Tohoku
J. exp.
Med.,
1975,
115, 263-269
Pheochromocytomas
Occurring
in 3 Members
in
a
Family TATSUO SATO, YUKIKO SATO, HISAICHI SAKUMA, KIYOSHI KOBAYASHI, YUKIO MIURA, KAORU YOSHINAGA and HIROKI WATANABE*
Departmentof Internal Medicineand Departmentof Urology,* Tohoku University Schoolof Medicine,Sendai
SATO, K,
and
T.,
SATO,
Tohoku
J.
exp. bilateral
previously
reported of
urinary are
H.
1975,
15
KOBAYASHI,
(3),
cases
or
chemical
assay
for
K., MIURA,
Occurring
in
263-269•\•\Three
pheochromocytomas
familial
asymptomatic
particularly
H.,
115
adrenal
catecholamine
catecholamine
SAKUMA,
Pheochromocyytomas
Med.,
exhibiting
stage
Y.,
WATANABE,
in
are Japan.
The
detection
and
emphasized.•\•\familial assay;
a
Family.
members
of
a
kindred
presented of and
diagnosis
YOSHINAGA, in
rate
pheochromocytoma
Y.,
3 Members
in
together tumor
with
growth,
the
importance
this
type
pheochromocytoma;
of
the of tumor urinary
hypertension
Familial occurrence of pheochromocytolna has been established recently as a significant phenomenon (Steiner et al. 1968). Up to date, more than 300 cases of pheochromocytoma proved at either surgery or autopsy have been reported in Japan (Yoshinaga 1973). Among them, seven separate families affected with pheochromocytoma have been described (Miura et al. 1968; Sato et al. 1971; Shiraiwa et al. 1971; Ando et al. 1971; Nishio et al. 1972; Kondo et al. 1974; Mori et al. 1974). It is the purpose of this paper to record an additional family in which 3 members out of 5 siblings had bilateral adrenal pheochromocytomas and to discuss the problems concerning tumor growth, urinary catecholamine excretion at an asymptomatic stage of the disease and usefulness of catecholamine determination for the correct diagnosis. CASE REPORTS Case 1. Y.S., a 24-year-old male plasterer, was admitted first to the Tohoku University Hospital in 1961 with chief complaint of sudden loss of vision. Family history was nothing particular, except that his father died of brain he morrhage at the age of 54. Father was hypertensive and diabetic for years. Five siblings were all well at this time. The blood pressure was 200/130 and phentolamine (Regitine) test was positive. Received
for publication,
December
14, 1974. 263
264
T. Sato
A
24-hr
jig
of
and
collection epinephrine
NE
inal
in
our
adrenal
pressure
to
our
of
present
the In
1970,
hospital
was
sent
at
to
our
On
5,
with about
sional
stiff
1974, a
neck,
212/120
palpable
hemiparesis
serum
of
physical
and
P
were
within
electrocardiogram metabolic
value
was
disclosed
of
on
the
cytoma
has
was
gas
left
At
had
elsewhere
not
by
one
youngest
sister
He
that
came
time, for
again
skin
his
to
urine
the
analysis
be
elevated
to
the
of
NE,
393 ƒÊg;
our
laboratory of
laminography
contained .
Right
to
walk.
blood
urea
nitrogen,
But
an
chest
oral
.
was
the revealed
and
a small
basal
and
mg/day).
Cl, , but
The
Intravenous kidney
K,
normal .
9.1
glucose
Na,
catecholamines VMA,
On
able
hypertrophy
urinary
.
pressure
examinations
including the
ventricular
configuration
.
.
occa
was
he
normal
of
speech
blood
gland
count,
film
output
The
abnormality
electrolytes
X-ray
in
Retinal
, but
Blood all
.
no
found
University
, there had been at the cold season
thyroid
showed
.
Tohoku difficulty
tall
warm.
Serum
left
cm
and
was
range.
and
illness
was
were
in
the and
167
.
slight
entered
depsite
was
sugar
mg/day
and
rise slightly
and
, his
proved
and
normal
(E , 26 ƒÊg; 7.0
significant was
specimens
present
reflex
normal
insuffiation
adrenal
weighing nmg
of
returned Case
Case
VMA
37,
scincigram
Abnormal
found
of
KW-I
pattern
a
no
below.
.
sister's
sweating
The
blood
+8%.
. blood
their Upper
pyelography urinary
tract
suprarenal
.
mass
left.
The
3.55
the
function
Retroperitoneal
74 .
were
diabetic
were
normal
kg
tendon
revealed rate
metabolite
normal
a
operation
hemiparesis the
graded
fasting
showed
age
of
and
examinations and
test
was
the
part
mentioned
were
right
onset
57 of
accelerated
cholesterol
tolerance
end
rate
in
in
sickness
the
the
the
[131I]Thyroid
with
rest
at
changes
this
examinations.
of
weighed
tumors.
sister's with
patient,
pulse
the as
catecholamines
the
and
discharged
reported
after
hospital
intolerance
hypertensive
years
further
before
patient with
revealed
9
about
history
heat
the
was
g,
catecholamines was
E
pheochromocytoma
resulted of
of Abdom
Postoperatively,
patient
case
values
1964).
together
the
short
This
inquiry
refused
6 months
admission,
The
27
benign
stimulation
in
and
urinary
he
weighing
typical
excretion
NE).
