Only in the past year and a half or so have congenital diseases due to
chromosome aberrations taken their place in the nosology of human medicine.
Their discovery was made possible by technical advances and especially by the
in-vitro cytologic cultures of Alexis Carrel. These methods first enabled the
number of human chromosomes to be calculated as 2n - 46 (33). Regardless of the
races studied and the technics used, this basic observation has not been
The arrangement of chromosomes observed in mitosis (late prophase or
prometaphase) allows us to distinguish the following criteria for each :
1. Ratio of total length to that of the neuter genome (A + X);
2. Ratio of the length of its shortest arm to its total length
3. Presence or absence of trabants (called "satellites" by some
authors). In the calculation of the above-mentioned ratios, this factor has not
been taken into account, nor has the heterochromatic support of these
On the basis of a critical study of the data furnished by Buckton,
Jacobs and Harnden; Chu and Giles; Fraccaro and Lindsten; Lejeune and Turpin;
Levan and Hsu; and Tjio and Puck, a committee meeting in Denver in April, 1960,
proposed a numerical system for the nomenclature of human chromosomes from 1 to
22, the X and the Y chromosomes retaining their literal designation. This
system has the advantage of being internationally understandable and is not the
creation of one author. In comparison with the nomenclature by means of
letters, it has the disadvantage of not being figurative. In the course of this
paper we shall follow the original designation by its international equivalent,
in accordance with the tables established in Denver.
At present, human chromosome aberrations fall into 2 major categories:
anomalies of number and translocations.
Anomalies of number, which are comparable with those anomalies that
occur experimentally in accordance with the mechanism of nondisjunction,
comprise trisomic individuals (2n + 1) and deficient individuals (2n - 1) ;
these are the poikilosomic anomalies.
The translocations known at the present time involve whole chromosomes
more often than segments of chromosomes.
Aberrations of number (poikilosomias)
This type of aberration may involve either autonomies or
The prime example of a human chromosome aberration that is
responsible for a congenital disease is trisomic mongolism (22, 23). This
discovery confirmed a theory that had been advanced independently by several
authors (3, 6, 36, 42). According to the nomenclature used by the French
authors (22), this is a Vh trisomia (21) . In rapid succession, this aberration
was confirmed in a child presenting Klinefelter's syndrome and mongolism (7),
then in 5 mongoloid infants (18), and finally in 3 others (4). Each author made
use of his own personal technic. The samples for the laboratory tests were
taken from the fascia lata, the skin or the bone marrow.
At present, trisomic mongolism, so far as we know, has been
established every tine confirmation of the diagnosis was sought. Further on,
however, we shall see that it can be masked by a translocation.
While opening a new chapter in the classification of human disease,
trisomic mongolism also has disclosed the conditions for the appearance of the
1. An incidence of approximately 20 per 10,000 births, which is more
in line with that of experimental nondisjunctions (6 to 7 per 10,000) than with
that of punctual mutations (20 per 1,000,000) ;
2. Consistent concurrence in identical twins, but usually lack of
concurrance in fraternal twins ;
3. Unusual recurrence of the disease in siblings (40), the reason
for which might lie in the mosaic development of siblings or in a translocation
4. Increased incidence with aging of the mother, a fact which is in
accord with experimental findings, since the incidence of nondisjunctions
induced by x-rays increases with aging of the ovules ;
5. The risk that a mongoloid mother and a nonmongoloid father will
produce a mongoloid child as readily as a nonmongoloid one, since the ovocyte
44A + 2X + Vh must in principle produce 22A + X + Vh and 22A + X ovules in
equivalent proportion. This possible transmission is the first clinical example
of a chromosome aberration being inherited.
Moreover, the hypothesis of a genetic imbalance induced by trisomia,
promoting by its action upon the modifying genes the resurgence in mongoloids
of certain dermatoglyphic characteristics that are closer to those of the lower
primates than to those of the previously evolved hand of the anthropoids,
merits mention (38, 39). We would propose a neologism to describe this
phenomenon i.e. "phyloteny" (phyle, tribe or race; and teino, retain).
With regard to the greater incidence of the minor signs of the
so-called "mongolism series" (mucocutaneous signs) among the nonmongoloid
collateral relatives and ascendants of mongoloid individuals (30, 35), it is a
subject which up to the present time has been interpreted in two different ways
that are not mutually exclusive.
For some authors the phenomenon is obviously the result of a
statistical bias, as the only individuals counted are allegedly precisely those
retarded ones which have the mucocutaneous stigmata transmitted to them by
their parents. Quite obviously, if one were to discover retarded individuals
with trisomic mongolism but without mucocutaneous stigmata, this would be proof
of a statistical bias, but such subjects remain to be found.
For other authors the phenomenon is a genuine one which they believe
to be the expression of a certain genetic predisposition to chromosome
aberrations. In fact, there is a case of mongolism and Klinefelter's syndrome
coexisting in the same subject (7) ; the simultaneous presence of mongolism,
Klinefelter's syndrome (24) and Turner's syndrome (1) has been observed in
siblings. Also, it is known that in Drosophila melanogaster the presence of a
minute gene on the X-chromosome frequently causes the loss of this chromosome
in the course of development.
