Developmental and Fetal Origins of Differences in Monozygotic Twins: From Genetics to Environmental Factors

By Isaac Blickstein

Developmental and Fetal Origins of Differences in Monozygotic Twins: From Genetics to Environmental Factors examines the major causes of discordance in monozygotic twins, from genetic, to environmental influences, including discussions on the genetic, epigenetic, fetal and environmental factors. Twin differences discussed include malformations, deformations and disruptions secondary to inequitable division of the early embryo, chromosome and single gene mosaicism, Nonrandom X chromosome inactivation, mitochondrial heteroplasmy, epigenetic variation, and variable and inequitable blood supply, among other influences. Differences in hemoglobin levels, placentation and amniotic fluid are also examined, while full color images illustrate discordant anomalies and twin differences throughout.

• Examines the major causes of discordance in monozygotic twins and their relevance for future studies and clinical management
• Discusses NIPT in MZ twins, twin imaging during fetal development, blood tests and forensic analysis
• Features contributions from international experts in twin genetics and developmental biology

• Language: English
• Publisher: Academic Press
• Release date: May 15, 2020
• ISBN: 9780128203071

Book preview

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Chapter 1

Introduction

Alexandra Matias,    Department of Obstetrics and Gynecology, Hospital de S. João, Faculty of Medicine, University of Porto, Institute of Research and Innovation in Health Sciences i3S, Porto, Portugal

Abstract

Identical twins: Their near perfect phenotypic resemblance has, for centuries, been a matter of curiosity, marvel and misconception. The term, however, is somewhat of a misnomer. Recent insights show that phenotypic as well as genetic differences between identical twins are the rule rather than the exception. Although they are similar, it would be wrong to call them identical.

Keywords

Identical twins; zygotic splitting; monozygotic twins

Outline

Outline

Zygotic splitting: where it all begins 3

Sharing: double trouble 4

Genotype versus phenotype: the grand finale 4

Identical twins: Their near perfect phenotypic resemblance has, for centuries, been a matter of curiosity, marvel and misconception. The term, however, is somewhat of a misnomer. Recent insights show that phenotypic as well as genetic differences between identical twins are the rule rather than the exception. Although they are similar, it would be wrong to call them identical.

Zygotic splitting: where it all begins

The phenomenon of zygotic splitting is rare. It represents a reproductive anomaly, and the anomalous nature of this deviation is reflected in the higher incidence of adverse outcomes in monozygotic when compared with dizygotic or singleton gestations. These unfavorable outcomes are the direct result of specific fetal and placental malformations.

The etiology of zygotic splitting has been investigated by clinicians and biologists for many decades. Only two more plausible have remained: genetic and infertility treatment. If there is a familial tendency, it is probably transmitted through the maternal line which means that there is a genotype more susceptible to splitting before fertilization. Assisted reproduction technologies, on the other hand, act by facilitating the process rather than initiating the splitting. As a consequence, iatrogenic conceptions are linked to an increase in the incidence of monozygosity in the entire population by 4%–7% worldwide, mainly with ovulation induction.

Sharing: double trouble

All twins, irrespective of zygosity, share the same uterus.

In the case of identical twins, it is increasingly clear that the only feature they really share is their origin from a single fertilized oocyte—the single zygote. Hence, the term monozygotic twins describes the actual origin rather than similarity or placentation process.

Though their DNA will be practically the same originally, the uterine or the in vitro milieu may switch on and off various genes which are responsible for the variability that will ultimately appear among the two cell lines. In fact, monozygotic twins may exhibit epigenetic changes that will affect their gene-expression profile.

The next level of sharing relates to a common chorion (placenta), and the anomalous sharing is often associated with unequal placental territories, eccentric/velamentous insertions of the umbilical cord, and various types of transplacental vascular anastomoses which may lead to an unbalanced sharing between the two fetal circulations. Specific adverse outcomes are related to a faulty placentation, such as fetal growth restriction with and without twin-to-twin trasnfusion syndrome (TTTS).

The third level of sharing relates to the whole of the placental structures, whereby the twin pair resulting from a monozygotic conception shares the same amniotic cavity (monochorionic monamaniotic twins).

Finally, the maximal level of sharing is seen in the various presentations of conjoined twins—perhaps the most complex anomaly found in clinical medicine—whereby twins share some of their organs.

