Baller-Gerold syndrome associated with congenital portal venous malformation

Abstract

We report a 4 year old boy in whom the clinical features of craniosynostosis and bilateral absent radii led to a diagnosis of Baller-Gerold syndrome. Additional congenital abnormalities included midface hypoplasia, atrial and ventricular septal defects, right hydronephrosis, partial sacral agenesis, and anterior ectopic anus. Evidence of portal venous hypertension was present from 8 months and a congenital portal venous malformation was discovered at 2 years. This is the first reported case of Baller-Gerold syndrome associated with a congenital portal venous malformation. We discuss the diagnostic confusion between this syndrome and other overlapping malformation syndromes and propose optimal evaluation strategies aimed at clarifying the nosology of these syndromes.

Full text

J
Med
Genet
1998;35:767-769
Baller-Gerold
syndrome
associated
with
congenital
portal
venous
malformation
Ravi
Savarirayan,
Paul
Tomlinson,
Elizabeth
Thompson
Abstract
We
report
a
4
year
old
boy
in
whom
the
clinical
features
of
craniosynostosis
and
bilateral
absent
radii
led
to
a
diagnosis
of
Baller-Gerold
syndrome.
Additional
con-
genital
abnormalities
included
midface
hypoplasia,
atrial
and
ventricular
septal
defects,
right
hydronephrosis,
partial
sac-
ral
agenesis,
and
anterior
ectopic
anus.
Evidence
of
portal
venous
hypertension
was
present
from
8
months
and
a
congeni-
tal
portal
venous
malformation
was
dis-
covered
at
2
years.
This
is
the
first
reported
case
of
Baler-
Gerold
syndrome
associated
with
a
con-
genital
portal
venous
malformation.
We
discuss
the
diagnostic
confusion
between
this
syndrome
and
other
overlapping
mal-
formation
syndromes
and
propose
opti-
mal
evaluation
strategies
aimed
at
clarifying
the
nosology
of
these
syn-
dromes.
(jMed
Genet
1998;35:767-769)
Keywords:
Baller-Gerold
syndrome;
portal
venous
mal-
formation
South
Australian
Clinical
Genetics
Service,
Women's
and
Children's
Hospital,
North
Adelaide,
South
Australia
5006
R
Savarirayan
E
Thompson
Department
of
Paediatrics,
Southland
Hospital,
Invercargill,
New
Zealand
P
Tomlinson
Correspondence
to:
Dr
Savarirayan,
Victorian
Clinical
Genetics
Service,
Royal
Children's
Hospital,
Parkville,
Victoria
3052,
Australia.
Received
28
August
1997
Revised
version
accepted
for
publication
23
February
1998
The
association
of
craniosynostosis
and
preax-
ial
upper
limb
malformations
was
first
reported
by
Baller'
in
a
26
year
old
woman
with
turricephaly,
short
stature,
right
radial
aplasia,
and
left
radial
hypoplasia.
Her
parents
were
third
cousins
twice
removed.
Gerold'
reported
a
16
year
old
boy
and
his
infant
sister
who
both
had
turricephaly
and
bilateral
absent
thumbs
and
radii.
Cohen3
suggested
the
name
Baller-
Gerold
syndrome
(BGS)
to
encompass
the
combination
of
craniosynostosis
and
preaxial
upper
limb
malformations,
and
to
date
at
least
23
patients
have
been
reported.'
2
4-18
The
BGS
phenotype
is
extremely
variable
with
expression
in
many
systems
(table
1).
The
condition
is
inherited
in
an
autosomal
recessive
manner.
Table
1
Manifestations
of
BGS
in
24
patients*
Manifestation
No
of
patients
(%)
Craniosynostosis
24
(100)
Hypo/aplastic
radii
19
(79)
Growth
retardation
13
(54)
Lower
limb
defects
9
(38)
Anal
defects
11
(46)
Urogenital
defects
10
(42)
Cardiac
defects
7
(29)
Central
nervous
system
defects
6
(25)
Mental
retardation
5
(21)
*Refs
1,
2,
4-18,
and
our
case.
