Autosomal disorders

Jérôme Lejeune, M.D.

Pediatrics, vol. 32, No. 3. September 1963, 326-337.


The rapid growth of human cytogenetics imposes, as a corollary, the progressive restriction of the scope of a talk on this subject. Two years ago, a quarter of an hour was sufficient for a general survey; today, a whole hour is filled with one topic only. without being a prophet, it can he seriously foreseen that some day, a Blackfan Lecture restricted to "the genic content of the short arm of chromosome 22" will be considered a very brief summary of the current knowledge.

I would like to discuss the general implications of the available data on autosomal disorders. Chromosomes are divided into sex chromosomes and non-sex chromosomes, which are generally called autosomes. My subject can be considered under three points of view : the recognition of autosomal disorders, the mechanism of their production and, finally, the practical or heuristic use of this knowledge, as it enables more to be learned.


Syndromes determined by autosomal disorders


The Numerical Abnormalities

The numerical abnormalities are no longer limited to classic mongolism, with its 47 chromosomes and its trisomy for No. 21.(1, 3).

The trisomy for chromosome 17, in which there occurs a typical deformity of the head, a small mandible, low set ears, other nonspecific malformations of heart, hands and feet, and severe mental retardation,(4) is also quite classic. Possibly more than 25 different patients suffering from this disease are now known.

The 13-15 trisomy with eyeball defects, polydactyly, cardiopathy, and mental defect, together with deformities of lips, palate, skin, and ears (5) is also well established.

These three syndromes, each clinically distinct and rather easy to diagnose, once the physician becomes aware of their existence, are determined by an excess of genetic material. Hence we can keep in mind a preliminary conclusion: excess of genetic material is harmful, and the effect of genic dosage can be so marked as to prevent the development of the embryo.

Such an arrest of developrnent is possibly the reason trisomies for big chromosomes such as a 1 or a 3, for example, have not been observed. This hypothesis is confirmed by the lethal effect of total triploidy found in some abortion products (6, 7) and the existence of a diploid-triploid mosaic in a severely malformed infant, previously described (8).

Other possible instances of trisomies or, more precisely, of extra small acrocentric chromosomes, have been recorded in relation to various clinical syndromes, ranging from Sturge-Weber syndrome, (9) schizophrenia, (10) congenital hypotonia, (11) and mental deficiency, (12) to malformations rather close to mongolism (13) or to the 17 trisomy (14). In all these cases great uncertainty remains concerning the identity of the extra chromosome or even its etiologic significance (12, 15). Presumably, the apparently small acrocentric element reported in these instances is a chromosome modified as the result of translocation or deletion or of other rearrangements. This uncertainty precludes determination of what part of the genome is involved in the extra element.

This problem of chromosomal rearrangements is well exemplified only in instances of translocations between acrocentric chromosomes, perhaps because other translocations are selectively disadvantageous, or perhaps because some observational bias (16) has as yet prevented their recognition.


The Structural Abnormalities

Depending upon the size of the elements involved, the structural abnormalities can be classified in three categories.

Translocations between big and small acrocentric chromosomes are rearrangements between a member of the 13-15 group and one of the 21-22 group. For simplicity, any member of the 13-15 group can be symbolized by the number 13 in brackets [13], the translocation itself being noted by the mark ~ (Fig. 1).

The first example known in our species was that of 22 ~ [13] type. This was found in a retarded child with multiple lesions of the vertebrae (Polydysspondyly) (17).

This type was also found in a family with speech and mental retardation (18) and again in a father and his child (19) without phenotypic effect linked to the translocation.

A word must be said about the criteria of recognition of the chromosomes involved in these rearrangements, for the diagnosis of the anomaly is not based merely on the abnormal chromosome but on the normal ones also. For instance, if two chromosomes 21 and only one chromosome 22 are present, the translocated one would be supposed to be a chromosome 22.

In view of the difficulty of distinguishing between 21 and 22, this diagnosis remains rather uncertain. Nevertheless, the genetic analyses can in some instances confirm the cytologic inference, as in the family (18) in which a mother, carrying a 22 ~ [13] translocation, had a typical mongol child with a free 21-trisomy with out the translocated chromosome. In such a case, if the translocated acrocentric chromosome had been a 21, the mother would have had only one 21 free, and nondisjunction of this would have been unlikely.

