Abnormalities of autosomes


Conférence de Sao Palo, 1962. In Mammalian Cytogenetics, 189-207, 1962. Ed. Pergamon, Oxford.


The continuous increase of human cytogenetic knwoledge impose the task of frequent reviews. To avoid the difficulty of an exhaustive catalogue, we can restrict the present talk to autosomal disorders and, to discuss the subject under the three main point of view of the actual research :

- the definition od syndromes

- the circunstances of the production of chromosomal abnormalities

- and the use wich can be made of the present knowledge.


I - Definition of autosomal syndrome

Autosomal syndromes can be viewed as three broad categories, more or less overlapping each other wich are :

- excess of genetic material,

- rearrangment of normal amout of material

- and less of some part of the chromosomal set.


A - Excess of genetic material

Most of the cases now published concern numerical abnormalities, wich by the presence of an extra chromosome realize excess of genetic material, essentiually by trisomy of an element.

Three conditions are well established and characterized by the presence of 47 chromosomes.


Due to the presence in triplicate of the chromosome 21 (L EJEuNE, 1,2,3).


For a big acrocentric of the 13-15 group (4)

Trisomy 17

For a chromosome of the 16-18 group, most probably 17 (5).

The number of cases observed in those three trisomies os great enough to individualize each of them chromosomically, as well as discussed here but it is at least interesting to note that children affected by trisomy (13) are alike each other in the same way that mongoloids do. The typical picture includes eye ball defects, polydactyly, congenital heart defect, and various difformities of lips, palate, skin and ears. Also a severe mental retardation and an extremely poor survival expectancy are main features of the disease.

In trisomy 17, typical difformities are also found, reminent occiput, low set ears, small mandibule, and malformations of heart, hands, and feet with severe mental retardation. The vital prognosis is also very poor.

Various other clinical syndromes have been recorded in correlation with the presence of an extra small acrocentric chromosome (like a 21 or a 22).

Sturge Weber Syndrome (HAYWARD, BOWER, 1961), Schizophrenia in a child (TuRNER, JENNINGS, 1961). Congenital hypotenia (DuNN, FORD, Ausberg, MILLER, 1961), and (ZELLWEGER, MIKADO, 1961) and mental deficiency in monozygous female twins (BIESELE, SCHMIDT and KAWLIS, 1962, and SCHMIDT, BIESLE ans LAWLIS, 1962) mongolism like syndrome in two sibs (VISLE WEHN and MOHR, 1962) and complexe malformations trisomy 17 like among two sisters (GASTAVSON, HAGBERG, FINLEY et FINLEY, 1962).

The identity of the extra piece in these instances is difficult to establish and, for the present moment, these observations are isolated cases we must await accumulation of comparable data before new syndromes can be isolated.

In spite of this early stage of the question a general consideration can be drawn :

- first, excess of genetic material is generally deleterious.

- secondly the bigger the extra element is, the more severe the clinical syndrome - For example chromosome 17 is bigger than 21 and trisomy 17 is much less viable than mongolism. chromosome (13) is a little bigger than (17) and trisomy (13) is and the failure to thrive is still more pronouced than in trisomy (17).

If we consider that, by all probability the genes contained in the extra chromosome are perfectly normal by themselves, it follows that excess of genetic information is harmfull by itself and we will come back on this question later.


B - Rearrangment of genetic material

Most of the rearrangments actually well established concern acrocentrics chromosomes, essentially, i. e. group 13-15 and group 21-22.

The overhelming majority of these structural changes is a fusion of the two acrocentrics chromosomes who combines to form a new metacentric one, with a minimal, but unavoidable loss of chromosomal material.

Depending upon the element involved, we can easely recognize four classes.

Translocation between big and small acrocentrics

The first example known in our spicies was that of a 22 - 13 type found in a retarded child with multiple lesions of the vertebrae (podyspondylie) (TuRPIN, LEJeuNE, LAFOuRCADE et GAuTIER, 1959).

