Chromosomal Aberrations in Pernicious Anemia

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Chromosomal Aberrations in Pernicious Anemia
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
Chromosomal
Study
By
B
of
of Three
A.
KOSMAS
Y NOW,
Aberrations
in pernicious
have
usually
et
reported
al.1’
Court
Brown
Astaldi
morphology
in
Berman19
ever,
the
a
found
modal
Recently,
aneuploidy
and
pernicious
anemia;
in
malignant
certain
case
studied
with
in
Forteza
and
during
sion,
demonstrated
particular
interest.
relapse
aneuploidy;
in
reported
modal
showed
anemia.
no
increased
in
were
we
present
of pernicious
and
vitamin
of
the
G 21
in
and
incidence
5
of
patients
with
of the
also
in 3 of 9 cases
following
Powsner
reminiscent
were
paper
the
and
in their
cases;
howother
chromosomal
an
findings
of 5
On
number
chromosomes
these
monosomy
cells
abnormalities.
chromosomes
there
were
B#{225}guena.5 In this
encountered
previously
1958,
Ford
Gr#{228}sbeck,#{176}
in studies
pernicious
individual
Similar
chromosomal
25 of 70
significant
thin
and
interpretation,
in a variety
of
because
results
negative.
In
and
any
changes
long
and
normal
was
documented
reports
in which
untreated
neoplasms.
both
find
MacDiarmid15
in his
patterns
studied,
to
DAMESHEK
modal
number
of 46; subsequently,
to possible
technical
faults
in prepa-
described
alterations
by
chromosomal
cases
woman
abnormally
number
abnormalities.
al.2’3
well
perhaps
essentially
anemia
Therapy
WILLIAM
scant
de Ia Chapelle
failed
et
been
than the normal
these
findings
et al.7 and
AND
only
of pernicious
respectively,
hand,
other
have
are available,
described
as
Anemia
and after
MITUS
Curiously,
anemia
been
a case
4 cases,
J.
aberrations
counts
of less
author
attributed
ration.’0
and
before
W.
conditions.
studies
obtained
chromosome
the same
Cases
KIossoGLou,
chromosomal
clinical
in Pernicious
findings
present
the
in
one
findings
anemia.
of
3
The
B12-induced
remis-
chromosomes
was
of
METHODS
The
Direct
three
cases of pernicious
marrow
chromosomal
anemia
with aneuploidy
are described
studies
were
performed
according
viously
described.’4
Peripheral
blood
leukocyte
cultures
were
carried
of Moorhead
et al.16 Skin fibroblast
cultures
were performed
according
bone
Harnden12
clature
with
was
modifications.24
The
combined
Denver1
and
in the APPENDIX.
to the method
preout by the method
to the method
of
Patau’8
system
of
nomen-
used.
RESULTS
Chromosomal
Studies
1.A.M.
Bone
From
(NECH
marrow.
the
Blood
#151-761)
Studies
Research
were
Laboratory,
done
on
Pratt
October
6,
Clinic-New
1962
with
England
the
Center
patient
Hospital
in
and
the
Department
of Medicine,
Tufts
University
School
of Medicine,
Boston,
Massachusetts.
This investigation
was supported
by Public
Health
Service
Grant
No. CA 04168-06
from the National
Cancer
Institute.
Presented
in part at the National
Meeting
of the American
Federation
for the Clinical Research,
Atlantic
City, N. I., May 3, 1964 and at the Xth Congress
of the Internanational
Society
of Hematology,
Stockholm,
Sweden,
August
30-September
4, 1964.
Submitted
June 17, 1964; accepted
for publication
July 7, 1964.
662
BLOOD,
VOL.
25,
No.
5
(MAY),
1965
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CHROMOSOMAL
relapse
ABERRATIONS
and
the
before
patient
vitamin
was
counted
The
in
and
and
morphologic
also
the
breaks
presence
“giant”
1963)
consisted
in
of
when
therapy
63 and
in
48
cells.
5 of
in
the
aberrations
breaks
On
and
shown
constrictions),
chromosomes
lacking.
15, 1963
months
and
counted
are
present
morphologic
were
cells
noted
(secondary
of chromatid
chromosomes
13
in relapse
the
occasions
gaps
4 and
November
with
3 in remission
on photomicrographs.
were
and
of
(February,
after
number,
three
14, and
plates
analyzed
aberrations
chromatid
and
663
ANEMIA
on February
metaphase
modal
on
PERNICIOUS
remission
chromosome
distribution
and
therapy
B12. Forty-eight
were
the
IN
majority
and
gaps.