Genotype versus phenotype: the grand finale

Monozygotic twins (MZ) are indeed very much alike, even though they will never be identical. Differences between MZ twins have been reported including: discordance for phenotype, karyotype, major malformation, growth, or intrauterine death of the cotwin. This phenotypic discordance in MZ twins is not the result of a single cause but a combination of diverse postfertilization events: chromosomal mosaicism, imprinting, postzygotic gene mutation, skewed X inactivation, and asymmetrical mitochondrial DNA distribution, among others. Therefore a complex and dynamic combination of genetic, epigenetic, and environmental factors acts in concert to shape genotype and redefine the final phenotype. It is clinically relevant to know that MZ twins may not be totally identical in order to reshape the follow-up, management, treatment, education, and understanding of the putative differences that may arise throughout life. Several types of professionals (obstetricians, pediatricians, other medical doctors, psychologists, teachers, judges, etc.), parents, and the family should be well aware of possible differences between MZ twins. They do exist. They are real.

Faced with the overwhelming evidence that identical twins are in reality nonidentical, we decided to write this book. With it, we aim to unite the various facts and perspectives formulated and unveiled by some of the leading experts in the field. We are sure it will be of value to all —from parents to professionals, doctors to lawyers, siblings, and twins.

Chapter 2

Biology of monozygotic twinning

Isaac Blickstein,    Department of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, Israel

Abstract

It is unclear when the terms zygosity and chorionicity were used for the first time. Most likely, these terms could have been used no earlier than the late 19th or the first two decades of the 20th century, the time when the correlation between embryology and placentation was first established. Notwithstanding the nebulous timing of this nomenclature, vivid descriptions of the extreme similarity of twins abound.

Keywords

Monozygotic twins; etiology of zygotic splitting; placentation; zygosity

Outline

Outline

Introduction 8

Prevalence of monozygosity 11

Monozygosity as a teratogenic event 13

Chorionicity and amnionicity 14

Dichorionic monozygotic twins 14

Monochorionic–biamniotic monozygotic twins 19

Monochorionic–monoamniotic twins 26

Chorionicity versus zygosity 30

Etiology of monozygosity 32

Familial monozygotic twinning 32

Infertility treatment 34

Ovulation induction 34

Assisted reproduction techniques 36

Triggers of zygotic splitting 38

Lack of involution of a codominant axis 39

Breach of the zona pellucida integrity 39

Cell repulsion theory 41

The oocyte propensity theory 44

Polyembryony and monozygosity 44

The oocyte propensity theory 46

Oocyte predestination 47

Binary fission 48

Control by the zona pellucida51

The sequence of events 52

Epilogue 53

Epidemiological highlights 53

References 54

Introduction

It is unclear when the terms zygosity and chorionicity were used for the first time. Most likely, these terms could have been used no earlier than the late 19th or the first two decades of the 20th century, the time when the correlation between embryology and placentation was first established. Notwithstanding the nebulous timing of this nomenclature, vivid descriptions of the extreme similarity of twins abound. One example is the parable told by the Talmud scholar Rabbi Meir about twin brothers who lived in one city—one was appointed king, and the other took to highway robbery. At the king’s command, the city officials were told to hang the robber, but when the assembled populace saw what was about to happen, they challenged the officials who were about to commit a regicide in their view. At this moment, the king realized the nature of his subjects’ confusion and ordered that the robber be freed from the threat of the gallows.

The phenomenon of twins having remarkable phenotypic resemblance at some point led to the concept of identical twins. This, however, was subsequently proved to be a misnomer in the sense that despite the remarkable similarity, phenotypic as well as genetic differences between identical twins are the rule rather than the exception. It has been observed that so-called identical twins often do not share the same placenta. Thus it slowly became clear that the only feature that these twins share is their origin from a single fertilized oocyte—the single zygote. Hence, the term monozygotic twins describes the actual origin rather than similarity and placentation. Eventually, higher-order monozygotic multiple pregnancies were identified, clearly showing that the phenomenon of single zygote splitting is not restricted to twins.

The possibility of a single zygote producing twins (or higher-order multiples) continues to be a matter of great discussion among scholars. In the simplest sense, the phenomenon of zygotic splitting is definitely exceptional, or as it was conceptualized by Aristotle—praeter naturam—outside the common order of nature. It is thus not surprising that scholars before the era of modern embryology and before the term zygote was defined were convinced that the reason that monozygotic twinning occurred must relate to a preconception event, or what today would be termed a prezygotic event. At this point, however, before the biological concepts of zygosity are discussed, it will be interesting to briefly review the opinions of prominent scholars of the middle ages.

The first such individual, Saint Thomas, also known as Thomas of Aquin or Aquino (1225–1274, Fig. 2.1), was an Italian Dominican priest, a philosopher and theologian (Pangallo). When confronted with the impossibility that the human embryo, which possesses a spiritual soul from the moment of conception, is subdivided during the first 2 weeks of life, he replied (in what could be today understood) that because the human individual as well as the spiritual soul are indivisible, "It is certainly true that, in monozygotic twins, neither the spiritual soul nor the human individual is subdivided, as such. Subdivision, not per se but per accidens, occurs in the substrate material, giving rise in this way to a new embryonic reality which, in the very instant of the subdivision, is informed by another spiritual soul created immediately by God. Monozygotic twins thus maintain a great resemblance as regards the substrate material, but each one possesses, in the first act, their own human, numerical and personal identity, being unique and unrepeatable."