Normal
165
respectively.
normal.
urinary
another
laboratory His
April
Since
an
a be
excretion,
(NE).
10-50 ƒÊg/day,
was to
al.
catecholamine
tumor,
histamine
33 in
make
but
Hospital
tumor
et
of
and
adrenal
1974.
(Sato age
catecholamine.
The
April,
the
to
(156 ƒÊg/day),
Ca
until
high
norepinephrine
jig
thought and
adrenalectomy
that
no
the was
authors
of
right
140 ƒÊg/day
clinic
underwent
jig 0-10
However,
(approximately
was
a
normal
pressure.
abnormally
3,200 were
gland
returned
blood
visited
of
and
Histologically,
left
high
(E)
revealed
revealed
extirpated.
in
urine
laboratory
exploration
The
of
et al.
3,
NE to
2. was
area 10
g
per
g
his
job.
M.K., admitted
was was
of
a
explored
tissue.
Postoperative
wet
the
May The
26-year-old to
on
extirpated.
Yonezawa
house
wife, City
7 , 1974 tumor
and
course
the
Hospital
a
benign
contained
youngest in
March
0 .44 was
pheochromo mg
of
uneventful
sister 1970
of , for
E and
Case
1
evaluation
and he
and
of
her
hypertension.
years.
the
obtained
attacks the
a
with
She
occasional
Since
and
VMA
pheochromocytoma
was
Physical
The
Skin
white
41%,
blood
cholesterol after serum
total
The
protein
basal
Both
specimen
which and
diagnostic
for
take
a
member
of
On
December
20
g
and
in
tological left
published
and
the
patient
the
time
of
Case
slight
3.
on
high observed of
no
and
male
read
at
the
baby 240/130.
diagnosis
of
revealed
no
all
were
laboratory
the
and
Ca,
range.
to
of
these
values
consult
family
were
24-hour
74 ƒÊg
a
occurrence
her
found
Cl
normal
A
that
bilateral
was
K,
and
Serum
electrocardiogram
contained
recommended
83
sugar.
curve
positive.
therefore,
because
urine
E,
1,054 ƒÊg were
surgeon
of
pneumography,
adrenal were
content
tumors, found
benign
(Sato
and
abdomen.
were
Na,
within
film
the
all
about
the
tumor,
and
the
patient
was
bilateral
supra
expected.
typical
the
were X-ray
in
no
including
retroperitoneal
gland,
NE
sugar
of
neck
found
blood
possible
as bilateral
been
eyes
hematocrit
Normal
members
1970,
1974
of
25
mg/g
of
g
successfully E
wet
in
the
right
removed.
pheochromocytoma.
3.21
et
weighing
and
tissue.
His
content A
of
report
the
of
this
al.).
operation,
the
asymptomatic.
blood
No
pressure
tumors
in
elder
sister
has
the
remained
neck
have
normal
arisen
up
to
report.
K.H.,
already
normal
our
adrenal
since
has
headache
because
in
this
clinic
On
and
years
relatively
a May
in
32-year-old 10,
the
distress
and
of
case. being
was
When
excretion this
wife,
She
morning.
urinary in
house
1974.
her
in
Case
and
sister
catecholamine
However, busy
of
normotensive had
children
was
admitted of
adrenalectomy
(200 ƒÊg/day she
2,
complained
refused
in further
care.
The
in
only 1970,
average)
was
examinations
patient
had
had
two
deliveries. On
woman
0.37
4
cases.
was and
but
tests
and
the
month gradually.
healthy
and
protein,
reported,
of other
mass
nitrogen
to
from
was
was
was
our
left
7th
results,
plus
Chest
We
found
23,
the
During
sent
were
diagnosis
tumor
case
to
familial
masses
a still
tongue
electrolytes
tyramine
because
specimens
small
urea +7%.
VMA.
incision
urine
renal
of
lips,
one ml.
pheochromocytoma
transabdominal to
blood
been
mg
positive
palpable
Serum
and
had
23
the
puffy
of
3
crises.
increased
was
Hemoglobin
mg/100
was
Regitine
no
10,800.
test.
rate
gave
eyes,
showed
312
and
metabolic
normal.
NE
to
head, and
was
tolerance
birth
last
hypertensive
sweating,
pressure
1961)
in
attacks
premature blood
frequent
1970,
the
the
suspected.
