Congenital Human Anomalies Due to Chromosome Aberrations.

Jérôme LEJEUNE, Raymond TURPIN, M.D.

Congrès - Londres - 1961.Some Genetic Aspects of Congenital Defect pp.69-76.


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 disputed.

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 (centromerel index);

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 trabants.

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 gonosomes.



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 disease :

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 classification.

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 (42).

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 personal examples.

Next, a case of Turner's syndrome with negative chromatin and the genetic formula 44A + X, published by Ford, Jones, Polani, de Almeida and Briggs (8).

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 corpuscle.

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 observation.

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 without mosaicism.

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 great.

Translocations are either isolated or are associated with karyotype anomalies, the pathologic effects of which are known.


Isolated translocations

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.


Associated translocations

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.


Further possibilities

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 (31).

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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