Hypothalamic Hypothyroidism and XXY/XY
Sex Chromosome Mosaicism
Report of a Case
DOUGLAS SCHREIBER, M.D.,
WALDEMAR PALUTKE, M.D.,
AND MARGO P. COHEN,
M.D.
Departments of Medicine and Cytogenetics, Wayne State University
School of Medicine, Detroit, Michigan
ABSTRACT
of Klinefelter's syndrome
with sex chromosomal mosaicism are welldocumented, and a normal male karyotype in skin or peripheral blood does not
negate the diagnosis. 2,3,9,13 T h e abnormal
cell line containing the extra X chromosomal complement may be found in
gonadal tissue, and its presence in the testes
is considered requisite for the characteristic changes in the seminiferous tubules and
Leydig cells that occur in this syndrome. 8
Results of leukocyte and skin fibroblast cultures are generally correspondent, however,10,14 unless the abnormal cell line is
present only in the testes, or is not detectable at all (XY Klinefelter).
VARIANT FORMS
Received July 10, 1975; accepted for publication
August 8, 1975.
Supported in part by die Detroit General Hospital
Research Corporation.
Address reprint requests to Dr. Cohen: Department of Medicine, Wayne State University School
of Medicine, 540 East Canfield, Detroit, Michigan
48201.
675
Altered thyroid function in patients with
Klinefelter's syndrome has been observed
frequently, although frank hypothyroidism appears to be rare. A number of
patients with low thyroidal 1311 uptake
values and variable responses to TSH
stimulation have been reported. 6,15 Measurements of circulating TSH were not performed in those studies, however, and
the nature of the thyroid disorder remains
undefined.
In our patient, the demonstration of an
abnormal sex chromosomal line in skin
fibroblasts, but not peripheral blood, and
the finding of chemical hypothyroidism
with a low serum TSH, were considered
of interest in light of the above discussion.
Report of a Case
T h e patient, an 18-year-old black boy,
was first seen because of a five-year history
of gynecomastia, which had become more
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Schreiber, Douglas, Palutke, Waldemar, and Cohen, Margo P.: Hypothalamic
hypothyroidism and XXY/XY sex chromosome mosaicism. Report of a case.
Am J Clin Pathol 65: 675-679, 1976. An 18-year-old boy with clinical
features of Klinefelter's syndrome in whose case the buccal smear was
chromatin-negative and chromosomal analysis of peripheral blood revealed
46 XY karyotype is described. Diagnosis was confirmed by demonstration
of an XXY cell line in cultured skin fibroblasts. Low circulating thyroxine
levels were found despite absence of clinical hypothyroidism, and TSH
was barely detectable. T h e studies are consistent with an isolated deficiency
of thyrotropin-releasing hormone in a patient with XY/XXY mosaicism. (Key
words: Klinefelter's syndrome; Mosaicism: Hypothyroidism.)
676
SCHREIBER, PALUTKE AND COHEN
A.J.C.P. —Vol. 65
Laboratory Results
^ ^
^H
^ ^
Fie.
:ased
1. Note bilateral gynecomastia, increased
carrying angle, and feminine body contour.
marked in the preceding year (Fig. 1).
intil
He had been the shortest in his class until
ving
the tenth grade (age 15 years), following
which he had had a spurt of growth and
llary
achieved a height of 166 cm. Axillary
-14
and pubic hair had appeared at 13-14
rnal
years of age, and maturation of the external
;ars.
genitalia had begun at the age of 16 years.
He had never shaved and was without
lout
libido. Weight gain had been excessive
ssive
during the preceding 4 years. He had
noticed some frontal headaches, and minilini-
Initial laboratory studies showed a normal blood count, urine, and SMA-17,
with the exception of an elevated alkaline
phosphatase value (68 units; normal < 45)
that proved to be 96% thermolabile, thus
being of skeletal origin. X-rays of the chest
and skull were unremarkable; hand films
revealed that the patient's bone development corresponded to his chronological
age. Brain scan was unremarkable.
