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1.  Juvenile granulosa cell tumor presenting as isosexual precocious puberty: A case report and review of literature 
The differential diagnosis for precocious puberty in a young female includes peripheral causes. This case report documents a rare cause of isosexual precocious puberty, a juvenile granulosa cell tumor of the ovary–and a brief literature review. A 7-year-old girl presented with rapid onset of pubertal development and elevated estradiol levels. Abdominal ultrasound revealed a mass in the right adnexa. Other causes of precocious puberty were excluded. Elective surgery was planned, but the patient presented to the emergency room with torsion of ovary. She underwent an exploratory laparotomy for tumor resection and right salpingo oophorectomy. Pathology reported a juvenile granulosa cell tumor of the ovary. Postoperatively, she experienced a cessation of vaginal bleeding and estradiol levels normalized. Early stage disease has good prognosis. Adjuvant chemotherapy is not indicated in this setting.
PMCID: PMC3659885  PMID: 23776871
Juvenile granulosa cell tumor; precocious puberty; ovarian tumour; paediatric endocrinology
2.  Precocious puberty secondary to a mixed germ cell-sex cord-stromal tumor associated with an ovarian yolk sac tumor: a case report 
Ovarian tumors are the least common cause of sexual precocity in girls. Mixed germ cell-sex cord-stromal tumors associated with a yolk sac tumor of the ovary are rare neoplasms, of which only a small number of well-documented cases have been described so far. Here, we report precocious puberty in a four-year-old Egyptian girl caused by a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary.
Case presentation
A four-year-old Egyptian girl was referred to our pediatric endocrinology unit for evaluation of bilateral breast budding, pubic hair and vaginal bleeding. On examination, we found that her breast enlargement and pubic hair were compatible with Tanner III. A thorough workup revealed a large mass in her right ovary. Magnetic resonance imaging ofher brain showed that her pituitary gland was normal. A hormonal assay revealed high levels of estradiol, 280 to 375pmol/L; progesterone, 5.3 nmol/L; testosterone 38.9 pg/mL; and androstenedione, 4.1 ng/mL. Her basal and stimulated levels of luteinizing hormone and follicle-stimulating hormone were low. Tumor markers levels were high, with a total inhibin of 1,069U/L and an alpha-fetoprotein of 987 μg/L. Her chromosomes were normal (46XX). Our patient underwent an explorative laparotomy and a solid tumor localized to her right ovary was identified. A right salpingo-oophorectomy was performed and the histopathological diagnosis was a mixed germ cell-sex cord-stromal tumorwith a yolk sac tumor of the ovary. Postoperatively, she was started on treatment with chemotherapy. Our patient is doing well without evidence of tumor recurrence or metastasis during eight months of postoperative follow-up.
Although a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary is a rare occurrence, it should be considered in the differential diagnosis for a prepubescent girl with an abdominal mass and precocious puberty.
PMCID: PMC3414798  PMID: 22734844
3.  Etiology of precocious puberty, 10 years study in Endocrine Reserch Centre (Firouzgar), Tehran 
Background: Precocious puberty, as early physical development and low final height might lead to psychosocial problems.
Objective: To evaluate etiology and clinical feature of precocious puberty in a cohort of Iranian children.
Materials and Methods: In this case-series study, 44 girls and 8 boys with precocious puberty referred to Endocrine Reserch Centre (Firouzgar), Institute of Endocrinology and Metabolism (Hemmat Campus), were examined in a 10 years period of time.
Results: Mean age of girls and boys was 7.43±1.4 years and 5.8±2.1 years respectively. Most of the patients fell within the age category of 7-7.9 years old (40.9% for girls and 50% for boys). Patients, concerning etiology of precocious puberty were classified in three categories: 42.6% of patients had central precocious puberty (CPP), including idiopathic CPP (87.5%) and neurogenic CPP (12.5%). 23.3% of patients had peripheral precocious puberty (PPP), including congenital adrenal hyperplasia (CAH) (42.8%), ovarian cysts (28.4%), McCune-Albright syndrome (14.2%) and adrenal carcinoma (14.2%). 34.1% of girls and 25% of boys had normal variant puberty including premature thelarche (57%), premature adrenarche (38%) as well as premature menarche (4.7%l).
Conclusion: The most common etiology of precocious puberty in girls was idiopathic central precocious puberty and premature thelarche, while in boys they were neurogenic central precocious puberty and CAH. Therefore precocious puberty in girls is usually benign. In boys, CNS anomalies should first be considered in the differential diagnosis of CPP. Therefore brain Magnetic Resonance Imaging (MRI) is mandatory in all cases.
