Laron Syndrome - From Man To Mouse

Zvi Laron • John J. Kopchick (Editors)

Laron Syndrome - From Man to Mouse

Lessons from Clinical and Experimental Experience

ISBN: 978-3-642-11182-2 e-ISBN: 978-3-642-11183-9DOI: 10.1007/978-3-642-11183-9Springer Heidelberg Dordrecht London New York

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EditorsZvi Laron, MDSchneider Children’s Medical Center of Israel, Endocrine Research Unit,Kaplan Street 14, 49202 Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University,Israele-mail: laronz@clalit.org.il

John J. Kopchick, PhDEdison Biotechnology Institute and Department of Biomedical Sciences, Ohio University, 1 Water Tower Drive, The Ridges, Athens, OH 45701, USAe-mail: kopchick@ohio.edu

“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

vii

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.

Preface

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 LaronAthens, Ohio, USA John J. KopchickDecember 2009

ix

Part I Clinical Aspects

1 History of the Israeli Cohort of Laron Syndrome Patients (1958–2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Zvi Laron

2 Early Investigations: Characterizations of the Circulating Growth Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Zvi Laron

3 Clinical Evidence of Growth Hormone Resistance in Patients with Laron Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Zvi Laron

4 Diagnosis of Laron Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Zvi Laron

5 Genetic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Orit Shevah and Zvi Laron

5.1 Genetic Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Orit Shevah and Zvi Laron

5.2 Hypothesis of the Origin of Laron Syndrome . . . . . . . . . . . . . . . . . 47Zvi Laron and Orit Shevah

5.3 Are the Pygmies Laron Syndrome Patients? . . . . . . . . . . . . . . . . . . 50Zvi Laron

6 Clinical Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Zvi Laron

7 Perinatal Development in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . 59Zvi Laron and Rivka Kauli

8 Linear Growth Pattern of Untreated Laron Syndrome Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Zvi Laron and Rivka Kauli

Contents

x Contents

9 Head Shape, Size, and Growth of Untreated Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 91Zvi Laron and Rivka Kauli

10 Sexual Development in Patients with Laron Syndrome . . . . . . . . . . . . . 101Zvi Laron and Rivka Kauli

11 Sex Hormone Binding Proteins and Sex Hormones in Untreated and IGF-I Treated Patients with Laron Syndrome. . . . . . . . . . . . . . . . . 119Zvi Laron and Rivka Kauli

11.1 Sex Hormone Binding Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119Zvi Laron

11.2 Sex Hormones in Untreated Patients with Laron Syndrome . . . . 121Zvi Laron and Rivka Kauli

12 The Adipose Tissue in Patients with Laron Syndrome. . . . . . . . . . . . . . 125Zvi Laron

13 Investigations to Determine the Cause of Obesity in Patients with Laron Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135Zvi Laron, Shira Ginsberg, and Nahum Vaisman

14 Nonalcoholic Fatty Liver Disease (NAFLD) in Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143Zvi Laron

15 Serum Lipids in Patients with Laron Syndrome. . . . . . . . . . . . . . . . . . . 149Zvi Laron

16 Adiponectin and Leptin in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . 157Zvi Laron and Hannah Kanety

17 Muscle Force and Endurance in Untreated Adult and IGF-I Treated Children with Laron Syndrome . . . . . . . . . . . . . . . . 161Zvi Laron

18 Bone Mineral Density in Untreated and IGF-I or Alendronate-Treated Patients with Laron Syndrome . . . . . . . . . . . . 165Zvi Laron

19 Muscle–Bone Relationship in Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Yoram Epstein, Amir Hadid, Zvi Laron, Daniel S. Moran, and Nahum Vaisman

19.1 Bone Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Yoram Epstein, Amir Hadid, Zvi Laron, and Daniel S.Moran

19.2 Lean Body Mass (LBM) in Patients with Laron Syndrome . . . . . 173Zvi Laron and Nahum Vaisman

Contents xi

20 Imaging Findings in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 175Liora Kornreich and Zvi Laron

21 Ocular Findings in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Dan H. Bourla and Dov Weinberger

22 Hearing in Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . 209Zvi Laron, Omer Zarchi, and Joseph Attias

23 The Teeth in Patients with Laron Syndrome. . . . . . . . . . . . . . . . . . . . . . 213Zvi Laron

24 Hair, Skin, and Nails in Patients with Laron Syndrome . . . . . . . . . . . . 219Zvi Laron

25 Hand, Foot, and Organ Size and Growth in Untreated and IGF-I Treated Patients with Laron Syndrome. . . . . . . . . . . . . . . . . 227Zvi Laron and Aviva Silbergeld

25.1 Hand Size and Growth of Untreated and IGF-I Treated Laron Syndrome Patients . . . . . . . . . . . . . . . . 227Zvi Laron

25.2 Foot Size and Growth in Untreated and IGF-I-Treated Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Zvi Laron and Aviva Silbergeld

