Endokrynologia Pediatryczna Pediatric Endocrinology

Vol. 3/2004 Nr 4(9)
Endokrynologia Pediatryczna
Pediatric Endocrinology
Precocious puberty in children triggered by a hypothalamic
hamartoma – report of 3 cases and literature overview
Przedwczesne dojrzewanie płciowe spowodowane przez hamartoma
podwzgórza
Jerzy Starzyk, 1Dominika Januś, 2Bożena Starzyk, 3Wiesław Urbanowicz, 4Stanisław Kwiatkowski,
1
Dorota Tylek-Lemańska
1
Department of Pediatric and Adolescent Endocrinology
Radiology Department
3
Urology Department
4
Department of Pediatric Surgery, Polish-American Children’s Hospital, Faculty of Medicine, Jagiellonian University, Cracow, Poland
1
2
Address for correspondence:
Jerzy Starzyk, MD, PhD, Department of Pediatric and Adolescent Endocrinology, Polish-American Children’s Hospital,
Faculty of Medicine, Jagiellonian University, Cracow, Poland, 265 Wielicka St., 30-663 Kraków, Poland,
e-mail: [email protected]
Key words: precocious puberty, hypothalamic hamartoma, long-acting gonadotropin releasing hormone agonist
Słowa kluczowe: przedwczesne dojrzewanie, hamartoma
STRESZCZENIE/
STRESZCZENIE/ABSTRACT
The investigations included 3 children aged 2 (female Patient 1), 2.4 (male Patient 2) and 8.1 years (male Patient
3) with rapidly progressing isosexual precocious puberty (IPP), in whom breast and pubic hair development and
menstrual bleeding or testicular enlargement occurred at the age of 3 months, 1 month and 6 years, respectively. MRI
showed pedunculated hypothalamic hamartoma (HH) in Patient 1 and sessile HH in Patients 2 and 3, which were
non-progressing in size over the 4-years follow-up period. Apart from IPP no other abnormalities were noted such as
neurological signs and symptoms, diabetes insipidus or anterior hypophyseal insufficiency. The children were treated
employing a long-acting GnRH analogue (Diphereline) at the dose of 3.75 μg administered every 4 weeks over the
mean period of 4 years which resulted in a decreased intensity and/or complete regression of IPP signs and gonadal
axis suppression. Simultaneously, pretreatment height age/bone age ratio improved in all patients from 0.7; 0.8; 1.02
to 1.0; 1.02; 1.07, respectively at the time of last visit. We suggest that regardless of the morphological type of HH,
in cases without progression of HH and other endocrine and neurological abnormalities, treatment employing a longacting GnRH-analogue seems to be well founded.
Badaniami objęto 3 dzieci w wieku 2 lat (pacjentka1), 2,4 lat (pacjent 2) oraz 8,1 lat (pacjent 3) z gwałtowną
progresją izoseksualnego przedwczesnego pokwitania (pp), u których objawy pp takie jak powiększenie gruczołów
piersiowych i owłosienie łonowe oraz krwawienie lub powiększenie jąder wystąpiły kolejno w 3 mż, 1 mż oraz w 6
rż. Badanie MRI okolicy podwzgórzowo-przysadkowej ujawniło guz uszypułowany podwzgórza u pacjentki 1 oraz
Vol. 3/2004, Nr 4(9)
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guzy nieuszypułowane podwzgórza u pacjentów 2 i 3. Nie stwierdzono progresji zmian w okresie 4 lat obserwacji.
Poza pp guzy nie powodowały zaburzeń neurologicznych, moczówki prostej ani niedoczynności przedniego płata
przysadki. Leczenie zachowawcze długodziałającym analogiem GnRH w dawce 3,75 ug co 4 tygodnie w ciągu
4-letniego okresu leczenia spowodowało zmniejszenie lub całkowitą regresję cech przedwczesnego pokwitania.