PMCID: PMC4163256  PMID: 25242967
Central precocious puberty; Peripheral precocious puberty; Premature thelarche; Congenital adrenal hyperplasia
4.  Central Precocious Puberty and Granulosa Cell Ovarian Tumor in An 8-Year Old Female 
Pediatric Reports  2013;5(3):e13.
Ovarian tumors associated with hormonal changes of the peripheral iso-sexual precocious puberty are of common presentation. We describe here a rare case of juvenile granulosa cell tumor in a female with central precocious puberty (CPP). An 8-year old girl with CPP presented with vaginal bleeding four months after the diagnosis and before starting treatment with gonadotropin-releasing hormone (GnRH)-analogs. Suppression of basal follicle-stimulating hormone (FSH) level, elevation of serum estradiol, progesterone and Cancer Antigen-125 were documented. Abdominal ultrasound examination (US) and magnetic resonance imaging showed a pelvic mass affecting the left ovary. A left salpingo-oophorectomy was performed and the mass was totally resected. Juvenile granulosa cell ovarian tumor was diagnosed. One month post surgery, estradiol and progesterone decreased to values of the first evaluation and FSH increased; Cancer Antigen-125 resulted normal while ultrasound pelvic examination showed absence of pelvic masses. In our patient, the tumor had grown very quickly since hormonal data demonstrated a CPP without any evidence of ovarian mass on US only four months before diagnosis. The overstimulation of the FSH or aberrant activation of FSH receptors may have contributed to the development of the mass.
PMCID: PMC3812530  PMID: 24198925
central precocious puberty; juvenile granulosa cell; ovarian tumor; children
5.  Precocious pseudopuberty due to an autonomous ovarian follicular cyst: case report with a review of literatures 
BMC Research Notes  2013;6:319.
Small follicular cysts are commonly found in the ovaries of prepubertal girls, and in most cases, they are of no clinical importance. These cysts are usually self-limiting and resolve spontaneously. However, occasionally, these cysts may enlarge and continue to produce estrogen, resulting in signs of sexual precocity. Here, we report a case of precocious pseudopuberty associated with an autonomous ovarian follicular cyst.
Case presentation
A 5.9-year-old girl initially presented to a local clinic with vaginal bleeding and a large unilateral ovarian cyst. At 6 months after the initial acute episode, the patient visited our hospital as the ovarian cyst had persisted and increased in size. Endocrinological examination showed elevated estrogen levels and suppressed gonadotropin levels on GnRH stimulation test. Also, no skin pigmentation or bone anomaly was noted. Based on these observations, laparoscopic cystectomy was performed, and histologic analysis confirmed the diagnosis of a follicular cyst. After the laparoscopic cystectomy, the patient’s hormone levels returned to normal and no ovarian cyst was detected by ultrasound.
As autonomous ovarian cysts are usually self-limiting disorder, no treatment is necessary. Therefore, surgical management should be deferred as long as possible to avoid the risk of repeat surgery, as pseudoprecocious puberty due to autonomous ovarian cysts can resolve spontaneoulsy and frequently recurs. Precocious pseudopuberty with an ovarian cyst may be due to granulosa cell tumor or may be one symptom of the McCune-Albright Syndrome (MAS). A careful longer-term follow up of patients with autonomous ovarian cysts and/or molecular studies may be necessary in such cases.
PMCID: PMC3766658  PMID: 23937919
Precocious pseudopuberty; Autonomous ovarian follicular cyst; Laparoscopic
6.  The Multifaceted Granulosa Cell Tumours—Myths and Realities: A Review 
ISRN Obstetrics and Gynecology  2012;2012:878635.
Background. Granulosa cell tumors (GCTs), representing ~2% of ovarian tumours, are poorly understood neoplasms with unpredictable and undetermined biological behaviour. Design. 5 unusual presentations of GCT and a retrospective 14-year (1997–2011) surgical pathology review based on patient sex, age, tumour type and concurrent pathology findings are presented to discuss the “myths and realities” of GCTs in the context of relevant evidence-based literature. Results. The 5 index cases included (1) a 5 month-old boy with a left testicular mass, (2) a 7-day-old neonate with a large complex cystic mass in the abdomen, (3) a 76-year-old woman with an umbilical mass, (4) a 64-year-old woman with a complex solid-cystic pelvic mass, and (5) a 45 year-old woman with an acute abdomen. Pathological analysis confirmed the final diagnosis as (1) juvenile GCT, (2) macrofollicular GCT, (3) recurrent GCT 32 years later, (4) collision tumour: colonic adenocarcinoma and GCT, and (5) ruptured GCT. Conclusion. GCT is best considered as an unusual indolent neoplasm of low malignant potential with late recurrences that can arise in the ovaries and testicles in both the young and the old. Multifaceted clinical presentations coupled with the unpredictable biological behaviour with late relapses are diagnostic pitfalls necessitating a high degree of suspicion for accurate clinical and pathological diagnosis.