They
of
present
In
of
fragments
cells.
In
structural
and
remission
2 of 63 cells
fragments
no
relapse,
consisted
in only
Acentric
1963,
percentage
1.
acentric
were
November,
their
table
and
“giant”
anomalies
were
found.
G
Karyotypes
were
21 monosomy,
persisted
in
occasions.
the
remission
The
karyotyped
Peripheral
the
and
were
also analyzed
present
in
patient
isochromatid
G
21
(figs.
J. J.
(NECH
Bone
marrow.
plates
1-3,
Studies
therapy
after
6 months
in
the
cells
on
different
in
on
of 44 metaphase
found
each
of
November
plates
in another
G 21 monosomy
G
of the
was
were
15,
counted
21
was
Karyotypes
present
monosomy
and
observed
skin
cent
present
derived
the
cells
with
6
bone
an
extra
short
46,
in
from
fibroblasts,
onto
in
in 4.7 per
was
cells
translocated
were
of 16 metaphase
plates
were
seen.
Karyotypes
analyzed
leukocytes
was
cell.
1963)
A total
aberrations
2).
all
origin
change
two
aberrations
arms
of
and
44
45
6).
#158-112)
before
mission
was
(table
In
blood
This
of
occasions.
examined,
(table
1). Morphologic
aberrations
consisted
of A 2/E
18 translocation
and
2).
cells
undetermined
chromosome.
relapse
over
examined.
peripheral
of
cent
chromosomal
A total
(table
four
cells
cells,
chromosomes
2.
cells
per
respective
the cells
in figures
1-3
and table
2.
culture.
This
was performed
Crossing
on
of the
chromatin
100
structural
culture.
(November
15,
(table
1). No morphologic
performed
marrow
and
and
on photomicrographs
1 of 44 cells.
They
on eight
examined.
Skin fibroblast
were
examined
cent
45
in remission.
break.
performed
of the cells
on 16, 20 and 3 cells on the
present
in 25 per
cent
of
cells are shown
blood
leukocyte
with
per
in
numerical
1963
were
performed
originally
relapse
were
performed
and
of
and
44
on
therapy
in
on August
February
5, 1964
with
vitamin
remission
were
8, 1963
when
B,2.
counted
with
the
the
patient
patient
was
Thirty-nine
and
in
in re-
metaphase
also
analyzed
on
photomicrographs.
The
chromosomal
modal
distribution
on two
In
morphologic
relapse,
occasions,
present
in 3 of 39 cells.
rations
were
(table
1).
seen.
An
number,
both
aberrations,
In
remission
endoreduplication
the
in initial
cells
and
counted
remission
consisting
(February,
phenomenon
of
1964)
and
are
chromatid
percentage
their
shown
in table
breaks,
were
no
morphologic
aber-
was
encountered
once
1.
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From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
CHROMOSOMAL
ABERRATIONS
IX
PERNICIOUS
665
ANEMIA
&
‘I
#{149}1
‘I
H
I’
C6
C7
ft
C8
C9
D14
“
at
F19
F20
DiS
marrow
cent).
were
G
was
The
karyotyped
Peripheral
21
not
performed
monosomy
found
numerical
cells
blood
are
8
CU
C12
3f
U
Al
#{163}16
#{163}17
E18
021
022
‘I
Fig.
1.-Case
1 in relapse.
Above:
karvotvpe
of the same cell containing
Extra
chromatin
material
is translocated
The arrows
point to chromatid
breaks
Karyotypes
U
Gb
*1
D13
occasions.
!4
metaphase
45
onto
and
on
(16
in remission,
and
shown
leukocijte
plate
structural
in figure
culture.
from
chromosomes.
G
the
short
chromatid
15
per
and
cent)
but
of
cells,
originally
aberrations
was
present.
chromosome.
gaps.
present
in peripheral
This
21st
respectively,
present
table
Below:
is
isochromatid
chromosomal
4 and
marrow.
monosomv
arms
and
5
bone
21
in
on
both
the
bone
blood
in
each
(5.6
of
per
the
2.
performed
on February
5, 1964
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
666
KIOSSOCLOU,
%‘
U
fl3;
U
;inu
C?
