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Renal hypouricaemia in a patient with 48, XXYY syndrome

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Article

Renal hypouricaemia in a patient with 48, XXYY syndrome

Abstract and Figures

Studies on hypouricaemia observed in a patient with 48,XXYY syndrome revealed an abnormality in renal urate handling. His renal urate clearance was abnormally increased. Inosine administration and provocative tests using probenecid and pyrazinamide identified an isolated renal tubular abnormality with increased urate secretion. Since the serum urate in his brother with a normal sex chromosome constitution was also low, the association of renal hypouricaemia and 48,XXYY syndrome in this patient is probably coincidental. Although the brother was not investigated, these siblings may be a previously unreported case of familial hypouricaemia due to isolated renal hypersecretion.
Content may be subject to copyright.
Postgraduate
Medical
Journal
(1986)
62,
219-222
Renal
hypouricaemia
in
a
patient
with
48,
XXYY
syndrome
Hiromu
Nakajima,
Koji
Tajima,
Tadahisa
Nakajima,
Sayomi
Jida,
Seiichi
Sumi,
Norio
Kono,
Kaname
Moriwaki,
Kyohei
Nonaka*
and
Seiichiro
Tarui
The
Second
Department
of
Internal
Medicine,
Osaka
University
Medical
School,
Fukushima
1-1-50,
Fukushima-
Ku,
Osaka
553,
Japan
Summary:
Studies
on
hypouricaemia
observed
in
a
patient
with
48,
XXYY
syndrome
revealed
an
abnormality
in
renal
urate
handling.
His
renal
urate
clearance
was
abnormally
increased.
Inosine
administration
and
provocative
tests
using
probenecid
and
pyrazinamide
identified
an
isolated
renal
tubular
abnormality
with
increased
urate
secretion.
Since
the
serum
urate
in
his
brother
with
a
normal
sex
chromosome
constitution
was
also
low,
the
association
of
renal
hypouricaemia
and
48,
XXYY
syndrome
in
this
patient
is
probably
coincidental.
Although
the
brother
was
not
investigated,
these
siblings
may
be
a
previously
unreported
case
of
familial
hypouricaemia
due
to
isolated
renal
hypersecretion.
Introduction
The
48,
XXYY
syndrome,
first
reported
by
Muldal
&
Ockey
(1960),
is
a
rare
sex
chromosome
number
disorder.
Compared
to
47,
XXY
Klinefelter's
syn-
drome,
the
incidence
is
very
low
(Bloomgarden
et
al.,
1980).
Renal
hypouricaemia,
first
reported
by
Praetorius
&
Kirk
(1950),
is
a
unique
condition
characterized
by
low
levels
of
serum
urate
with
increased
renal
urate
clearance.
Harkness
et
al.
(1983)
reported
the
in-
cidence
of
renal
hypouricaemia
in
their
hospital
in
UK
as
1
in
23710.
According
to
de
Vries
&
Sperling
(1979),
there
are
three
mechanisms
responsible
for
renal
hypouricaemia,
namely
pre-secretory,
post-secretory
and
combined
defects
of
renal
tubular
urate
reabsorp-
tion.
More
recently,
renal
hypouricaemia
with
in-
creased
renal
tubular
urate
secretion
was
reported
by
Shichiri
et
al.
(1982).
Similar
findings
were
also
reported
by
Dumont
&
Decaux
(1983)
and
Sanz
et
al.
(1983).
Thus,
four
mechanisms
should
be
considered
in
the
study
of
renal
hypouricaemia.
We
report
a
patient
with
48,
XXYY
syndrome
and
renal
hy-
pouricaemia
possibly
due
to
the
fourth
mechanism,
renal
tubular
urate
hypersecretion.
Materials
and
methods
Case
report
The
patient
was
a
34
year
old
Japanese
male,
the
first
child
born
to
a
32
year
old
father
and
a
27
year
old
mother.