PMCID: PMC3449135  PMID: 23008780
7.  Precocious puberty in Turner Syndrome: report of a case and review of the literature 
Turner Syndrome (TS) is caused by monosomy or structural abnormalities of the X chromosome, with a prevalence of about 1/2000 females live birth. Most important clinical features of TS are short stature and gonadal failure. Approximately one third of girls with TS may undergo spontaneous puberty. Here we report on the case of a girl with a rare 45X0/47XXX mosaic TS exhibiting a precocious puberty.
Case report
The patient was diagnosed with TS at the age of 4 years, upon a diagnostic work-up for dysmorphic features. Chromosome analysis revealed a mosaic karyotype (45X0/47XXX). She presented with normal height and normal growth velocity so that Growth Hormone (GH) therapy was not started. She was referred to our Department at the age of 7 years and 10 months, because of vaginal bleeding. A physical examination revealed a Tanner stage III for breast and Tanner stage III for pubic hair development. Height and weight were within the normal range for age. Psychological evaluation showed moderate global developmental delay, together with emotional and social immaturity and reading difficulties. The growth rate was accelerated. Her bone age was 10 years. Pelvic ultrasound demonstrated increased size for age of both the uterus and the ovaries, with bilateral ovarian follicles. GnRH stimulation test revealed pubertal response of gonadotropins (peak LH 22.5 mIU/ml). MRI of the brain was normal. These clinical, radiologic and laboratory findings were consistent with a diagnosis of idiopathic central precocious puberty; therefore, GnRH analog therapy was started, in order to slow pubertal progression and to preserve adult stature. Furthermore, GH treatment was added to further improve adult height.
Our case highlights the possibility of precocious puberty as an atypical clinical feature of TS. Thus, precocious puberty may occur in TS girls when a dosage compensation by the cell line with more than two X chromosomes allows normal ovarian function. GnRH analog therapy in addition to GH treatment should be recommended in TS girls with precocious puberty in order to slow pubertal progression and to preserve adult stature.
PMCID: PMC3481396  PMID: 23075274
Turner syndrome; Precocious puberty; GnRH analog therapy
8.  Clinical and Laboratory Characteristics of Children Referred for Early Puberty: Preponderance in 7-8 Years of Age 
Objective: The aim of this study was to evaluate the girls referred to the pediatric outpatient clinic with a presumptive diagnosis of early puberty due to early onset of breast development or pubarche.
Methods: Within the study period, we evaluated 289 subjects referred for concerns about early onset of puberty. History, anthropometric data, bone age (BA), hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and dehydroepiandrosterone sulfate, as well as pelvic ultrasonography (USG)-derived ovarian and uterine volumes were analyzed.
Results: Of the 289 girls referred for early onset of pubertal development, 64 (22.1%) had false alarms for puberty. Of the remaining 225 girls, 41 (18.2%) were diagnosed as premature pubarche, 56 (24.9%) as premature thelarche (PT), and 128 (56.9%) as precocious puberty (PP). Girls with early-onset puberty had more advanced BA, greater uterine and ovarian volumes, and also higher LH values than subjects with PP and PT. Nearly half of these girls were 7-8 years of age. Body mass index (BMI) standard deviation score was significantly higher in the PP cases.
Conclusions: There is a need for primary care physicians to be more knowledgeable on puberty and on puberty problems. There seems to be a preponderance of PP in 7-8-year-old children . Increased BMI may have a role in the trend towards earlier onset of puberty
Conflict of interest:None declared.
PMCID: PMC3537288  PMID: 23261863
Pubarche; child; puberty; precox puberty; thelarche
9.  Gonadal germ cell tumors in children and adolescents 
Pediatric germ cell tumors (GCT) are rare tumors: 80% are benign, 20% malignant (2-3% of all malignant pediatric tumors). The gonadal sites (ovary and testis) account for 40% of cases.
