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Indian Pediatr 2014;51:
831-833 |
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Precocious Pseudopuberty due to Ovarian Causes
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Jeevarathnam Dhivyalakshmi, Shaila Bhattacharyya,
Rajeshwari Reddy and *KI Arulselvi
From the Departments of Pediatric Endocrinology and
*Pediatrics, Manipal Hospital, Bengaluru, India.
Correspondence to: Dr J Dhivyalakshmi, C/o Dr. A.
Karunagaran, 60/39, Model Hutment Road, CIT Nagar, Nandanam, Chennai 600
035, Tamilnadu, India.
Received: May 02, 2014;
Initial review: June 10, 2014;
Accepted: August 06, 2014.
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Background: It is important to
differentiate central from peripheral causes of precocious puberty
because of distinct management options. Case Characteristics: 4
girls with discordant pubertal development. Observations: All had
low basal and GnRHa stimulated FSH & LH level with high estradiol level.
Abdominal ultrasonogram helped in diagnosing precocious pseudopuberty-
ovarian cyst in 3 children and juvenile granulosa cell tumour in one.
Outcome: Case 1 and 4 underwent surgery in view of persistent cyst
and tumor, respectively. Rest were managed conservatively. Regression of
pubertal signs observed in all children during follow-up. Conclusion:
Precocious pseudopuberty can be differentiated from central precocious
puberty by GnRHa Stimulation test, bone age and abdominal ultrasound.
Keywords: GnRHa stimulation test, Juvenile
granulosa cell tumor, Ovarian cyst.
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Isosexual precocious puberty in girls is most
commonly gonadotropin dependent (central) and often idiopathic. However,
a discordant pubertal development (e.g., vaginal bleeding within 1 year
of breast development) indicates peripheral causes of precocious
puberty. The diagnosis of peripheral precocious puberty can be made
based upon the Tanner staging, bone age, ultrasound imaging and most
importantly, gonadotropin releasing hormone (GnRH) stimulation test.
Case Reports
Table I represent the details of the
four children. All four children were born full term, appropriate for
gestational age, never had a rapid growth spurt, and had no family
history of sexual precocity. Bone age was not significantly advanced
when compared with chrono-logical age in all 4 patients. Elevated
estradiol level with suppressed basal and GnRH analogue (GnRHa)
stimulated gonadotropin levels were observed. Since GnRH is not easily
available in our part of the country, we used GnRHa (Leuprolide acetate)
100 mg/m 2 subcutaneously.
All children were followed up (average of 2 years).
TABLE I Clinical and Laboratory Findings
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Case 1 |
Case 2 |
Case 3 |
Case 4 |
Age
|
4 y |
4 y 6 mo |
2 y 6 mo |
8 mo |
Weight, kg (SD) |
17 (0 to +1) |
17 (0)
|
15.4 (+1 to +2) |
9.1 (+1)
|
Height /length (SD) |
102.8cms (0) |
110cms (0 to +1) |
94.2 cms (+1 to +2) |
76 cms (+3) |
SMR staging |
Breast – Tanner 2 |
Breast – Tanner 2 |
Breast -Tanner 2 |
Breast – Tanner1 |
|
Pubic hair – Tanner 1 |
Pubic hair – Tanner 1 |
Pubic hair – Tanner 1 |
Pubic hair – Tanner 3 |
Bone age |
3 y 6 mo |
5 y |
2 y 6 mo |
1 y |
Estradiol (pg/mL) |
40 |
25 |
23.92 |
98 |
Peak LH levels (mIU/mL) |
0.1 |
0.1 |
0.3 |
0.1 |
Peak FSH levels(mIU/mL) |
0.1 |
0.2 |
1.2 |
0.1 |
TSH (µIU/mL) |
2.83 |
1.89 |
2.31 |
4.7 |
17 - OH P (ng/mL) |
0.35 |
0.7 |
1.5 |
1.8 |
Case 1 presented with breast development for 20 day
and vaginal bleeding for 2 days and had ovarian cyst (3x2 cms) which
enlarged over next 6 months follow-up (4.5x2 cms) and symptoms
persisted. Hence right Oophorectomy was done which led to a
histopathological diagnosis of benign ovarian cyst. Case 2 presented
with breast development for 10 day and vaginal bleeding for 1 day. Had
right ovarian cyst (3×3 cms) which regressed on follow-up. Case 3
presented with vaginal discharge and axillary hair growth for 4 months
and had multiple cafe au lait spots and bilateral enlarged ovaries
(>1mL) with left ovarian cyst (2×2 cms) suggestive of McCune-Albright
Syndrome. Skeletal survey showed no evidence of fibrous dysplasia. Cyst
regressed spontaneously during follow-up.