C8
bRhf
D13
C9
D15
Fig. 2.-Case
1 in relapse.
Above:
karyotype
of the same cell containing
Extra
chromatin
material
is translocated
“Giant”
chromosomes
the
patient
analyzed
absent.
with
in
on
patient
fibrobla$t
times,
were
CU
C12
#{163}16
#{163}17
#{163}18
021
CU
were
#149-671)
metaphase
plate
45 chromosomes.
onto the short
coiling
are
Thirty-six
This
on
was
the
obtained
arms
1).
10 cells
plates
Morphologic
(table
on
appeared
on any
of
21st
chromosome.
seen.
performed
skin
#{163}
from boiie
marrow.
Below:
C 21 monosomy
is present.
metaphase
(table
performed
Although
no mitoses
(NECH
remission.
culture.
in remission.
3. A. M.
imperfect
photomicrographs
Karyotypes
Skin
do
kk
D14
F19
five
DAMESHEIC
Ic b I
C6
also
AND
4#{231})
tt
with
MITIJS
of these
were
counted
aberrations
and
were
2).
February
to grow
occasions.
5,
and
1964
was
with
harvested
the
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
CHROMOSOMAL
ABERRATIONS
IN
PERNICIOUS
667
ANEMIA
‘C
‘I
A3
fl
C6
C8
C9
1
**
*A
D 13
D14
D15
F19
F20
.‘
.I
?s.XXJi
C?
C10
Cli
C12
I A
*
E 16
7
El
E18
*A
Fig. 3.-Case
low: karvotvpe
present
and
G21
xy
1 in remission.
of the same
cell
extra
chromosome.
G22
chromatin
Breaks,
gaps
blood
leukocyte
Above:
material
and
metaphase
containing
is
“giant”
45
plate
from
chromosomes.
bone
C 21
short
translocated
onto
the
chromosomes
seen
in relapse
marrow.
monosomv
arms
of
are
Beis
21st
no
more
31,
1964
present.
Peripheral
with
after
the patient
in remission,
x-ray treatment
to the
and
five
graphs.
age
metaphase
The
distribution
23 of 105
cells.
culture.
plates
chromosome
are
They
This
was
performed
19 months
after
the
spine
for partial
collapse
were
counted
modal
shown
consisted
number,
in table
and
the
also
cells
1. Morphologic
of chromatid
breaks,
on January
Schilling
test and 9 months
of T 11-T 12. One hundred
analyzed
counted
aberrations
gaps,
on
and
photomicrotheir
were
deletions,
percentpresent
reciprocal
in
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
668
KIOSSOGLOU,
translocations,
and
dicentric
occasional
Karyotypes
the
“giant,”
were
present.
The
cells
cells
This
present
and
are
an
in all cells
36
cells.
shown
figure
of
the
similar
analyzed
that
regardless
DAMESHEK
chromosomes
chromosomes.
(6
per
cent)
aberrations
in
arms
of
observed
of their
ring
“marker”
5 and
short
to
AND
monosomy
chromosome
in
enlargement
and
G 21
structural
enlargement,
fragments,
monocentric
on
numerical
karyotyped
acentric
bizarre
performed
karyotyped
present.
chromosomes,
MIniS
table
2.
G 21
in
modal
in
the
In
was
each
all
of
of
the
chromosome
was
first
was
patient,
number
(fig.
by
Astaldi
5, 6).
DISCUssIoN
In
an
1962,
untreated
100
modal
case
metaphase
number
per
cent
44
44
monosomies
monosomy
cell
with
caused
sented
report
hypodiploid
number
(32
In the
to
relapse
note
than
the
that
in
and
remission.
a common
was
taining
44
present
with
the
the
1 and
showed
G
were
no evidence
B,2
cent
A, C, D and
unlikely
only
of deletion.
of
C
all
1
counted.
was
coupled
B#{225}guena.5
hemic
the
in
onto
with
present
there
the
and
in both
appeared
the
the
piece
arms
material
of
analyzed
extra
short
significance
con-
inconstant
In all
an
to
abnor-
cells
with
instances
was
a normal
This
In
additional
chromosome
origin
cells,
were
number,
cells
It is inter-
chromosomes.
modal
preafter
increased
and
21#{176}
monosomy.
