Res Medica, Spring 1966, Volume 5, Number 2
Page 1 of 7
Sex Chromosome Abnormalities in the Male
Patricia A. Jacobs
Abstract
This article does not set out to give a comprehensive review of sex chromosome abnormalities in Man, nor even
in phenotypic males. Its purpose is more to outline a few general principles and show how they apply to one
group of individuals with one class of abnormality, namely males with abnormalities of number of either the X
chromosome, or the Y chromosome or of both.
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Res Medica, Spring 1966, 5(2): 18-23
doi: 10.2218/resmedica.v5i2.459
Jacobs, P. Sex Chromosome Abnormalities in the Mail, Res Medica 1966, 5(2), pp. 18-23
doi: 10.2218/resmedica.v5i2.459
SEX CHROMOSOME ABNORMALITIES
IN THE MALE
PATRICIA
A.
JA C O B S
Medical Research Council, Clinical Effects o f Radiation
Research Unit, Western General Hospital.
T h is article docs not set out to give a
com prehensive review of sex chrom osom e
abnorm alities in M an , nor even in phenotypic
males. Its purpose is m ore to outline a few
general principles and show how they apply to
one group of individuals with one class of
abnorm ality, nam ely males with abnorm alities
of num ber of either the X chrom osom e, or the
Y chrom osom e or o f both.
som es can be recognised with certainty, w hilst
the others can only be recognised as belonging
to one of a num ber of groups. Som e of these
groups contain only two pairs o f chrom osom es,
w hilst the largest group, consisting of m edium
sized subm etacentric chrom osom es, contains
as m any as seven pairs o f autosom es. U n ­
fortunately the X chrom osom e falls into this
category o f m edium sized subm etacentric
chrom osom es and, therefore, cannot be dis­
tinguished m orphologically from autosom e
pairs 6-12. N orm al m ales, therefore, have 15
chrom osomes in this group — 14 autosom es
and a single X chrom osom e, while normal
fem ales have 16 — 14 autosom es and two X
chrom osomes.
T h e Y chrom osom e, however, is one of the
sm allest chrom osomes in the human com ple­
m ent with its centrom ere very near one end
(acrocentric). It can usually be distinguished
from the autosom es that it m ost closely re­
sembles, those of pairs 2 1 and 22, by virtue of
M an has 46 chrom osomes consisting o f 22
pairs of autosom es, which are com m on to both
sexes, and two sex chrom osom es an X and a
Y . N orm al fem ales have two X chrom osomes
which are m orphologically indistinguishable
from one another, while m ales have one X
chrom osom e and one Y chrom osom e, which
are m orphologically dissim ilar. (Fig. 1, Fig. 2).
T h e main two criteria used in recognition of
chrom osomes are their length and the position
of the centrom ere or prim ary constriction. On
the basis o f these criteria only 4 pairs o f auto­
18
m a tin status o f th e in d iv id u a l gives valuable
in fo rm a tio n as to th e n u m b e r and, in fa vo u r­
able circum stances, th e size o f th e X c h ro m o ­
som e, as a b n o rm a litie s o f size o f th e X
chrom osom e are reflected in a b n o rm a litie s o f
size o f th e sex c h ro m a tin body. I t m u s t be
emphasised, how ever, th a t i t gives no in fo r m ­
a tio n a b o u t th e Y chrom osom e. T h u s in d iv­
iduals w h o are la ckin g a sex chrom osom e, X O
fem ales, and also n o rm a l X Y males arc b o th
c h ro m a tin negative, w h ile b o th X X X females
and males w ith K lin e fe lte r's syndrom e and an
X X X Y sex chrom osom e c o m p le m e n t have tw o
sex c h ro m a tin bodies in a p ro p o rtio n o f th e ir
cells.
the fa c t th at it n ever has sm all satellites on its
sh ort arm s, an d also b ecau se th e co n stitu en t
ch rom atid s o f th e Y ch ro m o so m e tend to b e
close to on e an oth er and arc often rather fu zzy
in appearan ce.