Case 4 presented with pubic hair for 2 month and
vaginal bleeding for 2 days, and had a multiloculated cyst (8×3.7×7 cms)
with thick internal echoes in right ovary suggestive of ovarian tumour.
Tumour markers (AMH, inhibin AB, HCG, AFP, CA-125) were within normal
limits. Right salphingoophorectomy revealed a Juvenile granulosa cell
tumour in follicular pattern without vascular or capsular invasion.
Peritoneal washings were negative for malignant cells (International
Federation of Gynaecology and Obstetrics – FIGO stage 1). Child is
currently doing well and pubertal signs have regressed on follow-up.
Discussion
Precocious puberty (PP) has been defined as the onset
of breast stage II development before the age of 8 years in girls [1].
It has to be differentiated from normal variant/ incomplete precocity (e.g.
premature thelarche, premature pubarche, and premature menarche). It is
usually classified as central precocious puberty (CPP), and
peripheral/precocious pseudo puberty (PPP). If more than one sign of
precocious puberty is present, or develops, or if the growth is
accelerated, or bone age is significantly advanced (>2SD), it is
unlikely to be a normal variant and warrants further investigations
[2,3].
CPP is gonadotropin dependent (hence True PP). The
sexual maturation is always complete and isosexual. CPP is more common
than PPP and is most often idiopathic. Significantly advanced bone age
(>2 SD), elevated (Pubertal level) estrogen, basal and GnRH stimulated
gonadotropin levels (Predominat LH response) suggests CPP [4]. PPP is
gonadatropin independent (hence Pseudo/Peripheral PP). Maturation is
most of the times incomplete/discordant with only one type of secondary
sexual characteristic developing early. All subjects in our case study
had discordant pubertal development. The causes of PPP are genetic
(McCune-Albright syndrome, DAX1 mutations, etc.), adrenal
(hyperplasia/tumours), ovarian (cyst/neoplasm), exogenous steroids and
long standing untreated hypothyroidism. In most cases of PPP bone age
may not be significantly (>2SD) advanced owing to shorter duration of
symptoms [3]. Highly elevated oestrogen levels with low basal and GnRH
stimulated gonadotropin levels suggests PPP.
Ovarian causes usually presents with isosexual
precocity. Virilisation is seen in androgen producing ovarian neoplasms
and adrenal causes. Adrenal causes are diagnosed by highly elevated
DHEAS and 17 hydroxy progesterone levels
[3]. Ultrasonogram will help further in delineating
adrenal and ovarian causes. Long standing hypothyroidism is the only
form of sexual precocity where growth retardation occurs [5].
Ovarian cysts occur in 2-5% of prepubertal girls.
Imaging studies (Ultrasound) help in differentiating benign/malignant
lesions. Cyst having few internal echoes suggestive of hemorrhage
without septation/calcification is mostly benign and requires
observation with follow-up ultrasound in 4-8 weeks. Surgery may be
required for large ovarian cysts (>20 mL) because of the risk of adnexal
torsion [6,7]. Aromatase inhibitors are used in the management of
persistent cyst [8]. Recurrent or persistent ovarian cyst with a solid
component in imaging suggests ovarian tumour. Juvenile granulosa cell
tumor was the most common ovarian neoplasms to present with precocious
puberty. Elevated serum Inhibin and Anti-mullerian hormone were found to
be a useful serum marker. Tumour staging (FIGO) is of greatest
prognostic value. Surgery is the mainstay of treatment. Patient in case
4 had FIGO stage 1, carrying a favorable prognosis. Adjuvant
chemotherapy is usually not indicated in this setting.
Five-year-survival rate is more than 90% for FIGO stage 1 and 20-25% for
advanced stages. Long term follow-up is necessary to detect recurrences
early [9,10].
The current study documents a rare etiology of
precocious puberty – Peripheral (Ovarian causes). Central precocious
puberty can be differentiated from peripheral type by
discordant/incomplete pubertal development, GnRH/GnRHa stimulation test
and imaging studies. Benign ovarian cysts should be managed
conservatively if the child is asymptomatic on follow up, thereby
avoiding unnecessary oophorectomy. Suspect ovarian neoplasm in ovarian
cyst with solid component or recurrence.
Contributors: All authors were involved in
patient management and manuscript preparation. JD will be the guaranter.
Funding: None; Competing interests: None
stated.
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