translocated
since
The
in
many
cells,
cells
E series
that
chromosome,
present,
aneuploid
of their
was
to
therapy
the data
because
present
paper,
addition
monosomy
origin
21
in
One
frag-
chromosomes
vitamin
44 chromosomes
namely
21
X’s.
of 46 chromosomes.
in these
3, irrespective
It is very
missing
study,
45 and
including
acentric
by Forteza
in this
number
anomaly,
of undetermined
chromosomes
mains
the
cells
reported
50
cells
of group
dicentric
that
in
and
on
of both
In addition,
still
al.2’3
a normal
found
absence
were
were
modal
C
involving
were
presented
in 6 to 45 per
21 chromosome.
from
results
normal
chromosomes,
of cases
performed
chromosomes
it is stated
reduced,
anemia
chromosomal
monosomies
chromatin
although
Furthermore,
present
were
simulating
authors4
had
of both
E 18 monosomy.
same
cent
chromosomes
changes
apparent
et
45
chromosomal
findings.
However,
frcm
that
normalization
was
not complete
Similar
number,
mality
of
of the
originated
where
.2
G
21
normal
size
and
of this
finding
re-
unexplained.
Structural
fragments
anomalies
were
also
#{176}The
C 21 pair
and
cent).
of
constrictions
of pernicious
less
chromosomal
C
the
cells,
per
3 cases
contained
cells
by
19 per
had
absence
of 1 X and
secondary
these,
cent
4 karyotypes
pairs,
exhibited
normalization
of
it would
appear
Of
a variety
12th
absence
occasional
therapy
he
and
described
11 per
and
5th
45 chromosomes
and
studied.
Only
chromosomes
15 and
were
found.
In a recent
csting
were
chromosomes.
of the
20,
ments
plates
anemia
of 46 chromosomes,
had
containing
of pernicious
satisfactorily
in
found.
the
As
form
these
could be easily differentiated
identified
as such.
of chromatid
were
observed
from
the
breaks,
gaps
and
acentric
(in cases
1 and 2) in the
C 22
pair
and
the
Y chromosomes
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
CHROMOSOMAL
ABERRATIONS
L.
iC)
4)4’)
.
a
IN
PERNICIOUS
669
ANEMIA
i
C’)
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more
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other
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because
aberrations
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E18
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Fig. 6.-Above:
Case 1, below: Case 3, both in remission.
diploid
cells from peripheral
blood leukocyte
culture.
One of the
in both cells is abnormally
large.
It
tI
“lost”
by
in
continue
an
to
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
OHROMOSOMAL
ABERRATIONS
propagate
IN
at a postzygotic
sent
a congenital
blastosis.
The
or
presence
ment
of
level.6’23
acquired
anemia
is a form
C 21 monosomy
of
are
in
neoplasia
for
material
some
and
of
Alternatively,
genetic
Indeed,
of neoplasia
675
ANEMIA
predisposition
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reminiscent
PERNICIOUS
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features
line
may
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are
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15 17
It
is of interest
and
that
the
relationship
very
there
the Ph
Down’s
some
acute
chronic
How
stated
series,
the
our
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chance
cent
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alkaline
leukemia.
changes
are
Certainly
C
21
the
that
monosomy
subjects.
in this
far
from
of the
the
100
per
consideration.13
Since
both
males
defect
Involvement
since
this
pair
C 21 pair
chromosome
may,
blastosis.
In
including
family
any
has
been
play
some
event,
studies
study
in
Down’s
of
being
in
in
mongolism20
syndrome
anemia
without
this
in
only
3 of
may
be
series
of 415
and
cannot
be
abnormality
the
metaphase
and
9 cases
of
and
females
.
C 21 pair
involved
a key
way,
be
further
would
chromosomal
be
were
and
to
the
sex
series
anemia
G-Y
series
into
autosomal
disturbances.
alterations
in
was
taken
an
development
studies
C-Y
is of particular
hematologic
the
2
derived
incidence
affected,
in hematopoiesis;
related
in
the
of chromosomes
in other
role
of the
of pernicious
age
than
plates
Thus,
with
is less
C-Y monosomy
et a!.,13 in a study
loss
examined.
even
lost
disorders,
Jacobs
chromosomal
cells
chance,
of the
may
in
G-Y
of
of all
by
the
instances
C 21 trisomy
or 22 haploidy
pernicious
or neoplastic
cent of the cells.
frequency
cent
found
interest
pair
monosomy
in the chromosomes
cells examined.