Ovarian GCTs:
Represent 30% of GCTs and 70% of neoplastic ovarian masses, being the most common ovarian neoplasms in children and teenagers. Benign and immature forms (teratomas) constitute about 80% of all ovarian GCTs, malignant forms represent 20% increasing during adolescence. The most common malignant entity in children is the yolk sac tumors (YST); dysgerminoma is frequent during adolescence and being bilateral in 10% of cases. Presentation is similar in malignant and benign lesions; abdominal pain (70-80%) and lower abdominal mass are common symptoms. Evaluation of alpha-fetoprotein (αFP) or beta subunit of human chorionic gonadotropin (βHCG) is essential to address the nature of the tumors: Their elevation means presence of malignancy. Surgery includes intraoperative staging procedures and requires ovariectomy or ovarosalpingectomy for malignant lesions, but may be conservative in selected benign tumors. Since malignant GCTs are very chemosensitive, primary chemotherapy is recommended in metastatic or locally advanced tumors.
Testicular GCT:
Represent 10% of pediatric GCT, and about 30% of malignant GCT with two age peaks: Children <3 years may experience mature teratoma and malignant GCTs, represented almost exclusively by YST, while adolescents may also show seminomas or other mixed tumors. The main clinical feature is a painless scrotal mass. Surgery represents the cornerstone of the management of testicular GCTs, with an inguinal approach and a primary high orchidectomy for malignant tumors, while a testis-sparing surgery can be considered for benign lesions. A retroperitoneal lymph node (LN) biopsy may be necessary to define the staging when the involvement of retroperitoneal LN is uncertain at imaging investigations.
Patients with gonadal malignant GCTs fare better than those with extragonadal mediastinal germ cell tumors (MGCTs) and survival rate exceeds 90% in localized forms. Chemotherapy has significantly improved the outcome of malignant forms since the introduction of platinum based regimens. The surgical procedure has to be performed in agreement with the ongoing protocols.
PMCID: PMC4204242  PMID: 25336799
Children; germ cell tumors; gonadal
10.  An unusual presentation of a usual disorder: Van Wyk-Grumbach syndrome 
Van Wyk-Grumbach syndrome (VWGS) is characterized by juvenile hypothyroidism, delayed bone age, and isosexual precocious puberty. A 10.7-year-old girl presented with premature menarche and isosexual precocity. She had delayed bone age and multicystic ovaries. High circulating levels of TSH with prepubertal LH confirmed the diagnosis of VWGS. Tendency to manifest sexual precocity in VWGS may be directly related to the severity of the TSH elevation. High circulating levels of TSH acting directly on FSH receptors are the actual mediators of precocity.
PMCID: PMC3169870  PMID: 21966653
Hypothyroidism; precocious puberty; Van Wyk–Grumbach syndrome
11.  Idiopathic central precocious puberty in girls: presentation factors 
BMC Pediatrics  2008;8:27.
It is sometimes difficult to distinguish between premature thelarche and precocious puberty in girls who develop breasts before the age of 8 years. We evaluated the frequencies of the signs associated with breast development and the factors influencing the presentation of girls with idiopathic central precocious puberty (CPP).
353 girls monitored 0.9 ± 0.7 year after the onset of CPP.
The age at CPP was < 3 years in 2%, 3–7 years in 38% and 7–8 years in 60% of cases. Pubic hair was present in 67%, growth rate greater than 2 SDS in 46% and bone age advance greater than 2 years in 33% of cases. Breast development was clinically isolated in 70 (20%) cases. However, only 31 of these (8.8% of the population) had a prepubertal length uterus and gonadotropin responses to gonadotropin releasing hormone and plasma estradiol. The clinical picture of CPP became complete during the year following the initial evaluation.
25% of cases were obese. The increase in weight during the previous year (3.7 ± 1.4 kg) and body mass index were positively correlated with the statural growth and bone age advance (P < 0.0001).
There was no relationship between the clinical-biological presentation and the age at puberty, the interval between the onset of puberty and evaluation, or the presence of familial CPP.
The variation in presentation of girls with CPP does not depend on their age, interval between the onset and evaluation, or familial factors. This suggests that there are degrees of hypothalamic-pituitary-ovarian activation that are not explained by these factors.
PMCID: PMC2459158  PMID: 18601733
12.  Ussefulnes of imaging techniques in the diagnostics of precocious puberty in boys 
Polish Journal of Radiology  2011;76(4):21-27.