He
had
enjoyed
good
health,
except
that
he
had
hypogonadism
(Tanner
stage
II),
recurrent
foot
ulcers
and
varicose
veins
of
the
legs.
On
examination,
he
was
found
to
be
eunuchoid.
His
height
was
171
cm,
weight
63
kg,
arm
span
157
cm
and
the
upper
to
lower
body
segment
ratio
1.04.
Skeletal
abnormalities
were
observed
including
cleft
palate,
genu
varus,
cubitus
varus,
clinodactylia
and
shortened
fifth
interphalan-
geal
bones
(Figure
1).
His
dermatoglyphics
was
abnor-
mal
in
decreased
total
finger
ridge
counts
(TFRC
47)
and
a-b
ridges
(right
25,
left
30).
Loop
patterns
were
predominant
(nine
out
of
ten
fingers).
Simian
creases
were
present.
His
I.Q.
was
60
(Wechsler
Adult
Intelligence
Scale).
He
did
not
show
aggressive
be-
haviour.
Laboratory
examinations
were
normal
except
for
hypouricaemia
(0.102-0.156
mmol/l,
nor-
mal
range,
0.162-0.360mmol/1)
and
hypercalcuria
(4.31-8.87
mmol/day,
normal
range,
less
than
3.80mmol/day).
Urinary
urate
concentrations
and
percentage
tubular
reabsorption
of
phosphate
were
within
normal
ranges.
Basal
gonadotrophins
as
measured
by
radioimmunoassays
were
elevated
(LH,
71.0
U/l,
normal
range,
3-15
U/1;
FSH,
51.2
U/l,
normal
range,
1.0-10
U/1).
Gonadotrophin
releasing
hormone
(LH-RH,
100
jig)
administration
resulted
in
C)
The
Fellowship
of
Postgraduate
Medicine,
1986
Correspondence:
H.
Nakajima,
M.D.
*Present
address:
Department
of
Medicine,
Division
of
Endocrinology
and
Metabolism,
Kurume
University
School
of
Medicine,
Kurume
830,
Japan.
Accepted:
1
August
1985
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220
CLINICAL
REPORTS.
....
....
..........
Palestinians:
iii.Ri.
Figure
1
Photograph
of
the
patient
representing
a
eunu-
choid
body
habitus
with
hypogonadism.
the
hyperresponses
of
gonadotrophins
(peak
values,
LH,
275.8
U/i;
FSH,
89.5
U/1).
Marked
hyalinization
of
seminiferous
tubules,
interstitial
fibrosis
and
lack
of
spermatogenesis
were
found
in
testicular
biopsy.
Chromosome
analysis
revealed
that
he
had
non-
mosaic
48,
XXYY
karyotype
without
translocations
(Figure
2).
His
younger
brother
(32
years
old)
and
mother
had
normal
chromosome
constitutions.
His
father
died
before
this
study
was
performed.
Hy-
pouricaemia
was
also
present
in
his
younger
brother
(0.150
mmol/l).
(Conversion
of
S.I.
units
to
metric
units:
serum
urate
1
mmol/l
=
16.67
mg/dl,
urinary
urate
1
mmol/day
=
166.7
mg/day,
urinary
calcium
1
mmol/day
=
39.5
mg/day).
Studies
on
urate
metabolism
Oral
inosine
administrations
were
performed
for
6
days,
400mg
(I.5
mmol)
every
6
hours,
and
serum
and
urinary
urate
were
examined.
Probenecid
1
g
(3.5
mmol)
or
pyrazinamide
3
g
(24.4
mmol)
were
administered
orally
after
an
overnight
fast
and
a
one
hour
control
period.
Clearance
studies
were
perfor-
med
with
an
interval
of
one
hour.
Serum
and
urinary
urate
were
measured
by
an
enzymatic
assay
(uricase-
catalase
method).
Normal
subject
data
of
the
proben-
ecid
and
pyrazinamide
tests
were
obtained
from
three
healthy
male
volunteers
of
the
same
age.
