Trisomy 8 syndrome owing to isodicentric 8p chromosomes: Regional assignment of a presumptive gene involved in corpus callosum development

Abstract

Two patients with trisomy 8 syndrome owing to an isodicentric 8p;8p chromosome are described. Case 1 had a 46,XX/46,XX,-8,+idic(8)(p23) karyotype while case 2, a male, had the same abnormal karyotype without evidence of mosaicism. In situ hybridisation, performed in case 1, showed that the isochromosome was asymmetrical. Agenesis of the corpus callosum (ACC), which is a feature of trisomy 8 syndrome, was found in both patients. Although ACC is associated with aneuploidies for different chromosomes, a review of published reports indicates that, when associated with chromosome 8, this defect is the result of duplication of a gene located within 8p21-pter. Molecular analysis in one of our patients led us to exclude the distal 23 Mb of 8p from this ACC region.

Full text

2
Med
Genet
1994;31:238-241
Trisomy
8
syndrome
owing
to
isodicentric
8p
chromosomes:
regional
assignment
of
a
presumptive
gene
involved
in
corpus
callosum
development
M
C
Digilio,
A
Giannotti,
G
Floridia,
F
Uccellatore,
R
Mingarelli,
C
Danesino,
B
Dallapiccola,
0
Zuffardi
Abstract
Two
patients
with
trisomy
8
syndrome
owing
to
an
isodicentric
8p;8p
chromo-
some
are
described.
Case
1
had
a
46,XX/
46,XX,
-8,
+
idic(8)(p23)
karyotype
while
case
2,
a
male,
had
the
same
abnormal
karyotype
without
evidence
of
mosaic-
ism.
In
situ
hybridisation,
performed
in
case
1,
showed
that
the
isochromosome
was
asymmetrical.
Agenesis
of
the
cor-
pus
callosum
(ACC),
which
is
a
feature
of
trisomy
8
syndrome,
was
found
in
both
patients.
Although
ACC
is
associated
with
aneuploidies
for
different
chromo-
somes,
a
review
of
published
reports
indicates
that,
when
associated
with
chromosome
8,
this
defect
is
the
result
of
duplication
of
a
gene
located
within
8p21-pter.
Molecular
analysis
in
one
of
our
patients
led
us
to
excludje
the
distal
23
Mb
of
8p
from
this
ACC
region.
(J
Med
Genet
1994;31:238-241)
Dipartimento
di
Genetica
Medica,
IRCCS
Ospedale
Bambin
Gessu,
Piazza
S
Onofrio
4,
00165
Roma,
Italy
M
C
Digilio
A
Giannotti
Biologia
Generale
e
Genetica
Medica,
Universita
di
Pavia,
CP
217,
I-27100
Pavia,
Italy
G
Floridia
C
Danesino
O
Zuffardi
Dipartimento
di
Ostetricia
e
Ginecologia,
Universiti
di
Catania,
Catania,
Italy
F
Uccellatore
Universita
di
Tor
Vergata,
Roma
e
IRCCS
Ospedale
CSS,
San
Giovanni
Rotondo,
Italy
R
Mingarelli
B
Dallapiccola
Correspondence
to
Dr
Zuffardi.
Received
2
September
1993
Accepted
for
publication
7
October
1993
Mosaicism
for
trisomy
8
results
in
a
character-
istic
syndrome
reported
in
more
than
100
patients.'4
We
report
on
two
patients
with
the
clinical
phenotype
of
trisomy
8
syndrome
owing
to
isodicentric
8p;8p
chromosome.
Case
reports
CASE
1
Case
1,
a
female,
was
born
to
healthy,
unre-
lated
parents.
She
was
the
product
of
the
second
pregnancy,
the
first
having
ended
in
spontaneous
abortion
at
6
months.
Vaginal
delivery
of
the
proband
occurred
at
7
months.
Birth
weight
was
2700
g.
The
perinatal
period
was
complicated
by
respiratory
distress
and
jaundice.
Feeding
difficulties
were
reported
in
the
first
months.
Psychomotor
development
was
delayed.