Urinalysis
glucose
al.
the
normal
count
increased
oral
of
was
respectively.
et
of
cell
in the
strongly
examinations
abnormality.
of
for
hypertensive ,
excessive
terminated
(Sato
frequent
In
severity
delivery,
tests
had
continued.
and
episodes
Thereafter
headache,
It After
she
birth.
palpitation
265
hypertensive
1968,
mature
pulsating
month.
repeated
in
in
frequency of
9th
revealed
pregnancy
convulsions.
the
history
baby
pregnancy,
complained
at
first
male
headache
second
Pheochromocytomas
Past
During
She
Familial
admission, in
no
physical distress.
examinations Ophthalmological
revealed examinations
a well
developed, of
fundi
well were
nourished normal
and
266 the
T. Sato et al. heart
was
abdomen. in
blood
rate
were
blood revealed
with
VMA
On
July
tumor,
was
extirpated
cortex.
g
she
in
The
right
adrenal
gland
was
a benign
in the
patient
the
tumor
operation, was
3
left
months
freed
urinary from
than was
0.36
excretion the
on
170/100
in
and
arising
from
one
the
third
enlarged
of as
a
pheochromocytoma.
were
and
the
the
basal thyroid fasting
24-hour
urine
250 ƒÊg
of
NE.
pneumography
the
left.
During
her
only
one
occasion.
It
minutes.
found
more
E
a
Retroperitoneal mass
adrenalectomy
was
behind
diagnosis
contents
underwent
weight,
leaving
several
and in
of
of
in
Results
electrolytes,
Analysis
mg/day).
to
and
72/min.
nodules
cholesterol,
14 ƒÊg
elevated
after
1974,
8.5
Histological
After
26,
serum
cold
normal.
suprarenal
pressure
spontaneously
oval
withdrew
blood
small
neck
was
electrocardiogram No
catecholamines, (5.0-5.5
a
the
rate
study,
were
in
pulse
limits.
including
of
mass
and
X-ray
nitrogen
normal
showed
palpable
120/70
normal
chemistry urea
was
the
disappeared
within
excretion
tomograms
hospitalization,
the
the
abnormal
However,
NE
chest
all
blood
no
was
urinalysis,
Blood
and
was
pressure
were
found.
sugar
There
blood
count,
metabolic scan
normal.
The
headache.
and of
2.52
a small, left
whole,
encapsulated,
adrenal
apparently
On mg/g,
well
gland. normal
and
was
chemical
This adrenal
removed.
assay,
respectively
.
catecholamine
returned
to
normal
Replacement
therapy
of
the
E
and
and steroid
later.
DISCUSSION This is the eighth kindred of familial pheochromocytoma in Japan. The present cases showed several interesting points, as mentioned below. Case 1 was initially thought to be usual or sporadic type of pheochromocytoma and contralateral adrenal gland was apparently normal at that time . However, questions remained in his slightly high excretion of urinary catecholamines despite normalization cf his high blood pressure and negative histamine provocation test (Sato et al. 1964). The patient had had no contact with us and never been deter mined for his blood pressure until the time of sister's operation . At this time, 9 years after the surgery, his urinary excretion of catecholamine was still high and the blood pressure was around 170/100. Existence of bilateral pheochromocytomas in his sister strongly suggested that he had probably another tumor in the other side of adrenal gland, but he refused further examinations again because he was asymptomatic. Elapsing another 4 years , total 13 years after the operation, he developed hypertensive cerebrovascular accident and was finally admitted to our clinic. Pheochromocytoma in the contralateral side which had grown to 10 g was found and removed. Discernible symptoms of pheochromocytoma appeared only about 6 months before the final admission . Case 1 discloses evidence that there is a tumor having such a slow rate of growth. During this 13 years, slightly high excretion of catecholamine into the urine had continued without any characteristic symptoms and he had worked as a plasterer as usual. This stage, therefore, could be considered as "chemical pheo-
F, female; M, male; ?, The reference numbers
not mentioned. are shown together with
TABLE 1.
the
Family
Familial
No.
pheochromocytoma
in Japan
268
T. Sato
chromocytoma." urinary
An
asymptomatic years,
there
is
relatively
way,
be
difficult,
be
the
most
In
Case
the
2,
such
urinary
an
pregnancy
al.
or
eclampsia
consecutively is
correctly
proposita
us
1961)
were
, not
many
developing
explained
despite
by
well
a
pheno
known
spontaneously
chemical
been
for
cases,
been
decreased
assay
It
and
examine
the
positive
was
extremely
to
has
that
with
time
pheochromocytoma
VMA
alone
of
had
to
these
be
It
or
of
during
diagnosed
led
could
asymptomatic
prior in
output
also
that,
secretion state
catecholamine
she
indicate
catecholamine
catecholamine,
high
but
as
.
might
in
Case
3,
would
procedure.
removed.
pregnancy
Slightly
years,
observations
catecholamine
actual
et
4
catecholamine.
to
progressively
(Sato
had
of
conclusive
aggravated tests
response
detection but
urinary
against
pressure
any
in
3.
than
Normotensive
of
tachyphylaxis
blood
In
stage
Case
more
These
abnormal
excretion
was
for
pheochromocytoma.
high of
example
continued
normotensive.
an
as
menon
had
and
symptoms
the
additional
catecholamine
et al.
this
familial
course
of
.