Precocious puberty (PP) is defined as the appearance of symptoms of puberty in girls before 8 years of age and in boys under 9. Statistically, it occurs much more frequently in girls, while it is a rare pathology in boys.
Over the period of 10 years, between 1999 and 2009, 39 girls and 17 boys aged 18 months – 9 years were diagnosed with precocious puberty,, and treated at the Endocrinology Clinic.
The following tests were performed in all children: physical and anthropometric examinations, abdominal ultrasound scan (US) with evaluation of adrenal glands, examination of testes in boys or breasts and pelvic organs in girls, evaluation of skeletal age and, in selected cases, CT scans of the abdomen, MRI of the CNS, and hormonal laboratory tests.
In the group of 17 boys the findings included: gonadotropin –dependent central puberty in 6 boys: idiopathic in 5 cases, and 1 case of a brain tumor – astrocytoma.
Gonadotropin-independent precocious pseudopuberty was diagnosed in 11 boys: congenital adrenal hyperplasia in 5; in 1case – hyperandrogenism caused by overactivity of 5-α reductase; in 2 subjects – adrenal adenoma; in 2 boys adrenocortical carcinoma was diagnosed and Leydig cell tumor of testis in 1.
1. Precocious puberty occurs less often in boys, but in our population it was found in 17 boys of 56 treated children, which constituted as much as 30%. 2. Precocious pseudopuberty was found in 64% of the boys with PP. 3. Adrenal and testicular tumors were the causes of precocious puberty in the youngest group of boys aged 18 months – 6 years.
PMCID: PMC3389942  PMID: 22802850
precocious puberty; boys; diagnosis
13.  Short stature and an interesting association 
Indian Journal of Human Genetics  2013;19(1):101-103.
Untreated hypothyroidism in children usually results in delayed puberty, but juvenile hypothyroidism causes isosexual precocious puberty in a rare syndrome called Van Wyk Grumbach syndrome, with a complete reversal to the pre pubertal state following thyroid hormone replacement therapy. We report here, a 7-year-old girl who presented with short stature, constipation and isosexual precocious puberty due to the long standing untreated severe hypothyroidism with this syndrome.
PMCID: PMC3722618  PMID: 23901203
Hypothyroidism; precocious puberty; short stature
14.  Premature Menarche Associated with Primary Hypothyroidism in a 5.5-Year-Old Girl 
Case Reports in Endocrinology  2011;2011:678305.
Children with hypothyroidism generally have delayed pubertal development. Rare association with precocious puberty may occur especially in long standing untreated patients. The cardinal features of hypothyroidism induced pseudo precocious pubertal development include thelarche, galactorrhea and menarche. Other characteristics features are an absence of sexual hair and retardation of linear growth. Its manifestation as isolated menarche has been rarely reported. Recently, a five and half year old girl presented to us with history of one episode of vaginal bleeding. A pelvic ultrasonogram revealed multiple cysts in both ovaries and subsequent investigations led to a diagnosis of autoimmune hypothyroidism.
PMCID: PMC3420754  PMID: 22937289
15.  Diagnosis and constitutional and laboratory features of Korean girls referred for precocious puberty 
Korean Journal of Pediatrics  2012;55(12):481-486.
Precocious puberty is defined as breast development before the age of 8 years in girls. The present study aimed to reveal the diagnosis of Korean girls referred for precocious puberty and to compare the constitutional and endocrinological features among diagnosis groups.
The present study used a retrospective chart review of 988 Korean girls who had visited a pediatric endocrinology clinic from 2006 to 2010 for the evaluation of precocious puberty. Study groups comprised fast puberty, true precocious puberty (PP), pseudo PP, premature thelarche, and control. We determined the height standard deviation score (HSDS), weight standard deviation score (WSDS), and body mass index standard deviation score (BMISDS) of each group using the published 2007 Korean growth charts. Hormone tests were performed at our outpatient clinic.
The PP groups comprised fast puberty (67%), premature thelarche (17%), true PP (15%), and pseudo PP (1%). Advanced bone age and levels of estradiol, basal luteinizing hormone (LH), and peak LH after gonadotropin-releasing hormone stimulation testing were significantly high in the fast puberty and true PP groups compared with the control group. HSDS, WSDS, and BMISDS were significantly higher in the true PP group than in the control group (P<0.05).
The frequent causes of PP were found to be fast puberty, true PP, and premature thelarche. Furthermore, BMISDS were significantly elevated in the true PP group. Therefore, we emphasize the need for regular follow-up of girls who are heavier or taller than others in the same age group.