At
14
months
of
age
weight
was
7100
g
(<3rd
centile),
height
75
cm
(25th
centile),
and
head
circumference
46
cm
(between
the
25th
and
the
50th
centile).
The
hair
was
fair
and
thin.
The
palpebral
fissures
were
horizontal.
There
was
an
alternating
internal
strabismus.
A
flat
angioma
was
noted
on
the
right
cheek.
The
nose
was
saddle
shaped
and
the
philtrum
long.
The
mouth
was
small
with
a
thick
lower
lip
and
high
arched
palate.
The
ears
were
low
set
with
a
flat
helix,
wide
concha,
and
prominent
antitragus.
The
neck
was
short
with
mild
webbing.
The
shoulders
were
narrow
with
epitroclear
dimples.
The
fingers
were
long
and
showed
camptodactyly
and
the
feet
were
large
with
deep
plantar
furrows.
Routine
laboratory
in-
vestigations
were
normal.
A
cerebral
CT
scan
showed
agenesis
of
the
corpus
callosum.
Echo-
cardiography
showed
valvular
pulmonary
stenosis
and
secundum
atrial
septal
defect.
CASE
2
Case
2,
a
male,
was
the
first
child
of
healthy,
unrelated
parents.
At
birth
the
mother was
20
years
old
and
the
father
21.
The
family
history
was
unremarkable.
One
previous
pregnancy
resulted
in
a
spontaneous
abortion
in
the
second
month
of
gestation.
First
and
second
trimester
ultrasound
in-
vestigations
were
normal,
but
a
reduced
bi-
parietal
distance
was
reported
in
the
third
trimester.
The
baby
was
born
at
term
by
vaginal
delivery.
Birth
weight
was
3150
g
(25th
centile),
length
53
cm
(50th
centile),
and
head
circumference
35
cm
(50th
centile).
The
early
weeks
were
complicated
by
stunted
growth.
The
patient
was
referred
to
us
at
the
age
of
2
months,
when
weight
was
3500
g
(<
3rd
cent-
ile)
and
head
circumference
37
cm
(10th
cent-
ile).
Physical
examination
(fig
1A)
showed
an
asymmetrical
skull
with
sparse
hair
and
hyper-
trichosis
of
the
frontotemporal
region.
The
forehead
was
high
and
prominent
with
slightly
depressed
temples.
The
eyebrows
were
sparse
and
elongated
and
the
eyes
deep
set
with
upward
slanting
palpebral
fissures.
Inner
canthal
distance
was
3-
1
cm
(>
97
centile).
The
nose
had
a
characteristic
"boxer
appearance"
with
a
wide
nasal
bridge
and
anteverted
nos-
trils.
The
philtrum
was
normal.
The
upper
lip
was
prominent
and
thick.
The
lower
lip
and
jaw
were
retracted
and
the
chin
was
rounded.
The
face
was
covered
with
a
fine
lanugo.
A
2
x
1
5
cm
cutaneous
haemangioma
was
noted
on
the
left
cheek.
The
ears
were
low
set
and
dysmorphic,
with
a
large
lobule,
an
incom-
pletely
folded
helix,
and
a
prominent
antihelix.
The
neck
was
short.
There
were
umbilical
and
bilateral
inguinal
hernias.
The
scrotum
was
empty.
The
fingers
were
flexed
and
the
distal
phalanges
were
short
especially
in
the
third
and
fifth
fingers.
The
nails
were
hypoplastic,
the
fifth
finger
nails
being
1
5
x
1-5
mm
in
size.
Deep
palmar
furrows
were
present
bilaterally
238
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Trisomy
8
syndrome
owing
to
isodicentric
8p
chromosomes
_.
A
.."
C
Figure
1
Case
2.
(A)
Facial
appearance,
(B)
deep
palmar
furrows,
(C)
cutout
oJ
chromosomes
8
from
two
selected
cells.
The
normal
chromosome
8
is
reproduced
in
duplicate
on
the
lower
left
and
upper
right
of
the
idic(8)
chromosome.
Figure
2 Case
1.
(A)
Cutout
of
Q
banded
chromosomes
8.
(B)
C
banding
of
two
idic(8).