In the 3 cases
that
Thus,
than
is likely.
to
found
In a control
found
of the
study,
6 to
higher
particular
reactions
occurs
was
1 chromosome
normal
males,
0.95 per cent
ranged
that
other
that
studied.
in normal
presented
families.
in
in both
related
disease
is
chromosomal
interesting
of
leukemoid
Inter-
stomach
is also
disorders,
phosphatase
the
further
of their
involvement
from
17 patients
with
no hematologic
was present
in not more
than
1 per
of 123
in only
members
chromosome
stomach
stomach.
of
warrants
hemotologic
cases,21’22
anemia
of the
the
in chronic
granulocytic
leukemia,
acute
granulocytic
leukemia,
the 21
granulocytic
the described
time.
of
with
of leukocytic
at this
21
of
carcinoma
findings,
C
carcinoma
carcinoma
and
as in the
the
instance
leukemia
pernicious
per
another
1 chromosome
syndrome
and
changes
our
as well
in association
of
anemia
of
involving
is
1 died
view
patients
chromosomes
and
in
monosomy
here
another
pernicious
and
in these
The
1 of our
of
between
intriguing
studies
in
that
mother
of this
of
pernicious
megaloanemia,
of interest.
SUMMARY
Numerical
in three
including
and
cases
morphologic
of pernicious
chromatid
breaks,
chromosomal
anemia
gaps
in relapse.
and
“giant”
aberrations
The
were
morphological
chromosomes
demonstrated
abnormalities
were
reduced
in
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CHROMOSOMAL
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IN
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Fig. 7.-Bone
below:
marrow
km remission
remission
following
aneuploidy
(45
countered
This
tissues,
e.g.,
a more
generalized
44
per
was
peripheral
1. Above:
normoblastic
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and
(6 to 100
chromosome.
smears of Case
showing
B12 therapy.
The
chromosomes)
cent
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blood
disorder.
of the
not
and
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in
relapse
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with
cells)
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possibly
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en-
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\Vright-Ciemsa
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other
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From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
678
KIOSSOGLOU,
It is postulated
that
acentric
fragments
ficiency
and
are
correctable
the
structural
had
short
of C 21 chromosomes
arms
the
a
basis
of the
Aberrationes
in
le
in tres
de
morphologic-fracturas
in le remission
numeric
consisteva
6 e 100
pro
cento
cellulas
e
generalisate
que
non
sed
que
illo non
esseva
pote
in duo
del
tres
acquired
predisposition
not
not
studied
to
Iste
.
morphologia
e 44
altere
translocate
monosomia
( in
per
exemplo
in
sanguine
que
suggestiona
persisteva
un
in
le
le fracturas
Le causa
usate)
del
non
chromatidic,
relationate
clar. Le
maniera
es
de
a base
e le signification
del
bracios
plus
remission.
al
del aneuploidia
morbo,
le curte
inter
solmente
a megaloblastosis
ad super
con
non
gigante-es
corrigite.
per le therapia
declaration
,
frequente
notate
tissus,
numeric
origine
)
alterationes
esseva
structural-i.e.,
Le
gigante-esseva
le plus
lo
esseva
anormalitates
B12. Le
chromosomas
cutanee,
esser
Le
a vitamina
e le chromosomas
le
chromosomal
in recidiva.
phenomeno
in
The
the
unexplained.
e chromasomas
anormalitates
excludite.
casos
de-
was
it
or
le constatation
predisposition
esser
chromatinic
materia
)
B12 e pote
o acquirite
non
le
( 45
como
etiam
corrigibile
ante
since
3 remains
hiatos,
acentric,
esseva
studiate
B12
were
un therapia
le anormalitates
de vitamina
gaps,
vitamin
INTERLINGUA
in
fibroblastos
Le
breaks,
to
patients
perniciose
sequeva
cellulas
le fragmentos
congenite
C21
del
(forsan)
postulate
carentia
e
anemia
C21
disordine.
le hiatos,
1 and
IN
aneuploidia
medullari
peripheric
Es
de
le chromosoma
afficiente
in
que
DAMESHFX
the
congenital
chromatidic,
reducite
chromatid
related
aneuploidy,
Since
in cases
numeration
casos
the
AND
of C 21 monosomy
cannot
be excluded.
extra
chromatin
material
translocated
onto
SUMMARIO
demonstrate
of
clear.
ensued,
on
significance
are
cause
is not
megaloblastosis
origin
and
namely
chromosomes
The
treatment,
disease
anomalies,
“giant”
correctable.
by
before
the
and
MITUS
del
de
(viste
patientes
que
un
monosomia
supernumerari
chromosomas
G21
inexplicate.
remane
APPENDIX
Case
Reports
1. A. M.
(NECH
#151-761)
A 74-year-old
Presbyterian
pastor
of Irish
origin
(the
father
of an apparently
normal
female
child,
now
21 years
old)
developed
progressively
severe
substernal
chest
pain
and a gradual
20-pound
weight
loss during
1961.
