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London Journal of Pediatric Endocrinology & Metabolism, 16, 9 0 1 - 9 0 5 (2003)

Association of Turner's Syndrome and Hypopituitarism:

A Patient Report
Carla Τ. Gallicchio 1 , Solange T.F. Alves', Hilda I. Ramos 2 , Juan C. Llerena 2 and Marilia M. Guimaräes 1

'Department of Pediatric Endocrinology, Martagdo Gesteira Instititute, Clementine Fraga Filho Hospital,
Federal University of Rio de Janeiro and 2 Department of Genetics, Fernandes Figueira Institute,
Oswaldo Cruz Fundaction, Rio de Janeiro, Brazil

ABSTRACT patient presents low levels of TSH with negative

Turner's syndrome (TS) is associated with a
wide spectrum of clinical features, such as short
stature and gonadal dysgenesis. While it is a
common chromosomal abnormality, the associ-
ation of Turner's syndrome and hypopituitar-
ism is an uncommon finding. We describe here a
girl with concomitant pituitary insufficiency and
gonadal dysgenesis. When she was 7 years old,
her mother reported that she suffered from
frontal headache, asthenia and delayed growth.
Basal laboratory thyroid evaluation suggested
hypothyroidism, with no evidence of auto-
immune disease association. She began taking
L-thyroxine. At age 11 years, short stature and
complaints of frontal headache still persisted.
She was still prepubertal and her bone age was
delayed by 2.2 years. Her karyotype was
compatible with 45,X/46,XX (100 cells analyzed
by FISH) and a CT scan showed empty sella. At
12 years of age, an anterior pituitary stimulation
test with insulin, gonadotropin-releasing hor-
mone (GnRH) and thyrotropin-releasing
hormone (TRH) showed gonadotropin, thyro-
tropin (TSH) and growth hormone (GH)
deficiency. Replacement therapy with GH was
begun and she grew 12 cm during the first year
of treatment. This report illustrates that, despite
the high incidence of sinusitis, short stature and
primary hypothyroidism in TS, we should con-
sider the presence of hypopituitarism when the
thyroid antibodies and inappropriately low
levels of gonadotropins for patients with
gonadal dysgenesis.
KEY WORDS
Turner's syndrome, gonadal dysgenesis, hypo-
pituitarism, empty sella
INTRODUCTION
In 1938, Turner described the clinical features
of seven patients with amenorrhea, infantile
genitalia, congenital webbed neck and cubitus
valgus 1 . This pathological syndrome was later
determined to be a condition of primary gonadal
failure associated with increased circulating plasma
levels of gonadotropins in the presence of normal
pituitary function 2 . However, postpubertal inappro-
priately low levels of gonadotropins have
occasionally been described in patients with
Turner's syndrome (TS) 3 " 6 . A few reports are avail-
able regarding central nervous system malforma-
tions, pituitary tumors and hypopituitarism in
TS 4 ' 7 ' 8 . The presence of an empty sella in patients
with Turner's syndrome has been reported twice 6 .
In the present study, we report a rare case of a girl
with mosaicism, empty sella in the presence of a
deficiency of gonadotropin, thyrotropin and growth
hormone.

Reprint address:
Carla Tavares Gallicchio PATIENT REPORT
Federal University of Rio de Janeiro - Endocrinology
Rua Soares Cabral 80/901 Laranjeiras Our patient was a 13 year-old girl who was
CEP 22.240-070 initially evaluated when she was 7 years old. She
Rio de Janeiro, RJ, Brazil was born in 1988, and there was no history of
e-mail: cgalicltio@ig.com.br

