Human Afflictions and Chromosomal Aberrations

397 Pages·1969·48.825 MB·English

by  Raymond Turpin, Jérôme Lejeune, P. Alexander and Z. M. Bacq (Auth.)

HUMAN AFFLICTIONS AND
CHROMOSOMAL
ABERRATIONS
RAYMOND TURPIN
Professor of Clinical Paediatrics, Paris Faculty of
Medicine, and Member of the French Academy of Sciences
and
JEROME LEJEUNE
Professor of Fundamental Genetics, Paris Faculty of
Medicine, and Director of Research for the French
National Centre for Scientific Research
&
PERGAMON PRESS
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Copyright © 1969
Pergamon Press Ltd.
First English edition 1969
This translation is based on
Les Chromosomes Humains (caryotype normal et variations pathologiques)
published by Gauthier-Villars, 1965
Library of Congress Catalog Card No. 68-18534
PRINTED IN GERMANY
08 013263 4
Preface to the English Edition
AMONG the great scientific movements initiating the study of human heredity,
history will no doubt pick out after Mendelism and genochemistry, chromo
some analysis. These fundamental principles have found in human physiopatho-
logy a new demonstration of their possibilities since the phenotypic wealth of
man, whether healthy or sick, is unrivalled.
This book, Human Afflictions and Chromosomal Aberrations, is the English
version of the French original of 1965. Only the chapter "Monozygotic Twin
ning and Chromosome Aberrations (Heterokaryotic Monozygotism)" has been
enriched by new advances which increase the interest of the problems raised by
this new type of pathological twinning.
As an introductory work it outlines the methods of analysis which lead to the
definition of the chromosome apparatus, the karyotype of the normal human
somatic cell. The description of these chromosomes, a source through DNA
of hereditary information and evolution, introduces the study of their aber
rations due to excess or deficiency.
Those who have not participated in this work or have not closely followed it
will see that the main models, archetypes and numerical or structural aberrations
were isolated in 1959 and were soon confirmed. Their discovery was not the
result of mere chance. In fact, the ingenious technique which permits the exact
count of the chromosomes of the somatic cell of man, In = 46, did not immedi
ately lead to the discovery of their aberrations. Before these were found it was
necessary to find patients likely to bear them. The authors of the discovery of
trisomy in mongolism with refined technique at the outset studied this disease
to verify a hypothesis advanced 22 years earlier by one of them. The same se
quence of events very soon followed in England, where the choice for study of
the forms of gonadal dysgenesis was governed by anomalies of the chromatin
body.
The discovery of chromosomal aberrations is thus a striking example of the
possibilities of confrontation of logic and experience.
These anomalies in our hereditary make-up do not merely have a scientific
appeal. They concern all who do not view without anxiety the increase in
congenital diseases. A doubtless approximate but reasonable estimate suggests
that patent and latent chromosomal aberrations affect some 4 in every 100 zy-
gotes and, after the play of intra-uterine selection, 1 per 100 viable neonates.
However, medical and socio-economic progress is more and more reducing the
effects of natural selection. Such progress is increasing the life expectancy of
these abnormal zygotes and, hence, the importance of the problems they pose.
Some of these problems concern the normal karyotype. A better discrimina
tion of the chromosomes founded on their morphological, biophysical and bio-
Vll
Viii PREFACE TO THE ENGLISH EDITION
chemical attributes is highly desirable. It is essential for the definition of morbid
types, the identification of rudimentary structural anomalies, the gene topology
of the chromosomes and analysis of a possible relation between chromosome
selection and cell specificity.
Other problems concern aetiological factors. It is important to establish the
real incidence and make clearer the pathogenetic possibilities: segregation,
"replication" and structural anomalies. Certain factors are exogenous: physico-
chemical; viral with chromosome tropism. Others are endogenous: inter-
chromosomal effects; predisposition of the genes to aberrations; and predispo
sition to aberrations and cancer.
The first congenital chromosomal aberrations compatible with life heralded
a new chapter in physiopathology. They encouraged the hope that progress in
the study of human cytogenetics would match that of drosophilian cytogenetics.
Now, barely 10 years after the start of these studies, the material for a new chap
ter in human pathology has been marshalled and continues to increase. Although
the progress of this young discipline has not yet fulfilled all the hopes pinned on
it, it nevertheless continues to gain in importance and interest.
Paris, July 1968 RAYMOND TURPIN
Preface
THE facts brought to light over the last 5 years in the study of human chromo
somes and their pathological variations form the basis of this book. These find
ings have opened up a hitherto closed chapter in human pathology and have
encouraged the development of a new branch of medicine. Though much has
been uncovered the knowledge gained will no doubt soon be outmoded. Modern
methods afford still unexplored possibilities and refined analytical techniques
may perhaps provide a fresh impetus to a study on the point of slowing down.