PMCID: PMC3534162  PMID: 23300504
Precocious puberty; Puberty; Premature thelarche; Body mass index; Sexual maturation
16.  Sex Cord Stromal Tumors–Unusual Presentations 
The sex cord stromal tumors (SCST) account for approximately 7% of all malignant ovarian tumors. They are endocrinologically active tumors of which granulosa cell tumors are the commonest. We describe an analysis of all cases of SCST managed, in our department over the last five years and discuss two cases of unusual presentation of these tumors.
Ten cases of SCST which were managed in the Department of Gynecology and Obstetrics at University College of Medical Sciences (UCMS) & associated Guru Teg Bahadur hospital, Delhi from Jan. 01 to Dec. 05 were analyzed.
Of the total 312 ovarian tumors which were operated in these 5 years, 73 (23.3%) were malignant, 10 cases (13.6%) out of the malignant ovarian tumors were SCST. The age of presentation varied from 4 to 70 years. Four women presented with lump abdomen as their chief complaint, 2 had postmenopausal bleeding, 2 presented with irregular bleeding per-vaginum, 1 woman had secondary amenorrhea and one young girl who was only 4½ years old developed precocious puberty. The majority of cases (70%) were granulosa cell tumors, 10% were fibromas and 20% thecomas. Maximum patients 9 (90%) were stage I at the time of surgery and only 1 case was stage IV with tumor infiltrating into omentum and gut.
SCST tumors are rare endocrine active tumors that are essentially unilateral, benign or with a low malignant potential. Though most patients present with one or a combination of symptoms ranging from abnormal vaginal bleeding, abdominal distention and abdominal pain, the signs of Paraneoplastic syndrome (PNS) may be the first indication of the presence of an ovarian malignancy and can even facilitate its diagnosis.
PMCID: PMC3257345  PMID: 23024526
Sex cord; Ovarian; Paraneoplastic; Precocious; Granulosa cell; Endometrial hyperplasia
17.  Leydig Cell Testicular Tumour Presenting as Isosexual Precocious Pseudopuberty in a 5 Year-old Boy with No Palpable Testicular Mass 
Leydig cell testicular tumors are very rare in children and cause isosexual precocious puberty. Palpable testicular mass or asymmetric testes are common findings on routine examination. We report on a 5-yr-old boy with a Leydig cell tumor of the testis presented with isosexual precocious puberty but no scrotal palpable mass. To our knowledge, this is the first reported Leydig cell tumor in a boy without palpable scrotal mass.
PMCID: PMC3687613  PMID: 23926374
Leydig-cell tumor; testicular; precocious puberty; neoplasm; testis
18.  McCune-Albright syndrome 
McCune-Albright syndrome (MAS) is classically defined by the clinical triad of fibrous dysplasia of bone (FD), café-au-lait skin spots, and precocious puberty (PP). It is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000. FD can involve a single or multiple skeletal sites and presents with a limp and/or pain, and, occasionally, a pathologic fracture. Scoliosis is common and may be progressive. In addition to PP (vaginal bleeding or spotting and development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone excess, Cushing syndrome, and renal phosphate wasting. Café-au-lait spots usually appear in the neonatal period, but it is most often PP or FD that brings the child to medical attention. Renal involvement is seen in approximately 50% of the patients with MAS. The disease results from somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, Gs alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurs during embryonic development. Diagnosis of MAS is usually established on clinical grounds. Plain radiographs are often sufficient to make the diagnosis of FD and biopsy of FD lesions can confirm the diagnosis. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available. Genetic counseling, however, should be offered. Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm. Treatment is dictated by the tissues affected, and the extent to which they are affected. Generally, some form of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of FD. Strengthening exercises are recommended to help maintaining the musculature around the FD bone and minimize the risk for fracture. Treatment of all endocrinopathies is required. Malignancies associated with MAS are distinctly rare occurrences. Malignant transformation of FD lesions occurs in probably less than 1% of the cases of MAS.
PMCID: PMC2459161  PMID: 18489744
19.  A Case of Atypical McCune-Albright Syndrome with Vaginal Bleeding 
Iranian Journal of Pediatrics  2011;21(3):399-403.
McCune-Albright syndrome (MAS) is a rare non-inherited disorder characterized by the clinical triad of precocious puberty, cafe-au-lait skin lesions, and fibrous dysplasia of bone.