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902 C.T. GALLICCHIO ET AL.
alcohol, drugs or cigarette use by her mother during
pregnancy. She had a full-term vaginal delivery
with a birth weight of 3,200 grams. We do not
know her length at birth. There were no major health
problems reported during her neonatal period.
When she was 3 years old, her mother noticed a
significant reduction in her body weight and height.
When she was 7 years old, because of short
stature, complaints of frontal headache and
asthenia, she was referred to a pediatric endocrinol-
ogist. Physical examination at that time confirmed
that her upper arms were short in proportion to her
trunk and lower limbs. Additionally, there was a
difference of 1.0 cm in length between her left and
right legs. Height and weight in relation to chrono-
logical age are presented in Table 1. The rest of the
physical examination was normal. Bone age,
determined according to the method of Greulich
and Pyle9, was 4 years behind chronological age
(CA). The first laboratory evaluation (Table 2)
demonstrated normal plasma levels of insulin-like
growth factor binding protein-3 (IGFBP-3) and low
plasma concentrations of insulin-like growth factor-
I (IGF-I), free thyroxine (FT4) and thyroid-
stimulating hormone (TSH), associated with nega-
tive thyroid antibodies (thyroglobulin and micro-
somal antibodies). Pharmacological replacement
therapy with L-thyroxine (6 pg/kg/day) was started.
During the next 4 years of follow-up, she has
been short, growing below the -3 SD curve accord-
ing to Brazilian standards 10 (Table 1). At 11 years
of age, her height was 116.4 cm (-4.2 SD) and
height 21.5 kg. She was still complaining of frontal
headache and was still prepubertal. On examina-
tion, cubitus valgus and epicanthus suggested the
possibility of Turner's syndrome. A diagnosis of
Turner's syndrome was confirmed by genetic
analysis. Initially the G-banded karyotype of
peripheral lymphocytes was thought to be 45,X/
46,X with a chromosome marker. However, re-
examination of her lymphocytes with fluorescence
in situ hybridization probes (DXZ1 and DYZ3)
confirmed a karyotype compatible with 45,X
/46,XX. Her bone age at the time of genetic
analysis was 8 years and 8 months. A new
endocrine assessment at that time showed abnormal
thyroid function associated with low levels of TSH
and high levels of FT4 (Table 2). Her hormonal
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profile prompted us to reduce the dose of
L-thyroxine to 75 pg (3.5 pg/kg/day). A computed
tomography scan (CT) of the sella turcica per-
formed at this time revealed herniation of the
arachnoid space into the enlarged sella turcica with
a homogeneous pituitary gland. Ultrasound sono-
graphy of the pelvis showed a small uterus.
When she was 12 years old, a new endocrine
evaluation was performed, including a combined
stimulation test using simultaneous intravenous
injections of 0.2 U/kg body weight insulin, 500 pg
TRH and 100 pg GnRH. Her basal and stimulated
gonadotropin, prolactin, growth hormone and TSH
plasma levels were low. Her Cortisol response was
normal, indicating normal functioning of the
pituitary-adrenal axis (Table 3). A new evaluation
revealed that thyroid antibodies (thyroglobulin and
thyroid peroxidase) remained negative. At that time
replacement therapy with growth hormone (1.0 IU/
kg/day at bedtime) was added to the L-thyroxine.
Follow-up evaluation is shown in Tables 1 and 2.
DISCUSSION
Turner's syndrome is one of the most common
chromosomal abnormalities, characterized by total
or partial deletion of one X chromosome. The main
clinical features of the syndrome include ovarian
dysgenesis and short stature. Patients with Turner's
syndrome are also susceptible to a number of other
pathologies, including sinusitis, autoimmune thy-
roiditis, osteoporosis, and cardiovascular and renal
disease". The incidence of autoimmune hypo-
thyroidism increases with age, but does not seem to
occur with increased frequency before the age of 10
years 12 . The prevalence of thyroid autoantibodies
has been shown to increase linearly with age,
reaching statistical significance for the prediction of
thyroid abnormalities at age 13-17 years 13 . Glück et
al. 14 did not show an increase in serological signs
of endocrine autoimmunity in young patients with
TS, suggesting that a putative association of
autoimmune thyroiditis does not exist from birth
and is not usually present in childhood.
The present report describes a girl with Turner's
syndrome, gonadotopin, thyrotropin and growth
hormone deficiencies, with normal levels of pro-
 TURNER'S SYNDROME AND HYPOPITUITARISM 903

TABLE 1

Clinical evaluation of the patient with Turner's syndrome

Year 1995" 1999 2000 * 2 0 0 0 ** 2001 ***

Chronological age (yr) 7.7 11.4 12 .3 12.9 13.3

Height (cm) 104.0 116.4 119.2 124.0 131.4

SD -3.6 -4.2 -4.9 -4.6 -3.8

Weight (kg) 16.9 21.5 23.5 25.5 28.0

SD -1.8 -2.0 -2.2 -2.2 -2.2

B M I (kg/m2) 15.6 16.0 16.6 18.0 16.3

Bone age (yr) 3.0 8.10 9.0 10.0 11.0

* First evaluation; * b e f o r e G H ; ** 6 m o n t h s after G H ; *** 1 year after G H .