Despite these discouraging aspects and the realization that this book would
be far from perfect and contain observations of very uneven merit, we agreed
to write it as requested.
We felt it useful to bring to the attention of doctors known examples of
congenital pathology which may affect any function or system and be of inter
est to the widest range of specialists. It also seemed to us of value to compile
for the benefit of researchers a bibliography as exhaustive as possible including
material published over a 5-year period from the first communication in 1959
to 31 December 1963. Obviously, the bibliography for 1964 cannot be complete.
From earlier publications we have taken only fundamental work or facts which
have become topical again because of chromosomal discoveries.
Following the Introduction we have divided the book into three parts.
The first deals with the necessary preliminaries, background and definitions
followed by the laboratory techniques; then the techniques of study and descrip
tion of the normal karyotype.
The second is devoted to anomalies in number or structure of the autosomes,
in particular, trisomies, translocations and aneuploidies.
The third combines numerical and structural anomalies in the gonosomes—
hermaphroditism,twin anomalies and the mechanisms and effects of gonosomal
aberrations.
In drafting the last two sections we had to rely on original sources, and present
the substance of numerous observations. This is bound to make the text more
cumbersome, but the available information does not lend itself to outline form.
It is certain that the order we have chosen will be upset in the near future.
Without wishing to prophesy, always a dangerous course in biology, we can
expect to see developments in acquired chromosomal pathology. This subject
may become, as important, if not more so, than that of constitutional pathology.
Care in assembling the most outstanding contributions does not exclude the
risk of omissions. Some readers may perhaps regret that work they consider of
value has not been included.
We would make it clear that we welcome any remarks, not viewing them as
ix
X PREFACE
criticism but as a contribution to a work which could not in the first instance
be entirely successful.
If this work paves the way to new research in the field under study, its purpose
will have been amply served. In no way does it claim to be a summa but rather
a gradus ad observationem.
Institut de Progenese, RAYMOND TURPIN and JEROME LEJEUNE
Paris, September, 1964
Acknowledgements
WE WISH to thank our colleagues and collaborators of the Faculty of Medicine
and the Institut de Progenese who helped to compile the original material
used in this book.
We also wish to thank the following organizations: the French Ministry of
National Education, the French Atomic Energy Commission, the National
Hygiene Institute, the National Centre for Scientific Research and the U.S.
National Institutes of Health and Joseph P. Kennedy Jr. Foundation whose
financial assistance made possible the setting up of the laboratories and develop
ment of the research of the Institut de Progenese.
Introduction
THE remarkable development of cytogenetics of lower species encouraged com
parable study of human cytogenetics, which was until recently, unfruitful due
to inadequate techniques. Only a few years ago man was still ignorant of the
exact number of his chromosomes but then a new technique of analysis trans
formed the situation namely "hypotonic shock".
Dispersion of the chromosomes made possible examination of in vitro mitosis
and definitely established at 46 the number of chromosomes in our species.
This new technique was put to immediate use by several laboratories, the
first investigations being guided by theoretical notions.
"Mongolism", the initial subject of research, was one of the best studied
congenital diseases. Regarded as a genetic disorder, not conforming with clas
sical Mendelian laws, its aetiology was the subject of much discussion. In 1959,
the hypothesis of its chromosomal origin was verified by the discovery of tri-
somy 21, thus establishing the validity of theoretical notions going back a
quarter of a century.
Moreover, the indications drawn from study of partial colour blindness and
the nuclear chromatin body in intersex states suggested anomaly of segregation
of the X chromosome. The discovery, after that of trisomy 21, of the Klinefelter
XXY syndrome and the Turner XO syndrome, confirmed the soundness of these
hypotheses.
Finally, the first translocation (G ~ D) was found because the child who
carried it displayed a syndrome of widely disseminated physical and mental
disorders. This simultaneous involvement of many systems suggested a con
stitutional anomaly due to a possible chromosomal aberration.
These initial successes, this sudden awareness of a morbid group with far-
reaching implications encouraged the setting up of numerous cytogenetic study
centres throughout the world, soon followed by accumulation of observations
based on more or less firm grounds. And this was only to be expected. But the
possibilities of such chromosomal prospects are, in fact, limited by its tech
niques and its subject.
A. Cytogenetic techniques use only very small samples of material taken from
few regions, usually, bone marrow, fascia or skin and blood. Even if more sam
ples, cultures and karyotypes can be obtained, such exploration is marred by
two weak points. First, it only extends to certain somatic cells and leaves aside
information which might be provided by the germinal cells. Secondly, it always
leaves open the possibility of mosaicism.
Cytogenetic techniques permit detection of numerical chromosome anomalies
and major structural anomalies. But to ask more would be unrealistic, or even
impossible. Within a group, in particular, group 6-12, identification of indi-
1 HA
1
2 HUMAN AFFLICTIONS AND CHROMOSOMAL ABERRATIONS
vidual pairs is at the verge of feasibility. For the X chromosome the incorpora
tion of 3H-thymidine provides a means of identification whether it be normal or
modified.