This type was found again by MOORHEAD, MELLMANN and WENARD, 1961 in a family with speech and mental retardation, and found again in a father and his child (LEJEuNE, LAFOuRCADE, ALLOITEAu and TuRPIN, 1962) without phenotypic effect linked to this translocation.

A word must be said about the criteria of recognition of the chromosomes involved in this rearrangment. In fact the diagnosis is not based merely on the abnormal chromosome but also in the normal ones. For instances if two 21 and on 22 are present the translocated one is supposed to be a 22 and conversely.

In view of the difficulty of distinction between 21 and 22, the diagnosis remains rather uncertain. Nevertheless the genetic analysis can in some instances confirm the cytologic inference, as in the family of MORRHEAD, MELLMAN and WEINAR, in wich the 22 13 translocated mother had a typical mongolian child with a free 21 trisomy without the transolcated chromosome. In such a case, would have been the translocated acrocentric a 21, the mother would have possessed only one 21 free an non disjonction for one would have not been taking place at first meiosis.

The 21 (13) type seems to be much more frequent and was the first recognized in the determinism of heretable mongolism.

The 21 (13) translocation carrier can produce diplo 21 gametes if the free 21 does migrate at the same pole than the translocated chromosome.

The number of instances actually known is enough to allow an esytimate of the occurence of this event :

26 translocated mothers are reported in litterature, to have given birth of these 22 have 45 chromosomes exhibit the translocation with a balanced caryotype and a normal phenotype ;

21 are entirely normals (phenotype and caryotype)

and 30 are mongols with 46 chromosomes with some transolcation.

14 other normal children, non examined, are probably equally repartited in both categories, translocated ones and non translocated.

Taking for granted that the haplo 21 are not viable, the four most likely categories are probably equally distributed, wich would lead to conclusion that non disjonction of the 21 does occur every two division in a translocated carrier mother.

In the case of translocated father (12 instances recorded), 45 children are born with only one of them being a mongol. the segregation between translocated and non translocated being 20 against 14 with 10 other children not tested.

Translocation between two small acrocentrics

A translocation realize a new element looking like a 19-20 or a 16. When both elements are 21, the gametes to be formed can be only diplo 21 and nulle 21, that is give rise either to abortion or to mongolism.

With the families of FORSMAN and LEHMAN, 1962, HAMERTON, BRIGGS, GIANNELLI and CARTER, 1961, ZELLWEGER, 1962, MuRKHEIGE, MILLER and BREG, 1962, DALLAIRE, FRASER and BOYES, 1962, a total of 16 children, all mongols, are born from a carrier parent.

On the other hand in the progeny of a (FRACCARO, KAIJSER, 1960 and LINDSTEIN) mosaic father there was on mongol and 4 normals, the occurence of normal children being probably related to the fact that the father was a mosaic for the translocated chromosome.

It is quite likely that in some instances, the translocation can be of the 21 22 type, a fact cery difficult to establish cytologically.

Translocation between two big acrocentrics chromosomes

Most of these translocations do not have phenotypical consequences. The first case observed was associated with Klinefelter syndrome, and another one was a mosaic, half of the cells being 46 and half having the translocation (LEJEuNE, TuRPIN, DECOuRT). The genetic transmission of this type of translocation is examplified in a remarkable family of WALKER and HARRIS, 1962, in wich there are 9 carriers and 8 normals in the progeny of carrier ancestor - in this instances the chromosome cannot be an isochromosome 13 13 or 14 14 or 15 15, but obviously an hybrid beacuse of the lack of trisomy 13 syndrome in this extensive pedigree.

Trisomy 13 syndrome by non disjonction has observed in a 46 chromosomes boy born from a translocated father, OIKAWA, GROMuLTS, HIRSHORN and NOVINS, 1962, but most of the other cases (BuHLER, ROSSIER, VuLLIET, 1961, FERGuSON and PITT, 1962, COOPER and HIRSHORN, 1961, MAKINO SASAKI KIKuCHI and YOSIDA, 1962, there is no records of a subsequent non-disjonction.