, pheochromocytoma
strongly should
and
be
kept
in
to
both
mother
properly
treated
members
of
this
that
symptoms
repeated than
bilateral
mind
VMA
toxicemia
of
pheochromocytoma
pheochromocytoma
and
(Fox
,
Since
rather
suspected
hazardous
other
pheochromocytoma pregnancy
fetus
et
al . 1969).
family
to
unless
with the
disease
Detection
discover
of
is
Case
additional
2
tumor
cases. Including been
the
reported
patients
in
are
Thus,
was
sister
was
in
two
patients
had
medullary
be in
order
to
detect If
adrenal the
family
be
than
or and
tumor including
of
frequent and
20
and
.
There
the
thyroid
was
found
gland in
that
when
tumor
children
of
one al.
1974).
and
more
a
patient
cases
and
after
and
is the
tumor
should
be
another
seen in
, it the
examined
should neck and
distribu sisters
(Family
No . ‡Z)
thirds one .
al.
of
these
In
the
had latter
1972)
with things other
are family prevent
taking family members in the
necessary
Moreover, followed
or
fourth
. pheochromocytoma
be .
6 male.
age
Two
to
these
siblings,
than
et
in
and
The
syndrome)
in
one
. two
(Furukawa
have data
female
family
, particular important urinary catecholamine
pheochromocytoma
were male
Pairs
was et
Clinical
12 as
type
estimating
bilaterally
cases,
30 .
case
pheochromocytoma
cases.
(Sipple's
one
even
18
often
(Mori
of
sporadic
18 as
son
with
of
these
twice
pheochromocytomas
additional familial
Of
ages
, sisters
emphasized
usual
detail
1.
more
total
adrenal
tumor
should to
accident.
of
bilateral
affected
a
Table
most
generations
parathyroid
history
the
were
carcinoma
It
8 families
, making
between
brother,
affected
seems
in
affected
concentrated
and
group,
family,
country
summarized
female
tion
present this
up
vascular to
search
all members periodically
References 1)
2)
Ando, M., Sugimoto , M., Okamoto, S., Tokunaga, K., Ikegami (1971) Ph , K. & Murakami, S. 361-362 eochromocytoma in younger and elder sister . Jap. Soc. int. Med. (Jap.), 60, . Fox, L.P., Grandi , J., Johnson, A.H., Watrous, W .G. & Johnson, M.J. (1969)
.
Familial
Pheochromocytomas
269
Pheochromocytoma associated with pregnancy. Amer. J. Obstet. Gynec., 104, 288-294. Furukawa, Y., Sato, T., Saito, S., Torikai, T., Matoba, N. & Watanabe, H. (1972) Sipple's syndrome with hyperparathyroidism. Metabolism (Jap.), 9, 628-643. 4) Kondo, T., Okajima, E., Imoto, T., Motomiya, Y., Matsushima, S. & Hayashi, I. (1974) Familial bilateral pheochromocytomas. Acta urol. jap. (Jap.), 20, 359-365. 5) lvtiura, Y., Sato, T., Abe, K., Mori, T., Suzuki, M., Ono, I., Saito, S., Sakurada, T., Furukawa, Y., Okuyama, M., Mihara, A., Yoshinaga, K., Yusa, T., Watanabe, H., Matoba, N., Sasano, N., Nakamura, K., Ito, Y. & Mitsuhashi, K. (1968) Clinical features of familial pheochromocytoma. Nihon Rinshyo (Jap.), 27, 1866-1879. 6) Mori, Y., Kiyohara, H., Kano, S., Ito, T. & Horiuchi, N. (1974) Three patients with pheochromocytoma occurring in a family. Jap. J. Urol. (Jap.), 65, 198. 7) Nishio, I., Masuyama, Y., Yamada, R. & Yoshitoshi, Y. (1972) A case of familial pheochromocytoma. Metabolism (Jap.), 9, 1067-1073. 8) Sato, A., Iwabuchi, S., Sato, T. & Watanabe, H. (1974) Pheochromoeytoma associated with pregnancy. World of Obstet. Gynec. (Jap.), 26, 1013-1016. 9) Sato, T., Seino, M., Kitahara, 0., Ono, I., Miura, Y., Abe, K., Yoshinaga, K., Sugita, A & Watanabe, H. (1971) Familial bilateral pheochromocytomas with medullary carcinoma of the thyroid. Jap. Heart J., 12, 405-413. 10) Sato, T., Shibata, A., Ishida, N., Yamada, A., Wada, Y., Yoshinaga, K. & Nakazawa, W. (1964) Paroxysmal and sustained type of pheochromocytoma. Nihon Rinshyo (Jap.), 22, 1398-1406. 11) Sato, T., Yoshinaga, K., Ishida, N., Rob, C. & Wada, Y. (1961) A new simple screening test for pheochromocytoma. Tohoku J. exp. Med., 74, 37-42. 12) Shiraiwa, Y., Futagawara, K., Kudo, S., Mikuni, T. & Funiu, T. (1971) Familial pheochromocytoma. Folia erulocr. jap. (Jap.), 46, 82. 13) Steiner, A.L., Goodman, A.D. & Powers, S.R. (1968) Study of a kindred with pheo ehromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: Multiple endocrine neoplasia, type 2. Medicine, 47, 371-409. 14) Yoshinaga, K. (1973) Diagnosis of adrenal hypertensions. Jap. Circulat. J., 37, 1045 1048. 3)
J. exp.
Med.,
1975,
115, 263-269
Pheochromocytomas
Occurring
in 3 Members
in
a
Family TATSUO SATO, YUKIKO SATO, HISAICHI SAKUMA, KIYOSHI KOBAYASHI, YUKIO MIURA, KAORU YOSHINAGA and HIROKI WATANABE*
Departmentof Internal Medicineand Departmentof Urology,* Tohoku University Schoolof Medicine,Sendai
SATO, K,
and
T.,
SATO,
Tohoku
J.
exp. bilateral
previously
reported of
urinary are
H.
