HUMAN CYTOGENETICS CLINICAL CYTOGENETICS JOHN L. HAMERTON DEPARTMENT OF MEDICAL GENETICS CHILDREN'S HOSPITAL OF WINNIPEG WINNIPEG, MANITOBA, CANADA Volume II 1971 A C A D E M IC P R E SS New York and London COPYRIGHT © 1971, BY ACADEMIC PRESS, INC. ALL RIGHTS RESERVED NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, RETRIEVAL SYSTEM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS. ACADEMIC PRESS, INC. Ill Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. Berkeley Square House, London W1X 6BA LIBRARY OF CONGRESS CATALOG CARD NUMBER: 70-107559 PRINTED IN THE UNITED STATES OF AMERICA FOREWORD Those who were involved in the beginning of the modern phase of human cytogenetics never fail to be surprised and delighted by the quan- tity and variety of discoveries made in a field which burgeoned hardly more than a dozen years ago. New techniques and the successful adap- tation of older ones, augmented by the application of principles derived from developments in genetics (especially plant and animal cytogenetics) to human investigations, have resulted in rapid advances. On the technical side, these developments were foreshadowed by the methods of Chrust- schoff and Berlin and by the work of Hsu and Pomerat, but the really important advances came with the use of metaphase-blocking and chromosome-spreading devices and with the greater accessibility of experimental material. It therefore became possible to apply these practical methods to the study of promising "clinical" areas which had heretofore been examined by "inspired guess," "prescience," or by "beckoning indicators" —genetic, cytological, clinical, or epidemiological. Later, simplication of the techniques permitted the extension of cyto- gentic work to human populations and here, especially, we are dealing with work in progress, as we are where the study of human chromosomes is helping linkage and mapping. It is here that we are particularly con- cerned with the difficult problem of chromosome identification. This work, in two volumes, is an accumulation of data on subjects as diverse as abnormal sex and soma development, sex determination and mental subnormality, dermatoglyphics and stature, gene and chromosome action, and chromosome behavior—both normal and abnormal, which only yesterday were practically uncharged territories of human genetics and which only now have reached a stage where synthesis and generali- zation begin to be possible. Dr. Hamerton has undertaken the heavy and difficult travail of bringing together this information in one source. He ix χ FOREWORD has adopted the symbolic designation of the human karyotype and shorthand notation devised by the Chicago Conference. He has been able to draw heavily on the results recorded over the years from clinical and survey cytological studies performed in the Paediatric Research Unit at Guy's Hospital. When faced with clinical descriptions and with the problems and difficulties of clinical terminology and classification, Dr. Hamerton has, in my opinion, succeeded in presenting a balanced view. Possibly not every clinical worker will agree with every statement made in this work, but the author has given references to a sufficient number of original works and reviews to allow the reader to make up his own mind on controversial issues. At the same time he has set out to provide a good deal of the fundamental theoretical and practical considerations on which the more applied aspects of human cytogenetics, with its host of clinical implications, must be based if the subject is not to be a sterile listing of deviant events. This book has been carefully planned and well written. I am con- fident that it will prove useful not only to the student of human genetics but also to those clinicians whose work brings them in close contact with, and who require an explanation of, cytogentic principles and facts, and who need a guide to the original works on human cytogenetics. PAUL E. POLANI Paediatric Research Unit Guy's Hospital Medical School London, England PREFACE The rapid development of human cytogenetics during the past thirteen years and the discovery of numerous human cytogenetic ab- normalities have opened up new aspects of both human genetics and pathology. As with most rapidly developing subjects, especially those bearing on human medicine, an extensive literature and a new terminology have developed. The discovery of the sex chromatin two decades ago and the correct human chromosome number a few years later was rapidly followed by the discovery of the first human chromosome abnormalities in the late 1950's. These discoveries were followed by a worldwide outburst of research on human chromosomes. The result has been the setting up of numerous units and groups and an unprecedented collaboration