Case
report
A
4
year
old
boy
was
referred
for
genetic
assessment.
He
was
the
product
of
an
in
vitro
fertilisation
pregnancy,
born
to
unrelated
parents
at
38
weeks
by
elective
caesarean
section
because
of
placenta
praevia.
Multiple
congenital
abnormalities
were
noted
and
com-
prised
ridged
metopic
suture,
midface
hypo-
plasia,
bilateral
radial
agenesis
with
absent
thumbs,
atrial
and
ventricular
septal
defects,
right
hydronephrosis,
partial
sacral
agenesis,
and
anterior
ectopic
anus.
Growth
parameters
at
birth
were
weight
2950
g
(25th
centile),
head
circumference
35
cm
(50th
centile),
and
length
49
cm
(50th
centile).
Blood
karyotype
was
normal
male,
46,XY.
A
diagnosis
of
VACTERL
syndrome
was
made.
At
4
months
his
head
shape
was
noted
to
be
unusual
and
premature
fusion
of
the
metopic
and
both
coronal
sutures
was
seen
on
skull
x
ray;
a
craniectomy
was
performed
when
he
was
8
months.
At
this
time
it
was
noted
that
he
had
splenomegaly
with
evidence
of
hypersplenism
(manifested
by
thrombocytopenia)
but
no
spe-
cific
cause
was
found
to
explain
these
findings.
At
15
months
he
was
seen
by
a
geneticist
who
raised
the
possibility
of
BGS
or
Fanconi
anae-
mia
as
possible
diagnoses.
No
evidence
of
spontaneous
or
inducible
chromosome
breaks
were
seen
on
specific
testing
and
the
diagnosis
of
BGS
was
made.
At
2
years
of
age
he
had
a
large
gastrointesti-
nal
haemorrhage
secondary
to
oesophageal
varices
discovered
on
upper
gastrointestinal
endoscopy.
Liver
function
tests
and
blood
clot-
ting
studies
were
normal
and
a
thorough
search
was
performed
looking
for
indications
of
primary
liver
disease.
This
included
a
sweat
test,
serology
for
hepatitis
B,
C,
and
cytomega-
lovirus,
serum
copper
studies,
a-l-antitrypsin
protein
electrophoresis,
and
liver
biopsy,
all
of
which
were
normal.
An
abdominal
ultrasound
examination
showed
a
spleen
11
cm
in
length
(normal
<7
cm)
with
hepatopetal
flow
in
the
splenic
vein.
A
subsequent
portal
vein
study
showed
appearances
consistent
with
cavernous
transformation
of
the
portal
vein
high
up
in
the
porta
hepatis,
indicating
previous
portal
vein
obstruction.
At
referral
(4
years)
his
weight
and
height
were
at
the
25th
centile
for
age
(15.8
kg
and
101
cm,
respectively)
with
head
circumference
at
the
97th
centile
(53.5
cm).
He
had
a
ridged
metopic
suture,
hypotelorism,
wide
nasal
bridge
(fig
1),
and
radial
clubbed
hands
with
absent
thumbs
(fig
2).
An
anteriorly
sited
anus,
pes
planus,
and
the
clinical
findings
of
portal
hypertension
and
a
ventricular
septal
defect
767
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Savarirayan,
Tomlinson,
Thompson
Figure
1
The
proband
aged
4
years.
Note
ridged
metopic
suture,
hypotelorism,
and
prominent
nasal
bridge.
(Photograph
reproduced
with
permission.)
Figure
2
Note
bilateral
radial
agenesis
with
absent
thumbs.
were
also
present.
His
development
was
normal
for
age.
In
the
light
of
the
paper
by
Huson
et
al,'9
cytogenetic
analysis
was
repeated
(on
G
and
C
banded
preparations)
to
look
for
heterochro-
matin
repulsion.