Informed
consent
was
obtained
from
all
the
subjects
and
the
patient.
Results
Serum
urate
concentrations
of
the
patient
ranged
from
0.102
to
0.156
mmol/l
(0.
126
±
0.016
mmol/l;
mean
+
s.d.,
n
=
10).
Percent
of
urate
clearance
to
creatin-
ine
clearance
(%Cur/Ccr)
was
high
(24-32%,
con-
trols,
4-13%)
with
a
normal
creatinine
clearance.
Inosine
administrations
resulted
in
increases
of
both
serum
(from
0.120
to
0.276
mmol/l)
and
urinary
(from
5.38
to
10.26
mmol/day)
urate
concentrations,
but
%Cur/Ccr
remained
unchanged.
Probenecid
adminis-
tration
caused
an
increase
in
%Cur/Ccr
reaching
.~~~~~~~~~~
..
.~~~~~~~~.
~~~~
.....
*~~~~~~~~~~~~~~~.*
.*....
...
..
.......18..
........~~~~~~~~~~~~~~~~~~~~~~~~~~.......
.~~~~~~~~~~~~~~~~~~~~~~~~~~~.
V~~~~~~~~~~~~~~~~~~~~~~~~~~~
..
..
Figure
2
Chromosome
analysis
of
the
patient
showing
non-mosaic,
48,
XXYY
constitution
without
transloca-
tions.
G-banding
patterns
of
sex
chromosomes
are
also
shown.
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CLINICAL
REPORTS
221
Table
I
Effects
of
oral
probenecid
and
pyrazinamide
administration
on
serum
urate
(s-UA),
urate
clearance
(Cur),
creatinine
clearance
(Ccr)
and
%Cur/Ccr.
Time
(hours)
s-UA
(mmol/l)
Cur
(ml/min)
Ccr
(ml/min)
%Cur/Ccr
Probenecid
-
1too
0.132
(0.281
0.055)
31.2(16.1
±
5.0)
97.8
(149
±
29.9)
31.9
(10.4
±
1.1)
Oto
1
0.114(0.248±0.062)
54.9(13.3±
3.0)
98.7(
97±
6.3)
55.6(25.9±
9.0)
1
to2
0.102(0.220±0.054)
72.8(32.0±
5.8)
88.9(
96±
15.9)
81.9(38.5±
10.1)
Pyrazinamide
-1
too
0.156
(0.362
±
0.061)
20.7
(11.4
±
3.9)
80.3 (131
±
6.6)
25.8
(8.6
±
2.9)
0
to
1
0.168(0.376
0.070)
12.9(
6.7
1.0)
110.0(132
±
3.0)
11.7(5.0
±
0.7)
1
to
2
0.174(0.382
±
0.065)
7.6(
2.2
±
0.4)
106.0(107
±
6.6)
7.2(2.0
±
0.3)
Data
from
age
and
sex
match
controls
(n
=
3)
are
in
parentheses
(mean
±
s.d.).
81.9%,
much
greater
than
in
the
control
subjects
(TableI).
After
pyrazinamide
administration,
final
%Cur/Ccr
in
the
patient
and
the
control
subjects
decreased.
The
decrements
were
72.2%
and
70.5
±
15.7%
(n
=
3)
from
the
basal
values
respective-
ly.
The
patient's
tubular
secretion
of
urate
as
estimated
through
a
pyrazinamide
suppression
test
was
27.6
nmol/ml
at
a
final
serum
urate
level
of
0.174
mmol/l.
Discussion
During
a
thorough
examination
on
a
patient
with
the
48,
XXYY
syndrome,
we
noticed
that
he
had
hy-
pouricaemia
uncomplicated
with
other
systemic
disor-
ders
known
to
cause
hypouricaemia.