L ittle d ifficu lty, therefore,
arises w h en d ealin g w ith ab n o rm alities o f n u m ­
ber o f the Y chrom oso m es as these can b e
easily recognised. T h e X ch ro m o so m e can n ot,
h ow ever, be distin gu ish ed
m o rph o lo gically
from the au to so m e pairs 6 -12 . It is th erefore
necessary, w h en d ecid in g w h e th e r or not one
is d ealin g w ith an ab n orm al n u m b e r o f X
chrom oso m es to con sid er, as w e ll as th e cyto ­
g en etic findings, th e e vid en ce from three other
sources, n am ely th e nu clear sex, th e clinical
findings and the results o f au torad iograp h y
un dertaken to d eterm in e the tim e at w h ich the
chrom oso m es synthesise D N A .
N u c le a r S ex
In a pro po rtio n o f nu clei o f non -dividin g
cells o f norm al fe m ale s there is a sm all b o d y
ab ou t 1
in d iam eter attach ed to th e nuclear
m em b ran e. Su ch a b o d y is n ever fo u n d in
sim ilar nuclei from norm al m ales (F ig. 3).
T h is b o d y was first described b y B arr and B e rt­
ram in 19 4 9 1 and is, th erefore, referred to as
the B arr b o d y or sex ch rom atin b od y. In d iv ­
iduals h avin g this b o d y are said to be Banpositive or ch rom atin p ositive, w h ilst th ose in
w h om it is ab sen t are said to be B arr negative
or ch rom atin negative. T h e re has been m uch
sp ecu lation sin ce the first observation o f sex
ch rom atin as to its n atu re, b u t it is n ow know n
that it represents an X ch rom oso m e w h ich is
in a d ifferen t state o f co n d en sation from the
o th er chrom osom es o f the cell. W h ile the
latter are un coiled and g e n e tically active, the
sex ch rom atin b o d y con sists o f the w h ole, or
the greater part, o f an X ch ro m o so m e w h ich
is con densed and presu m ab ly relatively in active.
It appears that fo r n orm al fu n ctio n th e c ell
needs on ly one X ch rom oso m e, and an y fu r­
th er X ch ro m o so m e present is, to a greater
0 r lesser exten t, in active, and represen ted by
a sex ch ro m atin b od y. T h u s th e m axim u m
n u m b e r o f sex ch rom atin bodies is on e less
than the n u m b er o f X chrom oso m es in the
cell. Sex ch rom atin can be seen in the c e l I s
o f a great m an y tissues in th e b od y, b u t it is
o ften studied in cells from the b u ccal m ucosa,
because these are very easily o b tain ed . Su ch
studies enab le large p o p u latio n s to be screened
for their X ch ro m o so m e status b y m eans o f a
sim p le and qu ick tech n iq u e. T h e sex ch ro­
µ
4 - 5
6 - 12 + X
13 - 15
19 - 20
16
1 7 - 18
21-22
Y
Fig. 1. Cell and Karyotype from a culture of the
peripheral blood lymphocytes of a norm al male.
19
group 2 1-2 2 results in the pro fou n d distu rb an ce
o f virtu ally every system in the b o d y ch aracter­
istic o f m on go lism . O n the o th er hand the
presence in an in d ivid u al o f an ad d ition al Y
ch rom oso m e, w h ich is o f a com p arab le size,
m ay be associated w ith no p h e n o typ ic ab n or­
m alities at all.
Fig. 3. Cell from the buccal mucosa of a normal
female showing a single sex chromatin body (Barr
body).
