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Differences in adiposity in Cushing syndrome caused by PRKAR1A mutations: clues for the role of cyclic AMP signaling in obesity and diagnostic implications.
[cushing syndrome]
The
cAMP
signaling
pathway
is
implicated
in
bilateral
adrenocortical
hyperplasias
.
Bilateral
adrenocortical
hyperplasia
is
often
associated
with
ACTH-independent
Cushing
syndrome
(
CS
)
and
may
be
caused
by
mutations
in
genes
such
as
PRKAR
1
A
,
which
is
responsible
for
primary
pigmented
nodular
adrenocortical
disease
(
PPNAD
)
.
PRKAR
1
A
regulates
cAMP-dependent
protein
kinase
(
PKA
)
,
an
essential
enzyme
in
the
regulation
of
adiposity
.
Although
CS
is
invariably
associated
with
obesity
,
its
different
forms
,
including
those
associated
with
PKA
defects
,
have
not
been
compared
.
The
purpose
of
this
study
was
to
characterize
the
phenotypic
and
molecular
differences
in
periadrenal
adipose
tissue
(
PAT
)
between
patients
with
CS
with
and
without
PRKAR
1
A
mutations
.
S
amples
from
adrenalectomies
of
51
patients
were
studied
:
patients
with
CS
with
(
n
=
13
)
and
without
(
n
=
32
)
PRKAR
1
A
mutations
and
a
comparison
group
with
aldosterone-producing
adenomas
(
APAs
)
(
n
=
6
)
.
In
addition
,
clinical
data
from
a
larger
group
of
patients
with
Cushing
disease
(
n
=
89
)
and
hyperaldosteronism
(
n
=
26
)
were
used
for
comparison
.
Body
mass
index
(
BMI
)
,
abdominal
computed
tomography
scans
,
and
cortisol
data
were
collected
preoperatively
.
PAT
was
assayed
for
PKA
activity
,
cAMP
levels
,
and
PKA
subunit
expression
.
BMI
was
lower
in
adult
patients
with
CS
with
PRKAR
1
A
mutations
.
cAMP
and
active
PKA
levels
in
PAT
were
elevated
in
patients
with
CS
with
PRKAR
1
A
mutations
.
I
ncreased
PKA
signaling
in
PAT
was
associated
with
lower
BMI
in
CS
.
Differences
in
fat
distribution
may
contribute
to
phenotypic
differences
between
patients
with
CS
with
and
without
PRKAR
1
A
mutations
.
The
observed
differences
are
in
agreement
with
the
known
roles
of
cAMP
signaling
in
regulating
adiposity
,
but
this
is
the
first
time
that
germline
defects
of
PKA
are
linked
to
variable
obesity
phenotypes
in
humans
.
Diseases
Validation
Diseases presenting
"obesity"
symptom
acute rheumatic fever
adrenal incidentaloma
aniridia
aromatase deficiency
carcinoma of the gallbladder
cohen syndrome
congenital adrenal hyperplasia
cushing syndrome
cystinuria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
familial mediterranean fever
heparin-induced thrombocytopenia
kabuki syndrome
monosomy 21
phenylketonuria
primary hyperoxaluria type 1
sneddon syndrome
werner syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated