History and terminology
In 1844 and 1846, Seguin described a particular type of mental
retardation which he called, "furfuraceous idiocy." His description is still
considered by such specialists as Benda (1962) to be the "most ingenious
description of the physical characteristics of the mongoloid growth
The term "mongoloid" was introduced later, following the racial
hypothesis advanced by Langdon Down (1866) who suggested that the mental
deficiency was related to the resurgence of traits of the mongolian races.
Fortunately, other types of mental deficiencies which he classified as negroid
and Malaysian, have been discarded from medical nosography; mongolism, however,
A recent proposal for avoiding the term mongolism was made by Allen et
al. (1961), who suggested the names "Langdon Down syndrome" or "21-Trisomy."
Unfortunately, "Langdon Down Syndrome" would represent the consecration of both
a historical error, since Seguin was the first to describe the condition, and
an etiological error, since the additionnal chromosome which causes the disease
has no relation to mongolian races. In the present review the disease will be
referred to as "21-trisomy" and the patients as "21-trisomics." Regardless of
the standards of its recognition, the 21 chromosome is by definition the
chromosome which produces "mongolism" when present in triplicate. The use of
such a specialized word may be premature, but the discovery of etiological
agents has always led to the renaming of diseases. Such accepted terms as
"staphylococcemia" and "hypoparathyroidism" seem no longer difficult to
understand, although they were undoubtedly considered unprepossessing at the
time of their introduction,
"Furfuraceous cretinism, with its milk white rosy and peeling skin,
with its short-comings of all integuments, which give an unfinished aspect to
the truncated fingers and nose; with its cracked lips and tongue, with its red,
ectopic conjuctive, coming out to supply the curtailed skin at the margins of
the lids" (Seguin, 1866 ) . . . is a quite obvious syndrome. The mark of
imperfect definition thrown on the bodies of the children, makes them so alike
that "il suffit d'avoir vu l'un d'entre eux pour ne plus risquer de les
méconnaitre" (Turpin, 1931).
Aside from this particular aspect, the major symptom of the disease is
mental deficiency. Although carefully studied by many investigators, the
21-trisomies do not basically differ from other feeble-minded persons, at least
from the point of view of intelligence tests. Dunsdon et al. (1960), have
recently stated that the I.Q. of these children is rarely greater than 80 per
cent. During the first years of life, however, the I.Q. may frequently be as
high as 70 per cent.
The progressive regression of the I.Q. of 21-trisomics is exemplified
by the large study of Oster (1953) and has been elsewhere discussed (Lejeune,
1960). This deterioration has recently been confirmed by Zeaman and House
(1962). The morphological picture of the 21-trisomic children and the
associated malformations are too well known to be reiterated. For a clinical
review, the reader is referred to the monographs of Øster (1953) and Benda
(1960). we will attempt to review the multiple components of the syndrome in so
far as they throw light on its occurrence, its nature, and its
I. Epidemiology of the Disease
The 21-trisomy is a relatively, common disease, possibly the most
frequent of all congenital anomalies.
Table 1 summarizes current data on its frequency at birth, which
is of the order of 1/600. There seems to be no difference in frequency between
mongolian populations (Japan and Hawaïï) and white populations (Europe,
|Carter and MacCarthy
|Collman and Stoller
|Schull and Neel (1962)||Hiroshima and
Maternal Aga Effect
Maternal age was the first factor recognized to be important in
the etiology of the disease. Shuttleworth observed in 1895 that nearly half of
the patients were the last-born of a large family. In 1909, he suggested that
the aging of the mother had probably an unfavorable influence, and considered
the 21-trisomics as "exhaustion products." Since these early observations,
numerous authors have studied the disease; the affect of maternal age has been
the only point of agreement in etiological research on 21-trisomy before the
recognition of the chromosomal aberration.
Paternal age, as well as birth rank, have been demonstrated to
have no influence (Jenkins,1933; Penrose,1933 and 1934). Recently, paternal age
has been implicated in the rare cases of transmission of 21-22 translocations,
(Penrose,1962 ); however, it is only the maternal age affect which seems to be
of statistical importance. Relevant data on this point have been presented by
Penrose (1961) and by Carter and Evans (1961). The graph shown in Figure 1 is
based on data of Carter and Evans. It should also be pointed out that a
maternal age affect has been observed in two other trisomies (17-trisomy and
13-trisomy) and is of the same order of magnitude (Lejeune, 1962).
Fig. 1. - Number of 21-trisomic children per thousand birth, relation with
the age of the mother (drawn after the data of Carter and Evans, 1961).
The characteristic clinicat features of the disease suggest that
21-trisomic children are affected from head to foot, in that every part of
their body shows small departures from normal. It is the accumulation of these
deviations, each of which is often at the borderline of the normal, which
permits the diagnosis of the disease.
Certain peculiarities are especially significant.
There is a vast literature on the dermal ridges of the hands and
feet of 21-trisomics. Extensive studies by varions authors stress four traits
which are thought to be typical of the disease (Crookshank, 1931; Penrose,1954;
Turpin and Lejeune, 1953b) :
1 ) The transversality of the ridges of the distal portion of
2 ) The medio-palmar position of the axial triradius (the t
3 ) The lunar loop on the hypothenar region.
4 ) The "simian line" crossing the palet transversely.
It bas been shown (Turpin and Lejeune, 1954a and b) that these
four traits have taxonomic significance, since they are typical of monkeys and
therefore permit a discrimination between monkeys and the anthropoids. The
apparent resurgence of phylogenetic characters in 21-trisomy leads to the
conclusion that a severe ge netic imibalance can overcome genic modifications
accumulated during species differentiation. Other trisomies, especially
13-trisomy, also show changes in the dermatographs (Uchida, Patau and Smith,
1962), and it appears that the genetic mechanism of these traits is based on a
complex interaction between numerous genes. A review of dermatoglyphic changes
in various imbalanced karyotypes leads to the same conclusion (Penrose,
Nuclear Segmentation of Polymorphs
Decreased nuclear segmentation of the polymorphonuclear
leukocytes was the, first cellular anomaly recognized in this disease.
Described in 1947 by Turpin and Bernyer and widely confirmed since
(Shapiro,1949; Lüers and Lüers,1954; Mittwoch, 1957 and 1961; Canevini and
Maderna, 1962), this shift to the left of the Arneth count is definitely not
related to the infections frequently observed in these children, but to a
constitutional anomaly of the nuclei. In addition, the so-called "drumsticks,"
i. e., the small appendices seen on the nuclei of polymorphs of females, are
rarer among 21-trisomic females than among normal women (Mittwoch,1961).
Predisposition to Leukemia
The high incidence of acute leukemia among 21-trisomic children
was recognized before the chromosomal cause of the disease was discovered. Many
authors (Schunk and Lehman, 1954; Bernard, Mathe, Delorme and Garnoud, 1955;
Krivit and Good, 1956; Merrit and Marris, 1956; Stewart, 1961; Wald, Gorges,
Li, Turner and Harnois, 1961; Holland, Doll and Carter, 1962 ), have
demonstrated the relation between the two diseases, and it can be stated that a
21-trisomic child has roughly a twenty fold greater risk of dying of acute
leukemia than a normal child.
The type of leukemia is sometimes lymphoblastic and sometimes
myeloblastic, but generally speaking it is an acute process. According to
Stewart (1961), most of the cases are of the stem-tell type, regardless of the
actual morphology of the pathologie elements. Also, it should be recalled that
the risk of congenital leukemia is extraordinarily high among 21-trisomics.
This type of disease is extrernely rare; although no final statistics can be
given, the excess of 21-trisomies is very great among congenitally affected
patients. It seems worth emphasizing that congenital leukemia has also been
observed in a case of 13-trisomy (Schade, Schoeller and Schultze, 1962). This
association between the 21-trisomy syndrome and the leukemic process and the
abnormal segmentation of the polymorph nucleus suggests that these congenital
malformations are fundamentally related to the underlying genetic cause of the
A genetic basis for the 21-trisomy disease was suspected long ago
on the basis of three sets of data: twin data, reproduction of 21-trisomic
mothers, and accumulation of the disease in exceptional families.
Data on Twins
Most of the available information in the literature is
summarized in Table 2, which is based on the combined data of ester (1953),
Allen and Baroff (1955), and Carter and Evans (1961). The most striking finding
is that dizygotic twins are as a rule discordant, and monozygotic twins always
concordant. This result excludes a specific effect of the uterine environment.
Nevertheless an exceptional case of monozygotic heterokaryotic twins has
recently been observed (Lejeune, Lafourcade, Scharer, de Wolff, Salmon, Haines
and Turpin, 1962), in which one of the twins was 21-trisomic and the other was
normal. This exceptional type of twinning will be discussed subsequently.
Table 2 - Sets of Twins Containing at Least One
21-Trisomic. After the data of Øster (1953), Allen and Baroff (1955), carter
and Evans (1961)
|One of Them 21-trisomic||Both
21-trisomics||No. of Pairs
|Monozygous (same sexes and identity
|Probably dizygous (same
|Zygosity not stated (same
Reproduction of 21-Trisomic Mothers
Very rarely 21-trisomie females procreate. Nothing is known
about pregnancies of normal women fathered by a 21-trisomic male although there
is no reason to suppose that 21-trisomic males are sterile. If unreliable
observations are excluded, eleven 21-trisomie mothers have been reported in the
literature (Table 3). As shown in Table 3, the affected mothers are relatively
young (at birth of their children). Contrarily their own mothers were rather
old at the birth of these trisomic mothers. This is in accordance with the
maternal age effect previously quoted. Fifteen pregnancies from these mothers
have been recorded. If monozygotic twins are counted as one zygote, these
pregnancies may be divided into five 21-trisomics (including a still-born), and
eight nontrisomics (including six normals, one mental defective and one
still-born). Thus, there is fairly good agreement between these data and a 1:1
segregation of a dominant character. The ratio is in accord with the
possibility of meiotic reduction in trisomies, who should produce in equal
number normal (haplo-21) and abnormal gametes (diplo-21).
Table 3-Progeny of 21-Trisomic Mothers
|Reference||Age of the Mother||Age of the
Mother's Mother||Father of the Child||Children
|Sawyer (1949); Sawyer and Shatter
(1957)||25||?||Father of the mother
(incest)||Normal girl; now a student 18 yr. old
|Lelong et al.
(1949)||30||42||Feeble minded (not
21-trisomic)||Boy, clinical syndrome of 21-tris.; dead 1 month
|Rehn and Thomas (1957); Stiles and Goodman
|Forssman and Thyssel (1957) Lehmann and Forssman
(1960)||20 (tris.-21)||42||Blind, epileptic (46
chromosomes N)||Normal boy (46 chromosomes N)
|Schlaug (1957)||29||39||Father of
the mother (incest)||Abnormal girl; syndrome very different from the
(tris.-21)||Brother of the mother
|Hanhart et al. (1961)||23
(tris.-21)||44||Feeble-minded (46 chromosomes
N)||Boy-Typical syndrome of 21-tris.; dead 1 1/2 yr.
