A COMPREHENSIVE EXAMINATION OF HUMAN TRIPLOIDY AND DIPLOID/TRIPLOID MIXOPLOIDY by Jason Christopher Carson BS, Allegheny College, 2004 Submitted to the Graduate Faculty of the Graduate School of Public Health in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2009 UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This thesis was presented by Jason Christopher Carson It was defended on May 27, 2009 and approved by Thesis Advisor: Urvashi Surti Ph.D Associate Professor Pathology School of Medicine University of Pittsburgh Committee Member: Eleanor Feingold Ph.D. Associate Professor Human Genetics Graduate School of Public Health University of Pittsburgh Committee Member: Susanne M. Gollin Ph.D. Professor Human Genetics Graduate School of Public Health University of Pittsburgh ii Copyright © by Jason C. Carson 2009 iii Urvashi Surti, Ph.D. A COMPREHENSIVE EXAMINATION OF HUMAN TRIPLOIDY AND DIPLOID/TRIPLOID MIXOPLOIDY Jason C. Carson, MS University of Pittsburgh, 2009 Triploidy is the presence of 69 chromosomes instead of the normal diploid number of 46 and can occur in a complete form or in a mixoploid state in which there are populations of diploid and triploid cells in the same individual. The extra haploid set can be of paternal or maternal origin. Triploidy is one of the most common chromosome aberrations seen in 1-2% of all recognized pregnancies and can lead to partial mole which can in turn lead to serious complications for the mother and fetus. Given the high incidence of chromosome abnormalities including triploidy and its impact on individuals with chromosomally abnormal pregnancies, a greater understanding of their etiology has a potential to contribute greatly to public health by enhancing the management and possible future prevention. Though complete triploidy is not compatible with postnatal survival, mixoploid individuals are capable of surviving into adulthood. Both syndromes have a broad phenotypic spectrum though it is generally less severe in mixoploids. Though much has been learned in the nearly half century since the first case report of diploid/triploid mixoploidy was published, many questions still remain. A major issue is a large between study difference in the ratio of diandric to digynic triploidy and the prevalence of partial hydatidiform mole. Additionally, there is a clear parent-of-origin effect on fetal and placental morphology as well as developmental age that is believed to be related to genomic imprinting. The goals of this paper include summarizing the current body of knowledge on triploidy and diploid/triploid mixoploidy, examining the remaining questions, and a side-by-side comparison of the two syndromes. An exhaustive literature search was undertaken which produced many case reports of triploidy and diploid/triploid mixoploidy as well as studies on the mechanisms leading to triploidy, phenotypic iv characteristics, and the characteristics of triploid cells. It appears that the complex pattern surrounding parental origin of the extra haploid set of chromosomes may have contributed to between study ascertainment bias. More complex studies with careful attention to detail must be undertaken to fully understand the etiology and pathophysiology of triploidy v TABLE OF CONTENTS PREFACE .................................................................................................................................................... xi 1.0 INTRODUCTION ............................................................................................................................ 1 2.0 THE PREVALENCE OF DIGYNY, DIANDRY, AND PARTIAL HYDATIDIFORM MOLE .... 8 2.1 EARLY CYTOGENETIC STUDIES: DIANDRY AND PHM PREDOMINATE ...................... 8 2.2 LATER MOLECULAR STUDIES: DIGYNY IS MORE COMMON, PHM IS LESS COMMON .............................................................................................................................................. 10 2.3 EXPLAINING THE DISCORDANT RESULTS ....................................................................... 13 3.0 MECHANISMS GIVING RISE TO TRIPLOIDY ......................................................................... 22 3.1 PRONUCLEAR STAGES AND EARLY MITOTIC ERROR .................................................. 22 3.2 DISPERMY ................................................................................................................................ 24 3.3 DIPLOSPERMY ......................................................................................................................... 26 3.4 INCORPORATION OF POLAR BODIES ................................................................................ 27 3.5 MEIOTIC ERROR AND GIANT OOCYTES ........................................................................... 