Human cytogenetics is still in its infancy and its constant progress
prevents making in 40 minutes a review of what we know and of what we would
like to know. So let's discuss what we can consider as being interesting in
chromosomal disorders as far as autosomes are concerned.
I think we better not discuss the sex chromosomes in which so many
different diseases are known. The particular interest of chromosomal disorders
is that they are introducing a new concept in the understanding of genetic
diseases. In most of the well-known genetic afflictions, a genic change is
involved. There is an error in the DNA molecule which produces, by a complex
mechanism that you know, a kind of misprint in the enzyme controlled by the
gene. This misprint changes the behavior of the enzyme and produces a
biochemical or morphological variation recognized as a disease. Most of the
genetic diseases are thought of in terms of an error in the genetic
information. When we are dealing with chromosomal imbalance, the situation is
entirely different. Not only in anima viti but also in human beings we know by
experimental demonstration, that the genic content of the chromosomes involved
is entirely normal. It is only a quantitative change which produces diseases.
When a chromosome is in excess, as in trisomy, or is lacking, as in monosomy,
we know that the genetic information is unchanged; but the repetition or the
omission of this perfectly all right message is the sole cause of the disease.
Redundancies and shortcomings have always been the pitfalls of talks and
conferences and it is interesting to see that this general law also applies to
chromosomal changes. The question is now to know why, and how this genic dosage
effect can be achieved.
Unfortunately, it is only too easy to show that excess of an autosome
is deleterious. Trisomy 21, which is related to the fact that one of the tiny
21 chromosomes is in excess (Lejeune et al., 1959) does produce the classical
picture that all of you know. If I recall this trisomic condition, it is only
to consider what kind of mask the disease is able to throw on the personal
features of the child, so as to make them apparently like each other. As you
know, the bridge of the nose is very flat; there is epicanthus, microcephaly
and so on. This particular mask is the same for all children and is
superimposed over the particular genetic makeup of the individual.
The same features of trisomy 21 are found in whites, Negroes, and in
Asiatic babies. Although vaguely reminiscent at birth of Asiatic traits, these
features are not at all racial. The characters change with the growth and in
the adult, only the dysmorphy persists, the same for all races. I will not go
very far into the description of this syndrome of trisomy 21, for it is very
well known to everybody. I would just remind you that together with many
deformities of internal organs, the disease has a signature on the hand.
Instead of having normal ridge patterns as everybody has, 21 trisomic
people have the ridges abnormally set so that the triradius in which there is a
convergence of the ridges, which is normally located in the root of the hand,
is in the middle of the palm. The two flexion creases, (let's say the "line of
heart" and the "line of head") are fused together in a transversal crease. I
will not discuss further the dermataglyphics because Dr. Uchida will speak
about this, but I wanted to include it to, give you the idea that the whole
individual is shifted from normal by the presence of the extra chromosome and
that we can predict just by clinical inspection what chromosome produces the
In other trisomies, like trisomy 18, in which a member of the pair
number 18 is in excess (Edwards et al., 1960) the picture is typical but very
different from trisomy 21. The children are rather small and many traits allow
the clinical diagnosis. They are microcephalic; they have a very small chin, a
short sternum and a narrow pelvis. The hands are held in the surrender position
and the first and the fifth fingers cover respectively the third and the
fourth. In the external ears the scaphoid dimple is rather flat and the helix
is poorly rolled. Those things are very small symptoms but we will see later
that they have possibly a very great genetic interest. The digits are very
short, have only one flexion crease instead of two; and most of them exhibit
arches on the finger prints.
In trisomy 13 a big acrocentric of the D group is in excess (Patau et
al., 1960). Here also the clinical picture allows diagnosis, and one can
briefly remember the deformities of these children. All of them are
microcephalic and have a very peculiar disturbance of the cephalic development:
the eyes are poorly developed ranging from pure anophthalmia to simple
microphthalmia. Harelip and cleft palate are common, and the ears are abnormal.