Autoradiography
B y treating cu ltures o f hum an cells w ith
tritium lab elled th ym id in e (a specific radio­
active precursor o f D N A ) , du rin g the tim e the
chrom oso m es are d u p licatin g their m aterial
p rior to division , it can be show n that there
is a m ediu m sized su b m e tace ntric chrom oso m e
in fem ales. T h is synthesises D N A som ew hat
ou t o f phase w ith all the oth er chrom osom es
in th e cell, in that it both starts and finishes
later. N o such chrom oso m e is present in cells
from norm al m ales. T h is ch rom oso m e is p re­
sum ed to be the “ in a ctiv e ” X w hich also form s
the sex ch rom atin b o d y, and it has been
show n that the n u m ber o f late-synthesisin g X
chrom osom es is one less than the n u m b er o f
X chrom osom es present in the cell. T o deter­
m in e w h ether such a ch ro m o so m e or ch ro m o ­
som es are present in the cell tritiu m -labelled
th ym id in e is usu ally added to the cultures
som e three to fo u r hours b efo re harvesting,
w hen the m ajo rity o f the chrom oso m es have
co m p leted or are in the final stages o f syn ­
thesis. S in g le layers o f the cells are then p re­
pared on a m icroscope slide and covered by a
layer o f p h o to grap h ic em ulsion w h ich blackens
w hen su itab ly exposed to a radio-active source.
B y this m eans an y ch rom oso m e, or ch ro m o ­
som e region, w h ich is actively syn thesisin g
D N A later in the syn th etic period can be
recognised (F ig . 4).
Fig. 2. Cell a n d K a r y o t y p e f r o m a c u l t u r e of t he
p er i ph er al b l oo d l y m p h o c y t e s of a n o r m a l female.
C linical Features
M u c h w ork rem ains to be done on the
clin ical expression o f ab n orm alities o f the
chrom osom es in m an. Y e t it is clear that in
general, ab n o rm alities o f the autosom es give
rise to very m uch m ore severe and w idespread
an om alies than ab n o rm alities o f the X and Y .
F u rth erm o re w here there are clin ical m an i­
festation s of ab n o rm alities o f the sex ch rom o­
som es these tend to affect m ain ly th e prim ary
and secondary sexual d eve lo p m e n t, though th ey
m ay also affect the m en tal d e ve lo p m e n t and
b eh avio u r o f th e affected in d ivid u al. T h u s the
presence o f an ad d itio n al sm all au to so m e in
20
sex chrom osome constitution.
T h e second
patient was an 8 year old m entally retarded
boy who was noted at birth to have a cleft soft
palate and who had subsequently been hos­
pitalised on a num ber of occasions for severe
respiratory infections. H e also had a number
of congenital anomalies, including h ypomandibulosis, a sinus on bridge of his nose, abnormal
dentition, curious facics and a systolic murmur.
Repeated observations on cells from a num ber
of tissues showed him to be chromatin negative
and autoradiography did not reveal any
chrom osome which synthesised D N A out of
phase with the others. It was, therefore, con­
cluded that the additional chrom osome was not
an X chromosome, but was an autosom e be­
longing to group 6-12 and that the patient was
trisomic for one of these autosom es.
Abnorm alities of the Sex Chromosomes
T h e more com m only encounted numerical
abnormalities of the sex chrom osome in males
are listed in T ab le 1, together with the sex
chromatin and autoradiographical observations
in these individuals. W h ile these are the only
abnormalities which will be considered in the
TABLE
Fig. 4. A normal female cell subsequent to treat­
ment with tr it iu m labelled th ymid in e which shows
one very heavily labelled medium sized submetacentric chromosome.
Chromosome
Constitu tion
B y way of illustration of how evidence from
sex chrom atin, clinical findings and autoradio­
graphy are correlated with the cytogenetic
observations two cases can be considered. From
cultures of both skin fibroblasts and peripheral
blood leukocytes, both of these were shown to
have 47 chromosomes, the additional chrom o­
some being a medium sized subm etacentric
chrom osome indistinguishable from the chrom ­
osomes of group 6 - 12 + X . T h e first patient
was a 28 year old man who presented at a subfertility clinic, his wife having failed to con­
ceive after 5 years of marriage. H e was of
average intelligence and the only clinical feat­
ure of note was the presence of small testes
and azoospermia.