30 3.6 POSTZYGOTIC DIPLOIDIZATION OF TRIPLOIDS ............................................................. 31 3.7 OTHER FACTORS CONTRIBUTING TO THE OCCURRENCE OF TRIPLOIDY .............. 33 3.8 MOSAIC OR CHIMERA? ......................................................................................................... 35 3.9 RECURRENT TRIPLOIDY ....................................................................................................... 36 4.0 CHARATERISTICS OF TRIPLOID CELLS ................................................................................ 38 4.1 MITOSIS AND PROLIFERATION ........................................................................................... 38 4.2 X CHROMOSOME INACTIVATION ...................................................................................... 39 4.3 DIPLOID/TRIPLOID MIXOPLOIDY AND TISSUE SPECIFICITY ...................................... 41 vi 5.0 PHENOTYPIC CHARACTERISTICS OF COMPLETE TRIPLOIDY ........................................ 43 5.1 PRENATAL DEVELOPMENT AND POSTNATAL SURVIVAL .......................................... 43 5.2 GENERAL MALFORMATION PATTERNS ........................................................................... 45 5.3 GENITAL ABNORMALITIES .................................................................................................. 48 5.4 ASSOCIATION WITH PARTIAL HYDATIDIFORM MOLE ................................................. 50 5.5 MOLAR GESTATION FROM TRIPLOID ZYGOTES ............................................................ 52 6.0 PHENOTYPIC CHARACTERISTICS OF DIPLOID/TRIPLOID MIXOPLOIDY ...................... 54 6.1 COMPARISON WITH COMPLETE TRIPLOIDY ................................................................... 54 6.2 GENERAL PHENOTYPIC TRAITS ......................................................................................... 55 6.3 SEX AND GENOTYPE SPECIFIC TRAITS ............................................................................ 57 6.4 DIFFERENTIAL DIAGNOSIS .................................................................................................. 58 6.5 TRIPLOIDY AND TRISOMY ................................................................................................... 59 7.0 PARENT-OF-ORIGIN EFFECTS .................................................................................................. 62 7.1 GENOMIC IMPRINTING ......................................................................................................... 62 7.2 EFFECTS ON EMBRYO MORPHOLOGY .............................................................................. 63 7.3 EFFECTS ON FETAL MORPHOLOGY ................................................................................... 64 7.4 EFFECTS ON PLACENTAL MORPHOLOGY ........................................................................ 65 7.5 EFFECTS ON GESTATIONAL AGE ....................................................................................... 67 8.0 LITERATURE REVIEW ............................................................................................................... 71 8.1 OVERVIEW ............................................................................................................................... 71 8.2 ASCERTAINING PARENTAL ORIGIN .................................................................................. 73 8.3 PHENOTYPE DISTRIBUTION ................................................................................................ 89 9.0 CONCLUSION ............................................................................................................................... 93 vii APPENDIX A: COMPLETE DATA FOR ALL CASES OF 2N/3N MIXOPLOIDY ............................... 98 APPENDIX B: COMPLETE DATA FOR ALL CASES OF COMPLETE TRIPLOIDY ....................... 113 APPENDIX C: PHENOTYPE DATA FOR ALL CASES OF COMPLETE TRIPLOIDY AND 2N/3N MIXOPLOIDY ......................................................................................................................................... 127 APPENDIX D: DATA USED IN THE CONSTRUCTION OF FIGURE 1 ............................................ 137 BIBLIOGRAPHY ..................................................................................................................................... 141 viii LIST OF TABLES Table 1. Genotype distribution of triploidy in selected studies .................................................................... 4 Table 2. Genotype distributions of triploidy according to parental origin in selected studies ...................... 5 Table 3. Prevalence of diandric versus digynic triploidy ............................................................................ 12 Table 4.