Obserwowano także poprawę prognozy wzrostu końcowego wyrażoną wskaźnikiem wiek wzrostowy/ wiek kostny,
odpowiednio: 0,7; 0,8; 1,02 (przed leczeniem) do 1,0; 1,02; 1,07 (przy ostatniej wizycie). Wydaje się, że niezależnie
od morfologicznego typu guza, w przypadku braku progresji zmiany oraz objawów neurologicznych i innych niż pp
zaburzeń endokrynologicznych, stosowane leczenie zachowawcze analogiem GnRH jest uzasadnione.
Introduction
As a consequence of the use of new brain imaging techniques, hypothalamic hamartoma (HH) is
now considered the most common cause of isosexual precocious puberty (IPP), especially in young
children [1, 2]. HH is a congenital malformation,
consisting of a tumor-like nodule mimicking a normal hypothalamus in the interpeduncular cistern,
and usually demonstrating an anatomical connection to the hypothalamus [1, 3, 4]. It can be associated with gelastic seizures, petit-mal or generalized tonic/clonic seizures, developmental delay, behavioral disturbances and dysmorphic syndromes
[5]. The indication for surgery of a HH associated
with IPP is controversial. At present, both medical
and surgical therapies are seen to variably influence precocious puberty and to slow progressive skeletal maturation [1, 6–9]. Current data support the
effectiveness and safety of long-acting Gonadotropin Releasing Hormone (Gn-RH) analogue therapy
for IPP due to HH [1, 3, 10–12], when the risk involved and the effect of surgery on endocrinological abnormalities is difficult to predict, even employing the recently refined microsurgical techniques. We present the auxological, hormonal and radiological outcome of long-acting Gn-RH analogue
treatment in children with IPP due to pedunculated
and sessile HH.
Patients and methods
The investigations included 3 children with rapidly progressing IPP aged 2 years (female Patient
1), 2.4 years (male Patient 2) and 8.1 years (male
Patient 3), in whom breast enlargement and menarche were noted at 3 months of age (Patient 1), while
testicular enlargement and pubic hair growth were
respectively observed at 1 month of age and 6 years
of life (Patient 2 and 3) (Table I). The diagnosis of
GnRH-dependent IPP was confirmed in all patients
by GnRH test (measuring luteinizing hormone (LH)
and folliculo-stimulating hormone (FSH) levels before and 20, 30, and 60 min after the administration
of 100 ug LHRH, (Ferring, Germany) in IV bolus.
Magnetic resonance imaging (MRI) of the hypothalamic-hypophyseal region was performed
employing a 1.5 Tesla MRI unit (Signa-Horizon,
Hi-Speed, General Electric, USA), with 3-mm slices obtained on sagittal and coronal planes using
SE T1 weighted sequences before and after contrast
enhancement (Magnevist). In Patient 1 MRI revealed a pedunculated tumor adjacent to the optic nerve chiasm and not communicating with the hypo-
Table I. Auxological data
Tabela I. Dane auksologiczne
Before treatment
Last visit
Patient
Thelarche
/ Testes
P
A
CA
HA
BA
HA/BA
GV
Thelarche
/Testes
P
A
CA
HA
BA
HA/
BA
GV
1.
III
II
+
2.3
3
4
0.7
11.1
II
III
–
9.3
10
10
1.0
4.3
2.
LT-14ml
RT-14ml
III
+
3
5
6
0.83
24.3
LT-9ml
RT-9ml
II
–
6.5 10.2
10
1.02 3.4
3.
LT-15ml
RT-18ml
IV
+
8.2
10.2
10
1.02
10
LT-10ml
RT-10ml
III
–
9.7 11.8
11
1.07 3.8
P – pubarche, A-axillarche, LT – left testis, RT – right testis, CA – chronological age, BA – bone age, GV – growth velocity (cm/year),
HA/BA – height age/bone age ratio
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Starzyk J. i inni – Precocious puberty in children triggered by a hypothalamic hamartoma...