Case Presentation
We report a girl with MAS, presenting initially with vaginal bleeding at the age of 17 months. Ultrasonography revealed unilateral ovarian cysts and ureteral and ovarian enlargement. Considering the clinical and paraclinical findings, the patient diagnosed as a case of gonadotropin-independent precocious puberty was treated with medroxy-progestrone acetate (MPA) for three months. During the follow up, recurrent episodes of bleeding, ovarian activation and cyst formation, as well as breast size development were reported. At the age of 5.5 years, fibrous dysplasia was detected, which in coexistence with precocious puberty confirmed the diagnosis of MAS. The patient had no cafe-au-lait skin macles during follow up.
Considering that clinical manifestations of MAS appear later in the course of recurrent periods of ovarian activation and cyst formation, a careful clinical observation and follow up of patients is necessary and the diagnosis of MAS must be kept in mind in cases with gonadotropin-independent precocious puberty.
PMCID: PMC3446187  PMID: 23056821
McCune-Albright Syndrome; Bleeding; Fibrous Dysplasia of Bone; Precocious Puberty
20.  Psychosocial Aspects in Girls with Idiopathic Precocious Puberty 
Psychiatry Investigation  2012;9(1):25-28.
Precocious puberty leads to discrepancies between physical and chronological age. The aim of the present study was to evaluate behavioral patterns and social competences in 34 girls with idiopathic precocious puberty.
Height, body weight, and BMI were determined, and pubertal development was assessed. The Korean-child behavior checklist (K-CBCL) was completed by parents.
1) Body weight and BMI were significantly higher in precocious puberty group than in the control group. 2) T scores of total social competence and school scales of K-CBCL were significantly higher in the precocious puberty group than in the control group. 3) T scores of externalizing problems and total behavior problems of K-CBCL were also significantly higher in the precocious puberty group. 4) T scores of thought problems and attention problems of K-CBCL were significantly higher in the precocious puberty group than the control group.
Although girls with precocious puberty had more behavioral problems, no significant differences were observed between the two study groups in terms of clinically-important T scores. However, the concerns of parents and patients regarding behavioral and emotional changes might be most important when evaluating psychosocial problems. Early recognition, sufficient understanding, communication with patients and parents regarding physical developmental difference from children in the same age, can improve the self-image of those with precocious puberty.
PMCID: PMC3285737  PMID: 22396681
Precocious puberty; Psychosocial problem
21.  Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis 
Oncogene  2011;31(12):1504-1520.
WNT, PI3K or RAS signaling pathways control specific stages of ovarian follicular development. To analyze the functional interactions of these pathways in granulosa cells during follicular development in vivo, we generated specific mutant mouse models. Stable activation of the WNT signaling effector beta-catenin (CTNNB1) in granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life or following targeted deletion of the tumor suppressor gene Pten. Conversely, expression of oncogenic KRASG12D dramatically arrests proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation and developed early-onset GCTs leading to premature death in a manner similar to the Ctnnb1;Pten mutant mice. Microarray and RT-PCR analyses revealed that gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. The concomitant activation of CTNNB1 and KRAS in Sertoli cells also caused testicular granulosa cell tumors that showed gene expression patterns that partially overlapped those observed in GCTs of the ovary. Although the mutations analyzed herein have not yet been linked to adult GCTs in humans, 1) other components of these pathways may be altered or mutated, 2) these mutations may relate to juvenile GCTs or 3) they may occur in tumors of other tissues where CTNNB1 is mutated. Importantly, our results provide strong evidence that CTNNB1 is the driver in these contexts and that KRASG12D and Pten loss promote the program set in motion by the CTNNB1.
PMCID: PMC3223552  PMID: 21860425
CTNNB1; KRAS; PTEN; granulosa cell tumor; ovary; testis
22.  Refractory Hypertension and Isosexual Pseudoprecocious Puberty Associated with Renin-Secreting Ovarian Steroid Cell Tumor in a Girl 
Journal of Korean Medical Science  2011;26(6):836-838.
Steroid cell tumor, not otherwise specified (NOS), are rare ovarian tumor, in addition, it is more rare in children. The majority of these tumors produce several steroid hormones, particularly testosterone. Estrogen also secreted by steroid cell tumor, NOS, but it is uncommon. Furthermore, hypertension is an infrequent sign in steroid cell tumor, NOS. An 8.5-yr-old girl with hypertension and frequent vaginal spotting visited at our clinic. On laboratory evaluation, secondary hypertension due to an elevated plasma renin level and isosexual pseudoprecocious puberty was diagnosed. Right solid ovarian mass was detected in radiologic tests. She underwent a right ooporectomy and it revealed renin and progesterone receptor positive steroid cell tumor, NOS. After operation, her blood pressure returned to normal level and vaginal bleeding disappeared. Even though this case is very rare, when hypertension coincides with virilization or feminization, a renin-secreting ovarian steroid cell tumor, NOS, should be considered.