On
the
first
culture,
C
banded
preparations
showed
variants
displaying
a
degree
of
heterochromatin
repulsion
but
sub-
sequent
cultures
failed
to
reproduce
this
finding.
The
normal
male
karyotype
was
confirmed.
There
was
no
evidence
of
increased
spontaneous
chromosome
instability
or
abnor-
mal
chromosome
hypersensitivity
on
testing
with
diepoxybutane
compared
to
controls.
Discussion
The
combination
of
craniosynostosis
affecting
various
sutures
and
preaxial
upper
limb
defects
is
characteristic
of
BGS.
Recently,
however,
several
authors,
including
Cohen
and
Toriello,20
who
initially
coined
the
term
"Baller-Gerold"
syndrome,
have
questioned
whether
BGS
is
a
distinct
entity.
The
wide
phenotypic
variability
seen
in
BGS
and
other
overlapping
conditions,
such
as
Fanconi
anae-
mia,
Roberts
syndrome
(RS),
and
the
VACTERL
association,
make
it
difficult
to
clarify
the
nosology
in
many
cases.
Our
patient
illustrates
this
confusion,
with
the
initial
diagnosis
being
VACTERL
association
which
was
subsequently
changed
to
BGS.
In
recent
medical
publications
there
are
sev-
eral
examples
of
diagnostic
confusion
among
these
phenotypically
similar
entities.
Fanconi
anaemia
was
diagnosed
in
a
child
previously
reported
by
Lewis
et
a!2'
to
have
BGS.
This
child
was
born
with
multiple
birth
defects
including
hydrocephalus,
growth
retardation,
and
cardiac,
anal,
and
limb
abnormalities.
Craniosynostosis
(right
lambdoid)
was
also
reported.
Chronic
thrombocytopenia
was
noted
at
3
years
and
led
to
the
consideration
of
Fanconi
anaemia,
which
was
proven
on
cytoge-
netic
testing.22
Rossbach
et
a!23
reported
two
brothers
diagnosed
with
BGS
(one
of
whom
had
previously
been
diagnosed
with
the
VACTERL
association)
until
severe
thrombo-
cytopenia
was
noted
and
chromosome
testing
showed
cytogenetic
abnormalities
consistent
with
Fanconi
anaemia
in
both
children.
Huson
et
al'9
reported
a
26
year
old
woman
with
bicoronal
craniosynostosis
and
bilateral
radial
and
thumb
hypoplasia
in
whom
the
initial
diagnosis
was
BGS.
A
skeletal
survey
per-
formed
to
investigate
short
stature
showed
lower
limb
abnormalities,
and
on
review
of
the
case
the
facial
phenotype
was
considered
con-
sistent
with
that
of
RS.
Cytogenetic
studies
showed
heterochromatin
"puffing"
characteris-
tic
of
RS.
These
cytogenetic
phenomena
were
seen
on
G
banded
metaphases
but
were
more
prominent
in
C
banded
preparations.
The
authors
considered
that
their
proband
had
a
"mild"
form
of
RS
and
raised
the
question
of
whether
BGS
is
a
distinct
entity
or
a
mild
phe-
notypic
expression
of
RS
and
suggested
that
cases
diagnosed
as
BGS
have
cytogenetic
analysis
and
that
known
RS
survivors
be
reviewed
for
craniosynostosis.
In
one
BGS
case
report,
the
authors
cite
that
craniosynostosis
has
not
been
reported
in
RS
in
their
attempts
to
differentiate
the
two
conditions.'8
Craniosynostosis
has
been
de-
scribed
previously
in
two
cases
of
RS."
24
We
therefore
suggest
that
craniosynostosis
may
well
be
a
manifestation
of
the
wide
phenotypic
spectrum
of
RS
that
has
been
unreported
or
not
specifically
looked
for.
We
suggest
that
the
presence
of
craniosynostosis
should
not
ex-
clude
the
diagnosis
of
RS.