The 21 ~ [13] type seems to be the most frequent translocation, and it was the first one recognized as a cause of heritable mongolism (85, 86, 87). In fact, a 21 ~ [13] translocation carrier can produce diplo-21 gametes if the free 21 migrates to the same pole as the translocated chromosome. Hence, after fertiIization, a hidden trisomy will be produced, two chromosomes 21 being free, the third one being involved in the translocation (Fig. 2).

Regular segregation can allow the transmission of the balanced translocation, so that the anomaly can be transmitted through generations in the same way as a dominant mendelian character.

A translocation between two small acrocentric chromosomes produces a new element. Because the long arms of the small acrocentrics are of roughly the same size as the arms of a 19-20 chromosome, the new element may be mistaken for such a chromosome. Translocations between small acrocentric chromosomes are of particular importance if the fused elements are both chromosome 21. A carrier of a 21 ~ 21 translocation can be phenotypically normal, although having 45 chromosomes only. But after meiosis, the gametes that are produced either contain the translocated chromosome (that is two 21) or have no 21 chromosome at all (Fig. 3). After fertilization, two types of zygotes will result, one-half carrying three chromosomes 21. (21-trisomic), the other half carrying only one (haplo-21). This last combination is probably lethal. The pregnancy involving haplo-21 eggs will end in a miscarriage, and all the surviving children will be mongols. In the literature, a total of 16 children born from a 21 ~ 21 carrier parent are known and all of them are mongols (20, 22, 23). In one family, (24) the sibship consisted of one mongol and four normal children, but the carrier father was in fact a mosaic, (25) or individual in whom more than one chromosome component could be found.

Translocations between two big acrocentric chromosomes, in most of the reported instances, have had no phenotypical consequences. The first case observed was associated with Klinefelter's syndrome (26); a second was a mosaic, with half of the cells normal, and half having the translocation (27). The genetic transmission of this type of translocation is exemplified in a remarkable family (28) in which there are nine carriers and eight normal individuals in the progeny of a carrier ancestor. In this instance the chromosome cannot be an isochromosome 13 ~ 13 or 14 ~ 14 or 15 ~ 15, but must be a hybrid 13 ~ 14 or, 13 ~ 15, or 14 ~ 15, because no case of trisomy [13] syndrome occurred in this extensive pedigree.

Trisomy [13] syndrome by nondisjunc-tion has been observed in another family. A boy with 46 chromosomes was born to a father carrying a [13] ~ [13] translocation (29). In the other families is no record of a subsequent abnormal segregation.

Other types of translocations involve an acrocentric chromosome and another type of chromosome. A small extra fragment on a big acrocentric, producing a probable partial trisomy, was observed in a child suffering f rom Sturge-Weber's syndrome (34). We recently observed a child with an extra piece on a chromosome [13]; with a clinical picture resembling that of the 17 trisomy, particularly in the abnormal frequency of arches in the digital prints, reported as typical of the trisomy 17 (35). A translocation between chromosomes 22 and 2, giving rise to a very big acrocentric chromosome, has been observed in a phenotypically normal mother; her daughter with a typical haplo-X Turner's syndrome, and two of her normal XY sons (36). Other translocations between nonacrocentric chromosomes have been reported in the oral-facial-digital syndrome (insertion on the 1) (37) and in an apparently normal girl (2 ~ 10 possible) (38).

Fig. 1 . Translocation 21 ~ [13]. During the time a 21 and a [13] lie close together, a break may occur near the centromere of each chromosome. The fragments can then recombine, either as in the original chromosomes (no detectable effect) or in a rearranged pattern producing a new hybrid chromosome: 21 ~ [13] and a centric fragment bearing the satellites. Varying amounts of chromosome material can be attached to the centric fragment, which is secondarily lost. The quantity of genes involved in this loss determines the eventual phenotypic effect of the translocation. This general process of rearrangement between acrocentrics is commonly referred to by the term "centric fusion," which is a little misleading.