Upon
admission
to the New
England
Center
Hospital
in October,
1962,
he was
found
to be a pale,
thin
man
with
grey
hair
and blue eyes. There
was
slight
icterus
of the
sclerae
and
the
edges
of the
tongue
were
smooth.
neurologic
positive
extremities
The
anemia.
Liver
and
spleen
examination
bilaterally.
but
blood
Many
were
not
showed
Vibratory
pain
findings,
of the
and
an
and
temperature
which
are
polymorphonuclear
palpable
and
increase
light
in
touch
sensations
sensations
presented
there
tendon
were
in
cells
table
were
was
reflexes
no
and
were
lymphadenopathy.
the
greatly
intact.
3, were
characteristic
hypersegmented.
The
Babinski
test
decreased
of
was
in
all
pernicious
The
bone
marrow
was
hypercellular
with
pronounced
megaloblastic
hyperplasia
(fig.
7); giant
metamyelocytes
were
noted.
The
myeloid-erythroid
ratio
was
1:1. The
megakaryocytes
were
decreased
in number
and were of the nonproductive
type.
Iron was abundant.
The Schilling
test showed
an excretion
of less than
1 per
cent
of vitamin
B19 in 24
hours.
Additional
laboratory
studies
included
total
serum
bilirubin,
1.4 mg.
per
cent with
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CHROMOSOMAL
ABERRATIONS
IN
PERNICIOUS
679
ANEMIA
1.2 mg. per cent of the indirect
variety;
serum
iron,
ing capacity,
zero. X-rays
of the gastrointestinal
tract
Administration
of parenteral
vitamin
B19, 100 g.
g./100
ml.; unbound
chest
were normal.
for 1 we:k
resulted
238
and
daily
bind-
iron
in a rapid
return of well-being
and in a peak reticulocyte
value of 22 per cent, 5 days after initiation
of therapy.
This was followed
by a more
gradual
rise in hemoglobin.
Subsequent
treatment
consisted
of vitamin
B12,
100
g.
twice
a week
for
4
weeks
and
100
thereafter
g.
at monthly
intervals.
When the patient
was seen again
in February,
1963, 4 months
after
initiation
of therapy, he was completely
asymptomatic.
The tongue
was now well papillated,
but abnormal
neurologic
findings
persisted.
Hematologic
data are shown
in table
3. No hypersegmented
polymorphonuclear
cells
were
noted.
The
bone
marrow
was
normal
with
normoblastic
maturation
(fig.
7).
On November,
was in excellent
shown in table
marrow
was
was
The
myeloid-erythroid
health.
3.
normal
ratio
( 13 months
There were
1963
after
was
3:1.
of vitamin
B19 therapy)
the patient
not abnormal
physical
findings.
Hematologic
data are
polymorphonuclear
cells were
noted.
The bone
erythroid
maturation.
The myeloid-erythroid
ratio
No hypersegmented
with
normoblastic
initiation
3.2:1.
2. J. J. (NECH
#158-112)
A 69-year-old
per cent. The
Swedish
born male
was
found
to have
a macrocytic
anemia
of 6.2
Gm.
childless
widower
working
as an industrial
designer,
started
cornplaining
of weakness,
fatigue
and a pinching
sensation
of his feet, 2 weeks
prior
to admission.
He had no peptic
symptoms.
Previous
surgery
included
tonsillectomy,
adenoidectomy, and bilateral
inguinal
herniorrhaphy.
There
was no exposure
to known
toxins.
Physical
examination
(August
8, 1963)
revealed
a fair-skinned
grey-haired,
wellnourished
male in no acute distress.
Sclerae
were mildly
icteric.
The tongue
was normal
in size, pale
and smooth
with marked
loss of papillation.
