chief of the Adrenal Steroid Disorders Program, Icahn School of Medicine, Mount Sinai School of Medicine, New York, NY
²⁴ Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
²⁵ Professor and Head of Department of Endocrinology, Osmania Medical College and Osmania General Hospital, Hyderabad, India.
²⁶ Professor of Pediatrics, The University of Cincinnati, Department of Pediatrics and Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, OH, USA
²⁷ Director of the Endocrine/Bone Disease Program, Saint Johns Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
²⁸ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY. Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh.
²⁹ CSO, ELPEN, Inc. & Director, Research Institute, Athens, Greece & Senior Investigator, Human Genetics & Precision Medicine, FORTH (ITE), Heraklion, Greece. Emeritus Scientific Director & Senior Investigator, NICHD, NIH, Bethesda, MD, USA
³⁰ Professor of Medicine, Emeritus, University of Washington, Seattle, WA
³¹ Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX

PMID: 25905381
Bookshelf ID: NBK279158

Excerpt

Congenital hypothyroidism (CH) is the most frequent endocrine-metabolic disease in infancy, with an incidence of about 1/2500 newborns [1, 2]. In the last 20-30 years the incidence of congenital hypothyroidism in newborns has increased from 1:4000 to 1:2000 [3, 4]. This phenomenon could be explained by using a lower b-TSH cutoff, that allowed the detection of an unsuspected number of children with neonatal hypothyroidism [5]. With the exception of rare cases due to hypothalamic or pituitary defects, CH is characterized by elevated TSH in response to reduced thyroid hormone levels. In absence of an adequate treatment, CH determines growth retardation, delays in motor development, and permanent intellectual disability.

Primary CH is determined by alterations occurring during the thyroid gland development (thyroid dysgenesis, TD [6]) or alterations in the thyroid hormone biosynthesis pathways (thyroid dyshormonogenesis). Less common causes of CH are secondary or peripheral defects in TSH synthesis and/or action, defects in thyroid hormone transport, metabolism, or action [7]. Table 1 shows a summary of the forms of CH with a genetic cause.

In the majority of cases (80-85%), primary permanent CH is associated with TD. These forms include developmental disorders such as athyreosis, ectopy, hemiagenesis or hypoplasia.

TD occurs mostly as sporadic disease, however a genetic cause has been demonstrated in about 2-5% of the reported cases [8]. Genes associated with TD include several thyroid transcription factors expressed in the early phases of thyroid organogenesis (NKX2.1/TITF1, FOXE1/TITF2, PAX8, NKX2.5) as well as genes, like the thyrotropin receptor gene (TSHR) expressed later during gland morphogenesis.

In the remaining 15-20% of cases, CH is caused by inborn errors in the molecular steps required for the biosynthesis of thyroid hormones, and generally it is characterized by enlargement of the gland (goiter), presumably due to elevated TSH levels [9]. Generally, thyroid dyshormonogenesis shows classical Mendelian recessive inheritance.

Rarely CH has a central origin, as consequence of hypothalamic and/or pituitary diseases, with reduced production or function of thyrotropin releasing hormone (TRH) or thyrotropin hormone (TSH) [10]. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.

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