Since
urate
synthesis
from
inosine
was
not
disturbed
in
the
patient,
the
presence
of
any
defects
in
purine
metabol-
ism
was
excluded
(Kondo
et
al.,
1977).
The
increased
%Cur/Ccr
suggested
that
hypouricaemia
observed
in
the
patient
was
a
result
of
abnormal
renal
urate
handling.
According
to
de
Vries
&
Sperling
(1979)
and
Shichiri
et
al.
(1982),
renal
hypouricaemia
can
be
classified
into
four
types
of
tubular
dysfunction,
hypersecretion
and
pre-secretory,
post-secretory
and
combined
defects
of
reabsorption,
using
probenecid
and
pyrazinamide
tests.
Inhibition
of
tubular
urate
reabsorption
by
probenecid
increases
%Cur/Ccr
in
normal
subjects
as
well
as
in
patients
with
pre-
secretory
defect
or
increased
secretion.
Pyrazinamide
suppresses
%Cur/Ccr
through
inhibition
of
tubular
urate
secretion
in
normal
subjects
as
well
as
in
patients
with
post-secretory
defect
or
increased
urate
secretion.
In
this
patient,
basally
elevated
%Cur/Ccr
further
increased
after
probenecid
administration.
Pyrazin-
amide
administration
resulted
in
almost
normal
de-
crease
of
%Cur/Ccr.
These
findings
suggested
that
hypouricaemia
in
this
patient
was
due
to
urate
hyper-
secretion.
His
tubular
secretion
of
urate
exceeded
the
95%
confidence
range
obtained
for
normal
subjects
by
Steele
&
Rieselbach
(1967).
This
finding
further
supports
the
possibility
that
urate
hypersecretion
existed
in
the
patient.
Since
the
serum
urate
level
of
his
younger
brother
was
also
low,
hypouricaemia
observed
in
this
patient
may
be
familial.
To
our
knowledge,
familial
cases
of
renal
hypouricaemia
due
to
hypersecretion
have
not
been
previously
reported.
As
his
brother
had
normal
chromosome
constitution,
it
appears
that
the
combin-
ation
of
the
two
rare
syndromes
observed
in
this
patient
may
be
coincidental.
This
report
indicates
that
detailed
investigation
including
family
studies
is
needed
in
characterizing
renal
hypouricaemia.
Serum
urate
estimations
in
chromosomal
abnormalities
are
also
warranted.
Acknowledgements
This
study
was
supported,
in
part,
by
Grant-in-Aids
for
Scientific
Research
(Nos.
59480214,
59480255,
59570484
and
59870040)
from
the
Ministry
of
Education,
Science
and
Culture
of
Japan
and
Basic
Research
Grant
from
the
Muscular
Dystrophy
Association
of
the
United
States.
We
wish
to
thank
Mr
Shigeaki
Kobayashi,
M.T.,
and
Mr
Shigemi
Motoi,
M.T.,
of
the
Central
Laboratory
for
Clinical
Investigation,
Osaka
University
Hospital,
for
their
skilful
technical
assistance
in
the
chromosome
analyses.
We
are
also
grateful
for
the
helpful
advice
received
from
Dr
Noriyuki
Suehara,
M.D.,
of
the
Department
of
Obstetrics
and
Gyn-
ecology
and
Dr
Kiyoshi
Miyai,
M.D.,
professor
of
the
Department
of
Laboratory
Medicine,
Osaka
University
Medical
School.
Finally,
we
also
wish
to
thank
Dr
Masayoshi
Shichiri,
M.D.,
of
the
Second
Department
of
Medicine,
Tokyo
Medical
and
Dental
University,
School
of
Medicine,
for
useful
discussions.
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222
CLINICAL
REPORTS.