In addition to trisomic mongolism, other examples of autosome
trisomia have been reported. These are isolated observations combining complex
malformations and retardation of intellectual awakening from the earliest
months of life.
One girl who attracted attention because of her numerous minor
anomalies, congenital heart disease and retarded mental de velopment was found
to have chromosome 17 (17) represented 3 times (5) ; the specimen for the
cytologic examination had been taken 3 hours after death intervened at the age
of 4 months and 10 days.
Another girl, in whom mental retardation was accompanied by harelip
and cleft palate, apparent congenital absence of the eyes and polydactylism of
the left foot had a medium acrocentric chromosome represented 3 times (29).
Prior to recording this case history, the same authors had studied a boy and a
girl, both with multiple malformations, heart disease and mental retardation,
and had found an extra chromosome that " seemed to belong to group E " of their
The discovery of trisomic mongolism raised two questions from the
very start: the nature of the chromosome identified and the reason for its
appearance. The nature of the chromosome hardly lent itself to discussion,
since it was identified as chromosome Vh (21), and the "accessory" chromosomes
(B of Zea Mays, for example) are genetically inactive and of variable size.
Its origin was suggestive, by experimental analogy, of the
nondisjunction responsible for the appearance of the triploid IV fly. The proof
of this would be furnished by the observation of a trivalent at meiosis in an
individual with monogolism. On the other hand, the karyotype study of the
progenitors of mongoloid subjects and of those with Klinefelter's or with
Turner's syndrome does not appear to have brought out, according to the
published data, anomalies of their karyotype (10), although there are examples
of 2A-X female mice that may be fertile. Upon investigation, the karyotype of
the normal fraternal twin brother of a mongoloid child appeared to be normal
On the other hand, in order to explain the repeated birth of
mongoloid children-for example, 4 or even 5 out of 8 children born to parents
neither of whom is mongoloid (40) - a germinal mosaic or a translocation would
be a highly acceptable answer.
After the discovery of mongolism as an autosome aberration, there
followed that of the gonosome aberrations.
These aberrations could be anticipated, since we knew of individuals
with gonadal dysgenesis of female morphology contradictorily endowed with a
male sex-chromatin pattern (negative chromatin) (80 % of the cases of Turner's
syndrome), and also of individuals with gonadal dysgenesis of male morphology
contradictorily endowed with a female sex-chromatin pattern (positive
chromatin) (80 % of the cases of Klinefelter's syndrome).
First there was a case of Klinefelter's syndrome with positive
chromatin and the genetic formula 44A + XXY, published by Jacobs and Strong
(21). This fact was quickly confirmed, and we ourselves have collected 10
Next, a case of Turner's syndrome with negative chromatin and the
genetic formula 44A + X, published by Ford, Jones, Polani, de Almeida and
Then, justifying the theory of nondisjunction, so to speak, Jacobs
et al. (19) published the case history of a woman whose female morphology was
not very pronounced, who had experienced her menopause very early and had a
"super-female" karyotype (44A + XXX).
Complementary studies carried out in subsequent months disclosed the
following specific findings :
1. The gonosome formula opposes two etiologic varieties of Turner's
syndrome: the 44A + X variety, with negative chromatin, and the 44A + XX
variety, with positive chromatin.
2. There are cases on hand (12) of 44A + X individuals with positive
chromatin that reopen the question of the interpretation of the chromatin
3. The gonosome formula XXY of Klinefelter's syndrome proves that
the masculinizing effect of the human Y-chromosome is superior to that of the
Y-chromosome of Drosophila, since the XXY fly is a fertile female. A case of
possible Vh/Y translocation (43) described below does not contradict this
4. In the study of the bone marrow of a case of Klinefelter's
syndrome, an XX/XXY mosaic formula was found (9). In another case, examinations
showed that about two thirds of the karyotypes had 47 chromosomes and one third
had 48 or 49 (skin biopsy) (2). Examination by means of tissue culture of the
bone marrow of an intersexual revealed an XY/XO mosaic with a Y-chromosome of
abnormal dimensions (16).
5. The karyotype study of intersexuals has the great advantage of
making it possible to separate the above varieties with abnormal gonosome
formulae from the following varieties: male pseudohermaphrodites with the
formula 44A + XY,(20, 25, 32) female pseudohermaphrodites with the formula 44A
+ XX (44), true hermaphrodites with the formula 44A + XX (13, 17, 45) and
In a clinical case of female eunuchoidism, confirmed after
discussion as a case of "pure gonadal dysgenesis," the karyotype led to this
pathologic condition being assigned the genetic formula 44A + XY (15).
According to the authors of another case history, which was difficult to
interpret but in this instance was of an anatomicoclinical nature, the pattern
was that of a "gonadal dysgenesis with the formula 44A + XY (28)."