Results of baseline endocrine studies are
given in Table 1. Serum thyroxine and
thyroxine-binding protein were both in the
hypothyroid range; thyroid-stimulating
hormone was barely detectable. Chlorpromazine stimulation for prolactin reserve
was pronounced, and response to clomiphene citrate was adequate (Table 2). Informed consent for stimulation with thyrotropin-releasing hormone could not be
obtained.
Buccal smear on two occasions was
negative for Barr bodies. Karyotype of
peripheral blood leukocytes showed only
one cell in 101 containing47 chromosomes;
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mal loss of scalp hair, in the previous year.
A history of mumps at the age of 12 years
was obtained; however, there had been no
known orchitis at that time.
T h e patient's height was 167 cm., weight
78 kg., and blood pressure 110/70 mm. Hg.
Beard, mustache and chest hair were
sparse. Axillary and pubic hair were adequate in amount, but the escutcheon was
of female distribution. Arm span was 171
cm., and lower extremity length was 91
cm. T h e thyroid was just palpable. Gynecomastia was apparent, and the nipples
were inverted. Examination of the heart,
lungs and abdomen disclosed no abnormality. Bilateral genus valgus and increased carrying angle of the arms were
observed. External genitalia were mature,
but the testes measured 2 x 1.5 X 1.5 cm.
bilaterally and were considered firm.
May 1976
HYPOTHYROIDISM IN XXY/XY MOSAICISM
Discussion
Comparison of results of leukocyte and
skin fibroblast cultures in Klinefelter's syndrome are not extensively reported. In 44
patients with 47, XXY karyotype studied by
Fr0land, 10 there was no difference between
the proportions of cells widi this chromoTable 1. Baseline Endocrine Values
Test
17-OH-steroids
17-keto-steroids
8:00 AM Cortisol
4:00 PM Cortisol
Urinary estrogens
Serum estradiol
Serum testosterone
TSH
T„
TBP
Free thyroxine index
131
1 uptake
Results (Normal Values
in Parentheses)
3 mg. per 24 hr. ( 2 - 6 mg. per
24 hr.)
10 mg. per 24 hr. (8-18 mg.
per 24 hr.)
10 ,xg. per 100 ml. ( 5 - 2 5 Mg.
per 100 ml.)
6 /Ltg. per 100 ml. (2-20 fig.
per 100 ml.)
44 /xg. per 24 hr. (10-100 fig.
per 24 hr.)
3.9 and 2.6 /xg. per 100 ml.
(0.8-3.5 Mg. per 100 ml.)
352 fig. per 100 ml. (3001,200 ng. per 100 ml.)
< 2 /xU. per ml. (<13 /xU.
per ml.)
32 ng. per ml. (46-107 ng.
per ml.)
186 ng. T 4 per ml. (180-260
ng. T 4 per ml.) (binding
capacity)
0.21 (.25-1.46)
7% at 24 hr. (25% at 24 hr.)
Table2. Gonadotropin and Prolactin Reserve
Time
Serum Prolactin
(ng. per ml.)
0
30 min.*
60 min.
90 min.
17.9
20.8
30.4
53.00
(ng per ml.)
LH
(ng. per ml.)
5.1
19.0
14.0
18.2
FSH
Baseline
After clomiphenet
* Chlorpromazine, 50 mg., administered intramuscularly,
mediately after zero time sample obtained.
t Clomiphene citrate, 50 mg., twice a day for 7 days.
im-
somal pattern in cultures of the two tissues;
approximately 90% of both leukocytes and
skin fibroblasts contained the abnormal
cell line. Rarer karyotypic variations of
Klinefelter's syndrome present similar proportions of cells with similar numbers of
abnormal cells in each tissue studied.
However, in one patient widi a 48, XXXY
karyotype, only 6.7% of leukocytes and
fibroblasts contained the 48 chromosomes.