1975,
15
KOBAYASHI,
(3),
cases
or
chemical
assay
for
K., MIURA,
Occurring
in
263-269•\•\Three
pheochromocytomas
familial
asymptomatic
particularly
H.,
115
adrenal
catecholamine
catecholamine
SAKUMA,
Pheochromocyytomas
Med.,
exhibiting
stage
Y.,
WATANABE,
in
are Japan.
The
detection
and
emphasized.•\•\familial assay;
a
Family.
members
of
a
kindred
presented of and
diagnosis
YOSHINAGA, in
rate
pheochromocytoma
Y.,
3 Members
in
together tumor
with
growth,
the
importance
this
type
pheochromocytoma;
of
the of tumor urinary
hypertension
Familial occurrence of pheochromocytolna has been established recently as a significant phenomenon (Steiner et al. 1968). Up to date, more than 300 cases of pheochromocytoma proved at either surgery or autopsy have been reported in Japan (Yoshinaga 1973). Among them, seven separate families affected with pheochromocytoma have been described (Miura et al. 1968; Sato et al. 1971; Shiraiwa et al. 1971; Ando et al. 1971; Nishio et al. 1972; Kondo et al. 1974; Mori et al. 1974). It is the purpose of this paper to record an additional family in which 3 members out of 5 siblings had bilateral adrenal pheochromocytomas and to discuss the problems concerning tumor growth, urinary catecholamine excretion at an asymptomatic stage of the disease and usefulness of catecholamine determination for the correct diagnosis. CASE REPORTS Case 1. Y.S., a 24-year-old male plasterer, was admitted first to the Tohoku University Hospital in 1961 with chief complaint of sudden loss of vision. Family history was nothing particular, except that his father died of brain he morrhage at the age of 54. Father was hypertensive and diabetic for years. Five siblings were all well at this time. The blood pressure was 200/130 and phentolamine (Regitine) test was positive. Received
for publication,
December
14, 1974. 263
264
T. Sato
A
24-hr
jig
of
and
collection epinephrine
NE
inal
in
our
adrenal
pressure
to
our
of
present
the In
1970,
hospital
was
sent
at
to
our
On
5,
with about
sional
stiff
1974, a
neck,
212/120
palpable
hemiparesis
serum
of
physical
and
P
were
within
electrocardiogram metabolic
value
was
disclosed
of
on
the
cytoma
has
was
gas
left
At
had
elsewhere
not
by
one
youngest
sister
He
that
came
time, for
again
skin
his
to
urine
the
analysis
be
elevated
to
the
of
NE,
393 ƒÊg;
our
laboratory of
laminography
contained .
Right
to
walk.
blood
urea
nitrogen,
But
an
chest
oral
.
was
the revealed
and
a small
basal
and
mg/day).
Cl, , but
The
Intravenous kidney
K,
normal .
9.1
glucose
Na,
catecholamines VMA,
On
able
hypertrophy
urinary
.
pressure
examinations
including the
ventricular
configuration
.
.
occa
was
he
normal
of
speech
blood
gland
count,
film
output
The
abnormality
electrolytes
X-ray
in
Retinal
, but
Blood all
.
no
found
University
, there had been at the cold season
thyroid
showed
.
Tohoku difficulty
tall
warm.
Serum
left
cm
and
was
range.
and
illness
was
were
in
the and
167
.
slight
entered
depsite
was
sugar
mg/day
and
rise slightly
and
, his
proved
and
normal
(E , 26 ƒÊg; 7.0
significant was
specimens
present
reflex
normal
insuffiation
adrenal
weighing nmg
of
returned Case
Case
VMA
37,
scincigram
Abnormal
found
of
KW-I
pattern
a
no
below.
.
sister's
sweating
The
blood
+8%.
. blood
their Upper
pyelography urinary
tract
suprarenal
.
mass
left.
The
3.55
the
function
Retroperitoneal
74 .
were
diabetic
were
normal
kg
tendon
revealed rate
metabolite
normal
a
operation
hemiparesis the
graded
fasting
showed
age
of
and
examinations and
test
was
the
part
mentioned
were
right
onset
57 of
accelerated
cholesterol
tolerance
end
rate
in
in
sickness
the
the
the
[131I]Thyroid
with
rest
at
changes
this
examinations.
of
weighed
tumors.
sister's with
patient,
pulse
the as
catecholamines
the
and
discharged
reported
after
hospital
intolerance
hypertensive
years
further
before
patient with
revealed
9
about
history
heat
the
was
g,
catecholamines was
E
pheochromocytoma
resulted of
of Abdom
Postoperatively,
patient
case
values
1964).
together
the
short
This
inquiry
refused
6 months
admission,
The
27
benign
stimulation
in
and
urinary
he
weighing
typical
excretion
NE).