between the geneticist and the cytogeneticist, on the one hand, and the clinician and the pathologist, on the other. Inevitably, this has resulted in many problems of communication among investigators from diverse back- grounds brought together as the result of their common interest in human chromosomes. Several attempts have been made to improve communication. Conferences have been held, papers read, and articles written, but still the gap exists, and it is my hope that this two-volume treatise will in some measure provide the basic understanding of this new science which is necessary before a meaningful communication among the various disci- plines can be established. The intention of these volumes is to present the field of human cyto- genetics in such a way as to be of interest not only to the geneticist and cytogeneticist but also to clinicians, pathologists, and medical students. The subject is presented in its historical context and examples are drawn and comparisons made not only within the human species but also be- tween the human and other members of the animal and plant kingdoms. In xi xii PREFACE this way it is hoped that some of the problems of chromosome behavior which are obscure when considered in relation to man alone will become that much clearer. This work, which was started in 1962 as a short monograph re- flecting the knowledge available at that time has developed into a full synthesis of human cytogenetics based on the much wider knowledge available today. The first volume deals with the general principles of cytogenetics in relation to man, and aims to present the theoretical back- ground necessary for a deeper understanding of the subject. It is hoped that it will serve as an introduction to the subject which will be of use to an investigator entering the field for the first time. The second volume deals with the clinical cytogenetics of man. The first three chapters consider the sex chromosomes and their abnormalities and the abnormali- ties of sexual development and differentiation. The fourth chapter con- siders some of the facts derived from a study of abnormal sexual develop- ment and differentiation, and, drawing on this data, presents a hypothesis on the normal mechanism of sex determination in mammals which has been developed over the past few years. The next four chapters deal with the major autosomal abnormalities found in human populations. The last two chapters consider chromosome abnormalities in relation to human pregnancy wastage and chromosome changes in neoplasia. The appendices to Volume I give some basic technical schedules which may be of some help to the novice investigator. The techniques are mainly those which have been tried over the past nine years and found useful in the Paediatric Research Unit, Guy's Hospital Medical School, London. Other appendices give, in full, the reports of the Denver, London, and Chicago meetings which are essential if a true historical perspective is to be obtained. No attempt has been made to obtain a completely exhaustive sur- vey of the literature and, despite a bibliography approaching 2000 refer- ences, many have been omitted, some from choice and some because I was unable to read or obtain them. My approach has been critical, and I have endeavored to provide not only a review of data but also critical comment where I felt this desirable. I would like to express my appreciation and thanks to my colleagues and friends for valuable discussions during the time this treatise was in preparation. In particular, I should like to thank Dr. Georgiana Jagiello who read the entire manuscript; her critique was invaluable during the final revision. My thanks are also due to my former Chief, Professor Paul E. Polani, for his understanding and forbearance while I was engaged in the preparation of this work as well as for reading the manuscript, for many valuable discussions, and for allowing me to use certain of his un- PREFACE xiii published data and illustrations. Many of the karyotypes and clinical photographs have come from the Paediatric Research Unit records, and I am grateful for being allowed to use them. I am extremely grateful to Dr. David Cox who expertly helped with much of the proofreading. I would also like to thank my former colleagues Dr. Rajinder Dhadial, Dr. F. Giannelli, Mrs. Ann Machin, and Dr. Angela Taylor for providing me with some illustrations and data both from their unpublished and pub- lished material. Any merit this work may have is the result of nine years of research and discussions with my many colleagues in the Paediatric Research Unit; the responsibility for any mistakes is, however, mine alone. I would also like to thank all those friends and colleagues who so kindly cooperated by allowing me to use their illustrations