The
idic(8)
on
the
left
has
one
centromere
active
and
one
inactive,
that
on
t,
right
has
both
centromeres
active.
(C)
FISH
with
IEl
shows
that
this
cosmid
hybridises
only
to
the
normal
chromosome
8.
The
chromosome
with
hybridisation
signals
is
counterstained
with
propidium
iodide,
that
on
the
right
is
stained
with
DAPI.
(D)
FISH
with
CRI-L40
and
pZ8.4
shows
signals
of
CRI-L40
at
8p22-23
both
in
the
normal
chromosome
8
and
the
idic(8).
The
large
signals
of
pZ8.4
are
localised
at
the
centromere
of
the
normal
chromosome
8
and
at
the
active
and
inactive
centromere
of
the
idic(8).
Chromosomes
are
positioned
as
in
(C).
(fig
1B).
Lower
limb
anomalies
included
varus
deformity
of
the
right
foot,
short
metatarsals
with
hypoplastic
toes
and
toenails,
cutaneous
syndactyly
between
the
second
and
third
toes
and
marked
plantar
furrows.
The
patient
was
moderately
hypertonic
and
developmentally
retarded.
Routine
laboratory
analyses
were
normal.
A
CT
scan
of
the
brain
showed
agene-
sis
of
the
corpus
callosum
and
a
cystic
tumour
in
the
occipital
region.
Echocardiography
and
angiocardiography
disclosed
a
ventricular
sep-
tal
defect
with
a
persistent
left
superior
vena
cava.
A
skeletal
x
ray
survey
at
2
months
showed
advanced
bone
age
(in
the
range
of
6
months
to
2
years),
scaphocephaly
with
synostosis
of
the
sagittal
suture,
13
pairs
of
ribs
with
a
hypo-
plastic
left
first
rib,
rarefaction
of
the
proximal
humeral
metaphyses,
a
"bone
within
bone"
image
in
the
vertebral
bodies,
and
asymmetri-
cal
ossification
of
the
femoral
heads.
The
distal
phalanges
were
hypoplastic
and
absent
in
the
right
fifth
finger
and
fifth
toes.
Renal
ultra-
sound
was
unremarkable.
The
patient
died
at
home
of
congestive
heart
failure
at
4
months.
Cytogenetic
studies
CASE
I
Chromosome
analysis
was
performed
on
lym-
phocyte
and
fibroblast
cultures.
In
both
tissues
mosaicism
was
detected
with
the
normal
cell
line
present
in
11
out
of
40
and
five
out
of
25
cells
respectively.
In
the
abnormal
cell
line,
one
chromosome
8
was
replaced
by
a
long
f
submetacentric
chromosome
interpreted
as
an
isodicentric
8
with
a
breakpoint
at
p23.
The
abnormal
chromosome
showed
a
single
prim-
ary
constriction
with
inactivation
of
the
second
centromere
in
the
great
majority
of
the
cells
though
two
centromere
constrictions
were
clearly
identified
in
a
few
cells
(fig
2
A,B).
Thus
the
proband's
karyotype
was
interpreted
as
46,XX/46,XX,
-8,
+
idic(8)(qter
-
p23::
p23
-
qter).
A
fibroblast
cell
line
(652/9
1)
is
available.
The
parents
had
normal
karyotypes.
In
situ
hybridisation
was
performed
with
cosmid
1
lEl
(D8S7
locus
mapping
to
8p235)
isolated
from
a
LA08NC01
flow
sorted
cosmid
library6
and
with
probe
CRI-L40
(locus
D8S35
mapping
at
about
23
cM
from
the
tip
of
8p
proximally
to
D8S75).
In
some
experiments
quicker
detection
of
chromosome
8
was
achieved
by
using
CRI-L40
together
with
the
alphoid
probe
pZ8.4
specific
for
the
chro-
mosome
8
centromere.
The
probes
were
biotin-16-dUTP
labelled
by
nick
translation
according
to
the
Boehringer
Mannheim
proto-
col.
Conditions
for
cosmid
1
lEl
in
situ
hybridisation
were
as
desCribed
by
Lichter
et
al7
using
CotI
DNA
(BRL)
instead
of
human
placental
DNA
to
block
repetitive
sequences.