These
cases
emphasise
the
potential
for
error
in
making
a
diagnosis
of
"BGS"
or
"VACTERL
association"
in
children
with
this
spectrum
of
anomalies
without
first
excluding
conditions
such
as
Fanconi
anaemia
or
RS,
which
have
an
overlapping
phenotype
and
a
diagnostic
test
available.
Both
of
these
condi-
tions
were
carefully
excluded
in
our
case.
The
portal
venous
malformation
described
was
not
associated
with
any
predisposing
factors
including
neonatal
sepsis,
neonatal
umbilical
vein
catheterisation,
surgical
or
blunt
abdominal
trauma,
extrahepatic
biliary
lesions,
768
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Baller-Gerold
syndrome
chronic
liver
disease,
or
a
hypercoagulable
state."
This,
combined
with
the
fact
that
thrombocytopaenia
and
splenomegaly
was
first
noted
at
8
months
of
age
in
this
boy,
points
towards
a
primary
developmental
malforma-
tion
of
the
portal
vein
causing
portal
venous
obstruction
rather
than
portal
venous
throm-
bosis
resulting
from
a
secondary
aetiology.
Portal
venous
malformations
have
not
been
described
previously
in
BGS
and
this
report
expands
the
phenotypic
spectrum
of
the
disor-
der.
We
propose
that
the
optimal
evaluation
of
patients
with
the
spectrum
of
anomalies
described
in
our
patient
should
include
cytoge-
netic
testing
for
RS
and
Fanconi
anaemia,
periodic
haematological
screening
(looking
for
abnormalities
suggestive
of
Fanconi
anaemia
that
can
first
present
up
to
10
years),
and
a
skeletal
survey.
The
reasons
for
doing
this
are
twofold.
Firstly,
it
will
help
clarify
the
nosology
of
these
overlapping
conditions
until
these
entities
are
understood
at
a
molecular
level.
Secondly,
and
most
importantly,
it
will
allow
the
appropriate
management
and
family
coun-
selling
to
be
given
in
these
cases,
as
RS26
and
Fanconi
anaemia"
can
be
detected
prenatally
and
the
clinical
management
in
Fanconi
anae-
mia
is
markedly
different
from
that
of
RS
and
BGS.
It
is
important
to
note
that,
although
diepoxybutane
breakage
is
the
best
currently
available
cytogenetic
indicator
of
Fanconi
anaemia,
false
negatives
do
occur.
This
is
related
to
the
marked
underlying
genetic
(locus)
heterogeneity
in
the
condition
with
as
many
as
eight
complementation
groups
being
described
and
three
genes
having
been
mapped.28
Some
of
these
complementation
groups
do
not
display
cellular
hypersensitivity
to
crosslinking
agents
such
as
diepoxybutane.
Thus,
the
potential
exists
for
the
diagnosis
of
Fanconi
anaemia
to
be
still
theoretically
tenable
after
a
negative
diepoxybutane
test.
This
is
our
rationale
for
advocating
"periodic"
haematological
screening
during
childhood
in
these
cases,
even
after
a
"negative"
diepoxybu-
tane
test.
As
more
of
the
genes
causing
Fanconi
anaemia
are
identified,
specific
mutation
analy-
sis
in
these
suspected
patients
will
become
the
definitive
diagnostic
test.
Finally,
we
agree
with
Cohen
and
Toriello'0
who
suggest
that
the
diagnosis
of
BGS
be
con-
sidered
only
after
careful
exclusion
of
these
overlapping
entities
and
propose
the
above
evaluation
of
all
patients
with
this
spectrum
of
abnormalities.
The
authors
wish
to
thank
Mr
David
David,
Australian
Cranio-
facial
Unit,
for
referral
of
the
patient
and
the
clinical
photographs.
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769
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doi: 10.1136/jmg.35.9.767
1998 35: 767-769J Med Genet
R Savarirayan, P Tomlinson and E Thompson
congenital portal venous malformation.
Baller-Gerold syndrome associated with
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