Figure 2. Cranial MRI of Patient 2 demonstrated sessile (HH
– arrow)
Rycina 2. MRI czaszki u pacjenta 2
Figure 1. Cranial MRI of Patient 1 demonstrated
pedunculated (HH – arrow)
Rycina 1. MRI u pacjenta 1
thalamus and the cavernous sinuses, measuring 9 x
9 x 12 mm (Fig. 1), while Patients 2 and 3 were
shown to have a sessile tumor situated on the floor of the anterior cranial fossa, adjacent to the mamillary bodies and optic nerve chiasm but not infiltrating the said chiasm, and extending to the hypothalamus, measuring respectively 12 x 11 x 10 mm
(Fig. 2) and 12 x 11 x 13 mm (Fig. 3). In none of the
patients did the tumor impair the CNS flow, result
in elevated intracranial pressure or compression of
the optic nerves and cavernous sinuses. No neurological and behavioral abnormalities were noted, or
diabetes insipidus or anterior pituitary insufficiency.
In all the patients conservative treatment was initiated with a long-acting Gn-RH analogue (Diphereline, Beaufour Ipsen) at the dose of 3.75 ug i.m. administered every 4 weeks, with age at onset of the-
Figure 3. Cranial MRI of Patient 3 demonstrated sessile (HH
– arrow)
Rycina 3. MRI czaszki u pacjenta 3
rapy being 2.3 years (Patient 1), 3 years (Patient 2)
and 8.2 years (Patient 3). The follow-up was from
1.5 to 5.6 years mean 3.5 years. In the course of therapy, all the patients demonstrated a partial or total regression of IPP signs according to Tanner (Table I), corresponding to the total or partial gonadal axis suppression detected in the children (Table II). The auxological analysis showed a decelera71
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Table II. Hormonal data
Tabela II. Parametry hormonalne
Before the treatment
FSH
basal
uIU/ml
(N < 0.1)
During the Diphereline treatment
Patients
LH
basal
uIU/ml
(N <
0.1)
LH max
(GnRH
test*)
uIU/ml
FSH max
(after
T
E2 pg/ml
GnRH
ng/ml
(N < 7.0)
stimulation)
(N < 0.5)
uIU/m
1.B.A.
2.17
35.7
6.87
11.1
42.6
0.11
0.82
1.16
13.3
0.09
2.W.A
1.2
16.9
1.48
1.24
3.35
4.28
0.6
0.28
2.55
0.07
3.A.Ł
1.92
12.2
2.26
4.39
5.91
1.99
0.79
0.63
-
0.22
LH basal
uIU/ml
(N < 0.1)
FSH
E2
T
basal
pg/ml
ng/ml
uIU/ml
(N < 7.0) (N < 0.5)
(N < 0.1)
* GnRH test was performed using 100 μg GnRH in i.v. bolus
ted growth rate in the course of therapy, from 11.1;
24.3; 10 cm/year in Patients 1, 2 and 3, respectively
to 4.3; 3.4; 3.8 cm/year. The predicted target height
expressed as the ratio of height age (HA) to bone
age (BA), determined according to Bayley-Pinneau
[13], was improved in Patients 1, 2 and 3 from 0.7,
0.83, 1.02 to 1.0, 1.02, 1.07, respectively (Table I).
No adverse side effects of the therapy were noted. A
follow-up MRI performed every year for the mean
period of 4 years showed stability of lesion shape,
size and signal intensity, what support their hamartomatous and non-progressive nature [1, 14].
Discussion
The association of HH with IPP is well
established [1, 2, 15, 16]. Patients with HH and
other suprasellar lesions (arachnoid cyst, germ cell
tumor, glial cell tumor) have physical signs of IPP
indistinguishable from those with idiopathic IPP
[17–20], although some of them present with a
higher post-GnRH stimuli gonadotropin response
than do children with idiopathic IPP [1, 18, 21].
The diagnosis of IPP due to HH is suggested by
onset of sexual precocity, before 2 or 4 years
of age (Rivarola) and concomitant neurological
abnormalities [5]. Nevertheless, patients with
the above mentioned lesions other than HH were
occasionally seen at the early age and presented
with some neurological failure, although different
from gelastic seizures [18, 19]. An excessive
postimulated gonadotropin release was noted only
in Patient 1, early onset of IPP in patients 1 and 2,
and none of them demonstrated any neurological
abnormalities. In accordance with the above data,
the diagnosis of HH in all three patients was based
72
on routine head MRI scans performed in all children
with IPP.