Among many other congenital deformities, the most typical is an aplasia of the
olfactory lobes, which classify the disease as arrhinencephaly. This disease,
described in this country rather recently, was in fact entirely and perfectly
described 300 years ago in Denmark by Bartholin who found in one stillborn all
the characters of the disease. This historical reference shows us that these
"new diseases" have always existed and are not an invention of cytogeneticists.
There is also a signature of the disease on the palm prints together with extra
digits in hands and toes. As Dr. Uchida will discuss later, cytogeneticists are
really reading the destiny of people an the hands and these minor stigmata are
a great help in the diagnosis.
From just the remembering of those three well-known syndromes, we can
draw the first conclusion: If the excess of a given segment of the genome is
able to produce a specific clinical entity that we can recognize, it follows
logically that genes located in this chromosome control more or less directly
the manifestation of those traits. If we find something wrong with an enyzme,
this does not prove that the structural gene of that enzyme is surely an the
chromosome involved, but at least that something controlling this thing is
located on that chromosome. All of the children carrying an extra piece of an
autosome have in common a very dramatic symptom-all of them are feebleminded.
For the moment this rule has no exception. We, must then ask ourselves why it
is so. The straightforward conclusion that there are "genes of intelligence"
located in chromosome 21, chromosome 18, chromosome 13 and every other autosome
is entirely unwarranted. The best representation of the situation is that in an
extremely complex and highly integrated system, any change is likely to
produce, besides its specific aspects, some degradation of the best performance
of the system. Thus, human intelligence is always suffering if some of its
substratum is abnormal. Indeed, it seems possibly a little too anthropomorphic
to state bluntly that human intelligence is the top performance of living
systems but cytogenetics does not rule out this idea.
Now let's see what not excess but lack of chromosomal material, like
in the "cri du chat" disease could do (Lejeune et. al., 1965). All the children
affected by this disease have a rather peculiar face. They have wide-spaced
eyes, epicanthus, rather small chin, and are very microcephalic. Otherwise,
their morphology is not greatly abnormal. In common, all the children have a
very particular cry which is the "symptome d'appel." In early infancy, they
have a highpitched, prolonged cry, which is by its plaintive tonality, very
reminiscent of the cry of distress of a young, suffering cat, hence the name of
the disease "cri du chat" disease. This is related to abnormality of maturation
of the larynx. Recent spectral analysis of the sound has confirmed the
similarities between the cry of the affected children and the cry of kittens.
The disease is related to the loss of part of the short arm of chromosome 5. To
my knowledge there are more than 70 cases now entirely investigated and all of
them have a deletion of a portion of chromosome 5. The signature of the disease
in the palm prints is essentially a moderate elevation of the axial triradius
and a straight, short, distal flexion crease. The problem was to know whether
those children were really suffering from genetic loss because it was generally
believed that monosomics having only one exemplar of a given segment of
chromosome should be lethal in man. This opinion was very widely accepted and
hence it was necessary to know that the fragment was really lost in that
disease and not only translocated somewhere else. A very peculiar family gave a
quite experimental answer to that question (Lejeune et al., 1963). In this
family, one case was a typical "cri du chat" syndrome. This girl had two
sisters who were feebleminded and did not have any symptoms of the cri du chat
syndrome but were really severely affected. By interrogation, it turned out
that another child, dead many years before the examination, had the cri du chat
condition. The grandfather remembered and told us spontaneously that the boy
had an abnormal cry like a little cat. The mother is phenotypically and
mentally normal but she has abnormal chromosomes. Her father has the same
abnormality of his chromosome and he transmitted it also to her sister.