TABLE 2

Follow-up laboratory evaluations

Year 1995* 1999 2000 * 2 0 0 0 ** 2001 *** Normal values

FT4 (ng/dl) 1.88 2.60 1.10 1.0 1.2 0.80-1.90

T j (ng/dl) 92.0 168 120 120 110 70-170

TSH (mlU/l) 0.08 0.004 0.013 0.026 0.003 0.40-4.0

IGF-I (ng/ml) 10.5 11.1 4.3 460 70-580

I G F B P - 3 (mg/l) 2.71 0.69 1.69-5.90

#
First evaluation; * b e f o r e G H ; ** 6 months after G H ; *** 1 year after G H .
FT 4 = free thyroxine; T 3 = triiodothyronine;: T S H = thyroid-stimulating h o r m o n e ; IGF-I = insulin-like g r o w t h factor-1;
I G F B P - 3 = IGF b i n d i n g protein 3.

TABLE 3

Basal and stimulated values of anterior pituitary hormones

Stimulation test Patient Normal subjects Turner's synd rome *

Basal Peak (90 min) Basal Peak Basal Peak

Cortisol ^ g / d l ) 7.0 20.6 6-25.0 >20.0

FSH (mIU/ml) 0.22 0.77 0.5-3.0 >5.0 High High

LH (mIU/ml) 0.70 0.70 0.5-3.0 >3 High High

G H (ng/ml) 0.1 0.14 0-10 >10

T S H (mIU/1) 0.022 0.024 0.40-4.0 16.2

P R L (ng/ml) 4.1 4.8 5-15.0 25-20.0

l7
* A c c o r d i n g to .
FSH = follicle-stimulating h o r m o n e ; LH = luteinizing h o r m o n e ; G H = growth h o r m o n e ; T S H = thyroid stimulating h o r m o n e ;
P R L = prolactin.

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904 C.T. G A L L I C C H I O ET AL.
lactin and Cortisol. Her plasma levels of FSH and
LH were low for a patient with gonadal failure. The
peculiar biochemical findings present in our patient
may be related to the presence of a concomitant
empty sella (ES). ES is an anatomo-radiological
picture usually characterized by the presence of
aranchnoidal herniation filled with cerebrospinal
fluid that compress the pituitary to the sellar wall.
Most of these children present with headache,
visual abnormality, compromised pituitary reserve
and hyperprolactinemia. Most cases, especially in
adults, are secondary to irradiation, pituitary tumor
or surgery. In children, ES is more often idiopathic,
probably resulting from developmental defects' 5 .
Our patient presented with frontal headache and
endocrine abnormalities.
There are reports in the literature of four
patients with hypogonadotropic hypogonadism and
Turner's syndrome 3 " 5 · 6 . The first was a girl with
thalassemia major, hemochromatosis and pituitary
insufficiency 5 ; the second was a patient with
immunodeficiency 16 ; in the third and fourth
patients, the hypogonadotropic hypogonadism was
attributed to either an autoimmune process or the
presence of empty sella 6 . These patients presented
with TS and low basal levels of gonadotropins,
Hashimoto's thyroiditis and partially empty sella.
These findings confirm that the association of auto-
immune thyroiditis and autoimmune hypophysitis
may be increased in patients with gonadal dys-
genesis. The difference between our patient and the
third and fourth patients above 6 is that our patient
presented with negative thyroid antibodies and very
low basal and stimulated TSH plasma levels.
Turner's syndrome is known to be associated
with other congenital malformations 3 and pituitary
adenomas 4 7 8 but, to our knowledge, the association
with empty sella and thyrotropin, gonadotropin and
growth hormone deficiencies is the first to be
described. There is one similar report in the
medical literature 3 of a young woman with Turner's
syndrome associated with hypopituitarism (TSH,
FSH, LH and GH deficiencies), ectopic localization
of the neurohypophysis and hypoplastic piuitary.
The difference between our patient and this one is
that in contrast to our patient, the co-existence of
primary and secondary hypogonadism delayed the
diagnosis of TS until their patient was 30 years old 3 .
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In conclusion, the present report demonstrates
an association of Turner's syndrome and hypo-
pitutarism. We therefore suggest that pituitary
function should be carefully investigated if empty
sella or other central nervous system abnormality;
central hypothyroidism and hypogonadotropic
hypogonadism are present in Turner's syndrome.
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