Based on location on MRI scans Arita et al.
classified HH into two types: the parahypothalamic
type – generally associated with IPP but
unaccompanied by seizures or developmental
delay, and the intrahypothalamic type – generally
associated with seizures and developmental
delay, as well as IPP in 50% of patients [22]. The
association of the shape of the HH (sessile or
pedunculated) with the presence of seizures and IPP
was also reported by other authors [3, 7, 23] who
noted a higher incidence of seizures in children with
sessile HH and IPP than in those with pedunculated
HH. Regardless of such a classification, some
authors found a correlation between the size of the
HH and the occurrence of seizures demonstrating
that no patients with a HH diameter of less than 10
mm had seizures, in contrast to all patients with
a HH of 25 mm or larger who had seizures [1,
3]. The mean diameter of the HH in our patients
ranged between 10 and 12 mm. In a female the
lesion was parahypothalamic and pedunculated,
while the lesions in both boys were partially
intrahypothalamic and sessile. The resection of
HH has been recommended as a treatment option
for selected cases, such as pedunculated HH, and,
independently of the shape of the lesion, in cases
of incomplete response to the initial GnRH therapy,
tumor mass enlargement or compression of adjacent
tissues causing progressive neurological deficit,
hydrocephalus or in cases of medically intractable
seizures [24–26]. Surgical resection of HH carries
an increased risk of morbidity and mortality and,
if removal is incomplete, does not arrest the sexual
precocity [1, 3]. In all three cases almost 4-year long-
Starzyk J. i inni – Precocious puberty in children triggered by a hypothalamic hamartoma...
acting GnRH analogue administration provided
a satisfactory and safe control of precocity and
growth, irrespectively of the morphological type of
HH. None of our patients presented with other then
IPP hormonal abnormalities, neurological signs and
symptoms or tumor progression. A limited number
of patients does not allow for formulating firm
conclusions, yet – in agreement with observations
made by other authors [1, 3, 10–12] – it appears
that in patients without neurological signs and well
monitored by MRI imaging, long-acting GnRHanalogue treatment can be recommended. When
these conditions are met, the morphological type
of HH seems not to have any significance when
patients are qualified for surgical treatment.
STRESZCZENIE/
STRESZCZENIE/ABSTRACT
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
De Brito V.N., Latronico A., Arnhold I. et al.: Treatment of gonadotropin dependent precocious pubert due to hypothalamic
hamartoma with gonadotropin releasing hormone agonist depot. Arch. Dis. Child., 1999:80, 231.
Beningfield S.J., Bonnici F., Cremin B.J.: Case reports. Magnetic resonance imaging of hypothalamic hamartomas. BR. J.
Radiol., 1988:61, 1177.
Mahachoklertwattana P., Kaplan S., Grumbach M.: The luteinizing hormone- releasing hormone–secreting Hypothalamic
hamartoma is a congenital malformation: natural history. J. Clin. Endocrinol. Metabol., 1993:77 (1), 118.
Lona Soto A., Takashi M., Yamashita Y. et al.: MRI findings of hypothalamic hamartoma: report of five cases and review of the
literature. Comput. Med. Imaging Graph., 1991:15, 415.
Minns R.A.M., Stirling H.T., Wu F.C.M.: Hypothalamic hamartoma with skeletal malformations, gelastic epilepsy and
precocious puberty. Dev. Med. Child Neurol., 1994:36, 173.
Lee. P.A., Page J.G.: Effects of leuprolide in treatment of central precocious puberty. J. Pediatr., 1989:114, 321.
Starceski P.J., Lee P.A., Albright A.L., Migeon CJ.: Hypothalamic hamartomas and sexual precocity: evaluation of treatment
options. Am. J. Dis. Child., 1990:144, 225.