The karyotype of these persons exhibited a deletion of the short arm
of chromosome 5 as in the typical cri du chat disease. The missing segment is
translocated to the end of one of the chromosome 13's. Measurements show that
the sum of the lengths of this deleted 5 and the augmented 13 is the same as
that of the normal 5 and the normal 13. Thus, the father of this woman carried
a balanced 5 to 13 translocation and transmitted it to his daughters, when the
mother transmitted a normal 13 and the deleted 5, then the child was a typical
cri du chat syndrome. In another child, she transmitted the normal 5 but the
big 13 and then the child became trisomic for this little segment, because she
had two normal exemplars and an extra one, stuck on the 13. This is then the
reciprocal of the deletion, that is trisomy for the very same fragment, which
is monosomic in cri du chat disease. Another girl was entirely normal because
she received a normal 5 and a normal 13. The two sisters who had received the
extra piece and who were trisomies were very severely mentally retarded. The
oldest girl has a particularly big and long nose, rather contrasting with the
sharp little nose in cri du chat.
The youngest died at seven months of age and unfortunately no
examination was possible. She was not obviously morphologically abnormal. She
was severely retarded and she had a very abnormal cry. You would ask what
should be the contrary of the cri du chat cry. She had a very raucous and
discordant voice and the parents said that the oldest one had exactly the same
voice when she was young. Unfortunately, we could not examine their larynx.
But with this first example of a disease in which we could know two
instances which are mirror images of each other, the idea arises that if we can
define a clinical type due, for example, to a trisomy, the contrary could
possibly exist and produce the mirror image of deformities and then be the
countertype of the disease. In that case the trisomy for the small fragment of
short arm of chromosome 5 is the countertype of the cri du chat disease. To
make clear, I should say that this instance of monosomy and trisomy for the
portion of short arm of chromosome 5 is now known in two other families, and
the picture of the reciprocal syndrome of the cri du chat will be, I suppose,
correctly described when those three different families can be matched
together. If types and countertypes do exist, we have to find out how they
should be looking alike. As you know, in case of translocation involving the
chromosome 21, a carrier mother should sometimes produce ova without any 21
chromosome and then have pure monosomic children, that is, haplo 21, having
only one 21 chromosome given by the father. Although more than 200 children
born from such mothers have been recorded, no such case is yet known (Lejeune,
1964). It can be considered that pure monosomy for chromosome 21 is not viable.
But it is possible that situations very close to pure monosomy do exist.
A child was observed to be a carrier of ring-21 chromosome (Lejeune et
al., 1964). One member of the 21st pair, instead of being shaped like a rod,
was a little ring. Some material was probably lost during the formation of the
ring. More interestingly the child had lost the ring in many cells which were
then entirely monosomic for chromosome 21. In the blood 95 percent of the cells
had forty five chromosomes without the ring; thus, the blood was quite purely
monosomic 21. In other tissue, 1/3 of the cells were monosomic, 2/3 having kept
the ring. All the abnormalities exhibited by the child were exactly the
contrary of the stigmata of trisomy 21. The child was very hypertonic instead
of hypotonic like the 21 trisomies. He had very big ears and they are small in
trisomy 21. The ear channel was very broad but it is very narrow in trisomy 21.
The nose is extremely salient (and that was calculated also in radiography) and
as you remember it is very flat in trisomy 21. Instead of having the epicanthus
in the inner part of eyelids, he had a kind of "hypocanthus" an the lower part
of the eye. A second case was recently described in this country (Reismann et
al., 1966). The child also had one little ring of the 21 and lost it in many
cells; and he had also the big ears, the prominent nose and an enormous
As I told you, for biochemical traits, the child examined had also the
contrary of trisomy 21, that instead of having elevated alkaline phosphatase of
polymorphs, he had a low value. Instead of having hypoeosinophilia, he had an
excess of eosinophils in his blood. And also for the tryptophan metabolism,
which is abnormal in trisomy 21, the ratio of 5-H.I.A.A. excretion in the urine
compared to kynurenin excretion, which is very low compared to normal in
trisomy, was very high in this child compared to normal. We have then the
notion that when one chromosome is absent, or partly absent, the deformity is
contrary to that produced by the excess of this particular choromosome.
I would just discuss another example of this type and countertype pair
which is a deletion of part of the long arm of chromosome 18, a disease which
has been recently individualized (Lejeune, et al., 1966, de Grouchy et al.,
1964). Affected children have an underdevelopment of the middle part of the
face with slanting eyes and epicanthus. Also they have abnormality of the
superior lip and of the insertion of the nose. The features are the same no
matter what the race of the child; the retraction of the middle part of the
face, and also the little fugal nodule and the special feature of the lip and
of the nose are found.