It has also been reported that leukocyte
and skin culture karyotypes agree widi
results from testicular and breast tissue
cultures in patients with 47, XXY and 48,
XXXY karyotypes 6 ; however, proportions
of cell lines were not presented in that
study. In two of ten mosaics reported by
MacLean, 14 leukocyte analysis showed a
normal 46, XY pattern, but cells harvested
from skin cultures showed triple cell lines
of 45, XO/46, XY/47, XXY in one individual, and 46, XY/47, XXY/48, XXXY in
the other. 46, XY/47, XXY patterns were
found in cultures of both tissues in the
remaining eight mosaics reported in this
series. Karyotype was 47, XXY in skin culture and 46, XY/46, XX/47, XXY in leukocyte culture in one mosaic reported by
Fr^land, although the proportions of the
various cell lines were not given. 46, XY/
47, XXY was found in cultures of both
tissues from another mosaic in this study.
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the extra chromosome in that cell was
consistent widi an X chromosome. Since
the clinical picture remained compatible
with Klinefelter's syndrome, but could not
be confirmed by cytogenetic study of
peripheral blood cells, skin biopsy with subsequent culture of skin fibroblasts for cytogenetics was performed to help determine
the presence of mosaicism. Karyotype
analysis of skin fibroblasts revealed 47
chromosomes in 5 of 39 cells (13%); the
extra chromosome in these cells was of the
C group, morphologically consistent widi
an X (Fig. 2). Karyotypes of all other cells
examined were unremarkable, showing a
46, XY pattern.
677
678
AJ.C.P. —Vol. 65
SCHREIBER, PALUTKE AND COHEN
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V
Btt
/i
nfliiJiMi
ft
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6-12
15
14
13
D
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19
n
20
^ h
16
ft
M
18
17
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21
•
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22
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Y
FIG. 2. Karyotype of cell line from cultured skin fibroblasts demonstrating 47
chromosomes, with extra chromosome of the C group.
T h e abnormal thyroid function found in
our patient is of interest in that serum
TSH was low. Unfortunately, the distinction between pituitary ("secondary") and
hypothalamic ("tertiary") hypothyroidism
could not be made since stimulation with
thyrotropin-releasing hormone could not
be performed. Nevertheless, the absence
of other demonstrable defects in pituitary
function (normal plasma Cortisol with diurnal variation; normal FSH, LH and prolactin, responsive to provocative stimulation; skull x-ray and brain scan unremarkable) suggest that the diminished TSH
was an isolated defect, possibly resulting
from deficient hypothalamic diyrotropinreleasing hormone (TRH). The marked
chlorpromazine-stimulated increase in
prolactin observed in our patient agrees
with the recently reported finding of enhanced prolactin response to TRH in four
patients widi Klinefelter's syndrome. 5 It is
of interest that in these patients the TSH
response to T R H was blunted, although
basal TSH was normal.
Thyroid abnormalities occurring with
Klinefelter's syndrome are not uniform.
Of 14 patients studied by Barr, 1 initial
131
I uptake and response to TSH were low
in seven, although none were clinically
hypothyroid. In one patient, the initial uptake was normal but the response to TSH
was low, while the reverse was observed
in another. Only one subject in this series
had normal 131I uptake and TSH response.
In the five cases reported by Davis,6
131
I uptake was decreased in three patients,
of whom two responded normally to exogenous TSH. T h e fourth subject had
borderline low initial uptake and normal
response to TSH, and both uptake and
TSH response were normal in the remaining patient. Of 27 patients described by
Plunket, 15 63% had low or borderline low
initial 131I uptake values and in 46% the
responses to TSH were subnormal. T h e co-
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•;ti (id «u
May
1976
HYPOTHYROIDISM IN XXY/XY MOSAICISM
existence of Klinefelter's syndrome and
cretinism has been described, 4,12 and cases
of Klinefelter's syndrome with hypothyroidism and elevated TSH levels have been
reported. 7,11 T h e present case is thus unusual in that hypothyroidism with low TSH
in a patient with Klinefelter's syndrome has
not previously been described.
Acknowledgments. Mrs. Norma Gohle provided technical assistance.
References
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and testicular tubular sclerosis. N Engl J Med
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I r J MedSci 141:19-24, 1972
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