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doi: 10.1136/pgmj.62.725.219
1986 62: 219-222Postgrad Med J
H. Nakajima, K. Tajima, T. Nakajima, et al.
syndrome.
patient with 48,XXYY
Renal hypouricaemia in a
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... Although several investigators described that the 48, XXYY syndrome also causes an aggressive personality similar to the XYY syndrome (13,14), the present patient did not show aggressive behavior, despite having induced many problems in hospital. This finding suggests that the aggressiveness depends on familial and social environment, rather than on a specific character of the 48, XXYY syndrome (15). The present patient showed hypouricemia with a level of 2.6mg/dl (normal range: 3.2-7.5). ...
... The present patient showed hypouricemia with a level of 2.6mg/dl (normal range: 3.2-7.5). The 48, XXYY syndrome associated with hypouricemia has been de scribed by Nakajima et al (15), who suggest that both diseases are coincidental. In their study, the patient's brother with normal chromosome constitution also had hypouricemia due to renal tubular hypersecretion of uric acid. ...
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A 56-yr-old man with hypogonadism, gynecomastia, and mental retardation was evaluated for chromosome constitution and thrombocytopenia. Chromosomal analysis demonstrated the mosaicism of 48, XXYY and 47, XXY in the peripheral lymphocytes. Twenty out of twenty-five cells were 48, XXYY karyotype and the remaining five were 47, XXY karyotype. Thrombocytopenia was the EDTA-dependent pseudothrombocytopenia type 1 (platelet agglutination). Serological examination suggests that the platelet agglutinin belongs to IgM-kappa type. The present case exhibited both EDTA-dependent pseudothrombocytopenia and the 48, XXYY syndrome. Although this combination may have occurred purely by change, the possibility of whether or not the mosaicism of lymphocytes produces platelet agglutinin remains to be clarified.
... In the present study, 16 .5%) and 5 (2/8, 25%) and SLC2A9 mutation of one patient located in exons 7 and11 (1/8, 12.5%). ...
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Background/aims Familial juvenile hereditary nephropathy (FJHN) is characterized by hyperuricemia due to severely impaired urinary excretion of urate. Hereditary renal hypouricemia is an inborn error of membrane transport. Because studies of inherited tubulopathy is rare, prevalence and diagnosis of these inherited tubulopathy increase with genetic testing.The aim of this study is to investigate prevalence of clinical features, biochemical profiles, and genetic analysis of patients with changes in serum uric acid levels in inherited tubulopathy. Main body The paper has written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. In this retrospective study, a total 65 patients with changes of serum uric acid levels and kidney dysfunction were investigated. Clinical features, laboratory data at initial presentation, management, and outcomes were collected. Forty studies (65 participants) included in this review. The mean ± SD of age of study patients in inherited tubulointerstitial kidney disease was 25.29 ± 14.69 years. Mean ± SD age of patients at time of diagnosis in inherited renal hypouricemia was 18.83 ± 10.59 years. Correlation between exon region in mutated UMOD, SLC22A12, and SLC2A9 genes and serum uric acid levels were assessed and revealed significant statistical correlation between exon region of SLC2A9 mutation and serum uric acid levels. Prevalence of progression to end-stage kidney disease in patients with inherited tubulointerstitial kidney disease and inherited renal hypouricemia were assessed 20% and 2.5%, respectively. There was nephrolithiasis in two patients (2/25, 8%) with inherited renal hypouricemia. Conclusions This study shows that UMOD and SLC22A12 gene mutations were responsible for majority of autosomal-dominant tubulointerstitial kidney disease and inherited renal hypouricemia, respectively.