Normal
165
respectively.
normal.
urinary
another
laboratory His
April
Since
an
a be
excretion,
(NE).
10-50 ƒÊg/day,
was to
al.
catecholamine
tumor,
histamine
33 in
make
but
Hospital
tumor
et
of
and
adrenal
1974.
(Sato age
catecholamine.
The
April,
the
to
(156 ƒÊg/day),
Ca
until
high
norepinephrine
jig
thought and
adrenalectomy
that
no
the was
authors
of
right
140 ƒÊg/day
clinic
underwent
jig 0-10
However,
(approximately
was
a
normal
pressure.
abnormally
3,200 were
gland
returned
blood
visited
of
and
Histologically,
left
high
(E)
revealed
revealed
extirpated.
in
urine
laboratory
exploration
The
of
et al.
3,
NE to
2. was
area 10
g
per
g
his
job.
M.K., admitted
was was
of
a
explored
tissue.
Postoperative
wet
the
May The
26-year-old to
on
extirpated.
Yonezawa
house
wife, City
7 , 1974 tumor
and
course
the
Hospital
a
benign
contained
youngest in
March
0 .44 was
pheochromo mg
of
uneventful
sister 1970
of , for
E and
Case
1
evaluation
and he
and
of
her
hypertension.
years.
the
obtained
attacks the
a
with
She
occasional
Since
and
VMA
pheochromocytoma
was
Physical
The
Skin
white
41%,
blood
cholesterol after serum
total
The
protein
basal
Both
specimen
which and
diagnostic
for
take
a
member
of
On
December
20
g
and
in
tological left
published
and
the
patient
the
time
of
Case
slight
3.
on
high observed of
no
and
male
read
at
the
baby 240/130.
diagnosis
of
revealed
no
all
were
laboratory
the
and
Ca,
range.
to
of
these
values
consult
family
were
24-hour
74 ƒÊg
a
occurrence
her
found
Cl
normal
A
that
bilateral
was
K,
and
Serum
electrocardiogram
contained
recommended
83
sugar.
curve
positive.
therefore,
because
urine
E,
1,054 ƒÊg were
surgeon
of
pneumography,
adrenal were
content
tumors, found
benign
(Sato
and
abdomen.
were
Na,
within
film
the
all
about
the
tumor,
and
the
patient
was
bilateral
supra
expected.
typical
the
were X-ray
in
no
including
retroperitoneal
gland,
NE
sugar
of
neck
found
blood
possible
as bilateral
been
eyes
hematocrit
Normal
members
1970,
1974
of
25
mg/g
of
g
successfully E
wet
in
the
right
removed.
pheochromocytoma.
3.21
et
weighing
and
tissue.
His
content A
of
report
the
of
this
al.).
operation,
the
asymptomatic.
blood
No
pressure
tumors
in
elder
sister
has
the
remained
neck
have
normal
arisen
up
to
report.
K.H.,
already
normal
our
adrenal
since
has
headache
because
in
this
clinic
On
and
years
relatively
a May
in
32-year-old 10,
the
distress
and
of
case. being
was
When
excretion this
wife,
She
morning.
urinary in
house
1974.
her
in
Case
and
sister
catecholamine
However, busy
of
normotensive had
children
was
admitted of
adrenalectomy
(200 ƒÊg/day she
2,
complained
refused
in further
care.
The
in
only 1970,
average)
was
examinations
patient
had
had
two
deliveries. On
woman
0.37
4
cases.
was and
but
tests
and
the
month gradually.
healthy
and
protein,
reported,
of other
mass
nitrogen
to
from
was
was
was
our
left
7th
results,
plus
Chest
We
found
23,
the
During
sent
were
diagnosis
tumor
case
to
familial
masses
a still
tongue
electrolytes
tyramine
because
specimens
small
urea +7%.
VMA.
incision
urine
renal
of
lips,
one ml.
pheochromocytoma
transabdominal to
blood
been
mg
positive
palpable
Serum
and
had
23
the
puffy
of
3
crises.
increased
was
Hemoglobin
mg/100
was
Regitine
no
10,800.
test.
rate
gave
eyes,
showed
312
and
metabolic
normal.
NE
to
head, and
was
tolerance
birth
last
hypertensive
sweating,
pressure
1961)
in
attacks
premature blood
frequent
1970,
the
the
suspected.