'eHybridisation
with
CRI-L40
(200
ng/slide)
he
plus
pZ8.4
(50
ng/slide)
was
performed
in
50%
formamide/2
x
SSC
with
500
x
salmon
sperm
DNA
at
37°C
for
12
to
16
hours.
Post
hybridis-
I
ation
washes
were
made
at
42'C
in
50%
forma-
e
mide/2
x
SSC
(three cycles
for
five
minutes),
and
then
in
0-1
x
SSC
(three
cycles
for
five
.i.
239
i
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Digilio
et
al
minutes).
Under
these
conditions
the
identifi-
cation
of
the
idic(8)
and
of
the
normal
chromo-
some
8
was
immediate,
though
other
chromo-
somes
showed
alphoid
hybridisation
signals
at
the
centromeres.
In
all
cases
the
detection
was
done
according
to
the
ONCOR
detection
kit
with
three
amplification
steps.
Chromosomes
were
counterstained
with
propidium
iodide
(1
jg/ml)
and
banded
with
DAPI
(0
5
gg/ml).
Microscopic
analysis
was
performed
on
meta-
phase
chromosomes
with
no
more
than
10
hybridisation
signals
and
with
at
least
one
spot
on
one
chromosome
8.
In
the
50
informative
cells
analysed
after
FISH
with
1
lEl,
28
hybridisation
spots
were
clustered
at
8p23.3
in
the
normal
chromosome
8
while
three
and
eight
signals
were
spread
along
the
normal
and
the
abnormal
chromosome
8
respectively
(fig
2C).
No
signals
were
found
in
the
central
portion
of
the
idic(8)
corresponding
to
band
8p23.
This
was
taken
as
an
indication
that
the
distal
portion
of
chromosome
8,
from
pter
to
D8S7,
was
missing
from
the
dicentric
chro-
mosome
8.
FISH
analysis
in
50
informative
metaphases
with
CRI-L40
and
pZ8.4
showed
signals
relative
to
CRI-L40
both
in
the
normal
(53
signals
clustered
at
the
subterminal
short
arm
8p22-p23)
and
in
the
dicentric
chromo-
some
8
(60
signals
lying
between
the
two
alphoid
ones).
In
some
cells
the
normal
or
the
isodicentric
chromosome
8
or
both
showed
two
CRI-L40
signals
that
were
localised
at
the
same
height,
one
on
each
chromatid
(fig
2D).
Signals
on
the
idic(8)
did
not
indicate
the
presence
of
more
than
one
D8S35
locus
in
any
cell.
Unclustered
signals
were
spread
along
the
normal
(seven)
and
the
abnormal
(16)
chromo-
somes
8.
Altogether,
a
similar
number
of
CRI-
L40
signals
was
found
in
the
normal
8
and
the
idic(8)
and
the
distribution
of
the
signals
was
taken
as
an
indication
that
sequences
homolo-
gous
to
CRI-L40
were
present
in
a
single
copy
in
the
dicentric
chromosome
8.
CASE
2
Chromosome
studies
performed
on
lympho-
cyte
(40
mitoses)
and
fibroblast
cultures
(30
mitoses)
showed
a
modal
number
of
46,
with
a
structurally
abnormal,
long,
submetacentric
chromosome
replacing
one
chromosome
8.
This
abnormality
was
interpreted
as
an
isodi-
centric
resulting
from
terminal
fusion
of
the
short
arms
of
two
chromosomes
8
with
func-
tional
suppression
of
one
centromere.
Thus,
the
karyotype
was
designated
46,XY,
-8,
+
idic(8)(qter
-
p23:
:p23
-
qter)
(fig
1
C).
The
parents
had
normal
chromosome
constitu-
tions.
Discussion
Most
if
not
all
subjects
with
trisomy
8
are
mosaics.4
Thus,
complete
trisomy
8
is
a
rare
abnormality
in
postnatal
life,
while
it
accounts
for
12%
of
autosomal
trisomies
found
in
spon-
taneous
abortions.8
Structural
anomalies
of
chromosome
8
resulting
in
full
blown
trisomy
8
syndrome
are
very
rare.
