Acta Paediatrica Japonica (1995) 37,347-351

Original Article

Association of empty sella and neuroendocrine disorders in

childhood

SEMA AKCURIN, GONUL OCAL, MERIH BERBERO~LUAND NIHAL, MEMIOCLU

Pediatric Endocrinology and Metabolism Department, Ankara Faculty of Medicine, Ankara, Turkey

Abstract Empty sella syndrome (ESS) is a multicausal entity. The incidence of primary empty sella syndrome
(PESS) in children with neuroendocrine dysfunction is not known. In the pediatric age group, frequency
seems to have been underestimated. A total of 117 cases of neuroendocrine disorders, including complete
growth hormone deficiency, primary hypothyroidism with pituitary resistance to thyroid hormone, obesity,
central precocious puberty, hypothalamic hypogonadism and central diabetes insipidus, have been studied
with computed tomography andor magnetic resonance imaging of sellar region for etiologic evaluation.
Twenty-one patients were found to have PESS. We noted a high incidence of PESS in children with
neuroendocrine dysfunction (17.9%). Children with neuroendocrine dysfunction should be investigated
with respect to PESS, and children with PESS recognized coincidentally should be studied with the
particular consideration of subclinical neuroendocrine dysfunction.

Key words childhood, empty sella syndrome, endocrinopathy.

Empty sella syndrome (ESS) describes the radiologic
appearance of a sella turcica. The definitive diagnosis of
ESS is made by computed tomography (CT) or magnetic
resonance imaging (MRI) if they demonstrate the low
density area consistent with cerebrospinal fluid in the
intrasellar region with a small rim of pituitary tissue in the
absence of any tumor. This condition is called empty sella.
The sella is described as partially empty if the
subarachnoid space dips below the plane of the sellar
diaphragm.'-l
Empty sella is common in adults with prevalence rates
from autopsy of approximately 6%: On account of the fact
that only a select group of patients referred for possible
endocrine dysfunction have been examined, the true
incidence of primary empty sella syndrome in children is
not known. In the pediatric age group, its frequency seems
to have been underestimated. Clinical findings in children
appear to be more frequent and more marked than in
adults. Empty sella syndrome is associated with a high
Correspondence: Sema Akqurin, Sedat Simavi sokak No: 17,
Doruk Sitesi B-Blok Daire:25. 06550, Ankara, Turkey.
Received 21 February 1994; revision 6 October 1994; accepted
7 October 1994.
incidence of endocrine dysfunction and neuro-ophthalmic
manifestations .1.2.4,6.7
In this report, we want to indicate the frequency of this
syndrome in children with various forms of neuroen-
docrine dysfunction examined with CT.
Methods
A total of 117 children, 15 with growth hormone
deficiency, I7 with primary hypothyroidism with pituitary
resistance to thyroid hormone, 40 with obesity, 20 with
complete precocious puberty, five with hypogonadotrophic
hypogonadism, and 20 with central diabetes insipidus have
been investigated with regard to sellar morphology. In all
patients lateral skull radiography, sellar CT and in some
cases MRI of sella turcica were obtained. The CT scans
with serial coronal and axial sections were performed
using a Picker 1200 SX scanner in the radiology
Department of Ankara Faculty of Medicine. Assessment of
visual field was performed in all cases in the
Opthalmology Department of the same faculty.
Fifteen patients with growth hormone (GH) deficiency
fulfilled the following criteria; peak GH level below
348 S Akqurin et al.
10 ng/mL after at least two pharmacological tests and
blunted physiological secretion, and height below-2.5 s.d.
for age and gender. The mean peak GH values obtained
after L-Dopa and insulin induced hypoglycemia tests were
4.02 k 0.18 ng/mL and 4.9 k 0.22 ng/mL, respectively. In
these children the mean integrated GH concentration of the
first 4 h of the nocturnal sleep was 2.14 f 0.26 ng/mL.
Secondary hypothyroidism was also evident in one patient.
In 17 congenital primary hypothyroid patients with
pituitary resistance of thyroid hormone, thyroid dysgenesis
was the etiologic factor in I 1 cases. Two of these patients
had ectopic thyroid glands. The remainder of cases had
thyroid dyshormonogenesis with goiters present at birth or
during infancy. They showed unsuppressed thyroid-
stimulating hormone (TSH) levels (25.35 & 1 I . 16 pU/mL)
in spite of high or normal serum thyroxine (T,) levels on
adequate supplementation therapy. During the follow-up
period their clinical and anthropometric parameters
became euthyroid. The mean T, value was at the upper
*
range of normal (T, : 10.19 I .45 pg/dL). The exaggerated
TSH response to TRH (mean delta TSH: 42.392
23.00 pU/mL j was obtained on adequate supplementation
therapy. The children with anatomic abnormalities detected
by a thyroid scan were treated permanently. Thyroxine
therapy was not discontinued in the rest because they were
euthyroid and did not develop hyperthyroidism with
generous doses of thyroxine during the follow-up period.
Forty obese patients with weight-length index (WLI)
greater than 120 and weight standard deviation score
(WSDS) greater than + 2 were not hypertensive. The
Fig. 1 Computed tomography scan of a patient.
determination of circadian rhythm of cortisol secretion was
used to rule out Cushing disease. Two of these patients
were Laurence-Moon- Biedl (LMB) Syndrome.
Twenty patients aged 2-9 years satisfied clinical and
hormonal criteria of central precocious puberty, including
gonadotropin releasing hormone (GnRH)-stimulated
lutehizing hormone (LH) > 10 mlU/mL (mean LH:
56.71 & 20.00 mlU/mL). They were examined with CT of
sellar region for differential diagnosis between idiopathic
and organic central precocious puberty.
Five boys aged 13.5- 18 years with micropenis andor
delayed puberty had hypogonadotrophic hypogonadism
with low testosterone and gonadotropin levels, blunted
gonadotropin response to GnRH stimulation and
unsatisfactory night time peak of gonadotropins. One of
these patients had Kallmann Syndrome.
Twenty patients were diagnosed as having central
diabetes insipidus on the basis of low urinary osmolality
( < 300 mmolkg), high plasma osmolality ( > 295 mmoV
kg), water deprivation and DDAVP tests.
Results
Twenty-one patients (five growth hormone deficiency, five
primary hypothyroidism with pituitary resistance to thyroid
hormone, seven obesity, two central diabetes insipidus, one
central precocious puberty, one hypogonadotropic hypo-
gonadism) were diagnosed as having primary empty sella
syndrome (PESS) based on CT andor MRI findings. Three
Fig. 2 Magnetic resonance imaging of a patient.
 Empty sella and endocnnopathies in childhood 349