The human karyotype can be modified by means of translocations that
are compatible with life. In the cases known up to now this involves
translocations among acrocentric chromosomes (centromere fusions). The
pathologic consequences of such translocations seem to be apparent in some
cases but not in others. This variability probably depends on the extent of the
loss of genetic material that accompanies the elimination of a centromere.
The possibility of clinically unapparent translocations poses the
problem of a possible morphologic variability of the human karyotype.
Considering the very high number of normal human karyotypes that already have
been identified, it does not appear that this variability could be very
Translocations are either isolated or are associated with karyotype
anomalies, the pathologic effects of which are known.
The first translocation (41) was discovered in the karyotype of a
child 4 1/2 years old, in whom trophic failure (abiotrophy), complicated by a
moderate but definite retardation of psychic development, was accompanied by
complex vertebrocostal malformations. We gave this complex condition the name
of " Polydysspondylia ".
In the absence of any other demonstrable etiology, a cause-andeffect
relationship between the translocation and the syndrome observed was discussed.
Only the discovery of a new example of this pathologic condition can confirm
this hypothesis. A centromere fusion T1 ~ Vs (13-22) gave the karyotype an
apparent 42A + Vs + (T1 ~ Vs) + XY formula.
Another variety of translocation (43) was observed in the karyotype
of a child who was, to all appearances, afflicted with a gonadal dysgenesis "
of the seminiferous tubules " as described by Grumbach (13) : clitoris in the
form of a penis ; urogenital sinus ; intraabdominal male genital apparatus ;
involution of Sertoli's cells in the seminiferous tubules with no spermatogenic
activity ; a small retrovesicular mass reminiscent of an exceedingly
hypoplastic uterus ; positive chromatin (55 %) ; dextrocardia. Following
discussion, the most reasonable interpretation of the karyotype anomaly
appeared to be that of a terminal translocation of a Vh segment (21) on the
Y-chromosome. The segmental deficiency of the Y-chromosome accompanying the
loss of the centromere is believed to have led to the upsetting of the balance
be tween the masculinizing and the feminizing factors in favor of the latter.
The chromosome aberrations that are responsible for mongolism or for
Klinefelter's syndrome can be accompanied by translocations.
An example of the first possibility (10) gave an apparent chromosome
number of 46 to a mongoloid karyotype, trisomia being masked by a translocation
between Vh and T (21 and 13,14 or 15).
An example of the second possibility 24 gave an apparent chromosome
number of 46, by virtue of centromere T ~ T fusion (14-15), to a 44A + XXY
karyotype characteristic of Klinefelter's syndrome.
In either case, no mention is made of pathologic signs connected
with the translocation. The problem unquestionably deserves further, more
detailed study. It cannot be resolved unreservedly in the negative.
Moreover, it is not impossible that a nondisjunction which is
already complicated by another (mongolism and Klinefelter's syndrome) may also
promote a translocation.
In all likelihood, the list of congenital diseases due to chromosome
aberrations is not yet complete. To the examples of aberrations that can be
explained in terms of nondisjunction or of terminal translocation, perhaps it
will be possible to add examples of other gross anomalies (numerical anomalies
and significant omissions or duplications). The present-day methods of analysis
being what they are, the alterations that do not cause significant morphologic
anomalies (intercalary translocations, minor duplications or omissions,
inversions) may easily escape notice.
In addition, these analyses must take two difficulties into
consideration. The first involves the possible coincidence of two aberrations :
for example, a translocation masking a trisomia. The other involves the
possible appearance of anomalies in the culture medium; the often numerous
polyploid cells ; the development of a clone with a 2n-1 karyotype ; even the
appearance of a slight but definite polyteny that doubles the length of all the
elements of the genome and allows one to discern a periodic structure of
associated chromatids (46).
Up to the present time, aberrations of number have been found to be
responsible for semifatal or fatal conditions. They cause severe alterations of
bodily development and more or less severe disorders of mental development.
The consequences of translocations are in proportion to the genetic
density of the segment that has been eliminated. This principle of experimental
genetics still remains to be demonstrated as valid in man. Certain facts are
conducive to accepting rather than rejecting it.
The systematic investigation of sex-linked characteristics
(achromatopsia, for instance) in families comprising an individual with a
gonosome aberration would permit the identifications of the parent responsible
for the nondisjunction. The accumulation of data would even make it possible to
discover the relative fertility of the various chromosome types of gametes
Following the example of mongolism, some chromosome aberrations are
perhaps capable of causing anomalies in the nuclear cytoplasm with morphologic
repercussions. It is known that the nuclear segmentation index* of the
polynuclear cells in mongolism 34 is abnormally low, and significantly so. This
peculiarity, the consequence of which is a shift to the left in Arneth's
formula, is a further justification for karyotype analysis if the condition is
accompanied by a congenital malformation.
Chromosome aberrations have opened a new nosologic chapter in human
medicine. The initial results are tending to overcome a significant lag in the
study of human heredity as compared with that of experimental heredity.
(*) The nuclear segmentation index is equal to the mean number of
nuclear segments per polynuclear neutrophil.
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