Fig. 2. Progeny of a carrier of a 21 ~ [13] translocation. In this simplified diagram, each chromosome is represented by one chromatin strand only, for sake of simplicity, although two chromatin strands are actually present at meiosis. The progeny shows the four types of possible children, of which only the three first are effectively observed, the type Haplo-21 being not known (probably lethal).

Fig. 3. Progeny of a 21 ~ 21 translocation carrier. At meiosis the new chromosome 21 ~ 21 has no homologue and must go directly to one pole, the other cell being entirely deprived of a 21 chromosome. As seen, the progeny can only include mongols or miscarriages. Note: In case of a 21 ~ 22 translocation, the transmission would be analogous to the case of a 21 ~ [13] translocation (Fig. 2).


The mechanism of production of chromosomal aberrations

Although the mechanisms are poorly known, we have at least some indications concerning predisposing factors and the time of occurrence of the aberration can be determined precisely in some particular instances.

Table I : Progeny of 21 ~ [13] translocation carriers.
Translocation CarrierNormal; 46 ckr.Normal; 45 chr. ; Translocation CarrierMongols; 46 chr.; Triso. 21 by TranslocationNormals; Unspecified KaryotypeTotal Children
Mothers (26)2122301487
Fathers (12)142011045


Predisposing Factors

Maternal Age:

The first predisposing factor to be recognized is the well-documented effect of maternal age on the frequency of trisomy 21 (39). This effect, observed long before the chromosomal anomaly was detected, is also found in other trisomies. In 25 cases of trisomy 17, the mean age of the mother at birth of the child was 35.2 ± 3.8 years, and in 13 instances of trisomy [13], the mean was 33.4 ± 1.7 years; these two means are statistically different from the general mean maternal age at time of delivery in western populations, which is between 26 and 27. This predisposition to abnormal segregation in relation to the aging of the mother can be compared to analogous data known in drosophila. In that insect, the older the mother, the greater is the risk of mitotic errors of segregation of an X chromosome, generating mosaic gynandromorphs by the loss of a ring X chromosome (40, 41).

Structural rearrangements:

The evidence that structural changes favor the abnormal segregation of the chromosomes involved in the change is obvious from data now at hand on the progeny of 21 ~ [13] translocation carriers. Briefly, the available literature includes 26 mothers carrying such a translocation, who had a total of 87 children. Three categories of children are expected : entirely normal ones, normals carrying the translocation, and mongols with the translocation. Table I sumiarizes the facts.

There is no statistical difference between the two groups of normal children and the group of mongols. If we assume that the haplo-21 combination is produced as frequently as the trisomy-21 condition, but is not viable, we can thus consider that one in every two divisions at meiosis gives rise to abnormal segregation of the free chromosome 21.

The very different figures in the progeny of fathers with translocation indicate that its risk of abnormal segregation could be such lower in the male, but the alternative hypothesis that unbalanced spermatozoa are less efficient than normal ones cannot be definitely rejected.

Besides this direct effect on the segregation of the chromosomes actually involved in the translocation and their nor-mal homologues, the likelihood of other chromosomes segregating abnormally might be affected. It is difficult to believe that the association between sex chromosome abnormalities and autosomal rearrangements cited above (XXY plus 14 ~ 15 transl) (26), (XXY plus 22 ~ [13] transl) (19), and (XO plus 2 ~ 22 transl) (36) can be purely fortuitous. Individually these changes are very rare, and their concurrence in these individuals leads to the tentative conclusion that autosomal rearrangements can increase the probability abnormal segregation for the sex chromosomes, which are not themselves inolved in the structural change.

This hypothesis can be related to the observation made in drosophila, that structural changes in autosomes do increase the frequency of abnormal segregation of the X, (42) especially if the X chromosomes themselves show structural changes (43). Also non random segregation of the Y chromosome can be produced by autosomal rearrangements (44).

It is not impossible that such structural changes could be more general than is now suspected, and that familial accumulation of various chromosomal disorders (45, 47) could be related to some undetected structural rearrangements in these families. Also, the hypothesis that one chromosomal imbalance increases the risk of another occurring in the same cell line could account for such complex conditions as XXX (48), XXXY (49) or XXXX (50) or XXXXY (51), or XXYY (52), or for the associations of two different disorders: 21 trisomy + XXY (53, 54), 17 trisomy + XXX (55), or 21 trisomy + 17 trisomy (56).