(1960)||22||22||Feeble minded||Normal boy
|Levan and Hsu
(1960)||?||?||?||Normal boy (46 chromosomes N)
|Thuline and Priest (1961)||14
(tris.-21)||p||?||Normal monozygous twin boys (46
chromosomes N) dead
minded||Normal boy, now 10 yr. old
foetus probably 21-trisomic
|Note: The subjects for which chromosomal
analyses are available are indicated: (tris.-21) or (46 chromosomes N).
Recurrence of the disease in a given family is a rare event. Most
of the cases are isolated occurrences in an otherwise normal family, but the
number of sibships including at least two 21-trisomics is significantly higher
than would be expected by chance alone (Penrose, 1934; Ester, 1953; Carter and
Evans, 1961). One exceptional instance includes a family of seven children,
five of whom are affected (Turpin and Lejeune, 1953a). Such cases suggest
existence of a particular mechanism for the disease. As will be discussed
subsecfuently, the occurrence of a balanced translocation in one of the parents
in these sibships explains the recurrence of the disease. Nevertheless, as
pointed out by Hamerton, Briggs, Giannelli and Carter (1961), even if
translocation cases are excluded, a small excess of recurrence still occurs in
some farnilies; these authors raised the problems of gonadal mosaics and the
familial tendency to abnormal segregation. The accumulation of minor stigmata
of the disease in healthy members of an affected family has also been reported,
such as furrowed tongue (Turpin and Caratzali, 1933; Turpin, Bernyer and
Teissier,1947) and elevation of axial triradius (Penrose,1954). The existence
of hypothetical genes which increase the chance of mis-segregation of
chromosomes should also be considered.
II. The Chromosomal Anomaly
Speculations on the etiology of mongolism from 1846 to 1959 are sa
numerous that it is difficult to imagine a factor which has not been
incriminated (see warkany, 1960, for review) . From the general data pointing
toward a constitutional disease which acts on numerous traits two authors
(Waardenburg,1932; Bleyer, 1934) drew the formal conclusion that the disease
was determined by a chromosomal aberration and accepted this etiology as the
only one possible. These two remarkable papers show that in biology logical
deductions may precede physical observation by a quarter of a century. Other
authors have also discussed the chromosomal hypothesis to explain exceptional
families (Penrose, 1939), or to explain the general data (Turpin and
Caratzali,1937; Fanconi, 1939). Nevertheless., the etiology of the disease
remained unproved until the observation of the 21-trisomy.
The Typical 21-Trisomy
Prior to 1958 the only published attempt to observe the
chromosomes of affected patients was the investigation of Mittwoch (1952); with
the limitations of the available techniques, she was unable to arrive at a firm
conclusion. She observed 24 chromosomal masses at meiosis and supposed that
this was explained by the somatic number of 48, which was the accepted diploid
number at that time.
Two years after the establishment of 46 as the correct somatic
chromosome number of man (Tjio and Levan, I956; Ford and Hamerton, 1956), an
affected child with 47 chromosomes was observed in Paris. A further study of
two other cases was completed in 1958 and the existence of an extra chromosome
in this syndrome was published in January 1959 (Lejeune, Gautier and Turpin,
1959b) . Additional confirmations were published by Ford, Jones, Miller,
Mittwoch, Penrose, Ridler and Shapiro (1959), Jacobs, Baikie, Court Brown and
Strong (1959), and Böök, Fraccaro and Lindsten (1959). Subsequently the
21-trisomy was demonstrated as the cause of the disease in all human races
(Makino, Tonomura and Matsunaga, 1960; Lee, Schmid and Smith, 1961; Kleisner,
1961; Conen, Bell and Rance, 1962).
As exemplified in Figures 2 and 3, the presence in triplicata of a
small satellited acrocentric chromosome can be established beyond any doubt in
suitable cells of affected individuals (for technical discussion, see Lejeune,
1960). Many authors have discussed whether the triplicated chromosome is number
21 or 22. In the "Denver agreement" it was stated that chromosomes should be
classed in decreasing order of length; if satellites are excluded, chromosome
22 is slightly longer than 21, thus emphasises the difficulty raised by the
A definite position must be taken in this byzantinian quarrel; it
can be presented as follows : The chromosome which produces the so-called
"mongolism" when in triplicate, is to be called 21. The other small acrocentric
pair is then numbered 22. It should also be pointed out, as accepted in Denver,
that if new morphological characters were found which would aid in recognizing
chromosome 21, they would not warrant a change of the already accepted
Fig. 2 - The 47 chromosomes of a 21-trisomic
Fig. 3 - Karyotype
of the preceding cell. Remark: three small acrocentrics with satellites
(21-trisomy). One of the 22 also exhibit satellites but less prominent.
The Trisomic State
The observation of three similar elements is not in itself
sufficient reason for accepting the hypothesis that the elements are homologous
chromosomes present in true trisomy. Fortunately, meiotic studies have been
performed on testicular biopsies of 21-trisomic males. The production of
trivalents has been recorded in a pure trisomic (Miller, Mittwoch and Penrose,
1960 ) and also in translocation carriers (Hamerton, Cowie, Giannelli, Briggs
and Polani, 1961).
Since the synaptic process is the best indication of homology, it
may be concluded that the trisomic nature of the disease is not only logically
established, but that it has been confirmed cytologically as far as it is
possible to do so in a species which does not possess polytenic giant
As previously stated, most of the 21-trisomics, perhaps 95 per
cent, exhibit three free 21 chromosomes and have a diploid chromosome number of
47. The first exception to this rude was reported by Polani, Briggs, Ford,
Clarke and Berg (1960), in a girl exhibiting only 46 chromosomes although
suffering from the typical clinical disease. Although the child was born of
normal parents (Carter, Hamerton, Polani, Gunalp and weller, 1960), she had
only four small acrocentric chromosomes. The extra 21 chromosome was found to
be attached to a large acrocentric chromosome of the 13-15 group. Such transfer
of chromosomal material was very similar to the first case of translocation
reported in man (Turpin, Lejeune, Lafourcade and Gautier, 1959), which also
occurred between a small and a large acrocentric chromosome.
