Laron Syndrome - From Man To Mouse Zvi Laron • John J. Kopchick (Editors) Laron Syndrome - From Man to Mouse Lessons from Clinical and Experimental Experience Editors Zvi Laron, MD John J. Kopchick, PhD Schneider Children’s Medical Center of Israel, Edison Biotechnology Institute and Endocrine Research Unit, Department of Biomedical Sciences, Kaplan Street 14, Ohio University, 49202 Petah Tikva, 1 Water Tower Drive, The Ridges, Sackler Faculty of Medicine, Athens, OH 45701, Tel Aviv University, USA Israel e-mail: [email protected] e-mail: [email protected] ISBN: 978-3-642-11182-2 e-ISBN: 978-3-642-11183-9 DOI: 10.1007/978-3-642-11183-9 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2010937974 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. 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In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) “I dedicate this book to the patients with Laron syndrome who heroically accepted many investigations to clarify their enigmatic disorder and subsequently to determine the therapeutic response to a new drug and to my devoted associates in our clinical and laboratory research” Zvi Laron “I would like to thank my ‘extended laboratory family, including undergraduate and graduate students, technicians, postdoctoral fellows, visiting scientists, and collaborators worldwide’” John J. Kopchick Preface It has been 50 years since the first family with Laron syndrome (LS, primary growth hormone (GH) insensitivity) was referred to the newly established Pediatric Endocrine Clinic at the Beilinson Hospital, Petah Tikva, Israel, a referral center now located at the Schneider Children’s Medical Center on the same campus. Since then, 64 patients have been diagnosed by the same team, investigated, and the majority followed by them, most at regular intervals, throughout childhood into adult age. This was the reason to base this book on the data accumulated from this cohort of patients forth- with called the Israeli cohort. It was also our privilege to be the first to determine its etiopathology and the first to study the effects of insulin-like growth factor-I (IGF-I) replacement therapy in these patients. The great amount of data accumulated during half a century in the large Israeli cohort of untreated and IGF-I treated LS patients is a unique source of knowledge which we thought should be shared and presented in a united manner. The clinical portion of this book represents a compendium of the Israeli team’s experience with LS from discovery, the struggle to define its pathogenesis, to deter- mine the consequences if not treated by IGF-I, and the results of long-term IGF-I treatment. Reference to studies by other investigators are included when found appropriate. During this 50 year-long journey, LS has proven to be a unique model to learn the effects of congenital IGF-I deficiency, the pharmacology of IGF-I, and the GH-IGF-I interrelationships. The fact that LS is a condition in which the action of pituitary GH is excluded permits the comparison between isolated GH deficiency and IGF-I defi- ciency as well as the comparison between the responses to IGF-I and hGH replace- ment therapies. To enable the comparison of findings in the same patient, we have identified certain patients by their initials. In an attempt to generate an animal model of LS (GH resistance/insensitivity and IGF-I deficiency), the GH receptor gene disrupted the “knock-out” mouse (or Laron Mouse) was produced in the Kopchick laboratory in 1991. Experiments that could not be carried out in humans could now be advanced in this GH insensitive mouse. We are happy to review the results of studies using these mice on aging, adipose tis- sue, reproduction, metabolism, and cancer. Also, tissue-specific effects on the brain, heart, and bone are reviewed. Thus, this book is a combination of data obtained in man on the Israeli cohort and the GHR−/−mouse. In each scenario, the action of GH is attenuated resulting in low levels of IGF-I. Similarities and differences between the mouse and human data are pointed out in Chapter 59. The data are both of academic as well as of practical clinical importance. vii viii Preface Professor Laron acknowledges all the