J Clin Res Pediatr Endocrinol 2014;6(2):116-118
DOI: 10.4274/Jcrpe.1187
Case Report
Acceleration of Puberty During Growth Hormone
Therapy in a Child with Septo-Optic Dysplasia
Gönül Çatlı1, Ayça Altıncık1, Ahmet Anık1, Korcan Demir1, Handan Güleryüz2, Ayhan Abacı1, Ece Böber1
1Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
2Dokuz Eylül University Faculty of Medicine, Department of Radiology, İzmir, Turkey
Introduction
ABSTRACT
Septo-optic dysplasia (SOD) is a heterogeneous disorder of the
central nervous system characterized by various endocrinological and
neurological findings. It is a complex disease caused by a combination
of genetic and environmental factors. Herein, we report the case of a
5.5-year-old girl who presented with short stature and strabismus.
Ophthalmological examination revealed bilateral optic nerve hypoplasia.
Ectopic posterior pituitary and bilateral optic hypoplasia were detected
on brain magnetic resonance imaging. The presence of bilateral optic
nerve hypoplasia and hypopituitarism led to the diagnosis of SOD. An
abated growth hormone (GH) response was found in the GH stimulation
test and GH replacement therapy was initiated. At the end of the first
year of clinical follow-up, secondary hypothyroidism was detected
and L-thyroxine was added to the treatment. At the age of 8.25 years,
thelarche was noted and 6 months later, the patient presented with
menarche. At this time, the bone age was 12 years and the basal
luteinizing hormone level was 7 mIU/mL. These findings indicated
acceleration in the process of pubertal development. We report this case
(i) to emphasize the need to investigate hypopituitarism in cases with
bilateral optic nerve hypoplasia and (ii) to draw attention to the fact that
during the follow-up of SOD cases receiving GH therapy, inappropriate
acceleration of growth velocity and rapid improvement in bone age may
be predictive of central precocious puberty development.
Key words: Septo-optic dysplasia, hypopituitarism, growth hormone,
precocious puberty
Conflict of interest: None declared
Received: 23.10.2013
Accepted: 04.02.2014
Septo-optic dysplasia (SOD) is a heterogeneous disorder
characterized by midline brain defects and pituitary hormone
deficiencies. In 1941, Reeves first reported the association of
optic nerve and septum pellucidum abnormalities (1). Fifteen
years later, the clinical signs observed in SOD were defined as
De Morsier syndrome. In 1970, hypophyseal dysfunction was
shown in patients with SOD (2). The incidence of this disease,
which is equally seen in both sexes, is 1/10 000 (2,3,4). Diagnosis
is made by the presence of two out of three criteria, namely,
optic nerve hypoplasia, hypopituitarism and midline brain defects
(septum pellucidum and/or corpus callosum agenesis/hypoplasia)
(2,3,4,5). SOD has a multifactorial etiopathogenesis and it has
been shown that mutations in HESX1, SOX2, SOX3 and OTX2
genes are responsible for less than 1% of cases (2,3,4). Although
many cases are sporadic, the frequency of autosomal recessive
inheritance is increased especially in consanguineous marriages.
Autosomal dominantly inherited cases have also been reported
(2). SOD is more commonly encountered in preterm babies and in
babies of young, diabetic or primigravida mothers (2,3,4).
In the present report, a 5.5-year-old girl diagnosed to have
SOD is presented. The patient was found to have optic nerve
hypoplasia, cranial magnetic resonance imaging (MRI) findings,
growth hormone (GH) deficiency, central hypothyroidism and at a
later date, developed central precocious puberty (CPP), a disorder
which is rarely reported to accompany SOD.
Case Report
A 5.5-year-old girl was referred to our clinic with complaints
of short stature, strabismus and decreased vision. She was born
at term with a birth weight of 3200 g and had mild retardation
in the early stages of development of gross motor skills. There
Address for Correspondence
Ayhan Abacı MD, Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey
Phone: +90 232 412 60 76 E-mail: ayhanabaci@gmail.com
©Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.
116
Çatlı G et al.