The number of instances of translocation in the literature is now
significant. Their general importance has been previously discussed (Turpin and
Lejeune, 1961), and their role in 21-trisomy has been recently reviewed
(Carr,1962 ). For the sake of simplicity they can be classified into two
categories, those between a large and a small acrocentric chromosome and those
between two small acrocentric chromosomes.
Translocation Between a Large and a Small
In general, the large acrocentric involved in this rearrangement
(see Fig. 4) cannot be cytologically recognized, although it certainly belongs
to the 13-15 group. For simplicity it will be referred to here as a (13)
chromosome; the number in bracket refers to the whole class and does not
specify whether the element is in fact a 13, a 14 or a 15 chromosome.
The small acrocentric is by definition chromosome 21, since it
produces the 21-trisomy syndrome if in triplicate. Several families have been
investigated in which the segregation of the rearranged chromosome has been
observed. The data are summarized in Table 4. At a first glance it can be
estimated that normal persons (46 chromosomes), normal persons with
translocations (45 chromosomes), and 21-trisomics with translocations (46
chromosomes), are observed in approximately equal proportions among the progeny
of carrier mothers.
It may be assumed that the reciprocal of the 21-trisomies (i.e.,
the haplo-21 zygotes) are produced in comparable number but do not survive. In
such a case the conclusion would be that once in every two meioses, there is a
mis-segregation of the free 21 chromosome. In other words, the translocation
completely disturbs the assomment of the 21 chromosome, and the free one and
the translocated one segregate independently (see Fig. 5). Table 4 is also
useful for the purpose of genetic counselling, as it shows that a translocation
carrier mother will as a rule give birth to a 21-trisomic child once in every
The picture concerning the fathers is quite different, as is seen
in the table; only two cases of trisomy-21, one of which is the propositus, are
recorded among 49 children. The reason for such a difference between orale and
female carriers is not understood.
Table 4 - Progeny of Carriers of a 21-(13) Translocation
|N.46 ||N.45 (T)||Tris.-21, 46 (T)
|Mothers: 32||23 ||26||25
|Fathers: 15||15|| 22||1 (
|( ) No. indicates the number of propositi;
(T) indicates carrier of translocation. Compiled from the data published by
Penrose et al. (1960); Carter et al. (1960); Penrose and Delhanty (1961);
Puckton et al. (1961); Hamerton et al. (1961); German et al. (1962); Sergovich
et al . (1962); Forssman and Lehmann (1962); Breg et al. (1962); Atkins et al.
(1962); Biesele et al. (1962); MacIntyre et al. (1962) Shaw (1962). * Only the
phenotype is known.
Fig. 4 - Translecation 21-13. During the time a
21 and a (13) lie close together, a break occurs close to the centromere of
each chromosome. The fragments recombine either in the previous way (no
detectable affect) or rearrange producing a new hybrid chromosome 21-13 and a
centric fragment bearing the satellites, which is secondarily lost. A varions
amount of chromosome material can he attached to the centric fragment. The
quantity of genes lost determine the eventual phenotypic affect of the
translocation. This general process of rearrangement between acrocentrics is
commonly referred to by the rather misleading term centris fusion.
Fig. 5 - Progeny of a carrier
of a 21-(13) translocation. In the simplified diagram, of meiosis each
chromosome is represented for sake of simplicity by one chromatid instead of
two. The progeny show the four types of possible children of which only the
three first are effectively observed, the type Haplo-21 being not known
Translocations Between Two Small
In this case it is difficult to tell whether the translocated
chromosome is formed by the fusion of a 21 and a 22, between two 21's or even
between two 22's. The recognition of the 21 is difficult in itself and becomes
particularly troublesome in cases of translocation. The nucleolar material,
divided among the satellites is the object of competition between the
acrocentric chromosomes, as shown by Nawaschin (1934). Hence the use of the
satellites as markers of 21 becomes misleading under these conditions.
The available data on the progeny of carriers of 21-(21) type
translocations are summarized in Table 5.
As illustrated in Figure 6 the progeny of an isochromosome 21-21
carrier should be composed exclusively of 21-trisomics, since the haplo-21
zygotes are probably lethal. The families described by Forssman and Lehmann
(1962) and Dallaire et al, (1962), seem to fit this prediction, being composed
of 13 21-trisomies among 13 children. Conversely, the family reported. by Shaw
(1969), is in favor of a 21-22 translocation since she finds 2 21trisomics
amont 18 children with seven normal children and eight translocation carriers.
Finally, the examples of mosaicism of Fraccaro et al. (1960) and Hamerton et
al. (1961), can be attributed to either type, as the appearance of normal
children is an insufficient reason to exclude the 21-21 type of
Although it has been reported that paternal age may act as a
predisposing factor this has net yet been proved in casas of 21-trisomy caused
by 21-21 translocation (Penrose, 1962). The only conclusion to be drawn from
the available data is that contrarily to the 21-(13) type, the 21-21
translocation induce 21-trisomy as often at least in the progeny of male
carriers than in the progeny of carrier mothers.
Before closing this brief discussion of the data it must be
stressed that many of the translocation 21-trisomies are not transmitted, but
arise de novo in the affected child (Gustavson, 1962; Carter, Hamerton, Polani,
Gunalp and weller,1960; Scherz,1962). Both a 2I-trisomic with 47 chromosomes
and a 21-trisomic caused by translocation have been observed in a sibship of
which both parents were normal (Penrose, 1963).