For certain acrocentrics the value of the satellites as a means of identification
is reduced by their variability and even by the possibility of secondary satelliza-
tion compensating for the loss of one of them, by centric fusion, for example.
There seems to be no point in hoping that present techniques will ever permit
identification of fine structural aberrations such as slight deletions or duplica
tions and, even less, inversions.
Giant human chromosomes, whether unrecognized or induced, are still to be
discovered.
In these conditions it is not surprising that chromosome topology based on the
study of erythrocyte phenotypes and enzymatic reactions is still very rudimen
tary.
B. The subject of cytogenetics is distinguished by a special diversity in fre
quency and semeiology.
1. The diversity in frequency, as can be judged from the neonatal period,
is certainly quite different from the original diversity.
If a meiotic anomaly is involved, the abnormal gametes are selected for
viability and fertility; if a mitotic anomaly is responsible, the pathological
ovum has a greater or lesser chance of surviving, depending on the aberration
it bears. If this selection did not operate, we should observe varieties such as
haplo 21 and OY which have not been reported. We should also find a greater
number of known varieties, such as the XO for example.
The first results of chromosome analysis of aborted eggs do not contradict
these suggestions.
Some reveal known varieties, others, aberrations incompatible with life, such
as triploidies. According to some exceptional observations, the latter appear
to be viable only in the mosaic state.
This antenatal selection continues after birth. Thus, the original diversity may
be accepted as very probable, since the chances of aneuploidy vary, in prin
ciple, with the chromosomes considered and are modified by ante- and postnatal
selection. This selection perhaps accentuates the difference in frequency of tri-
somy 21 and trisomies 13 or 18.
Despite the rigours of selection the varieties of chromosome aberrations are
many. It would not be a difficult task to describe them if many of these essential
aberrations did not involve different phenotypes.
This leads to increasing complexity for which mosaicism is chiefly responsible.
A classic XO or XXY anomaly may be modified by the joint presence of an XX
or another cell line. Depending on the size of the territory occupied by each of
these lines and the functional attributes of these territories and the predominant
form at the level of the primary gonads, more or less appreciable phenotypic
differences can be expected.
Structural aberrations add to this diversity, particularly in relation to
gonosomal aberrations. Many involve the XO anomaly but with nuances which
INTRODUCTION 3
still require individualization although this is often based on a very small num
ber of observations. It is impossible to pre-judge; only the future will decide.
At the moment, we must work within a framework not lending itself to brilliant
syntheses.
Other aberrations are concerned with the autosomes. For example, the pheno-
type of a variety of 22 ~ 13 translocation should theoretically vary with the
gene composition of the resulting deletion. According to the known facts this
indeed appears to be the case. With time, it is possible that this diversity will
be reduced to a few types each related to a particular region of chromosome
fragility.
Finally, karyotypic coincidence of aberrations in the number of autosomes
and gonosomes, or aberrations in number and structure is possible. Often, one
of the aberrations clinically gains the upper hand over the other; aneuploidy,
for example, is expressed in its usual form, and translocation often sufficiently
balanced to have been inherited is reflected in no sign, at least outwardly. This
reservation must be made. However it is quite possible, as well as desirable,
that semeiological progress will reveal certain phenotypic characters of trans
location hitherto latent.
2. The semeiology of diseases with chromosome aberrations is very char
acteristic. This feature brings closer together the different forms.
Most of the congenital disorders which make up this new morbid group are
characterized by delay in mental awakening and physical development with
hypotrophy and disharmony of growth. Against this background appear, de
pending on the chromosome varieties, visceral malformations, in particular,
neurosensory, cardio-aortal, renal and gonadal. These common features have
given rise to the idea of a partially non-specific semeiology of chromosome
aberrations. This concept is, if nothing else, premature. How can one predict the
future of an infant—the type of oligophrenic which he will become? If trisomy 21
is involved, long experience of this disease provides an answer, but for trisomy 13
or 18 or a partial deletion of the short arm of 5, this experience is still lacking.
We do not know the psychic future of these abnormal subjects whose life
expectancy is very short. It is even possible that their fraility will never allow
us to examine them up to the end of their growth period.
As the number of observations increases, anatomical inspection of mal
formations suggests certain relations between the chromosome varieties and
the lesions.
It is not surprising that these early and diffuse aberrations which affect
embryogenesis right from its initial stages, have in common the property of
disturbing overall physical and mental development of the individual and partial
development of some of his mechanisms. But the specificity of the aberrations
is reflected in the modes of dysembryogenesis.
Among such modes we would emphasize the importance of symptoms sug
gestive of a chromosome aberration and hence calling for inspection of the
karyotype.
The most typical example is that of the Barr interphase chromatin body, an
expression of the inactivation of an X chromosome. Any discrepancy between