The syndrome is also producing a kind of "hyper normality" of the
ears. The helix is overrolled, the anthelix is prominent and the scaphoid
dimple is extremely deep. These are minor points but they are just the contrary
of what we have seen in trisomy 18 in which the helix was poorly rolled and the
scaphoid dimple was quite flat.
Those children have also frequently a little dimple on the shoulder
and on the dorsal part of the phalango-metacarpal articulations. The morphology
of their fingers is exactly the contrary of what was seen in trisomy 18. The
digits are long "fusi-form," and fingerprints show a great excess of whorls.
All of the children have lost about one-half of the long arm of chromosome 18.
This disease was described in three cases but there are now other cases known,
not yet published. Two cases were observed in England by Dr. Insley who kindly
sent me the karyotypes and the picture. Other cases have been detected, in
Boston (Dr. Park Gerald) and another instance in Paris, which are mosaics. All
together it can be said safely that this new syndrome is an entity clinically
We could now try to discuss the interest of this concept of "types and
countertypes." First it makes an immediate improvement o£ semeiology:
observing a symptom which is shifted one way by excess and the other way by
loss and allowing to determine what is the precise point of action of a
particular chromosome. The second interest is possibly more general. To
understand how chromosome dosage can operate we have to build a logical model.
The basic rule in genetics is that one gene controls one enzyme or one specific
protein. If we just quantify this rule, we can figure out a first hypothesis to
explain these types and countertypes. In monosomy one gene produces in the
cells one unit of enzyme; in trisomy, three genes being present, three units of
enzyme will be produced. Then compared to normal with two genes the shift will
be in different directions in monosomy and in trisomy. Thinking in these terms
of quantity of enzyme is quite different from what is the biochemical results
of point mutations.
Let's take for example, PKU: one enzyme does not function, the
biochemical step is stopped and then the disease occurs. In the case of excess
of enzyme, the chemical reactions are entirely normal but just going too fast.
And if there is not enough enzyme, it is going too slowly but in both cases the
quality of the reaction is normal. We can then understand why a reaction going
fast would produce the contrary of a reaction going slow. Still it remains a
paradox: if types and countertypes are really mirror images for minor symptoms,
they are alike for major disasters. All the children are feebleminded. To
understand that, we can take an example and suppose that genes are like the
musicians in an orchestra, each of them playing his personal partition. Now if
some musician decides to play his partition slower than the rest of the
orchestra or if he decides to play faster than the others, in both cases the
result is bound to be cacophonic. But if the musician is changing his tempo,
not during a tutti but during a solo, then the fact of changing moderato to
pretissimo will produce one symptom and the change to a largo will make the
contrary. It is probably because the enzymatic processes are so much intricated
for building high functions like human intelligence that any shift is
deleterious. For morphological traits there is some degree of liberty in their
expression, which is obvious by the differences occurring in normal beings. It
is this possibility of variations which make possible the recognition of types
One gene-one enzyme, three genes-three enzymes is extremely naive
indeed. Nevertheless, even if not exactly true, this model does have a great
heuristic interest. If it represents a part of the truth, it would mean that in
chromosomal imbalance, children have the whole biochemical machinery right at
hand with just some steps running too fast or too slow. To control the speed of
a biochemical reaction is surely much more feasible by metabolites or
antimetabalites than to replace an entirely lacking enzyme. Indeed, these
crucial biochemical steps have yet to be discovered, and this construction is
far the mordent purely speculative. But if you remember that at birth one child
in every hundred is severely affected by such a chromosomal imbalance and will
suffer in his mind and his flesh for all his life, you will find that those
speculations are not academic but just an immediate challenge. This way of
research must be investigated for it is our only hope that someday we will be
able to do something for those children who, having not received an equitable
patrimony, are in the true sense of the term, the most disinherited of the
children of man.