Table 5 - Progeny of Carriers of a 21-(21) Translocation
|Fathers: 2 ||7||5||1(1)
|( ) No. indicates the number of propositi;
(T) indicates carrier of translocation. Compiled after the data of Hamerton et
al. (1961); Forssman and Lehmann (1962); Fraccaro et al. (1960); Show (1962);
Mukherjee et al. (1962); Dallaire et al. (1962).* Only the phenotype is
Fig. 6 - Progeny, of a 21-21 Translocation
carrier. At meiosis the new chromosome 21-21 has no homologue and moves
directly to one pole, the other cell being entirely deprived of 21 chromosome.
As seen the progeny can only include 21-trisomies or miscarriages. Note: In
case of a 21-22 translocation, the transmission would be analogous to the case
of a 21-(13) translocation (Fig. 5).
Although 21-trisomies seem to be affected in every part of their
economy, careful investigation has shown that sonne individuals, exhibiting the
21-trisomy syndrome in its classical form, or in a less clear cut picture
("mild affection") were, in part, mosaics. Their cell population was not
uniformly composed of 21-trisomie cells, but included a varying proportion of
normal, diplo-21. cells. The data are summarized in Table 6.
From these few data, it is not yet possible to deduce a
relationship between the percentage of the 21-trisomie tells and the mental and
physical status of the individual, although the patient with tetra-21 cells
showed a particularly severe mental retardation.
Related to this problem is the biological relevance of the
percentage observed. We have no good evidence that 21-trisomie cells and
21-diploid cells do not compete against each other under the conditions of
observation. If this indeed is the case, the number of mitoses observed is not
an unbiased estimate of the cells present in the sample studied. Secondly, the
number of biopsies which can possibly be made is limited, and only few regions
of the body can be examined. There are very good indications that mosaic
individuals can differ from one tissue to another (Fraccaro, Bott, Salzano,
Russel and Cranston, 1962). The physiological effect of this "geographical"
mosaicism could be very different depending upon whether a high percentage of
aneuploid cells was localized in one organ or another. Selection between
diplo-21 and tripla-21 karyotypes during embryonic development is another
Table 6 - Mosaics for 21-Trisomy
|Authors||Tissue||No. of Cells||Pourcentage of Karyotvpes||Remarks
|Clarke et al. (1961) mother 26 yr. father 26
yr.||Skin||89 ||53% ||47%
||Femelle 21/2 yr.; morphology and
dermatoglyphs are typical; I.Q. 100; no 21-trisomic cells in the blood
|44||38% ||62% ||
|Fitzgerald and Lycette (1961) mother ? father
51 yr.; low grade mental deficiency; diagnosis evident, few stigmata lacking
(no epicanthus no simian crease, normal ears)
|Gustavson and Ek (1961) mother 24 yr. father 29
12 yr.; had a brother 21-trisomic, dead at 6 months; low grade mental
defi-ciency; typical deformities; trisomy-21 plus a small metacentric (21-21)
|Nichols et al.
|Warren et al.
Typical aspect; annular pancreas; two other cases cited, one observed by Lytt,
the other by Conen
|Hayashi et al. (1962) mother 17 yr. father
||45%||Male 3 yr.; incomplete picture of
21-trisomy; I.Q. reported in the normal range
|Richard and Stewart
Typical case; low grade mental defi-ciency
|Lindsten et al. (1962)||Blood and
Mild clinical picture although diagno-sis is evident; borderline
|Blank et al. (1962) mother 40
Mother of a typical 21-trisomic; few stigmata of the disease
Association with Other Chromosomal Changes (21-Trisomy
The most frequent association is that of 21-trisomy and the
Klinefelter syndrome (XXY), resulting in a karyotype with 48 chromosomes.
Several cases have been described; Ford, Jones, Miller, Mittwoch, Penrose,
Ridler and Shapiro (1960), described the first case, followed by Lanman,
Sklarin, Cooper and Hirschhorn (1960) and Lehmann and Forssman (1960).
A case of monozygotic twins, both 21-trisomics + XXY, was
published in 1961 by Hustinx, Eberle, Ceerts, ten Brink and Woltring and a
similar case of twins has been recorded in our laboratory (Inst. Prog. obsv.
The expected converse association between 21-trisomy and the
Turner syndrome has not been reported. We have searched for 21-trisomic females
exhibiting pterygium colli and found one such case but her karotype was
21-trisomy, diplo-X. It is possible that the severe genetic imbalance of the XO
condition superimposed on the deleterious effect of the 21-trisomy does not
allow the embyronic development of such a zygote.
Another association with 48 chromosomes, 21-trisomy and
18-trisomy, has been described (Gagnon, Katyk-Longtin, de Groot and barbeau,
1961) but the malformed infant, exhibiting the physical stigmata of both
syndromes, was not viable.
Atypical cases, relating to chromosomal changes, have also been
described. A girl exhibiting a congenital malfor- mation looking somewhat like
21-trisorny but having probably a 21-16 translocation, has been reported by
Böök, Gustavson and Santesson (1961). Also a mosaic boy exhibiting in some
cells a very small extra chromosome has been recorded by Ilbery, Lee and Winn
(1961), and is considered a "partial 21-trisomic."
Other cases showing trisomy for a small acrocentric have been
quoted repeatedly. Firm conclusions on the genetic identity of the chromosomes
involved cannot be drawn from a consideration of these cases (Lejeune,
Possible partial trisomies involving very small translocations on
the 21 have also been reported: Chu, Rubinstein and Warkany (1961) and Gray,
Mutton and Ashby (1962). A few perplexing cases have been reported: a
borderline case with normal chromosomes by Schmid, Lee and Smith (1961); a
typical syndrome with normal karyotype by Hall (1962) (who could not exclude
mosacicism) ; and two trisomies for a small acrocentric with so-called
"non-mongoloid" mental deficiency by Zellweger, Mikano and Abbo (1962). Further
investigation of these cases seems highly desirable to define the clinical
disease as well as the chromosomal status.