early collaborators in the clinical studies, especially Prof. Athalia Pertzelan, Prof. Rivka Kauli, Dalia Peled, RN, Dr. Beatrice Klinger and Avinoam Galatzer, MA, (deceased), and Prof. Liora Kornreich. The con- tributions of the collaborators in our laboratory were crucial in elucidating the pathophysiology of the disease: immunology (Sara Assa, PhD), GH (Ruth Keret, MSc), IGF-I, and GHBP (Aviva Silbergeld, MSc), GH receptor (Rina Eshet, PhD) as well as our more recent collaborators in genetics and cancer (Orit Shevah, MSc) and (Pearl Lilos, MA, statistician). William H. Daughaday provided invaluable help in the early IGF-I (somatomedin-A) measurements and in the diagnosis of LS. John S. Parks collaborated in the early genetic evaluation. Thanks also to our coau- thors of the present text and Mrs. Gila Waichman and Mrs. Rachel Ronen (Endocrinology and Diabetes Research Unit) for their technical assistance in the preparation of the clinical manuscripts and Ms. Irit Lis, Ms. Shlomit Offman, and Mr. Howard Martel from the Medical Photography and Graphic Department, Rabin Medical Center, for their tremendous help during many years. We also wish to acknowledge the generous supply of IGF-I from Fujisawa Pharmaceuticals, Osaka, Japan. Professor Kopchick would like to cite his many colleagues over the years who helped with the work in the GH area. In particular, he is extremely proud of a young graduate student, Yihua Zhou, who first generated the mouse. Yihua went on to receive his PhD in Professor Kopchick’s laboratory and MD degree from Washington University in St. Louis. Additionally, Professor Kopchick would like to recognize his many students (both graduate and undergraduate), technicians, postdoctoral fellows, faculty colleagues, and visiting scientists who helped with the work. Also, through scientific collaborations involving this mouse, the Ohio University group has been able to make many international friends and colleagues, most of whom are cited in the following chapters. If for some reason we “missed” a publication, we are very sorry. Finally, Professor Kopchick would like to acknowledge the many funding sources that helped advance our studies including the Ohio Eminent Scholar Program (that includes a gift from Milton and Lawrence Goll), which provided funding for his endowed Professorship; and The Edison Biotechnology Institute, Molecular and Cellular Biology Program, Biomedical Sciences Department in the College of Medicine, Diabetes Research Initiative, and BioMolecular Innovation and Technology Partnership at Ohio University; NIH; USDA; and several corporate sponsors includ- ing Pfizer, Merck, Sensus, and DiAthegen. Last but not least, we wish to acknowledge the many people from Springer-Verlag GmbH, Berlin/Heidelberg, who assisted in the production of the book. Petah Tikva, Israel Zvi Laron Athens, Ohio, USA John J. Kopchick December 2009 Contents Part I Clinical Aspects 1 History of the Israeli Cohort of Laron Syndrome Patients (1958–2009) . 3 Zvi Laron 2 Early Investigations: Characterizations of the Circulating Growth Hormone . 9 Zvi Laron 3 Clinical Evidence of Growth Hormone Resistance in Patients with Laron Syndrome............................... 21 Zvi Laron 4 Diagnosis of Laron Syndrome.................................. 27 Zvi Laron 5 Genetic Aspects . 29 Orit Shevah and Zvi Laron 5.1 Genetic Investigations..................................... 29 Orit Shevah and Zvi Laron 5.2 Hypothesis of the Origin of Laron Syndrome . 47 Zvi Laron and Orit Shevah 5.3 Are the Pygmies Laron Syndrome Patients? . 50 Zvi Laron 6 Clinical Evaluation........................................... 53 Zvi Laron 7 Perinatal Development in Laron Syndrome . 59 Zvi Laron and Rivka Kauli 8 Linear Growth Pattern of Untreated Laron Syndrome Patients . 63 Zvi Laron and Rivka Kauli ix x Contents 9 Head Shape, Size, and Growth of Untreated Patients with Laron Syndrome........................ 91 Zvi Laron and Rivka Kauli 10 Sexual Development in Patients with Laron Syndrome ............. 101 Zvi Laron and Rivka Kauli 11 Sex Hormone Binding Proteins and Sex Hormones in Untreated and IGF-I Treated Patients with Laron Syndrome................. 119 Zvi Laron and Rivka Kauli