Dr. Harold Goodman
I wonder if you would be willing to speculate, Dr. Lejeune, about
one of the large problems that relates to this area. In particular what about
the occurrence in the normal population of deviants who have one or more of
these mongoloid traits. Also an occasional individual is seen who has almost
all arches who, of course, has apparently normal chromosomes.
This is an obvious question. I cannot give a final answer but when
we are speaking about trisomies, we have to consider that the children arc all
the same for the chromosome involved, but the genes inside the chromosome are
not identical, because alleles are different from one individual to the other.
Some alleles will produce much more enzyme than other alleles and then produce
a trait transmitted in a Mendelian way. We know that those genes are an these
chromosomes because they take part in the morphological syndrome, but they can
he present in normal people. Let's say that if a crooked little finger was
never present in trisomy 21, we would never be surprised that some people have
crooked little fingers and transmit it to their progeny. Just because it
appears that it is governed by genes in the chromosome 21, we are interested in
it. Then these normal variations are in fact just the material with which
syndromes arc expressed in trisomies and monosomies.
Dr. David Smith
Professor Lejeune, cytogenetics being in its infancy and thereby
open to changes of interpretation with advancing methods and knowledge, there
is one point that I would like to bring up and have you comment on. I would
appreciate it if it would be possible also for Dr. Yunis to make a comment in
this regard. The question pertains to the nomenclature of the chromosomes
themselves and to the decision as to whether it was 17 or 18 in triplicate in
the 18 trisomy syndrome. This decision was helped by the advancing methodology
in terms of the tritiated thymidine replicating pattern of the chromosome which
is ire triplicate. Similar type studies which were carried out by Dr. Yunis an
the Down's syndrome patients seem to indicate that it is the smaller of the two
chromosomes that is in triplicate which by the original designation would then
be chromosome 22 and with your indulgence, I would appreciate very much your
My comments will be very brief. When we are giving a number, a
numeral to a chromosome, it is purely a conveniece. Then the best is to say by
convention that we call 21 that chromosome which produces the syndrome when in
triplicate. If we can say later that this chromosome has such and such
property, that it is a little smaller than the other, that its thymidine
incorporation is not exactly the same and so on, that is for the better; but
there is no reason at all to change the etiquette we have put in it. That is
the same for trisomy 18 or trisomy 13, We have to make the blunt definition-one
day we give this number to that chromosome and no matter what will be the
definition of this chromosome we will get later, there is no reason to change
the number because, anyway, the numbers are entirely arbitrary. I must say that
I have measured as many chromosomes as anybody, and I am still unable to prove
that one is bigger than the other, then I just will stick to this very simple
Dr. Walter Nance
Dr. Eric Engel and I have recently studied a case which illustrates
some of the findings which Dr. Lejeune has just described in the 18 (E) long
arm deletion syndrome. This patient was a severely retarded, 12-year-old girl.
She had the long slender fingers, along with the somewhat abnormally placed
thumb that Dr. Lejeune has emphasized as being a component of the long arm
deletion syndrome. She also had the midfacial hypoplasia along with the deeply
convoluted ears that lie has emphasized. Of some interest, however, is the fact
that this patient also demonstrates a broad chest, pterygium colli, and ptosis
and these findings are features that have recently been emphasized by Dr. de
Grouchy as being common findings in the 18 (E) short arm deletion patients.
Chromosome studies in this individual showed an abnormal E group member which
was identified on the basis of morphologic and autoradiographic criteria as
being the 18 (E) chromosome. Late prophase preparations indicated that this is
a ring chromosome from which we infer loss of chromosomal material from both
the long and short arms of this E group member.
Dr. Lemons Yielding
It seems to me that the problem of gene dose might be more
understandable if we would include in our model the concept of regulator genes
because in that instance we could explain in the trisomy state, for example,
the occurrence of decreased enzyme levels as well as increased enzyme levels. I
wonder if you could comment on that.
I did not understand entirely your question but I think that you put
forward the regulating mechanism. This is a complex business but as far as we
know, the genie regulation as described in the term of operon does not apply to
diploid organisms, at least we don't have any clue to know how it should apply.