Table 1 Clinical features of 21 patients with PESS

~_______ ~

Patient Age(y) Sex Presenting complaint Sellar X-ray Sellar CT Visual field Neuroendocrine
and/or MRI examination dysfunction

1 18 M Short stature N PES N GHD + SechT

2 10 M Short stature N PES N GHD
3 12 F Short stature N PES N GHD
4 12 F Short stature N PES N GHD
5 10 M Short stature N PES N GHD
6 10 F Hypothyroid stigmata N PES N PrhT + PRTH
7 I F Hypothyroid stigmata N PES N PrhT + PRTH
8 2.5 F Hypothyroid stigmata N PES N PrhT + PRTH
9 II M Hypothyroid stigmata N PES N PrhT + PRTH
10 II F Hypothyroid stigmata N PES N PrhT + PRTH
11 7 M Obesity N PES N Obesity
12 9 M Obesity N ES N Obesity
13 II M Obesity + subj. visual defect N PES OA + RP LMB
14 13 M Obesity N PES N Obesity
15 10 M Obesity N PES N Obesity
16 8 M Obesity N ES N Obesity
17 10 M Obesity N PES N LMB
18 13.5 M Micropenis, anosmia N PES N Kallmann Syndrome
19 12 F Poly uria-poly dypsia N PES VFC CDI
20 I F Pol yuria-polydypsia N PES N CDI
21 5 M Signs of puberty N ES N CPP

PESS, primary empty sella syndrome: pES, partially empty sella; ES, empty sella; N, normal; OA, optic atrophy; RP, retinitis pigmentosa;
VFC, visual field constriction; GHD, growth hormone deficiency; Sec.hT, secondary hypothyroidism; PrhT, primary hypothyroidism;
PRTH, pituitary resistance to thyroid hormone; LMB, Laurence-Moon- Biedl Syndrome; CDI, central diabetes insipidus; CPP, central
precocious puberty.

of them had empty, and 18 had partially empty sella (for radiation. Breech delivery occurred in one case with
example see Figs 1.2). growth hormone deficiency. The sella turcica was normal
Eight of the patients were girls and 13 were boys. The in all patients with PESS on X-ray examination. In two
mean age was 9.95 f 3.27 years, ranging from 2 to 18 cases some sort of visual field impairment was confirmed:
years. No patient had a history of head trauma, central bilateral optic atrophy and retinitis pigmentosa in one case
nervous system infection or intracranial surgery or with LMB syndrome and visual field constriction in the
other with complete diabetes insipidus.
The clinical features of 21 cases with PESS are given in
Table 2 The frequency of PESS in various forms of Table I . The association of various forms of neuro-
neuroendocrine disorders endocrine dysfunction and PESS is also summarized in
Table 2. The total incidence of PESS in our patients was
Neuroendocrine disorder No. of patients No. of PESS 17.9%.
patients (YO)