Nishio S., Morioka T., Fukui M., Goto Y.: Surgical treatment of intractable seizures due to hypothalamic hamartoma. Epilepsia,
1994:35 (3), 514.
Nishio S., Shigeto H., Fukui M.: Hypothalamic hamartoma: the role of surgery. Neurosurg Rev., 1993:16, 157.
Lee P.: Laboratory monitoring of children with precocious puberty. Arch. Pediatr. Adolesc. Med., 1994:148, 369.
Vinchon M., Dhellemmes P.: Particularites pediatriques des tumeurs du troisieme ventricule. Neurochirurgie, 2000:46 (3),
323.
Colaco P.: Prococious puberty. Ind. J. Pediatrics., 1997:64 (2), 165.
Greulich W., Pyle S.: Radiographic atlas of skeletal development of the hand and wrist. Stanford University Press, Stanford
1959.
Turjman F., Xavier J.L., Froment JC. et al.: Late MR follow-up of hypothalamic hamartoma. Childs. Nerv. Syst., 1996:12 (2),
63.
Zuniga O.F., Tanner S.M., Wild W.O., Mosier Jr H.D.: Hamartoma of the CNS associated with precocious puberty. Am. J. Dis.
Child., 1983:137, 127.
Feuillan P.P., Jones J., Barnes K. et al.: Reproductive axis after discontinuation of gonadotropin-releasing hormone analog
treatment of girls with precocious puberty: long term follow-up comparing girls with hypothalamic hamartoma to those with
idiopathic precocious puberty. J. Clin. Endocrinol. Metab., 1999:84 (1), 44.
Valdueza J.M., Cristante L., Dammann O. et al.: Hypothalamic hamartomas: with special reference to gelastic epilepsy and
surgery. Neurosurgery, 1994:34, 949.
Rivarola A., Belgorosky A., Mendilaharzu H., Vidal G.: Precocious puberty in children with tumours of the suprasellar and
pineal areas: organic central precocious puberty. Acta Paediatr., 2001:90 (7), 751.
Starzyk J., Kwiatkowski S., Urbanowicz W. et al.: Suprasellar arachnoidal cyst as a cause of precocious puberty – report of 3
cases and literature overview. J. Pediatr. Endocrinol. Metab., 2002 (in press).
Starzyk J., Starzyk B., Bartnik-Mikuta A. et al.: Gonadotropin Releasing Hormone-Independent Precocious Puberty in a 5
Year-Old Girl with Suprasellar Germ Cell Tumor Secreting B-hCG and α-Fetoprotein. J. Pediatr. Endocrinol. Metab., 2001:14
(6), 789.
Uriarte M.M., Klein K.O., Barnes K.M. et al.: Gonadotrophin and prolactin secretory dynamics in girls with normal puberty,
idiopathic precocious puberty and precocious puberty due to hypothalamic hamartoma. Clin. Endocrinol. Oxf., 1998:49 (3),
363.
Arita K., Ikawa F., Kurisu K. et al.: The relationship between magnetic resonance imaging findings and clinical manifestations
of hypothalamic hamartoma. J. Neurosurg., 1999:91 (2), 212.
Boyko O.B., Curnes J.T., Oakes W.J., Burger PC.: Hamartomas of the tuber cinereum: CT, MRI, and pathologic findings,
AJNR, 1991:12, 309.
73
Praca kazuistyczna
Endokrynol. Ped., 3/2004;4(9):69-74
[24] Unger F., Schrottner O., Haselsbergeer K. et al.: Gamma knife radiosurgery for hypothalamic hamartomas in patients wwith
mediccally intractable epilepsy and prococious puberty. J. Neurosurg., 2000:92 (4), 726.
[25] Roszkowski M., Wolska A., Drabik K., Grajkowska W.: Surgical treatment of GnRH secretory hypothalamic hamartomas
causing precocious puberty. Neurol. Neurochir. Pol., 1999:33 (3), 587.
[26] Valdueza J.M., Crustante L., Dammann O. et al.: Hypothalamic hamartomas: with special reference to gelastic epilepsy and
surgery. Neurosurgery, 1994:34 (6), 949.
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