This survey of exceptional cases must be evaluated in the light of
the knowledge that probably more than 1,000 individuals with 21-trisomy have
been studied in varions laboratories and that even an apparently homogeneous
disease may show clinical variation. Every 21-trisomic has a unique complement
of genes on the 21 chromosome and many genic differences exist between the 21
chromosomes present in human population.
In addition, as in the case of mental retardation observed by
Ellis, Marshall and Penrose (1962), the extra chromosome can be rearranged,
resulting in trisomy for varions chromosomal segments.
Pathogenesis of the Chromosomal
General factors predisposing to abnormal segregation of
chromosomes have been recently reviewed (Lejeune, 1962) and only the data
directly relevant to 21 trisomy will be discussed here.
Characteristics of Chromosome 21
The presence of satellites on this chromosome and the relation
between these bodies and the nucleolus has led to the view that this type of
acrocentric could be at greater risk of abnormal segregation than others.
Mitotic association of acrocentric chromosomes is well substantiated
(Ferguson-Smith and Handmaker, 1961). Thus, chromosome 21 could be at greater
risk of translocation with another satellited acrocentric (Ohno, Trujillo,
Kaplan and Kinosita, 1961) . The existence of the (13)-trisomy (Patau, Smith,
Therman, Inhorn and Wagner, 1960) and of the numerous 21-(13) and 21-21
translocations previously reported strongly supports this argument. Also the
identical tune of replication of these two types of chromosomes points in the
same direction (Gilbert, Muldal, Lajtha and Rowley, 1962) .
The Interchromosomal Effect
The evidence that structural changes of chromosomes increase the
risk of abnormal segregation of the X chromosome has been amply demonstrated in
Drosophila by the work of Sturtevant (1944). The same affect seems to be
detectable in man.
The structural affect is clearly demonstrated in the progeny of
carriers of a translocation involving the 21. Moreover, the translocation can
induce abnormal segregation of the 21, even if this chromosome is not
transmitted to the trisomic child. This is well exemplified in the family
described by Moorhead, Mellman and wenar (1961), in which a mother carrying a
probable 22-(13) translocation gave birth to a child with a free 21-trisomy,
and without having received the translocated chromosome.
In a family described by Shaw (1962), the mother had an apparent
deletion of a small arm and satellite of a 21 (or 22). She had five children;
two were normal (both showing the "marker" chromosome), and three were
21-trisomies with 47 chromosomes (one of them exhibited the marker chromosome
and the other did not). In a second family the mother of two typical
21-trisomies with 47 chromosomes had a normal set of 46 chromosomes but
exhibited an excess of genetic material in one of the big acrocentrics. This
excess, possibly including part of the 21, is thought to be the cause of the
mild "stigmata" found in her phenotype. It seems likely that these chromosomal
rearrangements make the meiotic pairing unstable or irregular and thus increase
the risk of mis-segregation of homologues, or even of chromosomes which are not
homologous with the rearranged one.
A less likely possibility is that chromosome rearrangements
increase the risk of mis-segregation in the somatic cells. This is well known
in Drosophila melanogaster in which gynandromorph mosaics result from the
elimination of a ring-X chromosome (Brown and Hannah, 1952). Some data in man
also point in this direction. Segmentary heterochromia of the iris, supposed to
be due to chromosomal change when produced by irradiation (Lejeune, Turpin,
Rethore and Mayer, 1960), has been recorded in a normal child belonging to one
of the sibships described by Shaw and listed above (the mother with a possible
21-(13) translocation). Also this effect on meiotic and mitotic stability would
possibly explain the accumulation of chromosomal diseases in certain sibships
(Mosier, Scott and botter, 1961; Böök, Santesson and Zetterqvist, 1961;
Hauschka, Hasson, Goldstein, Koepf and Sandberg, 1962; Cooper and Hirschhorn,
1961; Benirschke, Brownhill, Hoefnagel and Allen, 1962; Johnston, 1961;
Zellweger and Mikano,1961) and it seems at least an attractive hypothesis to
suggest that familial recurrence of 21-trisomy could be explained by some
undetected structural rearrangements in the chromosomes of parents.
Such an instability of the karyotype could be related to the
occurrence in these families of a neoplastic process, such as leukemia (see
below) (Buckton, Harnden, Baikie and Woods, 1961; Miner, Breg, Schmickel and
Tretter, 1961; Hungerf ord, 1961).
Aging of the Mother
This predisposing factor, as previously mentioned, has no clear
cut counterpart in the experimental animal; at least the data are not
available. Nevertheless in the case of somatic loss of the ring X-chromosome
quoted above, the aging of the eggs has a very striking effect (Hannah,1955).
The same effect was found by Patterson, Brewster and Winchester (1932) on
production of XXY, but only if the eggs were irradiated with x-rays.