Urinalysis
glucose
al.
the
normal
count
increased
oral
of
was
respectively.
et
of
cell
in the
strongly
examinations
abnormality.
of
for
hypertensive ,
excessive
terminated
(Sato
frequent
In
severity
delivery,
tests
had
continued.
and
episodes
Thereafter
headache,
It After
she
birth.
palpitation
265
hypertensive
1968,
mature
pulsating
month.
repeated
in
in
frequency of
9th
revealed
pregnancy
convulsions.
the
history
baby
pregnancy,
complained
at
first
male
headache
second
Pheochromocytomas
Past
During
She
Familial
admission, in
no
physical distress.
examinations Ophthalmological
revealed examinations
a well
developed, of
fundi
well were
nourished normal
and
266 the
T. Sato et al. heart
was
abdomen. in
blood
rate
were
blood revealed
with
VMA
On
July
tumor,
was
extirpated
cortex.
g
she
in
The
right
adrenal
gland
was
a benign
in the
patient
the
tumor
operation, was
3
left
months
freed
urinary from
than was
0.36
excretion the
on
170/100
in
and
arising
from
one
the
third
enlarged
of as
a
pheochromocytoma.
were
and
the
the
basal thyroid fasting
24-hour
urine
250 ƒÊg
of
NE.
pneumography
the
left.
During
her
only
one
occasion.
It
minutes.
found
more
E
a
Retroperitoneal mass
adrenalectomy
was
behind
diagnosis
contents
underwent
weight,
leaving
several
and in
of
of
in
Results
electrolytes,
Analysis
mg/day).
to
and
72/min.
nodules
cholesterol,
14 ƒÊg
elevated
after
1974,
8.5
Histological
After
26,
serum
cold
normal.
suprarenal
pressure
spontaneously
oval
withdrew
blood
small
neck
was
electrocardiogram No
catecholamines, (5.0-5.5
a
the
rate
study,
were
in
pulse
limits.
including
of
mass
and
X-ray
nitrogen
normal
showed
palpable
120/70
normal
chemistry urea
was
the
disappeared
within
excretion
tomograms
hospitalization,
the
the
abnormal
However,
NE
chest
all
blood
no
was
urinalysis,
Blood
and
was
pressure
were
found.
sugar
There
blood
count,
metabolic scan
normal.
The
headache.
and of
2.52
a small, left
whole,
encapsulated,
adrenal
apparently
On mg/g,
well
gland. normal
and
was
chemical
This adrenal
removed.
assay,
respectively
.
catecholamine
returned
to
normal
Replacement
therapy
of
the
E
and
and steroid
later.
DISCUSSION This is the eighth kindred of familial pheochromocytoma in Japan. The present cases showed several interesting points, as mentioned below. Case 1 was initially thought to be usual or sporadic type of pheochromocytoma and contralateral adrenal gland was apparently normal at that time . However, questions remained in his slightly high excretion of urinary catecholamines despite normalization cf his high blood pressure and negative histamine provocation test (Sato et al. 1964). The patient had had no contact with us and never been deter mined for his blood pressure until the time of sister's operation . At this time, 9 years after the surgery, his urinary excretion of catecholamine was still high and the blood pressure was around 170/100. Existence of bilateral pheochromocytomas in his sister strongly suggested that he had probably another tumor in the other side of adrenal gland, but he refused further examinations again because he was asymptomatic. Elapsing another 4 years , total 13 years after the operation, he developed hypertensive cerebrovascular accident and was finally admitted to our clinic. Pheochromocytoma in the contralateral side which had grown to 10 g was found and removed. Discernible symptoms of pheochromocytoma appeared only about 6 months before the final admission . Case 1 discloses evidence that there is a tumor having such a slow rate of growth. During this 13 years, slightly high excretion of catecholamine into the urine had continued without any characteristic symptoms and he had worked as a plasterer as usual. This stage, therefore, could be considered as "chemical pheo-
F, female; M, male; ?, The reference numbers
not mentioned. are shown together with
TABLE 1.
the
Family
Familial
No.
pheochromocytoma
in Japan
268
T. Sato
chromocytoma." urinary
An
asymptomatic years,
there
is
relatively
way,
be
difficult,
be
the
most
In
Case
the
2,
such
urinary
an
pregnancy
al.
or
eclampsia
consecutively is
correctly
proposita
us
1961)
were
, not
many
developing
explained
despite
by
well
a
pheno
known
spontaneously
chemical
been
for
cases,
been
decreased
assay
It
and
examine
the
positive
was
extremely
to
has
that
with
time
pheochromocytoma
VMA
alone
of
had
to
these
be
It
or
of
during
diagnosed
led
could
asymptomatic
prior in
output
also
that,
secretion state
catecholamine
she
indicate
catecholamine
catecholamine,
high
but
as
.
might
in
Case
3,
would
procedure.
removed.
pregnancy
Slightly
years,
observations
catecholamine
actual
et
4
catecholamine.
to
progressively
(Sato
had
of
conclusive
aggravated tests
response
detection but
urinary
against
pressure
any
in
3.
than
Normotensive
of
tachyphylaxis
blood
In
stage
Case
more
These
abnormal
excretion
was
for
pheochromocytoma.
high of
example
continued
normotensive.
an
as
menon
had
and
symptoms
the
additional
catecholamine
et al.
this
familial
course
of
.