Peculiarities of Chromosomes Themselves:

The overwhelming majority of translocations involving acrocentric chromosomes show that, even though an observational bias is likely (16), this type of chromosome does have a special risk of undergoing rearrangements. Also, the relative harmlessness of loss of satellites shows their low content (if any) of genetic material.

The increased risk of acrocentric chro-mosomes undergoing a rearrangement is probably related to the presence of satellites. Because these bodies are joined in the resting nucleoli, the acrocentric chromosomes lie very close together during the entire interphase (57) and thus are more exposed to exchanges than other types of chromosomes.

Finally, the relative rates of DNA synthesis seem to show that chromosomes 21 and 14 have the same thymidine uptake rhythm, a functional peculiarity enhancing the possibility of fusion during the synthetic period (58).


The Time of Occurrence

With the general acceptance that non-disjunction was the basic mechanism for production of chromosomally unbalanced zygotes, the time of the accident was believed to be during the meiotic process, either at the first (reductional) division or at the second (equational) one. The meiotic accident is surely at work in case of trisomies appearing in the progeny of mothers (59) affected by trisomy 21 or in the progeny of translocation-carriers.

Nevertheless, it may be dangerous to consider that all autosomal or sex aneuploidies result from fertilization of an unbalanced gamete by a normal one or by fusion of two unbalanced gametes. One evident exception is the existence of mosaic individuals bearing two different cell lines, one normal, the other unbalanced. A few instances of diplo 21/triplo 21 mosaic individuals are now reported (60, 61); in sexual disorders, the mosaicism is much more frequent. In an exceptional observation, a chromosomal mosaicism for the sex chromosome was related to a mosaicism of the erythrocytes, for two different autosomal blood groups. This raises the possibility of fusion of two different zygotes in the formation of one individual (62).

More generally, the mosaics are genetically homogeneous, except for the chromosome concerned. The most likely explanation is that the abnormal segregation of the chromosome occurred after the zygote was constituted, during the early cleavage in the blastomere stage. The discovery of monozigotic heterokaryotic twins shows that this process can be as early as at the two blastomere stage. One observation concerned a couple of monozygous twin boys, one a typical trisomic 21 mongol, the other a perfectly normal individuals (63).

This type of twinning, previously observed in monozygotic twins, one XY, the other X0 (64, 65) shows that a mitotic error, just after karyogamy, can result in twins who differ by only one chromosome. These heterokaryotic monozygous twins are entirely comparable to mosaic individuals, the difference being that the two cell lines separated, each to form an individual, instead of remaining mixed in only one embryo.

Another reason to suspect that mitotic errors, after fertilization, can occur as early as karyogamy itself is that both sets of chromosomes, having lived for years in two entirely different individuals, are suddenly put together in an entirely new environment at least for the set coming from the father. That the beginning of the life together could be difficult, even at the cellular level, does not seem too surprising.

In this respect, it is to be remembered that the maximal loss of X chromosomes induced by x-rays in mice is observed (66) at the moment of the fecundation of the egg. Moreover, the chromosome must frequently lost is net the maternal X but the paternel one (67).

Another consideration about the time of occurrence of aberrations is related to their clinical manifestation. Late changes, producing an aneuploid cell line in an embryo may well remain entirely unnoticed if the proportion of aneuploid tells is too small to provoke detectable morphological or biochemical anomalies in the individual. Another phenomenon could also be at work: a selective advantage would favor the euploid line, if the aneuploid one were not represented from the first by a sufficiently large number of cells.

The postulate of a selective barrier against chromosomally unbalanced cells newly produced in the organism is a particular aspect of the general law of homeostasis. Some exceptions to this law are, however, already known, such as the appearance, late in life, of mutant clones having a particular chromosomal aberration. This is observed in granulocytic leukemia (68-71) or in Waldenstrom macroglobulinemia (72, 73). That the mutant line possesses a selective advantage, is apparent from the malignancy of these conditions. The chromosome imbalance of most invasive cancers is possibly related to a similar mechanism, but this is too broad a question to be discussed here (88).