The maternal effect, as far as experimental data are concerned,
appears to affect somatic cells more than the meiotic process. This possible
restriction to the blastomeric stage could be compatible with 21-trisomy, since
there are instances in which the occurrence of the chromosomal disease is
The Time of Occurrence of the
As discussed in the problem of translocations, there are
instances in which we can assume fairly safely that a diplo-21 gamete was
produced by a carrier parent. The same is true in the rare cases of
reproduction of a 21-trisomie mother. Only in these instances which are
obviously very rare (less than a few per cent of the total frequency of the
disease) can we assume confidently that the error occurred at the meiotic
In contrast, two types of data show that the error can be
postzygotic. The first concerns those cases of mosaicism in which obviously the
"variant cells" were produced after gametic fusion. The probability of a double
fertilization proposed by Gartler, Waxman and Giblett (1962) to explain their
case of hermaphroditism can certainly not apply to all the mosaics with
21-trisomy. The second evidence is furnished by the exceptional type of
twinning, the "heterokaryotic monozygotism" described by Lejeune, Lafourcade,
Scharer, de Wolff, Salmon, Haines and Turpin (1962). A pair of monochorionic
twins was observed who were identical for all the blood groups tested, but who
differed in that 21-trisomy occurred in one while a normal karyotype (and
phenotype) occurred in the other. A case of monozygotic twins differing in one
chromosome had been previously observed (Turpin, Lejeune, Lafourcade, Chigot
and Salmon, 1961; Lejeune and Turpin, 1961). This instance, an X0 Turner and
her XY normal monozygotic co-twin, is no longer unique, since a similar set of
twins has been recently observed by Edwards, Dent and Crooke (1963, cited by
Lindsten et al., 1963).
Figure 7 shows one possible way of producing these twins.
Alternatively the twins could arise from a 21-trisomie egg and a secondary loss
of the extra chromosome at the blasteromeric stage. In this second hypothesis
the normal twin would have been naturally "cured" of his congenital
If spontaneous mosaicism for the sex chromosome, as well as its
production in animals by irradiating the fertilized egg (Russel and Saylors,
1961), is taken into consideration, the general picture emerges that the most
sensitive stages of development are the time of the fusion of the gametes or
the first few cleavages of the blastomeres. If this hypothesis is true, it
could very well be that most of the 21-trisomies are not of gametic origin, as
generally accepted, but blastomeric, with the eventual death of the recripocal
Fig. 7 - Abnormal segregation of the
blastomeric stage. Only the 21 chromosomes are represented. First mitosis of
the zygote is normal. Then, one of the blastomeres divides normally, the other
one give rise to two abnormal cells: a 21-trisomic and a Haplo-21 (which
probably disappears). lf cleavage in two embryos occurs at this four cell
stage, the result is monozygotic heterokaryotic twins (see text). If only one
embryo develops, the result will be a diplo 21/triplo 21 mosaic (see
The Leukemic Process
The strong association between 21-trisomy, free or by
translocation (German, DeMayo and Bearn, 1962), and acute leukemia is well
known. New karyotypic studies have led to precise results. Tough, Court Brown,
Baikie, Buckton, Harnden, Jacobs, King and McBride (1961), reported five cases
of apparently unchanged karyotype in the peripheral blood of 21-trisomic
children affected by an acute leukemia. These authors raise the possibility
that the true leukemic cells were not, in fact, recorded in the mitoses and
that this negative finding is not definite.
Recently, leukoblastic abnormality was observed in a 21-trisomie
girl in whom a chromosomal variation leading to an abnormal karyotype of 54
chromosomes was observed in the bone marrow and in the blood (Lejeune, Berger,
Haines, Lafourcade, Vialatte, Satge and Turpin, 1963). The hemorrhagic
disorder, which was characterized by purpura and bleeding, necessitated many
blood transfusions, was diagnosed at birth and was still present at 2 years and
2 months. Analysis of cells revealed a chromosomal complement which varied from
47 to 55 and showed that each number was correlated with a specific karyotype.
The additional chromosomes were (in increasing number) small acrocentrics (v),
big acrocentrics (T), medium sized metacentrics (M) and small metacentrics
Two facts emerged from this study : (1) Every karyotype of an
immediately greater number contained all the supernumeraries found in the
karyotype of an immediately inferior number, plus one; (29) every new
supernumerary occurred twice before the acquisition of a new one. The general
data are summarized in Table 7.
Although this apparent evolution of a clone is not yet
substantiated by other observations, it is worth noting that a previous
observation of a 47/49 mosaic was reported in the bone marrow of a 21-trisomie
girl by Piazzi and Rondinini (1961) (it is not known if this child was
suffering from leukemia). The observation by boss and Atkins (1962) of another
21-trisomie with leukemia also showed 47/49 mosaicism in the blood, In both
these instances the 49 chromosome karyotype was due to a typical 21-trisomy
with two additional small acrocentrics (21-22).
The availability of only three cases for study prevents any
generalization, but it is tempting to suppose that is was not by chance in the
three instances now known that the karyotypic variations started with the same
type of chromosome and with the appearance of two additional identical
Other examples of the presence in duplicata of additional
chromosomes in neoplastic disease have been reported. One case concerns
apparently normal big acrocentrics (13-15) (Sasaki, 1961), and another
obviously rearranged giant acrocentrics in cells of exudate of cancerous origin
(de Grouchy, Vallee and Lamy, 1963).
The possibility of chromosomal interaction resulting from the
trisomy in the causation of leukemic process in the 21-trisomie children is for
the moment an open question, as also are the possible laws controlling the
karyotypic changes in these neoplastic growths.
Table 7 - Association Between Karyotype and Chromosome
Number in the Cells of a Trisomy-21 Patient with Leukemia
|No. of Chromosomes||Karyotvpe||No. of
|Exceptions : One cell with 51 chromosomes :
tris.-21 + 2v + 1T + 1M; one cell with 53 chromosomes : tris.-21 + 2v + 2T + 1M
+ 1c. - the symbols used, described in Lejeune (1960), represent: v = group)
(21-22); T = group (13-15); M = group (6-12-X); c = group (19-20).
