In 1866, when Langdon-Down (1) published his historic description of a
group of mental defectives whose physiognomy resembled features normally
exhibited by the Mongolian race, he thereby introduced to the scientific world
one of its most irritating and elusive etiological puzzles. Over the past
century, mongolism has been the most meticulously studied and differently
interpreted syndrome of mental deficiency. The voluminous literature on this
medical enigma includes the observations and experimentations of not only
pediatricians, neurologists, psychologists, and psychiatrists, but also many
other scientific specialists.
In this communication, we are concerned primarily with reporting our
demonstration of the chromosomal basis of mongolism. We believe, however, that
it is essential to acknowledge and remark upon the many revealing clinical
studies which were influential in the development of our hypothesis. A review
of the literature describing the clinical research on mongolism indicated four
general features of the disease.
Mongolism is a constitutional disease. Mongolian children are mongols
from their heads to their feet. The possible deductions from the concordance of
the condition in monozygous twins and the habitual discordance in dizygous
twins strongly suggest genetic determinants. The extremely rare cases of
mongolien women giving birth either to normal (2) or to mongolien children (3)
also support the existence of an inherited mechanism. Although a hypothesis of
a dominant mutation could be drawn from the foregoing data, it would imply a
mutation rate more than a thousand times greater than any other rate known in
Mongolism presents certain traits of a familial disease. Two facts
suggest an hypothesis of polygenic inheritance. First, although the recurrence
of the disease among siblings is extremely low, it appears to be higher than
chance alone would explain. Secondly, a slight but still significant excess of
minor mongolian stigmas has been noted among the near relatives of mongolian
Mongolism is influenced by nongenic factors. The principal factor
affecting the incidence of mongolism is the age of the mother. Discovered and
directly incriminated by Shuttelworth in 1906 (5), this fact has since been
confirmed by every work on the subject and is actually the only point of
agreement in the whole literature on mongolism. All of the invoked influences
of heredosyphilis and fetal injuries have been unsubstantiated.
Mongolism displays features of a regressive entity. Occurring with the
same features in every human race, the disease seems to be characterized by a
regressive evolution of the human type. The dermatoglyphic traits which allow
the diagnosis of mongolism by the inspection of palm prints are taxonomically
specific of low monkeys and markedly different from those of anthropoids
These clinical facts have provided a basis for describing and
classifying mongolism. In our opinion, the disease may be defined as a
constitutional change that is influenced by genetic factors and the biological
state of the mother and that always produces a variant of the human type.
Consideration of this definition led us to the conviction that the discovery of
a chromosomal abnormality would be the only means of fitting together the
diverse existing data. Conceiving of a single dominant event acting on
polygenic deterrninants, we began our study of the chromosomes of mongols. The
definition we had adopted stimulated our thinking along the lines of the well
known research on Drosophila melanogaster. We were impressed with the very
satisfying model that the haplo (or triplo) IV Drosophila presented. Compared
to a normal fly, the triplo IV has as rough and as badly delineated chape as a
mongolian child when he is compared to a normal child. Of course, we recognized
the weak point of such a parallel, that "feeblemindedness" is not easily
detected in a fly!
The study of the chromosomes of the three mongols who were our first
patients was delayed until our technique of tissus culture was judged reliable.
For the details of the technique and an expanded discussion of the results of
the study, we refer the reader to another paper (7). The first step was the
aseptic removal of a fragment of connective tissus. The tissus was then grown
in a test tube for a week. The outgrowth of cells on a coverslip allowed,
without the addition of mitosis-blocking drugs, the observation of normal
mitotic figures. An hypotonic treatment was used to disperse the chromosomes,
and the preparation was flattened by air dryine. Microscopic observations which
revealed the chromosomes and their arrangement were then photographed. To
individualize and classify the chromosomes, a photo enlargement was made, which
was then carefully cut so that each pair could be reconstructed by matching the
two homologues. (See fig. IV.1 showing the microscopic view of the 46 normal
human chromosomes, in this case of a girl. Figure IV.2, the karyotype, shows
the reconstruction of the chromosome pairs from the photo enlargernent.)