T h e cells of his buccal
mucosa were chrom atin positive and autoradio­
graphy showed that he had a medium-sized
subm etacentric chromosomes which synthe­
sised D N A late in the synthetic period. It was,
therefore, concluded
that the additional
chromosome was an X and the patient an ex­
ample of K linefelter’s syndrome with an X X Y
1
Sex
Chromatin
No. of Late
Synthesising
M ediu m Sized
Chromosomes
XXY
+ ve
1
XXXY
+ + ve
2
XXXXY
+ + + ve
3
XXYY
+ ve
1
XYY
— ve
0
p resent article it must be remembered that
abnormalities of structure of both the X and
Y chromosomes are encountered which may
replace a normal sex chromosome o r be
additional to them. Furtherm ore it is very
common to find, especially in individuals with
abnormalities of the sex chromosomes, that not
all the cells of the body have a uniform con­
stitution, but that there are two or more cell
lines present which can be distinguished
cytogenetically, usually because they differ in
their number of chromosomes. One of the
cell lines may be normal or all may be abnor­
mal. and the resulting clinical picture depends
on the constitution of the constituent cell
lines and their relative frequency and distrib21
and more severely affected than those with two
additional X chromosomes. T h e y also show
a num ber of additional congenital abnorm al­
ities. T h e ir testes are usually extrem ely small
and often cannot be defined clinically. Som e
underdevelopm ent of the penis or scrotum is
usually found, som etim es linked with hypo­
spadias, and the degree of underdevelopm ent
of the secondary sex characters is often very
marked. T h ere are usually marked skeletal
abnormalities present, am ong them some
degree of fusion or synostosis of the ulna and
radius.
A ll X X X X Y individuals described
have been low grade mental defectives.
ution in the body, especially in the gonads.
T h u s an individual who has two cell lines, one
with 46 chrom osomes and an X X Y sex chrom ­
osome com plem ent may, if his gonad is largely
comprised of X Y cells, be clinically indisting­
uishable from a norm al m ale. Conversely, if
his gonad is largely comprised of X X Y cells he
may be clinically indistinguishable from a
“ pure” X X Y individual.
X X Y M ales
T h e presence of a single extra X chrom osome
is by far the com m onest abnorm ality of the
sex chrom osom c com plem ent found in man.
T h is is associated with the features of sem in­
iferous tubule dysgenesis or K lin efelter’s
syndrome. T h ese features are som ewhat vari­
able but hypogonadism is always present.
Before puberty, however, regressive changes
take place characterised by m arked degener­
ation and hyalinization or the sem iniferous
tubules, unusual numbers of Leydig cells and
the absence of spermatogenesis. T h ese feat­
ures m ay be accom panied by abnorm alities of
developm ent of the secondary sex characters
such as sparse growth of facial hair, fem ale
head or body hair distribution and develop­
m ent of breast tissue.
Furtherm ore X X Y
males tend to be rather tall and eunoichoid in
proportion, their leg length being long in rela­
tion to their height. T h e I.Q . of males with
an extra X chrom osom e is on average lower
than that of the norm al population, such males
being found significantly m ore often in instit­
utions for the m entally defective than in the
general population.
XXYY
M ales with an additional X and an addit­
ional Y chrom osom e are clinically sim ilar to
the X X Y male. T h e y have small testes and
show a similar range of abnorm alities of de­
velopm ent o f the secondary sex characters.
T h e y are fairly uncom m on, and all those so
far described have been m entally defective.
T h ere is also some suggestion that they are
taller than the X X Y males and that they are
unusually prone to the developm ent o f acro­
megaly.
X X Y Y males were also found to
com prise one third of all chrom atin positive
males in an institution for crim inal and hard
to manage m ental defectives — a proportion
far higher than that found in ordinary mental
defective institutions. It has therefore been
suggested that the presence of an additional
Y chrom osome m ay be a predisposing factor
to crim inal beh aviour.
XXXY
XYY
M ales with two additional X chromosomes
are m uch less com m on than males with a single
additional X chrom osome. T h e y also exhibit
the features of K linefelter’s syndrom e but they
are m uch more severely affected. T h e ir testes
are very small and the abnormalities of de­
velopm ent of the secondary sex characteristics
arc usually very marked.