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To the Editor. —We read with interest the article entitled "Hypouricemia due to an Increment in Renal Tubular Urate Secretion" by Shichiri et al published in the October 1982 Archives (142:1855-1857). These authors described two patients with hypouricemia due to augmented uric acid clearance that was greatly increased by the administration of oral probenecid therapy. They concluded that increased urate secretion by the renal tubule was probably responsible for the hypouricemia of both patients and, to their knowledge, this is the first description of increased tubular urate secretion as a variety of renal hypouricemia.At the Fourth International Symposium on Human Purine and Pirimidine Metabolism (Maastricht, the Netherlands, June 1982), we described five patients with hyperuricosuria who had recurrent nephrolithiasis and who did not normalize their uric acid excretion while receiving an essentially purine-free diet.1 Furthermore, all were hypouricemic and showed evidence of an abnormal uricosuric response when given
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Inborn hypouricemia due to isolated renal tubular defect is a rare disorder. Thus far eight documented families with this condition have been reported. In reviewing the data on these families, hyperuricosuria was found to be a constant associate of the hypouricemia, and hypercalciuria, mainly of the absorptive type, was frequently associated. Urolithiasis appears to be common. The mode of inheritance of this hypouricemia was autosomal, probably recessive. The magnitude of renal urate clearance and the effects on it of probenecid and pyrazinamide suggest the inborn renal hypouricemia to be of two types, due to defective re-secretory tubular urate reabsorption and to total defective tubular urate reabsorption. The question of the renal tubular abnormality for urate transport being the primary defect or secondary to an abnormal metabolite is discussed.
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In order to study the effects of raising the hypoxanthine concentration in plasma on its metabolism and renal handling, the effects of intense exercise have been investigated in a patient with xanthine oxidase deficiency. Despite the 90-fold increased concentration of hypoxanthine in plasma above resting levels in normal individuals, the intracellular concentration of the initial product of hypoxanthine in cells, IMP, was unaffected. Evolution may have stabilized intracellular nucleotide concentrations against the large fluctuations in plasma hypoxanthine which occur during exercise. The renal handling of hypoxanthine is consistent with 'filtration'. In contrast, xanthine clearances may exceed those for creatinine and urinary concentrations do not correlate with those for creatinine; 'secretion' may be involved. Xanthine excretion may reflect guanine breakdown. A retrospective survey of urate concentrations in blood from 47 420 patients followed by further selected investigations detected 2 women with persistent marked hypouricaemia and high urinary urate clearances, 'Dalmatian' hypouricaemia. High pressure liquid chromatographic analysis of plasma extracts can distinguish xanthine oxidase deficiency from other causes of hypouricaemia.
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Characteristics of a 16-yr-old male with a 48,XXYY karyotype are presented; this chromosome constitution was demonstrated consistently in four tissue studied. Basal gonadotropins were elevated, and serum testosterone varied between 3.2-4.0 ng/ml. A pronounced rise was observed in LH after LRH administration with a lesser rise of FSH. The testis displayed hyperplasia of the interstitial cells, tubular atrophy, absent spermatogenesis with preservation of some Sertoli cells, and peritubular fibrosis. The phenotypic, behavioral, endocrine and pathological features of this patient are compared with those found in males with the 47,XXY and 47,XYY syndromes. The 48,XXYY phenotype may result from compounding effects of the additional X and Y chromosomes.
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We present 1 patient with hypouricemia and hyperuricosuria. Serum uric acid level ranged between 1.5 and 1.9 mg/dl and uric acid fractional excretion between 20 and 28%. Apart from that the renal function was normal. The pyrazinamide suppression test gave a normal response showing nearly complete suppression of urate excretion. The uricosuric response to sulfinpyrazone was normal too. The renal tubular response to extracellular fluid volume contraction induced by furosemide indicated a normal tubular sensitivity to extracellular fluid volume variations. From these results we conclude that our patient has a specific tubulopathy characterized by uric acid hypersecretion.
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Two patients had hypouricemia due to increased uric acid clearance. Their daily urinary uric acid excretions were normal. In both patients, pyrazinamide decreased urinary uric acid clearance to almost while probenecid increased it markedly. No other renal tubular or metabolic abnormalities were found. The serum electrolytes and the urinary electrolytes excretions showed no abnormalities. It appears that increased secretion of uric acid in the renal tubule is most probably responsible for hypouricemia in these patients. This report adds to the list of hypouricemic conditions due to a new isolated renal tubular abnormality.