Puberty and Septo-Optic Dysplasia
was no consanguinity between the parents. Her three siblings
were stillborn. On physical examination, her body weight was
21 kg [+0.47 standard deviation score (SDS)], height was 98.5
cm (-3.04 SDS) and body mass index was 21.6 kg/m2 (+2.32
SDS). She had truncal obesity and external strabismus in the left
eye. The patient had no dysmorphic features and showed no
pathologic neurological finding. Her pubertal development was
consistent with Tanner stage I. Complete blood count, liver and
renal function tests and routine urine analysis were within normal
limits. Thyroid function tests and prolactin level were also normal
[thyroid-stimulating hormone (TSH) 1.69 mIU/mL (normal= 0.45), free thyroxine (fT4) 1.41 ng/mL (normal=0.8-1.9)]. Bone age
was consistent with 3.5 years (Greulich-Pyle). A GH stimulation
test using insulin showed a peak GH level of 0.12 ng/mL and
a peak cortisol level of 19.4 µg/dL. In the ophthalmological
examination, bilateral optic nerve hypoplasia was reported.
Cranial MRI revealed an intact septum pellucidum with bilateral
optic hypoplasia, ectopic neurohypophysis and agenesis of
the hypophyseal infundibulum (Figure 1). The bilateral optic
hypoplasia and findings of hypopituitarism led to a diagnosis
of SOD. Echocardiography and speech audiometry revealed
normal findings. Because of the cranial MRI findings, a second
GH stimulation test was not performed and based on the results
of the first test which showed an inadequate GH response to
hypoglycaemia, recombinant human GH treatment in a dose of
25 µg/kg/d was initiated. At the end of the first year of treatment,
the patient’s growth velocity reached 12.2 cm/year and her bone
age was consistent with 4.5 years. During follow-up, the patient
developed hypothyroidism [(TSH= 4.61 mIU/mL (normal= 0.4-5),
fT4= 0.78 ng/mL (normal= 0.8-1.9)]. The results of thyrotropinreleasing hormone (TRH) stimulation test was consistent
with central hypothyroidism (peak TSH at 60 minutes 10.8
mIU/mL), thus L-T4 replacement therapy at a dose of 2
µg/kg/d was initiated. At the age of 8.25 years, the patient was
noted to show onset of breast development (Tanner stage II).
In subsequent months, she underwent a rapid progression
of puberty and only six months later, she presented with
menarche. At this time, her bone age had advanced to age 12
years. Her basal follicle-stimulating hormone, luteinizing hormone
Figure 1. In the T1-weighted sagittal section; a) ectopic neurohypophysis (white arrow) is present in the hypothalamic region
outside sella turcica. In the middle line, no hypophyseal infundibulum
(arrow head) is present. In the T2-weighted coronal section; b) septum
pellucidum is present in the middle line (arrow). In the coronal section
fat-suppressed; c) hypoplastic bilateral optic nerves are demonstrated
(arrows)
and estradiol levels were 6.47 mIU/mL, 7 mIU/mL and <20
pg/mL, respectively. These clinical and laboratory findings showed
that our patient had an accelerated and rapidly progressive CP.
Gonadotropin-releasing hormone analogue treatment (triptorelin
acetate 3.75 mg/IM every 28 days) was initiated.
Discussion
Clinical signs of SOD are quite variable. In addition to midline
brain abnormalities, dysmorphic findings pertaining to the cranium
(microphthalmia, anophthalmia, etc.) and to the musculoskeletal
system can also be observed (3,6,7,8). Currently different
definitions are being used for SOD. Some authors designate this
rare disorder as SOD complex which presents with endocrine,
central nervous system and skeletal abnormalities (7). Riedel et al
(9) have suggested that the association of optic nerve hypoplasia
and anterior pituitary hormone deficiency should be defined as
an SOD variant when a normal septum pellucidum is present.
According to this description, the current case can be defined as
an SOD variant, because she showed signs of hypopituitarism
and bilateral optic nerve hypoplasia without any midline brain
defects.
Frequently, the first clinical sign in cases with SOD is decreased
vision due to optic nerve hypoplasia. Neurological signs, which
may mimic hemiparesis and epilepsy, may also be observed.
Cases with sensorineural hearing loss, anosmia, cardiac and
esophagus abnormalities, as well as cases with minimal or no
cortical disorders have also been reported (7,10,11). Signorini
et al (4) evaluated 17 patients with SOD and reported that they
all had optic nerve hypoplasia; 14/17 had midline brain defects;
9/17 had anterior pituitary hormone deficiencies; and 7/17 had
cortical developmental malformations. In our patient, neurological
signs, hearing loss, cardiac pathology, or any other dysmorphic
signs accompanying anterior pituitary hormone deficiencies and
bilateral optic nerve hypoplasia were not present. Our patient
was also found to have ectopic neurohypophysis, which has
been reported in 50% of cases with SOD syndrome (11).