The use of cytogenetic knowledge

One of the basic questions in any discipline is the value of the knowledge already gathered. What are its possible uses?

Human cytogeneticists are not collecting rare syndromes in order to realize a kind of chromosomal taxonomy of congenital deformities. The real goals of this type of research are two: One is its immediate application for practical medicine, the other is its use in raising questions and suggesting their solutions. This second, heuristic, use may be the more important goal.


Practical Use

The first evident application is in the refinement of diagnosis and the establishment of the chromosomal basis of constitutional disease. If one considers that more than 1% of live births are affected by a detectable chromosomal abnormality, the task of cytogeneticists in helping the clinician is enormous. Although sexuel disorders are excluded from this brief review, their early recognition and the decision concerning their therapeutical correction is so important that it can be safely stated that, in a few years, karyological diagnosis of sexually ambiguous cases will be considered as a routine step.

Also, genetic counselling can be directly based upon cytogenetical investigation, especially in cases of translocation. The fact, previously quoted, that nearly one third of the progeny of a mother carrying a 21 ~ [13] translocation is composed of mongols, indicates that every family in which one mongol child is born should be examined, especially if the mother is young. In this case, detection of translocation carrier parents could help to prevent the recurrence of the disease. Also the catastrophic progeny of the 21 ~ 21 translocation carriers could be prevented.

More broadly, the discovery of a translocation, even perfectly balanced, could be considered as a real eugenic danger; possibly routine examination of the chromosomal set will be considered some day as a useful complement of the actual prenuptial medical examination.


The Heuristic Use of Chromosomal Aberrations

This use can be envisaged for theoretical research as well as for medical application. Determining the location of the individual genes on the human chromosomes, the "mapping" of the chromosomes, is the most obvious theoretical task. The use of small deletions occurring in some translocations (16) as well as the interpretation of eventual partial trisomies (34) have been proposed as tools for such research. In these cases, a search was made for evidence of a deficiency or excess of functioning genes that could be correlated directly with the cytologic evidence of an abnormal amount of given chromosome.

The main difficulty lies in the quality of the characters chosen as "markers." For example, the dermatoglyphic anomalies observed in mongolism (specifically the Simian crease) were tentatively related to hypothetical genes located on the chromosome 21 after the discovery of the trisomy (59). However, their existence in other different constitutional anomalies, the trisomy [13] for example, or in pseudohypoparathyroidism, investigated in Boston, seems to show that even such a precise and localized morphological feature can be controlled by complex genotypic interaction.

Heterokaryotic monozygous twin studies could possibly be used for genic localization; for instance, besides the symptoms of mongolism the only difference found in the two twins previously mentioned was that the mongol had straight hair while the normal had curly hair. This discrepancy could be taken as a presumption that the gene governing curly hair is sensitive to genic dosage of chromosome 21, but is not a proof that the "curl gene" is on the 21 chromosome.

Notwithstanding these difficulties there is no doubt that the accumulation of data on partial trisomies or partial deletions will become a useful tool in investigating the alleles which are sensitive to genic dosage.

Biochemical disorders are much easier to deal with, once they have been recognized. The best example now available is possibly that of alkaline phosphatase. In order to understand the data, we must consider the Philadelphia chromosome observed in granulocytic leukemias. In this disease, it is known that there is a decrease of the activity of alkaline phosphatase in the granulocytes and also that leukemic cells carry a deletion of the long arm of one of the chromosomes 21 (68). The hematologic evolution of the affection shows a strong correlation with the relative number of cells carrying the Ph1 chromosome in the peripheral blood (69).

It was thus interesting to know if mongols who carry the trisomy 21 (that is, present in triplicate the segment which is lost in the Ph1 chromosome), have a higher enzymatic activity than normal people. This is indeed the case (74). The alkaline phosphatase activity of granulocytes of mongols is approximately 1.5 times greater than the control value. Thus the 3 to 2 ratio, found for chromosome 21, applies also to the enzyme activity. Further publications on this comparison of mongols and normal children have substantiated this observation (75, 76), and even demonstrated that this excess of enzyme is not due to the appearance of younger polymorphonuclear cells (77), another hematologic trait typical of trisomy 21 (82). These relationships are summarized in Table II.