, pheochromocytoma
strongly should
and
be
kept
in
to
both
mother
properly
treated
members
of
this
that
symptoms
repeated than
bilateral
mind
VMA
toxicemia
of
pheochromocytoma
pheochromocytoma
and
(Fox
,
Since
rather
suspected
hazardous
other
pheochromocytoma pregnancy
fetus
et
al . 1969).
family
to
unless
with the
disease
Detection
discover
of
is
Case
additional
2
tumor
cases. Including been
the
reported
patients
in
are
Thus,
was
sister
was
in
two
patients
had
medullary
be in
order
to
detect If
adrenal the
family
be
than
or and
tumor including
of
frequent and
20
and
.
There
the
thyroid
was
found
gland in
that
when
tumor
children
of
one al.
1974).
and
more
a
patient
cases
and
after
and
is the
tumor
should
be
another
seen in
, it the
examined
should neck and
distribu sisters
(Family
No . ‡Z)
thirds one .
al.
of
these
In
the
had latter
1972)
with things other
are family prevent
taking family members in the
necessary
Moreover, followed
or
fourth
. pheochromocytoma
be .
6 male.
age
Two
to
these
siblings,
than
et
in
and
The
syndrome)
in
one
. two
(Furukawa
have data
female
family
, particular important urinary catecholamine
pheochromocytoma
were male
Pairs
was et
Clinical
12 as
type
estimating
bilaterally
cases,
30 .
case
pheochromocytoma
cases.
(Sipple's
one
even
18
often
(Mori
of
sporadic
18 as
son
with
of
these
twice
pheochromocytomas
additional familial
Of
ages
, sisters
emphasized
usual
detail
1.
more
total
adrenal
tumor
should to
accident.
of
bilateral
affected
a
Table
most
generations
parathyroid
history
the
were
carcinoma
It
8 families
, making
between
brother,
affected
seems
in
affected
concentrated
and
group,
family,
country
summarized
female
tion
present this
up
vascular to
search
all members periodically
References 1)
2)
Ando, M., Sugimoto , M., Okamoto, S., Tokunaga, K., Ikegami (1971) Ph , K. & Murakami, S. 361-362 eochromocytoma in younger and elder sister . Jap. Soc. int. Med. (Jap.), 60, . Fox, L.P., Grandi , J., Johnson, A.H., Watrous, W .G. & Johnson, M.J. (1969)
.
Familial
Pheochromocytomas
269
Pheochromocytoma associated with pregnancy. Amer. J. Obstet. Gynec., 104, 288-294. Furukawa, Y., Sato, T., Saito, S., Torikai, T., Matoba, N. & Watanabe, H. (1972) Sipple's syndrome with hyperparathyroidism. Metabolism (Jap.), 9, 628-643. 4) Kondo, T., Okajima, E., Imoto, T., Motomiya, Y., Matsushima, S. & Hayashi, I. (1974) Familial bilateral pheochromocytomas. Acta urol. jap. (Jap.), 20, 359-365. 5) lvtiura, Y., Sato, T., Abe, K., Mori, T., Suzuki, M., Ono, I., Saito, S., Sakurada, T., Furukawa, Y., Okuyama, M., Mihara, A., Yoshinaga, K., Yusa, T., Watanabe, H., Matoba, N., Sasano, N., Nakamura, K., Ito, Y. & Mitsuhashi, K. (1968) Clinical features of familial pheochromocytoma. Nihon Rinshyo (Jap.), 27, 1866-1879. 6) Mori, Y., Kiyohara, H., Kano, S., Ito, T. & Horiuchi, N. (1974) Three patients with pheochromocytoma occurring in a family. Jap. J. Urol. (Jap.), 65, 198. 7) Nishio, I., Masuyama, Y., Yamada, R. & Yoshitoshi, Y. (1972) A case of familial pheochromocytoma. Metabolism (Jap.), 9, 1067-1073. 8) Sato, A., Iwabuchi, S., Sato, T. & Watanabe, H. (1974) Pheochromoeytoma associated with pregnancy. World of Obstet. Gynec. (Jap.), 26, 1013-1016. 9) Sato, T., Seino, M., Kitahara, 0., Ono, I., Miura, Y., Abe, K., Yoshinaga, K., Sugita, A & Watanabe, H. (1971) Familial bilateral pheochromocytomas with medullary carcinoma of the thyroid. Jap. Heart J., 12, 405-413. 10) Sato, T., Shibata, A., Ishida, N., Yamada, A., Wada, Y., Yoshinaga, K. & Nakazawa, W. (1964) Paroxysmal and sustained type of pheochromocytoma. Nihon Rinshyo (Jap.), 22, 1398-1406. 11) Sato, T., Yoshinaga, K., Ishida, N., Rob, C. & Wada, Y. (1961) A new simple screening test for pheochromocytoma. Tohoku J. exp. Med., 74, 37-42. 12) Shiraiwa, Y., Futagawara, K., Kudo, S., Mikuni, T. & Funiu, T. (1971) Familial pheochromocytoma. Folia erulocr. jap. (Jap.), 46, 82. 13) Steiner, A.L., Goodman, A.D. & Powers, S.R. (1968) Study of a kindred with pheo ehromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: Multiple endocrine neoplasia, type 2. Medicine, 47, 371-409. 14) Yoshinaga, K. (1973) Diagnosis of adrenal hypertensions. Jap. Circulat. J., 37, 1045 1048. 3)