GHD 15 5 (33.3)
PrhT + PRTH 17 5 (29.4)
Obesity 40 7 (17.5)
Discussion
CDI 20 2 (10)
CPP 20 1 (5) Empty sella syndrome is a multicausal anatomical and
HH 5 I (20)
clinical entity. It is frequently described in obese,
Total 1 I7 21 (17.9) multiparous and hypertensive women.2.3.s.7+10
An association
with endocrine disturbances has been more often noted in
PESS, primary empty sella syndrome; GHD, growth hormone children, whereas it can occur without clinical signs or
deficiency; PrhT, primary hypothyroidism; PRTH. pituitary
symptoms in adults. Shulman et al. found that empty or
resistance to thyroid hormone; CDI. central diabetes insipidus;
CPP, central precocious puberty; HH, hypogonadotropic partially empty sella was present in 24% of children who
hypogonadism. had undergone CT scanning for evaluation of growth
350 S Akprin et al.
hormone deficiency, precocious puberty, or suspected
central nervous system dysf~nction.~ Costigan et al.
reviewed reports of 29 children with PESS associated with
significant hypothalamopituitary dysfunction.'
Primary empty sella syndrome can be classified as
primary or secondary. Primary, idiopathic or spontaneous
empty sella is characterized by congenitally defective or
weakened sellar diaphragm, thus allowing the extension of
the suprasellar cistema into the sella. This hemiation may
flatten the pituitary gland against the floor of the sella
resulting in a pituitary dysfunction. Increased intracranial
pressure is also considered an important contributing
factor. There is common association of PESS with
pseudotumor cerebri and systemic hypertension.2 An
empty sella which develops subsequent to shrinkage of
intrapituitary tumor or cyst by surgery and/or radiotherapy
is referred to as s e c ~ n d a r y . ' . ~ . ~ - ~
The etiology of PESS is unclear in most cases.
Congenitally incomplete sellar diaphragm should not
prevent herniation of the subarachnoid space into the sella.
Adverse perinatal events acting as unrecognized pituitary
insult can cause an empty el la.'.^ Infarction of
unrecognized pituitary adenoma or rupture of intrasellar
epithelial cyst are other possible explanations for PESS.'s5
Autoimmune pituitary atrophy might be the primary cause
of ESS since serum pituitary antibodies are found in more
than 70% of patients with ESS.9 In some patients, the
relation between ESS and &active adenohypophyseal
hyperplasia to peripheral glandular failure (adrenals.
thyroid and gonads) with or without replacement therapy is
unclear." Almost one-third of the reported cases of PESS
are familiaL2
The true incidence of PESS in children is not known.
According to Radfar and Shulman, more than 20% of
children with endocrinopathies have an empty sella.' We
found that 17.9% of our patients, in whom CT scanning
was performed because of the presence of the endocrine
disturbances, had a primary empty sella. Our result was
close to these findings. The majority of the patients were
boys (@/I 17; 54.7%), and there was a lack of the female
preponderance that is seen in adults.
Reports of ophthalmological examinations were
obtained in all of the cases. Visual defects were present in
9.5% of our cases. In the pediatric age group, it seems that
the incidence of ocular symptoms is not significant:
Costigan indicates that PESS occurs in only 1% of all
patients with sellar enlargement identified radiologically.2
In our cases, sellar enlargement was not observed. In 21
cases, signs of pituitary tumor were not found. Arterial
hypertension did not appear in any of the patients.
It is apparent that there is significant association
between the PESS group and a history of adverse perinatal
events, and multiple pituitary deficiency, with a
particularly high prevalence among patients with growth
hormone deficiency.' In our study, breech delivery
occurred in one case with growth hormone deficiency.
The clinical presentation of PESS may include
headaches, hydrocephalus, benign intracranial hyperten-
sion, non-traumatic rhinorrhea, pseudotumor cerebri,
pyogenic meningitis, craniofacial alterations, Carpenter's
syndrome besides endocrinopathies, and ocular and
neurological symptoms.'.2.4.s.7.'n-12
None of these clinical
presentations was detected in our cases.
In PESS, isolated growth hormone deficiency is
commonly ob~erved.~.~-' Radfar et al. reported that 19
(24%) of 78 children examined by CT scanning for
evaluation of suspected growth hormone deficiency had an
empty el la.^ Pocecco et al. found a highly significant
difference in the incidence of PESS in children with
growth hormone deficiency (56%) compared to patients
without any endocrine abnormalities (2.3'%0).~ Surtees et al.
performed sellar CT in 26 children with growth hormone
deficiency,8 and 58% had an empty sella turcica. We also
noted a high incidence of growth hormone deficiency in
PESS (33.3%).
It is reported that an adenohypophyseal hyperfunction
changes the morphology of the sella turcica." Thyroid
ablation in mice and rats produces a progressive sequence
of pituitary hyperplasia, enlargement and adenoma.
Marked pituitary enlargement creates a predisposition to
the infarction of the gland or damages the diaphragm
sellae. Thyrotroph regression observed after thyroxine
replacement therapy exposes the pituitary gland and sella
to cerebrospinal fluid pressure producing an empty el la.'^
We may conclude that: (i) PESS is more frequent in
children than assumed; (ii) it appears that in cases of ESS
in children, endocrine abnormalities occur much more
commonly than in adults; (iii) a careful clinical
assessment, investigation of the hypothalamopituitary axis
to detect endocrine disorders not yet clinically evident, and
a regular follow-up of children with ESS would be
prudent.
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