Clinical signs of pituitary hormone deficiencies, which range
from isolated single hormone deficiency to panhypopituitarism,
can be observed in SOD cases (2). Signs of hormone deficiency
may not be present initially and may develop over time (6).
GH deficiency, adrenal insufficiency, hypothyroidism, pubertal
disorders (early or late puberty) and inappropriate antidiuretic
hormone syndrome have all been reported in patients with SOD
(8). Hypophyseal endocrine disorders are reported in 65.9% of
the patients and the most frequent one is GH deficiency (40.9%)
(2). Morishima et al (7) reported that all three cardinal signs were
observed in 30% of patients with SOD, while hypopituitarism
and septum pellucidum agenesis were detected in 62% and
60% of the patients, respectively. Atapattu et al (2) reported that
diabetes insipidus (DI) accompanied anterior pituitary hormone
deficiencies in 21.5% of patients, while DI was an isolated sign in
only two cases. Quvrier et al (8) detected cerebral malformation
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Çatlı G et al.
Puberty and Septo-Optic Dysplasia
(septum pellucidum agenesis) in 25% of SOD patients diagnosed
with bilateral optic nerve hypoplasia. In the current case, isolated
GH deficiency was found to exist at presentation and central
hypothyroidism developed during the follow-up. Although bilateral
optic nerve hypoplasia was detected in MRI, no anatomic
abnormality was observed in either septum pellucidum or in the
corpus callosum.
While delayed puberty has been frequently encountered in
SOD patients, occurrence of CPP associated with SOD is less
often. Hanna et al (9) reported early and rapidly progressive
puberty in three and delayed puberty in four out of their 13
SOD patients. Husemann et al (10) found precocious puberty in
one out of five patients with SOD. Ladjouze et al (11) reported
CPP in four patients (2 were males), who were being followed
with a diagnosis of SOD and GH deficiency. This relatively rare
concomitance of GH deficiency and CPP has been more frequently
reported in SOD patients in whom SOD was accompanied by
arachnoid cysts (5,9,10,11,12). Although the mechanism of CPP
development in SOD patients is not known, it has been proposed
that it might develop due to the effects of hypothalamic lesions
(11). According to KIGS (Pfizer International Growth Study)
database, 0.6% of patients receiving GH therapy developed CPP,
without any obvious reason (13). Although it has been suggested
that the underlying reason for CPP in patients with SOD might be
GH therapy, precocious puberty has also been reported in SOD
patients who were not receiving GH therapy (14). Obesity due
to hypothalamic dysfunction can also develop in SOD patients
during the follow-up. Based on this information, Ladjouze et al
(11) proposed that the underlying cause of CPP in patients with
a developmental defect of the hypothalamic pituitary area might
be hypothalamic dysfunction. Our patient was found to show an
accelerated pubertal development during her follow-up, while she
was receiving GH treatment, onset of breast development rapidly
followed by occurrence of menarche. Although it was suggested
that one of the causes of CPP in these patients might be GH
therapy, as marked weight gain was observed during the followup, we tend to agree with those who suggest that precocious
puberty or accelerated progression of puberty might develop
secondary to hypothalamic dysfunction. In these patients,
acceleration in bone age and growth velocity before pubertal
signs are reported. Therefore, it has been proposed that this
condition has frequently delayed the diagnosis of GH deficiency.
On the other hand, when GH therapy is initiated, the increase in
growth rate may be interpreted in favor of efficacy of GH therapy
and CPP may be misdiagnosed in these patients (11). In our
patient also, before onset of pubertal signs, the acceleration in
growth rate and improvement in bone age were first interpreted
as a GH effect.
118
In conclusion, with this case report, we would like to
emphasize that (i) patients diagnosed with bilateral optic nerve
hypoplasia should be investigated for anterior pituitary hormone
deficiencies, (ii) inappropriate acceleration of growth velocity
and rapid improvement in bone age may be predictive for CPP
development during the follow-up of SOD patients receiving GH
therapy.
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