To
the
best
of
our
knowledge
only
one
patient
has
been
reported
with
mosaic
trisomy
of
a
portion
of
the
short
arm
and
the
entire
long
arm:
dic(8)(qter-
p21:
:p2l
-qter).9
Our
case
2
seems
to
be
the
first
example
of
a
non-mosaic
idic(8p;8p).
The
distal
location
of
the
break
in
8p
produced
an
apparently
stable
idic(8)
chromosome
and
thus
the
patient
was
in
fact
functionally
trisomic
for
nearly
the
whole
of
chromosome
8.
If
mosaicism
with
a
normal
cell
line
is
not
present,
the
chromo-
some
anomaly
must
have
originated
either
prezygotically,
possibly
during
parental
mei-
osis,
or
in
the
zygote
itself
after
sister
chroma-
tid
exchange.
The
association
with
a
normal
cell
line
in
the
case
reported
by
Ray
and
Hunter9
and
in
our
case
1
suggests
a
postzygo-
tic
origin
of
the
dicentric
chromosome
8.
FISH
findings
in
case
1
indicate
that
the
isochromosome
is
not
symmetrical,
having
one
breakpoint
betwen
D8S7
and
D8S35
and
the
other
one
proximal
to
D8S35.
Presumptive
isochromosomes
Xl'0'
and
y'2-14
have
been
reported
to
be
asymmetrical
after
quantitative
DNA
analysis.
Thus,
asymmetrical
exchanges
between
sister
or
homologous
chromatids
could
be
a
frequent
mechanism
of
formation
of
those
chromosome
rearrangements
usually
designated
isochromosomes.
Trisomy
8
syndrome
is
characterised
by
craniofacial
dysmorphism,
skeletal
abormali-
ties,
cardiovascular
and
urogenital
malforma-
tions,
deep
palmar
and
plantar
grooves,
mental
retardation,
and
agenesis
of
corpus
callo-
sum.
2
Our
cases
show
most
of
these
features.
Interestingly,
case
2
had
several
features
found
in
the
Coffin-Siris
syndrome.'5
They
include
sparse
scalp
hair,
coarse
facial
appearance,
facial
lanugo,
thick
upper
lip,
micrognathia,
camptodactyly,
hypoplastic
fifth
finger
nails,
haemangioma,
congenital
heart
disease,
and
mental
retardation.
Thus,
at
least
in
the
neo-
natal
period,
there
seems
to
be
a
striking
overlap
of
dysmorphic
features
between
Coffin-Siris
and
non-mosaic
trisomy
8
syn-
drome,
in
which
deep
palmar
and
plantar
furrows
are
distinguishing
features.
ACC
is
a
common
finding
in
patients
with
trisomy
8
syndrome.
The
origin
of
this
anom-
aly
is
heterogeneous
and
it
has
been
reported
to
be
the
result
of
autosomal
recessive,
X
linked
dominant,
and
X
linked
recessive
muta-
tions.'6
Moreover,
the
defect
is
found
in
associ-
ation
with
different
chromosome
abnormalit-
ies
'7
including
aneuploidies
of
chromosome
8
as
mosaic
trisomies,4
short
arm
tetrasomies
owing
to
i(8p),'8
'9
duplications
of
different
portions
of
8p
secondary
to
unbalanced
trans-
20-24
call
locations,
or
the
so
called
inv
dup(8p).25
With
the
exclusion
of
these
latter
cases,
in
which
duplication
of
8p
was
concurrent
with
distal
8p
deletion
whose
limits
are
not
yet
defined,25
common
to
all
these
chromosome
8
imbalances
is
trisomy
8p2l-pter
(fig
3).
Thus,
it
is
likely
that
this
region
contains
a
gene
(ACC-8)
whose
duplication
can
interfere
with
normal
brain
development.
In
this
re-
spect,
NEFL
(neurofilament,
light
polypep-
tide),
whose
locus
is
at
8p2l
,32
could
be
a
candidate.