Translocation between acrocentric and non acrocentric chromosomes

Another type of translocation involve an acrocentric and another type of chromosome. So PATAu, THERMAN, SMITH, INHORN and PIKEN, 1961, found a small fragment on a big acrocentric extra realising a probable partial trisomy in a child suffering from Sturge Weber syndrome. Also WISCK, TIJDINK and STOLTE, 1961, report a possible translocation of a part of a 21 or a 18 on a 21.

In a child with a clinical picture close to the 17 trisomy particularly with abnormal frequency of arches in digits prints, reported as typical by uCHIDA, 1962.

Also, a translocation between a 22 and 2, giving rise to a very big acrocentric, has been found in a phenotypically normal mother, and her typical Turner Haplo X daughter (Institut de Progenèse obs. n° 420).

Translocation between two non acrocentric chromosomes

Have been invoked by PATAu, THERMAN, INHORN, SMITH and RuES, 1961, in the Papillon Leage Syndrome (insertion of the 1), and BOOK, SANTESSON and ZETTERQVIST, 1961, in an apparently normal girl (2 10 translocation possible).


The circonstancies of apparition of autosomal disorders

The above review of autosomal disorders allow to make clear some particularities in the apparition of these anomalies.


Predisposing factors

Maternal age

Known since the beginning this to play a role in mongolism (SHuTTELWORTH, 1909), tha agying of the mother is also significant in the two other trisomic conditions. In trisomy 17, the mean age of 25 mothers is 35,2 ± 3,8 at the birth of the affected child, and in 13 instances of trisomy (13) it is 33,4 ± 1,7. Both these means differ significantly from the mean maternal age in the general population.

Previous structural rearrangments

As examplified by the progeny of the mother carrying a 21 13 translocation the risk of abnormal segregation of the normal chromosomes is severly increased by the presence of the translocated one. Roughly one in every two meiotic product received an unbalanced set.

This deleterious effect of structural rearrangment on the meiotic stability is possibly not restricted to the homologues of the chromosomes involved in the translocation. it can be remembered that we have encoutered the XXY constitution associated with 22 13 translocation in a family and with a 13 13 in another case, while a 2 22 was found in a Turner haplo X case.

These translocations being very rare by themselvesn abd sexual aneuploidies being rather uncommon also, it is hard to believe these combinations of autosomal translocation and sexual aneuploidies are merely coincidental. More precisly these three observations indicate that autosomal changes produce a general impairement of the meiotic stability. This fact is known in Drosophila in wich (STuRTEVANT, 1944) an autosomal rearangment increases the frequency of abnormal segregation of the X chromosome.

Particularities of chromosomes themselves

The overhelming majority of translocation involves acrocentric chromosomes. Even if an observational bias is likely (TuRPIN and LEJEuNE, 1961), this type of chromosome seems to have a special risk of undergoing rearrangments.

This risk acrocentrics is probably related to the satellites, because these nucleus organises being joined in the resting nucleoli, the acrocentrics lies very close together during whole interphase (OHNO, TRuJILLO, KAPLAN and KINOSITA, 1961).

Also, the relatives rates of DNA synthesis (THuLINE, MALDAL, LATTHA and ROWLEY, 1962) shows after this authors that 21 and 14 have the same thymidine uptake rythm, a functionnal particularity enhancing the possibility of fusion during the synthetic period.

Time of occurence of the aberrations

We know with certainty that in case of constitutional anomalies, the aberration has occured extremely early, so that the individual is homogeneous for it. Although the meiosis has been generally believed to be the critical period. Three are increasing evidence toward a later occurence.

The observation of mosaicism for trisomy 21, eight now reported (CLARK and al. 1961, FITZGERALD and al. 1961, GuSTAVSON and al. 1961, NICHOLS, 1961, WAREN and al. 1961, HAYASHI and al. 1962, RICHARD and al. 1962, LINDSTEN and al. 1962) are the proof that aberration can occur during the first clivage division of the zygote.