25.3 Organ Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Zvi Laron

26 Lifelong Serum Growth Hormone Levels in Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Zvi Laron and Orly Efros

27 IGF-I Binding Proteins in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . 241Zvi Laron

28 Serum Prolactin in Untreated and IGF-I Treated Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247Zvi Laron and Orly Efros

29 Thyroid Hormones in Untreated and IGF-I Treated Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 255Zvi Laron and Rivka Kauli

30 Insulin Secretion and Carbohydrate Metabolism in Patients with Laron Syndrome: From Hypoglycemia to Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Zvi Laron

31 Liver Enzymes in Patients with Laron Syndrome . . . . . . . . . . . . . . . . . 273Zvi Laron and Tsvia Karmon

xii Contents

32 The Hematopoietic System in Patients with Laron Syndrome . . . . . . . 283Zvi Laron

33 Cardiovascular Aspects in Laron Syndrome Patients . . . . . . . . . . . . . . 293Mickey Scheinowitz, Micha S. Feinberg, Michael Shechter, Zvi Laron, and Rivka Kauli

33.1 Heart Functions in Untreated and IGF-I-Treated Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293Mickey Scheinowitz, Micha S. Feinberg, and Zvi Laron

33.2 Endothelial Function in Adults with Laron Syndrome (Primary Growth Hormone Insensitivity) . . . . . . . . . . . . . . . . . . . 298Michael Shechter and Zvi Laron

33.3 Intimal Thickness of the Extracranial Arteries in Untreated Adult Patients with Laron Syndrome . . . . . . . . . . . . . . 300Zvi Laron

33.4 Cardiovascular Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303Zvi Laron and Rivka Kauli

34 Kidney Functions in Untreated and IGF-I Treated Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 307Zvi Laron

35 Sleep and Sleep Disorders in Patients with Laron Syndrome . . . . . . . . 317Zvi Laron, Rivka Kauli, and Eyal Rosenzweig

35.1 Sleep Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317Zvi Laron and Rivka Kauli

35.2 Severe Obstructive Sleep Apnea (OSA) . . . . . . . . . . . . . . . . . . . . . 318Zvi Laron

35.3 Additional Polysomnographic Examinations of Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 318Eyal Rosenzweig and Zvi Laron

36 Neurological Aspects in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 321Zvi Laron

37 Orthopedic Problems in Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . 323Zvi Laron and Rivka Kauli

38 Psychological Aspects in Patients with Laron Syndrome. . . . . . . . . . . . 325Zvi Laron

39 Adjustment and Rehabilitation Problems of Children, Adolescents, and Adults with Laron Syndrome. . . . . . . . . . . 335Zvi Laron

40 Laron Syndrome Patients with Congenital IGF-I Deficiency Seem Protected from Malignant Diseases . . . . . . . . . . . . . . . 339Zvi Laron, Rachel Steuerman, and Orit Shevah

Contents xiii

41 Lifespan and Mortality of Patients with Laron Syndrome . . . . . . . . . . 341Zvi Laron

42 IGF-I Treatment of Patients with Laron Syndrome . . . . . . . . . . . . . . . . 343Zvi Laron

43 IGF-I Stimulation of Head Growth in Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381Zvi Laron

44 Effects of Long-Term Administration of IGF-I on the Adipose Tissue and Carbohydrate Metabolism in Children with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389Zvi Laron

45 Comparison of the Growth Promoting Response of IGF-I in Children with Laron Syndrome with that of hGH in Children with Isolated GH Deficiency . . . . . . . . . . . . . . 409Zvi Laron

46 IGF-I Treatment of Adult Patients with Laron Syndrome . . . . . . . . . . 413Zvi Laron

47 Adverse Effects Encountered During IGF-I Treatment of Patients with Laron Syndrome . . . . . . . . . . . . . . . . . . . . . 419Zvi Laron

48 Summary of the Clinical History: The Laron Syndrome Clock . . . . . . 425Zvi Laron

Part II The Growth Hormone Receptor “Null” Mouse or the Laron Mouse

49 The Laron Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429John J. Kopchick and John D. Blischak

50 Role of GH/IGF-I Deficiency in Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . 433Edward O. List

51 Body Composition, Adipose Tissue, and Energy Balance . . . . . . . . . . . 441Darlene E. Berryman

52 Metabolism and Metabolic Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . 451Lucila Sackmann-Sala, D. R. Bailey Miles, and John J. Kopchick

53 Skeletal Muscle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465Juan Ding and John J. Kopchick

xiv Contents

54 Cardiac Function in GHR−/− Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473Diana Cruz-Topete and John J. Kopchick

55 Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481Shigeru Okada and Jacob Wright-Piekarski

56 GHR Knockout and the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489Elahu S. Gosney and John J. Kopchick

57 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495Brian D. Bower and John J. Kopchick

58 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507Bruce Kelder

59 Conclusions and Future Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513John J. Kopchick, Hiroyoshi Tanda, Darlene Berryman, and Zvi Laron

Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525