Figure 2.1 Francisco Zurbarán. The Apotheosis of Thomas Aquinas. 1631, oil on canvas. Museo Provincial de Bellas Artes, Seville, Spain.

The second scholar was Saint Albertus Magnus, also a Dominican monk, and perhaps the most eminent naturalist and philosopher of the 13th century (Fig. 2.2). Inspired by the studies of the Arabic physician Avicenna and by Aristotle’s works, Albertus Magnus tried to explain the production of twins in his De Animalibus. He suggested that mechanism of sexual delight for the female and the shape of the uterus, may act to produce conjoined twins from incomplete division of semen (Thijssen, 1987).

Figure 2.2 Albertus Magnus depicted in a 1980 German postal stamp.

The twinning process was not only discussed by the Catholic theologians. The Rabbis who wrote the Talmud also indirectly considered the generation of monozygotic twins. First, the authors consider the creation of Esau and Jacob, and suggest that the birth order was established by two different drops (of semen?). In what could be envisioned as an early expression of the comes in first goes out last concept, Jacob was formed first but was born after Esau. The Talmudic narration also considers the claim of a husband who suspected the fidelity of his wife because she gave birth to twins following a single postmarital coital event. To solve this problem, the scholars commented that the twin sons of a prominent Rabbi were formed from one drop but were phenotypically different.

Surprisingly, the prezygotic origin of monozygotic twinning, as viewed by ancient scholars who knew nothing about the cellular counterparts of procreation, was not refuted. Of particular importance is the concept of Thomas of Aquino, because current knowledge holds that identical twins actually do exist at the very moment of splitting the zygote into two cells. Immediately thereafter, however, and albeit their DNA is practically the same, the uterine or the in vitro milieu may switch on and off various genes which are responsible for the range of similarity and dissimilarity that ultimately will appear among the two cell lines. Thus the ability of splitting a single zygote must be an inherent characteristic of the zygote. In simplistic terms, identical twins apparently exist at the two-stage preembryo, and the triggering of splitting apparently begins at some unknown instant before this stage. It follows therefore that splitting at a latter stage can never result in purely identical twins.

Whatever the cause, splitting is certainly a pathological process related to numerous anomalies in the fetuses and, particularly, in the placenta. As a result of this pathology, monozygotic splitting is associated with an incredibly increased risk of adverse perinatal outcomes. This chapter discusses the biology of zygotic splitting, its relation to abnormal placentation, and the correlation of both to the pathology of monozygosity.

Prevalence of monozygosity

Zygosity is the term that describes the number of zygotes from which a multiple pregnancy is produced. In the simplest form, twins may either be monozygotic (i.e., produced from a single zygote) or polyzygotic, namely, dizygotic, trizygotic, etc. (i.e., produced from two, three or more zygotes). Logically, when the number of fetuses is greater than the number of zygotes, a monozygotic component exists. For example, a dizygotic triplet gestation denotes a triplet pregnancy produced from a monozygotic pair plus a singleton.

The incidence of monozygosity is completely unknown, because the a priori number of zygotes is unknown. This is particularly true for spontaneous conceptions in which the number of ovulations in a given cycle can never be ascertained in retrospect. In contrast, monozygosity can be assumed in gestations following assisted reproduction, where the number of fetuses is greater than the number of transferred zygotes (i.e., embryos). This assumption is likely to be correct following single embryo transfers (Blickstein et al., 1999). For example, a twin or a triplet pregnancy following a single embryo transfer is in all probability a monozygotic pregnancy, whereas a quadruplet pregnancy following a double embryo transfer might theoretically result from two monozygotic twin pairs or from one monozygotic triplet pregnancy plus a singleton conception. The converse, however, is not true, and one cannot establish zygosity when the number of transferred embryos is the same or greater than the number of fetuses. For example, a twin pregnancy following a double embryo transfer may be monozygotic from only a single successful implantation or, more likely, dizygotic set from two different implantations.

The fact that monozygotic twins frequently are of the same gender has been used to estimate their prevalence within a given population. The idea is quite simple, assuming that each conception is stochastically independent, that is that the mating between a spermatozoon and an oocyte is at random and thus the gender of the conception is also at random. In such a circumstance, an equal chance exists for having a male or a female, and in dizygotic pairs of having a male/male, female/female, male/female, or female/male combination. It follows, that in a population of dizygotic twins, the prevalence of like-sex pairs is assumed to be equal to that of unlike-sex