More precisly the discovery of monozygotic heterokaryote twins shows that this process can be as precoius as the two blastomatic stage, having given twins both non mosaic, one normal the other typical trisomic 21 (LEJEuNE, LAFOuRCADE, SCHARER, DE WOLFF, SALMON, HAINES et TuRPIN, 1962).

this type of gemellity previously observed in monozygotic twins one XY the other XO (TuRPIN, LEJNE, LAFOuRCADE, CHIGOT, SALMON, 1962) shows that both aberration, loss of a chromosome and gain of it can occur in mitotic process so early that instead of a mixed mosaic the result is two twins identicals but for the chromosomal abnormalities.

These accidents, after meiotic process, can a priori occur in much later stage and remain entirely unoticed due to the small proportion of abnormal cells.

in some instances, a selective advantage of the mutant cells can lead to the constitution of a "clone" developping inside the hert and being related to a neoplastinc growth.

Neoplastic mosaicism

In the case of granulocytic leukaemia a specific deletion of half the long arm of the 21 chromosome realizing the Ph1 chromosome, was first described by NOWELL and Hungerford, 1960, and widely confirmed since.

It is not the place here to discuss the causal relationship between the clinical disease and the chromosomal changes (TOuGH, COuRT BROWN, BAIKIE, BuCKTON, HARNDEN, JACOBS and WILLIAMS, 1962) and it is sufficient to say that all observations concord to show that the Ph1 clone does behave as if he was the stem of the leukaemia cells.

in the same context entire back of a small acrocentric in acute myeloid leukaemia has been reported (RuFFIE and LEJEuNE) and the parallelism between the two types of lesions is obviously very interesting.

Concerning the other carcinogenic changes, specific chromosome abnormalities are reported in many instances but no clear picture is presently emerging but for macroglobulinaemia with a big extra chromosome (BOTTuRA, FERRARI, VEIGA, 1961, GERMAN, BIRD and BEARD, 1961, BERNISCHKE, BROWNHILL and ENOuGH, 1961, PFEIFFER, KOSENOW and BMER, 1962). Also in myeloide metaplasia a deletion of a medium sized was found in three different causes. LEJEuNE et SALMON, 1961, GROuCHY and LAMY, 1962, SOLARI, SVERDLICK and VIOLA, 1962n but only the Ph1 chromosome is sufficiently established to be definitely considered as truly related to the disease.


Possible use of present cytogenetic knowledge


Clinical genetic and counselling

The use of caryotypic analysis in the diagnosis of congenital abnormalities is obvious. if we consider that more than 1/100 of the live birth are affected by a sexual or autosomal aberration, the clinical use of cytogenetics become an autotanting help to the paediatrician and to the obstetrician.

Also the potential danger of occurence of a disease in a particula family can be measured.

In the common autosomal disease, particularly in mongolism, the prognosis on the eventual recurrence of the disease in further offspring in an affected shipship can not be reasonnably estimated. translocated mother 21 13 have 1 chance in 3 of having another mongol, the translocated father having much lower risk. Hence a sound advice can be given and catastrophic family, like in case of 21 21 translocation will be prevented.

this progenetic use impose the systematical examinations of young mothers of mongols. Also analyses of various other conditions represent an enormous amout of work. This task requires the establishment of a cytogenetic laboratory in every big city of the civilized world.


Research prospects

The research prospects are still broader and with reason because we need better understanding of things, before trying to act upon them.

The most evident way is the analysis of genetic content of given chromosome.

Briefly this research can be undertaken on three directions in increasing order of precision :

- clinical manifestation

- biochemical troubles

- and antigenic or enzymatic changes

The clinical analysis, is the easiest in term of the tools used, wich is here medical observation actually available, but is also the less precise.