PMCID: PMC3102882  PMID: 21655074
Pseudo-Precocious Puberty; Hypertension; Ovarian Neoplasms; Renin-Secreting Tumor
23.  Causes and Types of Precocious Puberty in North-West Iran 
Iranian Journal of Pediatrics  2012;22(4):487-492.
Precocious puberty is of concern because of the underlying disorders, the short adult stature, and the psychosocial difficulties. This study was carried out in order to evaluate the characteristics of children referred to pediatric endocrinology clinic with diagnosis of precocious puberty.
In a cross-sectional study between February 2007 and September 2009, all of the children referred to pediatric endocrinology clinic in North-West Iran with diagnosis of precocious puberty were recruited.
Data of 106 girls (82.2%) and 23 boys (17.8%) were analyzed. Mean age of the patients at the time of referral was 6.6±2.8 years (ranging 0.3-14 yr), which was 7±3.9 (ranging 0.3-14 yr) for boys and 6.6±2.5 (ranging 0.8-12 yr) for girls (P=0.6). Out of 129 subjects, 56(43.4%) had precocious puberty, 71.4% (35 cases) of them were due to central precocious puberty and 28.6% (16 cases) were pseudo-precocious puberty. 73 out of 129 subjects (56.6%) were due to normal variants of puberty, normal puberty, and no puberty. 87.5% of subjects with central precocious puberty were idiopathic.
Most of children referred with diagnosis of precocious puberty have benign normal variants. Most of cases with precocious puberty are affected with central precocious puberty, especially with idiopathic form of it.
PMCID: PMC3533149  PMID: 23430037
Puberty; Precocious Puberty; Etiology; Children; Thelarche; Adrenarche; Menarche
24.  Extraovarian Granulosa Cell Tumor of Mesentery: A Case Report 
Extraovarian granulosa cell tumor (GCT) is a very uncommon tumor, assumed to arise from the ectopic gonadal tissue along the embryonal route of the genital ridge. A 54 years old female patient presented with a mass and acute pain in abdomen. Exploratory laparatomy revealed hemoperitoneum with a large mesenteric mass measuring 13 × 12 cm in size, showing extensive areas of haemorrhages. Histopathological examination of the excised mass showed features of adult-type GCT. As the patient had a history of hysterectomy with bilateral salpingo-oophorectomy 10 years ago for ‘‘leiomyoma” with no evidence of GCT of the ovary in the histopathology report, a diagnosis of extraovarian GCT was made. A diagnosis of extraovarian GCT should be carried out after excluding any previous history of GCT of the ovary. Tumor rupture with haemoperitoneum is a well-known complication of GCT. Extraovarian GCT is a rare tumor with only 10 cases reported in literature. The case is presented for its rarity.
PMCID: PMC2997286  PMID: 21152176
25.  Pathological and Incidental Findings on Brain MRI in a Single-Center Study of 229 Consecutive Girls with Early or Precocious Puberty 
PLoS ONE  2012;7(1):e29829.
Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed.
To evaluate the outcome of brain MRI in girls referred with early signs of puberty in relation to age at presentation as well as clinical and biochemical parameters.
A single-center study of 229 consecutive girls with early or precocious puberty who had brain imaging performed. We evaluated medical history, clinical and biochemical factors, and four groups were defined based on the outcome of their MRI.
Thirteen out of 208 (6.3%) girls with precocious puberty, but no other sign of CNS symptoms, had a pathological brain MRI. Importantly, all 13 girls were above 6 years of age, and 6 girls were even 8–9 years old. Twenty girls (9.6%) had incidental findings on brain MRI. Furthermore, 21 girls had known CNS pathology at time of evaluation. Basal LH was significantly higher in girls with newly diagnosed CNS pathology compared to girls with a non-pathological MRI (p = 0.025); no cut of value was found as values overlapped.
A high frequency of 6–8 year old girls with precocious puberty in our study had a pathological brain MRI, which could not be predicted from any clinical nor biochemical parameters. Thus, we believe that girls with precocious pubertal development of central origin before 8 years of age should continue to be examined by a brain MRI.
PMCID: PMC3257249  PMID: 22253792

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