Obviously regulation plays a tremendous role in the explanation; it is the main
reason why I said that the simple arithmetic I was giving was just extremely
naive. For the moment there is no logical model which we can safely produce and
try to test by experiments.
Dr. Lemone Yielding
Ithink it is especially interesting when we consider that a more
complex organism has a problem of differentiation. If repressors of various
sorts play a large role in differentiation, then if we have a gene which
produces a large concentration of repressors, then it is easy to see how we
could disturb the whole process of differentiation.
That is obvious. It doesn't matter in fact to the theory whether the
gene is a structural gene or a repressor gene. The genie dosage effect will be
different on the end result but the mechanism will be the same.
Dr. Frederick Hecht
In Down's syndrome, as well as in the other autosomal trisomies, the
mean maternal age is increased. This is usually taken to be evidence that the
majority of cases are due to maternal nondisjunction; therefore, the individual
has an extra addition of the mother's autosome. Is there any evidence that the
children resemble the mother more than the father?
That is an old question that has been especially investigated by
British workers, by Dr. Penrose in particular. He found that there were, as far
as blood groups are concerned, large similarity with the mother, but this is a
very tricky problem. Susceptibility to a difference in blood groups between
fetuses and the mother is great; then it could be just a selection effect. If
the trisomies which are weaker than normal fetuses do not resemble their
mother, they are possibly discarded. There is no clue as far as I know to tell
that trisomy 18 or 13 are more alike the mother than they should be. The notion
that the accident is occurring during the meiosis in the woman is for the
moment a simple hypothesis which must not be taken for granted. It is just an
Edwards, J. H., D. G. Harnden, A. H. Cameron, M. V. Crosse and O. H.
Wolff. 1960. A New Trisomic Syndrome. Lancet 1:787.
Grouchy, J. de, P. Royer, Ch. Salmon and M. Lamy. 1964. Deletion
partielle des bras longs du chromosome 18. Path. et Biol. 12:579-582.
Lejeune, J., M. Gauthier and R. Turpin. Les chromosome humains en
culture de tissus. 1959. C. R. Acad. Sci. Paris 248:602.
Lejeune, J. 1964. The 21-Trisomy. Current Stage of Chromosomal
Research, ed. A. G. Steinberg and A. G. Bearn. Progress in Medical Genetics,
Vol. III, New York: Grune and Stratton, Inc. pp. 144-177.
Lejeune, J., J. Lafourcade, R. Berger, J. Vialatte, M. Boeswillwald,
Ph. Seringe, and R. Turpin. 1963. Trois cas de délétion du bras court du
chromosome 5. C. R. Acad. Sci. Paris 257:3098-3102.
Lejeune, J., J. Lafourcade, R. Berger and M. O. Rethore. 1965. Maladie
du cri du chat et sa reciproque. Ann. Genet. 8:11.
Lejeune, J., R. Berger, M. O. Rethore, L. Archambault, H. Jerome, S.
Thieffry, J. Aicardi, M. Broyer, J. Lafourcade, J. Cruveiller, and R. Turpin.
1964. Monosomie partielle pour un petit acrocentrique. C. R. Acad Sci. Paris
Lejeune, J., R. Berger J. Lafourcade, and M. O. Rethore. 1966. La
délétion partielle du bras long du chomosome 18. Individualisation d'un
nouvel état morbide. Am. Genet. 9:32.
Patau, K., D. W. Smith, E. Therman, S. L. Inborn and H. P. Wagner.
1960. Multiple Congenital Anomaly Caused by an Extra Chromosome. Lancet 1:790.
Reismann, L. E., S. Kasahara, C. Y. Chung, A. Darnell and B. Hall.
1966. Antimongolism. Studies in an infant with a Partial Monosomy of the 21
Chromosome. Lancet 1:394.
1. Presented at the International Seminar on Medical Genetics,
University of Alabama Medical Center, Birmingham, Ala. September 2, 1966.