Furtherm ore all
X X X Y individuals so far described have been
m entally retarded — the m ajority of them
being found amongst low er grade mental
defectives.
U ntil recently relatively little was known
about males with one additional Y chrom o­
som e . Such individuals seem to be rare and
the few cases described in the literature
ranged from a norm al fertile m ale examined
because one of his children was a m ongol, to
a num ber of m entally retarded children with
undescended testes. H owever, n o clear pic­
ture of the X Y Y male had emerged, partly
because they are indeed rather uncom m on and
partly because there is no easy way such as
nuclear sexing, of recognising them in the
population. R ecently, however, a chrom osome
survey of the inmates of a hospital for psycho­
pathic criminals and for crim inal and hard to
m anage m ental defectives has been com pleted
XXXXY
M ales with three additional X chromosomes
are, as expected, even more uncom m on
22
m ales a tte n d in g a su b fertility clin ic”. F u rth er­
m ore there is grow in g evid en ce th at th e pres­
en ce o f an addition al Y ch ro m o som e m ay
co n trib u te to psyco p ath ic and crim inal be­
haviour.
It is, therefore, evid en t th at m ales
w ith abnorm alities o f the sex ch ro m o som e
co m p lem e n t co n trib u te very sign ifican tly to
hum an p athology.
and it was show n th at 9 o f th e 314 m en exam ­
ined had an X Y Y sex ch ro m o som e co n stit­
ution*.
C lin ic a l exam in ation o f th e 9 X Y Y
m ales show ed them to b e unrem arkable, w ith
a pp aren tly n orm al testes and gen italia.' H o w ­
ever, they w ere sign ifican tly taller than the
oth er m ales in the in stitu tio n — in fact in this
particular in stitu tio n one in three of th e m ales
6 ft. and over in h eigh t had an addition al Y
chrom osom e.
W h ile the freq u en cy o f X Y Y
males in the general p o p u latio n is n o t know n
there is no d o u b t th at their freq u en cy in this
p articular gro up o f patients is very m uch great­
er than could be ex p ected b y chan ce. T h is
data suggests that th e X Y Y m ale is a clin ically
unrem arkable tall m ale, w h o is un usually pre­
disposed to aggressive and crim inal behaviour.
In con clusion it m u st b e rem em bered that,
w h ile som e o f the m ore bizarre abnorm alities
of the sex chrom osom es w h ich have been de­
scribed in this article are extrem ely rare, ch ro m ­
atin p ositive m ales are co m m o n . T h e ir in cid ­
en ce at birth is ab ou t 2 per thousand, w h ich ,
if w e assum e there is no d ifferen tial m o rtality,
m eans th at there are ab ou t 100,000 such in­
dividuals in th e p opu lation o f Britain at pres­
ent. T h e y form a b o u t 1 % o f all m ale m ental
defectives and h ave been show n to com prise
over 10 % o f all azo sp erm ic and oligosperm ic
REFERENCES
1. Barr, M. L. and Bertram, E. G. A morpho­
logical distinction between neurones of the
male and female, and the behaviour of the
nucleolar satellite during accelerated nucleoprotein synthesis, Nature (Lond.) 163, 676,
1949.
2. Casey, M. D., Segall, L. J., Street, D. R.
K. and Blank, C. E. Sex chromosome ab­
normalities in two state hospitals for patients
requiring special security, Nature 209, 641,
1966.
3. Jacobs, P. A.. Brunton, M., Melville, M. M„
Brittain, R. P. and McClemont, W. F.
Aggressive behaviour, mental subnormality
and the XYY male, Nature 208, 1351. 1965.
4. Price. W. H., Strong, J. A., Whatmore, P. B.,
and McClemont, W. F. Criminal patients
with XYY sex-chrom osom e complement.
Lancet i, 565, 1966.
5. Ferguson-Smith, M. A., Lennox, B., Mack, W.
S. and Stewart, I. S. S. Klinefelter’s syn­
drome: Frequency and testicular morphology
in relation to nuclear sex, Lancet 2, 167, 1957.
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