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Case report

Indian Pediatr 2014;51: 831-833

Precocious Pseudopuberty due to Ovarian Causes


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.

 

 

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.



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/m2 subcutaneously. All children were followed up (average of 2 years).

TABLE I  Clinical and Laboratory Findings
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.

References

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