and for pro- viding me with original and sometimes unpublished material. Detailed acknowledgments are included in the caption for each figure. I would like to express my sincere appreciation to my wife, Irene, not only for her patience and forbearance while this book was in prepa- ration, but also for her expert preparation of the bibliography and for her help with the indexing. I also thank Miss V. M. McGuire who not only helped with the preparation of Appendix I but also read Chapter 2 (Volume I). My thanks are also due to Mrs. A. Besterman who did most of the line drawings on very short notice and to Mr. L. Kelberman who helped with the photography and the general preparation of the illustrations. I should also like to thank the following for help with the general prepara- tion of the manuscript: Mrs. Hilary Aggett, Mrs. Wendy Foster, and Mrs. Barbara Saunders. Miss S. Burnett prepared some of the early drafts; the final manuscript was typed by Mrs. J. Colley. To all of them my sincere thanks. Finally, I should like to thank the staff of Academic Press for their help and patience throughout the production of these volumes. During the period this treatise was in preparation, my research was supported by the Spastics Society, the Agricultural Research Council, and, latterly, the Canadian Medical Research Council. JOHN L. HAMERTON CONTENTS OF VOLUME I General Introduction Cytological Techniques Chromosome Structure and Cell Division The Human Somatic Chromosomes The Human Meiotic Chromosomes Heterochromatin and Genetic Inactivation Chromosome Mutation I Chromosome Mutation II Technical Schedules A Proposed Standard System of Nomenclature of Human Mitotic Chromosomes The London Conference on the Normal Human Karyotype Report of the Chicago Conference-1966 Author Index-Subject Index xv Chapter 1 ABNORMAL SEX CHROMOSOME COMPLEMENTS IN THE MALE I. Klinefelter^ Syndrome and Variants Klinefelter and his colleagues (1942) described a characteristic syn- drome in nine male patients who had gynecomastia and a specific form of hypogonadism comprising small testes with hyalinized seminiferous tubules and absent spermatogenesis but with intact Leydig cells. The urinary gonadotrophins were increased to a level comparable with that found in castrates, but there was no increase in estrogen production. A normal or increased 17-ketosteroid production with either normal or subnormal development of the secondary sexual characteristics was also noted. The breast tissue showed marked hyperplasia of ducts and prolif- eration of interstitial connective tissue. This syndrome is now well established in clinical practice and con- tributes significantly to infertility in the male. Nelson and Heller (1945) and Heller and Nelson (1945) have shown that neither gynecomastia nor eunuchoidism need necessarily be observed and that the most out- standing feature is the presence of small testes with generally hyalinized tubules (Ferguson-Smith et al, 1957). The small size of the testes is generally detected first at puberty when they fail to enlarge. Polani (1962) has stated that gynecomastia is more obvious in the more sthenic subjects but that a slender body build is commonly asso- ciated with eunuchoid bodily proportions and narrow shoulders. There is frequently poor androgenic response, lack of secondary sexual charac- 1 2 1. ABNORMAL SEX CHROMOSOME COMPLEMENTS-MALE teristics, and feminine distribution of pubic hair (Fig. 1-1). Intellectual subnormality is common (Pasqualini et ai, 1957), and a higher incidence of this condition is found in populations of mentally subnormal males. The condition is often difficult to diagnose clinically before puberty un- less routine sex chromatin or chromosome tests are carried out. Affected individuals can be divided into two classes: those who are chromatin-positive and those who are chromatin-negative. The chromatin- positive group have been termed true Klinefelter's syndrome, while the chromatin-negative patients have been termed false Klinefelter's syn- drome (Nelson, 1956). The validity of this term is, however, doubtful (Polani, 1962; Overzier, 1963a) since at the time when the syndrome was first described Klinefelter and his colleagues had no knowledge of the chromosome constitution or sex chromatin of their patients. It would therefore seem more correct to use the eponym Klinefelter's syndrome FIG. 1-1. Two patients with chromatin-positive Klinefelter's syndrome, (a) Age 15 years. Note absence of pubic hair, eunuchoid proportions, and slight breast development, but otherwise normal external genitalia, (b) Age 21 years. Feminine distribution of pubic hair, mastectomy scar under left nipple, slight gynecomastia on right. [Reproduced by permission of (a) Dr. R. J. Harrison and (b) Dr. A. W. Spence.]