For example, the dermatoglyphics troubles observed in mongolism (specifically the simien crease) were tentatively related to hypothetical genes of the 21 chromosome after the discovery of the trisomy (Lejeune, 1960) but its existence in various conditions, trisomy (13) for example, or in pseudo hypoparathyroidiom, seems to show that even a so precise and localised morphological feature can be controlled by quite comple genetypic interaction.

In exceptionnal instances, heterokaryotic monozygotic twins, localisation of genic factors is possibly more practically. For instance the only phenotypic difference between the normal and trisomic 21 monozygotes previously cited is curled hairs in the normal and flat hairs in the mongol. This difference does not prove that alleles for flat hairs are carried by the 21 chromosome, but are indication that genes in the 21 can do something directly or indirectly on this phenotypical.

Also, accumulation of data on partial trisomies or on partial deletion could become a usefull tool in the detection of genes, sensitives to genic dosage.

The biochemical investigation is more difficult because we have fist to find what is to be looked for. our personnal trials, JEROME, LEJEuNE et TuRPIN, 1960, partly confirmed by O'BRIEN, GRSHEK and STREAMER, 1960, and in accordance with previous reports of GERSHOFF, MAYER and KuLCZYCKI, 1959, and recent work of O'BRIEN and GROSHEK, were printing in direction of a particular anomaly of tryptophane metabolism in trisomic 21 children.

The main difficulty in these investigations in wich negative results cannot be considered as definite, is the absence of simple biochemical test, like enzymatic reaction with purified extrait of tissue. This difficulty can be overseen in some very favorable instances, in wich the enzymatic process is easely detectable at cellular level.

It is known that alkaline phosphatase, cytologically detectable, as well as biochemically, is decreased in granulocytes of chronic myeloid leukaemia (VALENTIN W.B., BECK W.S., J. Lab. Clin. Med. 1951, 38, 39). The deletion of distal part of the 21 in this disease, and the triplication of the 21 in mongolism lead. ALTER, POuRFAN and DOBKIN, test the phosphatasic activity of the granulocytes of mongols. the increase of activity, found in 35 mongols, is highly significant and in the proportion of 3 to 2 compared to normals. Very soon, TRuLOWITZ, KIRMAN and MASEK, 1962, confirmed these observation in 22 mongolian girls and KINGS, COLLINS and BAIKIE, 1962, on 32 mongols boys and 28 mongolian girls.

These observations : diminution when part of the 21 is deleted (PH1 chromosome) and increase when 21 is in triplicate (mongolism), lead to the conclusion that genes controling alcaline phosphatase activity of polymorph could be located on the distal part of the long arm of the 21.

Trying to summarise the data now available on the 21, we can judge that this very small chromosome plays a very important role, as appears from the following table :

PolymorphsGeneral phenotype
Normal diplo 21normalnormal
Constitutionnal triplo 21low segmentation of nucleiMongolism
excess of alcaline phosphataseFrequency of acute leukaemia x 20
Clonal deletion of part of long arm (Ph1)Diminution of alcaline phosphataseChronic myeloid leukaemia
Clonal loss of a 21?acute myeloid leukaemia

This heuristic importance of chromosomal research in acquired disease will equal and possibly depass that of study of congenital chromosomal errors. It is at least likely that many genetic loss or gain, incompatible with embryologic development but compatible with celle survival do occur in neoplastic lines; and this new tool of approaching the general problem of cancerogenesis as just been put in action only vanguard battles having been fighted, and won.

As the general prospect of medicine remains the fondamental axima, "divinum est opus sedare dolorem", the ultimate goal of cytogenetics, after having been ontiological research on constitutional disease will be pathogenic study of the consequencies of chromosomal aberrations.

So, the next progress to be accomplished are toward palliative therapy. In case of genetic overdosage for example, there are no theoretical reason why deviated metabolism (ence discovered), could no be adequately controlled by appropriate means.

Even if this goal is very remote it represents the hope that cytogenetic instead of remaining a chromosomal taxenomy of diseases will someday become a tool to prevent and even alleviate the errors of the hereditary fatum.