However,
among
the
12
informative
cases
trisomic
for
different
portions
of
8p
as
240
group.bmj.com on July 14, 2011 - Published by jmg.bmj.comDownloaded from

241
Trisomy
8
syndrome
owing
to
isodicentric
8p
chromosomes
M,
mat
(30)
M,
F,
mat
(29)
F
M,
mat
(28)
-
M,
pat
(26);
F,
mat
(31
)
F,
mat
(27)
-
F,
mat
(24)
M,
pat
(20);
M,
mat
(23)
LF,
mat
(21);
F,
mat
(22)
Three
cases:
2
M,
1
F
(18,19)
Figure
3
Extent
of
8p
duplication
in
patients
with
and
without
agenesis
of
the
corpus
callosum
(ACC).
Below:
patients
with
ACC
and
8p
duplication
secondary
to
translocation
(
)
or
to
mosaic
i(8p)
(-J.
Above:
patients
without
ACC
and
8p
duplication
secondary
to
translocation
(.).
M
and
F
indicate
that
the
patient
is
male
or
female,
mat
and
pat
indicate
maternal
and
paternal
origin
of
the
duplication.
Reference
numbers
are
in
parentheses.
Only
patients
in
whom
specific
brain
investigations
have
been
performed
were
considered.
products
of
unbalanced
translocations,
only
five
display
ACC
(fig
3).
If
we
exclude
the
case
reported
by
Stengel-Rutkowski
et
al,30
triso-
mic
for
8p23
-
pter,
in
which
the
absence
of
ACC
could
be because
of
the
location
of
the
ACC-8
gene
proximal
to
8p23,
the
proportion
of
cases
trisomic
for
the
postulated
ACC-8
gene
and
with
ACC
is
5/11.
Conversely,
all
the
three
properly
investigated
supernumerary
i(8p)
cases,'8
19
tetrasomic
for
the
entire
8p,
display
ACC
(fig
3).
To
explain
these
observa-
tions
we
are
forced
to
assume
that
three
alleles
of
the
presumptive
gene
produce
a
product
in
a
concentration
that
can
be
critical
for
ACC
development
while
four
alleles
produce
a
con-
centration
that
is
always
above
the
critical
threshold.
It
must
be
noted
that
the
presence
or
absence
of
ACC
is
independent
of
the
parental
origin
of
the
gene,
thus
excluding
an
imprinting
effect,
and
it
is
also
independent
of
the
sex
of
the
patient
(four
females:four
males
with
ACC;
three
females:four
males
without
ACC)
(fig
3).
Interestingly,
ACC
has
also
been
reported
in
one
patient
with
distal
8p
deletion.33
Since
imprinting
of
a
gene
located
in
the
unbalanced
region
cannot
account
for
this
finding
and
abnormalities
of
the
corpus
callosum
have
never
been
reported
in
the
numerous
patients
with
8p
deletion,433
this
case
could
have
a
more
complex
rearrangement
also
involving
a
partial
duplication.
The
find-
ing
that
our
case
1,
although
duplicated
for
nearly
the
whole
of
chromosome
8,
is
not
duplicated
for
the
distal
23
Mb
from
D8S35
to
8pter,
indicates
that
the
ACC-8
gene
lies
in
the
distal
half
of
the
chromosome
8
short
arm,
proximally
to
D8S35.
The
authors
wish
to
thank
Dr
S
Wood,
Vancouver,
and
Dr
M
Rocchi,
Bari,
for
providing
probes
1
lEl
and
pZ8.4.
They
also
thank
Professor
M
Fraccaro
for
helpful
discussions.
This
work
was
supported
by
Telethon-Italy
(project
"Correlation
between
cerebral
malformations,
neurological
impairment
and
extension
of
chromosomal
duplication
in
patients
with
inv
dup
(8p)")
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by
the
Associazione
Italiana
per
lo
Studio
delle
Malformazioni,
ASM
Milano.
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doi: 10.1136/jmg.31.3.238
1994 31: 238-241J Med Genet
M C Digilio, A Giannotti, G Floridia, et al.
callosum development.
a presumptive gene involved in corpus
8p chromosomes: regional assignment of
Trisomy 8 syndrome owing to isodicentric
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