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Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation.
[cushing syndrome]
Inactivating
germline
mutations
of
the
probable
tumor
suppressor
gene
,
armadillo
repeat
containing
5
(
ARMC
5
)
,
have
recently
been
identified
as
a
genetic
cause
of
macronodular
adrenal
hyperplasia
(
MAH
)
.
We
searched
for
ARMC
5
mutations
in
a
large
cohort
of
patients
with
MAH
.
The
clinical
phenotype
of
patients
with
and
without
ARMC
5
mutations
was
compared
.
Blood
DNA
from
34
MAH
patients
was
genotyped
using
Sanger
sequencing
.
Diurnal
serum
cortisol
measurements
,
plasma
ACTH
levels
,
urinary
steroids
,
6
-
day
Liddle
's
test
,
adrenal
computed
tomography
,
and
weight
of
adrenal
glands
at
adrenalectomy
were
assessed
.
Germline
ARMC
5
mutations
were
found
in
15
of
34
patients
(
44
.
1
%
)
.
In
silico
analysis
of
the
mutations
indicated
that
seven
(
20
.
6
%
)
predicted
major
implications
for
gene
function
.
Late
-
night
cortisol
levels
were
higher
in
patients
with
ARMC
5
-
damaging
mutations
compared
with
those
without
and
/
or
with
nonpathogenic
mutations
(
14
.
5
±
5
.
6
vs
6
.
7
±
4
.
3
,
P
<
.
001
)
.
All
patients
carrying
a
pathogenic
ARMC
5
mutation
had
clinical
Cushing
's
syndrome
(
seven
of
seven
,
100
%
)
compared
with
14
of
27
(
52
%
)
of
those
without
or
with
mutations
that
were
predicted
to
be
benign
(
P
=
.
029
)
.
Repeated-measures
analysis
showed
overall
higher
urinary
17
-
hydroxycorticosteroids
and
free
cortisol
values
in
the
patients
with
ARMC
5
-
damaging
mutations
during
the
6
-
day
Liddle
's
test
(
P
=
.
0002
)
.
ARMC
5
mutations
are
implicated
in
clinically
severe
Cushing
's
syndrome
associated
with
MAH
.
Knowledge
of
a
patient
's
ARMC
5
status
has
important
clinical
implications
for
the
diagnosis
of
Cushing
's
syndrome
and
genetic
counseling
of
patients
and
their
families
.