Table II : anomalies of the 21 chromosome
Polymorpho-nuclear CellsGénéral Phenotype
Normal (diplo 21)NormalNormal
Constitutional Triplo 21low segmentation of nuclei (82)Mongolism twenty-fold increase of acute leukemia frequency (84)
Clonal Deletion of part of long arm (Ph1) (68)Diminution of aïkaline phosphatase (83)Chronic myeloid leukemia
Loss of a 21 (70)(?)Acute myeloid leukemia

Two preliminary conclusions are suggested by the data in the Table. First, there is probably on chromosome 21 a segment containing genes Which normally control leukopoiesis. Excess of them raises the risk of acute leukemia, a partial loss of them is linked with chronic granulocytic leukemia. The existence of Haplo 21 clones in some cases of myeloblastic leukemia could mean that the degree of the loss can influence the evolutive type of the disease. Secondly, the correlation between alkaline phosphatase activity and the chromosomal dosage of chromosome 21 raises the problem of the localization of an "alkaline phosphatase gene" an the distal part of chromosome 21. It has to be stressed that file present data do not prove that the structural gene is on this locution, but they do demonstrate that "same gene (or genes) doing something" to the alkaline phosphatase is (or are) there.

Such inferences from somatic aberrations will probably extend rapidly to other forms of clonal mutations. There are reasons to believe that many changes can be observed in tissue culture which would not be compatible with embryonic development. This research would give a double reward, one the study of chromosomal changes of the type occurring in cancerous tissue, the other a contribution toward the mapping of genes. Even in established cell strains, sudden modification of alkaline phosphatase activity in clones has been reported (79). This could furnish another source of information to relate this enzymatic fonction to chromosomal changes, if modification of enzyme activity could be correlated with chromosomal changes.

Another way of mapping, closer to the conventional manner of linkage study, is to follow a translocated chromosome through generations in large families to see if it does carry a genetic marker, in particular a blood group factor. As yet no definite statement can be made about results obtained with this method which some day will undoubtedly allow the autosomal localization of marker genes; for example, the ABO locus may possibly be located on a [13] or 21 chromosome (78).

From these data, chromosome 21 would seem a very important chromosome, in fact, the autosome about which we know the most. Yet, in a paradoxical way, this state of affairs probably means also that the 21 is one of the less genetically important chromosomes, precisely for the reason that it can suffer so many changes and still permit the development of the embryo or the survival of a clone. Indeed, if gross changes involved really basic genes, such changes would not be compatible with life.

Research into Pathogenesis: research an the pathogenesis of syndromes is so far in the future that it may be considered utopian to mention it in this context. Briefly, the main goal of such research, besides that of eventually localizing a few genes on some chromosomes is the understanding of the biochemical mechanism by which an excess of genetic material, otherwise perfectly normal, can produce a very severe abnormality.

As a tentative hypothesis, the law "one gene-one enzyme," could be extended to a quantitative assessment: "two genes-two enzymes in diploids, three genes-three enzymes in trisomics." The deleterious effect of this excess of enzyme in trisomics might be an unfavorable increase in same metabolites and/or a relative deprivation of others (by accelerated turnover of the metabolite by a side reaction).

No metabolic abnormalities have yet been found in trisomy 13 and trisomy 17 and systematic, studies have yielded few significant results in mongolism. Nevertheless, in this disease there are indications that a disorder of the intermediary metabolism of tryptophane may be of importance (80, 81). While the hypothesis of an accelerated turnover has yet to be solidly based on observational data, the gene/enzyme dose relationship found for alkaline phosphatase is at least in agreement with such a scheme.

It is much easier to block a specific enzyme than to replace a missing one. Thus, a trisomic condition might be more favorable for future therapy than is now sup posed. It is for the moment purely theoretical to speculate on this prospect. Nevertheless, a relation bas to be established between chromosomal accidents and their metabolic consequences before any palliative therapy can be thought of.

Then and only then will cytogenetics be able to alleviate these errors of partition of the human patrimony and to help those disabled patients who are, in true sense of the word, the most disinherited of the children of men.



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