Liver
and
spleen
were
not
palpable
and there
was no lymphadenopathy.
The
neurologic
examination
revealed
diminished
touch
sensation
over
both
ankles
and
feet,
absent
vibratory
sensation
over
both legs and absent
knee and ankle
jerks.
It is of interest
that
the patient’s
mother
died
of carcinoma
patient,
a
of the stomach.
which
showed
the
findings
of pernicious
anemia,
are presented
in
3. Many
of the polymorphonuclear
cells were
hypersegmented.
The bone
marrow
was hypercellular
with
prominent
megaloblastic
hyperplasia;
many
giant
metamyelocytes
were noted.
The myeloid-erythroid
ratio was 0.7:1.
Megakarocytes
were present
and were
of the nonproductive
type. Iron was present.
PAS
staining
of the nucleated
red
blood
cells
Blood
findings,
table
was
negative.
The
Schilling
test
hours.
Additional
cent
with
1.4 mg.
acid;
showed
laboratory
per
uric
acid, 7.5 mg.
capacity
of zero);
serum
2.3 Gm./100
ml.; serum
testinal
tract
enteral
vitamin
and
an
excretion
of
studies
cent
of
per
cent;
the
less
than
included
indirect
serum
variety;
iron,
175
chest
were
B12, 1000 g.
normal.
Treatment
every
other
day
cent
of
vitamin
bilirubin,
gastric
analysis
ml.
zg./lOO
consisted
for 2 weeks
intervals.
the patient
was seen again
in February,
apy,
he was completely
asymptomatic.
The tongue
ings were
only slightly
improved.
Hematologic
morphonuclears
were
normally
segmented.
The
normoblastic
maturation
of the erythroid
series.
mal. The myeloid-erythroid
ratio was 1.7:1.0.
This
normal
per
serum
protein,
6.6 Cm./100
ml.; albumin,
4.3
LDH,
420 units
(normal
50-128
units).
monthly
When
3. A. M. (NECH
one
total
in
24
mg.
per
showed
no
free
(unbound
Cm./100
X-rays
B12
2.0
iron
ml.;
of
the
binding
globulin,
gastroin-
of the administration
of
and 1000 jg subsequently
parat
1964,
6 months
after
initiation
of therwas well papillated.
Neurologic
finddata
are shown
in table
3. The
polybone
marrow
was
normocellular
with
Granulocytic
maturation
was also nor-
#149-671)
74-year-old
widowed
children,
evidenced
female
fatigue,
of Jewish-Russian
loss of appetite
extraction,
and
loss
of
mother
weight
of 3 apparently
(5 pounds).
She
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
680
KIOSSOCLOU,
also
complained
of
a
burning
sensation
of
the
tongue,
MITUS
pins
and
AND
needles
DAMESHEK
in
the
legs
and
numbness
of her toes of 15 weeks
duration.
Twenty
years
previously,
the diagnosis
of
pernicious
anemia
had been
made;
she was treated
with liver extract
injections
and made
a good
recovery.
She continued
with these
injections
for 13 years
but had discontinued
them during
the past 7 years.
Physical
examination
revealed
a grey-haired
woman
in no
acute
distress
with pallor,
an atrophic
tongue
and no organ
enlargement.
Abdominal
and
patellar
reflexes
were
absent
and the ankle
jerks
were
diminished.
Vibratory
sensation,
position
sense
and pin prick
sensation
in both
legs were
diminished.
The
Romberg
test
was positive.
Blood
findings
at
that
polymorphonuclear
moderate
time
cells
erytbroid
frequently
and
The
were
Schilling
hours.
test
Additional
juice,
serum
1962)
partial
showed
and
postoperative
per month.
In April,
course
back
pain
1963,
and
July
of less
include
unbound
her
x-ray
1.5:
3.
Many
of
hypercellular
the
with
metamyclocytes
were
Megakarocytes
were
1.
satisfactory.
Gm./100
ml.;
of
was
no metastases
patient
status
of
1 per
carcinoma
The
hematologic
than
cent of vitamin
B19 in 24
hydrochloric
acid
in gastric
capicity
of 239 zg. per cent;
globulin,
3.4
Gm./100
ml.
and
and positive
guaiac
test in the stools,
radiologic
was done.