Examination of the chromosome arrangement of a normal female cell
(fig. IV.2) will show a total of seven groups, including the X. The bottom row
has four telocentric elements, with the centromere located at the end of the
chromosome; the Y is absent. The first pair, Vh, has two small heterochromatic
arms just beyond the centromere. The second pair, Vs, does not have these
characteristic appendices. The full 46 chromosomes are present due to the
existence of XX.
In contrast to the 46 chromosomes of the normal cell, our work has
demonstrated that the mongolian cell has a total of 47 chromosomes (fig. IV.3),
in particular, three instead of two Vh chromosomes. The karyotype for a
mongolian boy (fig. IV.4) shows that the supernumerary on the bottom row is of
the Vh type and that the Y is normal. For the mongolian girl, there are also 47
chromosomes and one extra Vh. The Y is absent, and the XX chromosomes are
We presented the first descriptions of our findings on three mongols
in January 1959 (8) and again on March 9, 1959 (9). Soon afterwards Ford and
his colleagues (10) at Harwell confirmed our work in the one case that they
studied. Jacobs and colleagues (11) at Glasgow followed shortly with similar
observations on six cases. In May, Book and Fraccaro (12) at Uppsala reported
similar observations on three cases and also confirmed the presence of three
chromosomes of the Vh type.
At this writing, .our own group of mongols numbers 15, all of whom
exhibit a characteristic extra Vh chromosome. Added together, data now exist
based on the study of 25 mongols (3 Swedish, 7 English and 15 French). Each of
the studies has confirmed the presence of the extra chromosome, even though the
results were obtained on different tissues by different workers using different
methods. In our opinion, the question of whether a normal variation of the
basic chromosome number occurs in a fresh tissue culture is net relevant to the
work. If only indisputable figures are recorded, there is no variation, at
least in the 300 mitoses in mongolism thus far observed.
IV.1. - Microscopic view of the 46 chromosomes of a normal girl
Fig.IV.2. - Karyotype of Fig.
IV.1; 22 autosomic pairs of chromosomes + 2 X chromosomes.
Fig. IV.3. - Characteristics of
chromosomes in a boy with mongolism; 47 chromosomes
Fig. IV.4. - Karyotype of Fig.
IV.3; 22 normal autosomic pairs + 1 X chromosome and 1 Y chromosome. Note the
extra chromosome (arrow) of the Vh type.
The Origin and Influence of the Vh
Our cytological findings strongly suggest a trisomy, that is, the
presence of three "normal" Vh chromosomes. One possible and plausible
explanation for this anomaly is the occurrence of a non-disjunction process
during the meiosis. Conceivably, the two homologous chromosomes, instead of
each separating and migrating to its own pole, clamp together and migrate to
the same pole. Observations on the fourth chromosome of D. melanogaster
strongly support this explanation. Earlier work has shown that non-disjunction
processes are increased by the aged female flies, a finding that corresponds
well with our human data.
The presence of a trisomy serves to explain the reproductive
characteristics of mongolien mothers. In as much as chromatic reduction occurs
unequally in a trisomy, some eggs will receive two Vh chromosomes, and others
only one; mongolien eggs will result in the first circumstance and normal eggs
in the second. The unequal reduction theory also provides a means for
explaining the production of either normal or mongolian children.
The trisomic theory can elucidate the resurgence of simian stigmata
on the mongols palm prints. Modificator genes, accumulated through evolution,
have rendered the gene determinants of these stigmata recessive. The presence
of triplicate genes in the Vh chromosome could make them dominant by a gene
dosage affect. The minor mongolien stigmata that may be displayed by relatives
of mongols could be accounted for by the statistical bias in the diagnosis of
mongolism and by the fact that the disease is individualized merely by the
accumulation of certain small signs in an imbecile child. The possibility
should not be overlooked that even when two parents do not carry the gene
determinants of mongolien physical stigmata, they may still produce a Vh
trisomic imbecile. Because the child did not display the typical features of
the disease, he might be diagnostically excluded as a mongol. The authors have
already encountered this bias, which can be demonstrated easily with
mathematical models, in one of their "borderline" cases.