The Genic Confient of the 21 Chromosome
The study of chromosomal duplication (or deletion) as a means of
detecting genes which show a dosage affect has been a very powerful tool in
experimental cytogenetics. Its application to the mapping of human chromosomes
has been attempted, especially in the 21-trisomy syndrome. In such research
very great care has to be exercised in the selection of phenotypic
characteristics as "markers." Fine and immutable morphalogical traits, like
dermatoglyphs, have been proposed, but their alteration in all three different
types of trisomies (see above) prevent any conclusion about the precise
location of the hypothetical genes controlling them.
Comparisons between members of a monozygotic heterokaryotic set of
twins for somatic traits are also possible, since these individuals are
genetically identical except for one 21 chromosome. In the case quoted above,
the 21-trisomic differed from his normal co-twin by having straight hair,
whereas the normal boy has curly hair. It connot be concluded that the
"straight hair gene" is on chromosome 21, but only that some genes on this
chromosome interfere with the manifestation of this character.
The difficulty of genetic analysis with morphological traits is
well known. Biochemical characteristics seem more satisfactory as they are
probably nearer to the primary products of gene activity.
Alkaline Phosphatase Activity of Polymorphic
The estimation of alakaline phosphatase activity in polymorphic
leukocytes provides an apparently simple biochemical test applicable at the
cellular level. Since the first repart of Alter, Lee, Pourfar and Dobkin
(1962), numerous publications have confirmed the fact that alkaline phosphatase
activity is higher in 21-trisomics than in normal children. The ratio of
activities is of the order of 3 to 2, and is strikingly similar to the ratio of
21 chromosome numbers (Trubowitz, Kirman and Masek, 1962; King, Gillis and
Baikie, 1962). No correlation his found with the Arneth count (Lennox, White
and Campbell, 1962), or with the neutrophil count (King, Gillis and Baikie,
1962). Thus the relation between alkaline phosphatase activity and the
karyotype seems independent of the tendency of 21-trisomies to incur
infections. The tentative localization of the structural gene on the 21
chromosome is nevertheless rendered insecure by the negative correlation
between this enzymatic activity and prepubertal age, which suggests that a
correlation may exist with the level of sex hormones (Alter, Dobkin, Pourfar
and Lee, 1963). Nevertheless the conservative hypothesis that genes affecting
alkaline phosphatase activity are located on the 21 can reasonably be made,
with the reservation that other genes, possibly many, can also influence this
Another indication that alkaline phosphatase activity may be
related to the genes on chromosome 21 arises from the observation of a deleted
small acrocentric (Ph1 chromosome) in leukocytes of patients suffering from
chronic granulocytic leukemia (Nowell and Hungerford, 1960; Tough, Court Brown,
Baikie, Buckton, Harnden, Jacobs and Williams, 1962). If the deleted chromosome
is indeed the 21, the low phosphatase activity found in this disease (Valentine
and Beck, 1951) could be attributed to the loss of the locus involved.
In addition the observation of haplo-(21 or 22) clones in acute
myeloblastic leukemia (Ruffie and Lejeune, 1962) supports the supposition,
drawn from the Ph1 chromosome, that genes exist on the 21 which are concerned
with the regulation of polymorphonuclear production.
It must be stressed that this second type of inference is based
on the assumption that the Ph1 chromosome is really a deleted 21. This tempting
assumption, although not proved, could also account for the shift to the left
of the low Arneth count in 21-trisomics. By this hypothesis a simple mechanism
could be postulated: a balanced karyotype gives normal counts, a triplo-21
depresses the lobulation of the nuclei of the polymorphs and a partial or total
deletion of the 21 leads to an excessive proliferation of this type of
As has been shown in the paragraph concerning leukemias in
21-trisomics, an extra supernumerary of this same acrocentric type can also be
encountered in the leucoblastic reaction. The significance of this last effect
is not immediately apparent, but we can at least imagine that hyperrepression
of the granulocytic differentiation could result in blastic proliferation.
Biochemical changes may be more sensitive indicators of gene
overdosage than cellular effects. Many biochemical traits have been reported to
be peculiar in 21-trisomies. Thus blood calcium level (Stern and Lewis, 1958)
and serum esterase level (Stern and Lewis, 1962) are reported to be lower in
21-trisomics than in normal individuels, whereas the serum uric levels (Fuller,
Luce and Mertz, 1962) are reported to be higher. In a systematic search for
biochemical changes related to 21-trisorny, tryptophan metabolism has been
investigated, and a decreased urinary excretion of xanthurenic acid and of
5-hydroxyindolacetic acid has been reported (Gershoff, Hegsted and Trulson,
1958; Gershoff, Mayer and Kulcyzcki, 1959; O'Brien, Groshek and Streamer,
1960). As observed by Jerome, Lejeune, and Turpin (1960) and Jerome (1962), a
decreased excretion of 5-hyclroxyindolacetic acid, xanthurenic acid, kynurenic
acid, and indolacetic acid seems to be a biochemical symptom of the disease. No
direct relation between these metabolic changes and chromosomal constitution
has yet been established, although acceleration of some steps by enzymatic
overdosage has been discussed. This hypothesis of over production of enzymes by
trisomics seems to be confirmed by the alkaline phosphatase data, but cannot
yet be related to experiments in other species. In bacteria, however, there are
indications that genetic overdosage induces an excess of enzymatic
Although chromosomal research has greatly improved our knowledge of
the disease, the pathogenesis of 21-trisomy has still to be discovered.
Two main questions need to be answered:
1. How can normal genetic information be deleterious if in excess
2. What biochemical changes are produced by this imbaIance of the
The cytogenetic epoch of 21-trisomy has obviously not closed, but it
is hoped that a biochemical era will soon open. The discovery of specific
metabolic changes in 21-trisomies would be an outstanding advance, and the
successful control of these changes, if realizable, would receive a most
precious reward: the first reasonable hope of correcting the catastrophic
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