This showed
some
irregularity
of the
There
1962.
examination
Giant
was
absent
free
iron binding
3.7
revealed
was
table
was
type.
findings
per cent;
23,
in
marrow
ratio
an excretion
gastroscopy
on
presented
bone
megaloblastosis.
myeloid-erythroid
total proteins
7.1 Gm./100
ml.; albumin,
total bilirubin
of 0.1 mg. per cent.
Because
of vague
abdominal
discomfort
examination
of the gastrointestinal
tract
stomach
wall
was performed
are
The
nonproductive
laboratory
113 pg.
iron,
and
The
of the
25,
hypersegmented.
hyperplasia
encountered.
present
(June
were
the
was
spine
the
was
stomach.
started
satisfactory
(table
demonstrated
Subtotal
3),
a partial
The lesions
were
successfully
treated
with deep
x-ray
therapy
row examination
in July,
1963, was found
to be normocellular
myeloid
forms
but normoblastic
erythroid
elements.
No tumor
The
patient,
when
last seen
on January
31, 1964,
was
hematologic
status
was within
normal
limits
(table
3).
gastrectomy
present
and
on vitamin
the immediate
B12, 1000 g.
but
she
collapse
of
developed
T 11-T
12.
to the spine.
A bone
marwith moderate
increase
in
cells were
found.
feeling
reasonably
well
and
ADDENDUM
Six patients
had abnormal
in the chromosomes
of the
analyzed
was present
in 4
Polyploidy
(21.4
per cent)
12 additional
cases of pernicious
anemia
were
studied.
findings.
Hypodiploidy
was present
in 5 of them.
Monosomy
C-Y series,
ranging
from
9.8 to 30.4 per cent
of total
cells
patients.
“Giant”
chromosomes
were
present
in 5 instances.
was found
in another
patient.
One patient
with a stein
line
of
45
a
Since
this
paper
chromosomes
was
prepared,
exhibited
Y chromosome.
Structural
present
in 6 cases.
These
had normal
chromosome
reciprocal
DID
aberrations,
were
largely
findings.
translocation.
Another
such as breaks,
corrected
after
patient
had
a
large
gaps,
and acentric
fragments
were
vitamin
B12 therapy.
Six patients
ACKNOWLEDGMENTS
We
of
wish
Mrs.
I)r.
to
Carol
Thomas
F.
acknowledge
the
Sheehan
and
Necheles
for
help
Mrs.
of
Dr.
Nanci
constructive
Arthur
Coleman
Spielvogel
for
skillful
for
clinical
technical
data
assistance,
in
Case
1,
and
of
criticism.
REFERENCES
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standard
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somes.
2. Astaldi,
Lancet
1:1063,
C., Strosselli,
E.,
1960.
and Air#{244},
R.:
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A.,
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and
for
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leukocytes
of
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therapy
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for
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and
-,
cytog#{233}n#{233}tiquesdans
8.
dence
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osservazioni
clell’anemia
of
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citoge-
2.
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count
197:1080,
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emopatie:
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dell’
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Air#{244},R.:
netiche
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681
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emopat-
cromosomni
perniciosa
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PERNICIOUS
ndlle
sui
Alterazioni
-,
IN
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and
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human
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L.
The
communication.
1)100(1
12:
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682
KIOSSOGLOU,
Kosmas
tology,
A. Kiossoglou,
Blood
Research
Center
Hospital,
W.
I. Mitus,
ratory,
ant
tory,
Research
Clinic-New
Professor
William
versity
and Instructor
School
of Medicine,
M.D.,
Pratt
M.D.,
Senior
Laboi’atory,
of Medicine,
Danzeshek,
School
and
Chief
M.D.,
Associate,
Tufts
Boston,
Center
Blood
University
Mass.
School
of
Director,
Hematology,
Hospital,
University
Research
Hospital,
Clinic-New
Boston,
Mass.
Assist-
of Medicine,
Research
Pratt
Labo-
and
Medicine,
Blood
DAMESHEK
AND
in HemaEngland
Tufts
Mass.
Center
Professor
of Medicine;
of
Research
Fellow
Pratt
Clinic-New
in Medicine,
Boston,
England
MITUS
Tufts
UniLabora-
England
From www.bloodjournal.org by guest on August 11, 2017. For personal use only.
1965 25: 662-682
Chromosomal Aberrations in Pernicious Anemia: Study of Three Cases
before and after Therapy
KOSMAS A. KIOSSOGLOU, W. J. MITUS and WILLIAM DAMESHEK
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