The discovery of the Vh trisomy provides a new basis for the etiology
of mongolism. From our research as well as that of several other investigators,
it now appears that this mysterious disease not only follows the general laws
of genetics but also is the first exemple of an autosomal aberration in our
species. We note, in this connection, our recent description of a second such
With the finding of the key to the etiology of mongolism, the next
goal of research is the elucidation of its pathogenesis. Despite the congeries
of different studies and approaches, the mechanisms and systems underlying the
pathogenesis still defy our best efforts and understanding. The challenge in
conquering this last problem before the development of therapeutic applications
now passes to the biochemists.
1. LANGDON-DOWN, J.: Ethnic classification of idiots, 1866.
2. SAWYER, G. M.: Case report: Reproduction in a mongoloid. Am. J.
Ment. Deficiency, 54: 204-206, 1949.
3. LELONG, M., BORNICHE, P., KREISLER AND BANDY: Mongolien issu de
mère mongolienne. Arch. franc. pédiat., 6: 231-238, 1949.
4. TURPIN, P., CARATZALI, A, AND ROGIER, A.: Étude etiologique de 104
cas de Mongolisme et considérations sur la pathologenie de cette affection.
Premier Congrès de la Federation internationale latine des Stés d'Eugénique,
p. 154-164. Masson Edit., Paris, 1937.
5. SHUTTLEWORTH, G. E.: Mongolien imbecility. Brit. M, J., 2: 661-665,
6. TURPIN R. AND LEJEUNE, J.: I. Analogies entre le type
dermatoglyphique palmaire des singes inférieurs et celui des enfants atteints
de mongolisme. C. R, Acad. Sciences (Paris, 238: 395-397, 1954; II. Étude
comparé des dermatoglyphes de la partie distale de la paume de la main, chez
l'homme normal, les enfants mongoliens et les simiens inférieurs. C. R. Acad.
Sciences (Paris), 238, 1449-1450, 1954.
7. LEJEUNE, J., TURPIN, R. AND GAUTIER, M.: Le Mongolisme, premier
exemple d'aberration autosomique humaine. Ann. de Génét., 2: 41-49, 1959.
8. LEJEUNE, J., GAUTIER, M. AND TURPIN, R. - Les chromosomes humains
en culture de tissus. C. R. Acad. Sciences (Paris), 248: 602-603, 1959.
9. LEJEUNE, J., GAUTIER , M. AND TURPIN, R.: Etude des chromosomes
somatiques de neuf enfants mongoliens. G. R. Acad. Sciences (Paris), 248:
10. FORD, C. E., JONES, K. W., MILLER, O. J., MITTWOCH, U., PENROSE,
L. S., RIDLER, M. AND SHAPIRO, A,: The chromosomes in a patient showing both
mongolism and Klinefelter syndrome. Lancet, l: 709-710, 1959.
11. JACOBS, P., BAIKIE, A. G., COURT BROWN, W. M. AND STRONG, J. A.:
The somatic chromosomes in mongolism. Lancet, 1: 710, 1959.
12. BÖÖK, J. A., FRACCARO, M, AND LINDSTEN, J.: Cyto-genitical
observations in mongolism. Acta paediat., 48: 453-468, 1959.
13. TURPIN, R., LEJEUNE, J., LAFOURCADE, J. AND GAUTIER, M.:
Aberrations chromosomiques et maladies humaines. La polydysspondylie à 45
chromosomes. C. R. Acad. Sciences (Paris) 248: 3636-3638, 1959.