Juvenile Granulosa and Theca Cell Tumor of the Ovary as a Rare Cause of Precocious Puberty: Case Report and Review of Literature

BackgroundThe differential diagnosis for precocious puberty in a young female includes peripheral causes. This case documents a rare cause of peripheral precocious puberty—a juvenile granulosa and theca cell ovarian tumor—and a brief review of the literature for this tumor type.CaseA 7-year-old girl presented with rapid onset of pubertal development and elevated estradiol levels. Menarche occurred 5 months after thelarche. A thorough workup revealed a large multicystic left ovary. Other causes of precocious puberty were excluded. She underwent an exploratory laparotomy and left salpingo-oophorectomy. Pathology reported a juvenile granulosa and theca cell tumor of the ovary, FIGO stage 1A. Postoperatively, she experienced a cessation of vaginal bleeding and estradiol levels normalized. A literature review found that early stage disease has an excellent prognosis and that adjuvant chemotherapy is not indicated in this setting.Summary and ConclusionJuvenile granulosa and theca cell tumor of the ovary is a rare cause of peripheral precocious puberty, even more so than juvenile granulosa cell tumor, due to the theca component. Treatment is surgical and an excellent prognosis is possible for early stage disease.     

The natural history of endocrine function and spermatogenesis in Klinefelter syndrome: what the data show

Once thought to be a chromosomal aberration associated with absolute sterility, Klinefelter syndrome may now be potentially treatable by testicular sperm retrieval coupled with intracytoplasmic sperm injection. With these therapeutic advances, azoospermic 47,XXY men now may have an opportunity for biological paternity. However, our knowledge of the basic mechanisms underlying germ cell loss and Leydig cell compromise is lagging, and is just now beginning to evolve and provide answers to some of the field's most vexing questions: how to maximize and preserve fertility in Klinefelter males many years or even decades before they wish to actively pursue fatherhood. This article reviews the development of the androgenic and spermatogenic compartments of the Klinefelter testis through puberty, and recommends that it is only with a clear understanding of the basic facts that a rational, considered approach to fertility optimization and preservation can be determined.     

Diagnosis and management of precocious puberty in atypical presentations of McCune-Albright syndrome: a case series review

BackgroundMcCune-Albright syndrome is a rare syndrome, classically defined as the triad of precocious puberty, fibrous dysplasia of bone, and café au lait lesions. Partial or atypical presentations of McCune-Albright syndrome, with only one or two of the classic symptoms, have been described in the literature and remain particularly challenging due to lack of diagnostic phenotype. In these patients, the utility of analysis of mutations in the gene of the α subunit of the stimulatory G-protein is limited and so the diagnosis is often based on clinical judgment. Three atypical cases of suspected McCune-Albright syndrome with gonadotropin-independent precocious puberty are presented.CasesCase #1: A 5-year-old female presented with painlesss vaginal bleeding and was found to have café au lait lesions. She was diagnosed with gonadotropin independent precocious puberty with eventual progression to gonadotropin dependent precocious puberty which was successfully treated with both letrozole and gonadotropin-releasing hormone agonist therapy. Case #2: A 3-year-old female presented with painless vaginal bleeding and was found to have café au lait lesions. She was diagnosed with gonadotropin independent precocious puberty and was successfully treated with letrozole. Case #3: A 5-year-old female presented with fibrous dysplasia and was found to have evidence of uterine and ovarian enlargement on ultrasound. She was diagnosed with gonadotropin-independent precocious puberty and was successfully treated with letrozole.Summary and ConclusionAlthough different in presentation, all three atypical cases of suspected McCune-Albright syndrome with gonadotropin-independent precocious puberty were successfully treated with aromatase inhibitors. This small case series shows the utility and efficacy of aromatase inhibitors in the setting of atypical cases of suspected MAS with gonadotropin-independent precocious puberty.     

Van Wyk and Grumbach syndrome: an unusual form of precocious puberty

An 8-year-old girl presented with precocious menstruation and growth delay. Laboratory data revealed hypothyroidism and an X-ray of the wrist showed a delayed bone age. The Van Wyk and Grumbach syndrome (VWGS) was diagnosed and thyroid replacement was started with resolution of the symptoms. The association of precocious puberty and/or polycystic ovaries, delayed bone age and hypothyroidism is known as the Van Wyk and Grumbach syndrome. Clinically this syndrome is a diagnostic challenge because hypothyroidism usually leads to pubertal and growth delay, whereas in case of VWGS hypothyroidism it leads to growth delay and precocious puberty. The pathophysiology of VWGS is not yet clear, but the most accepted theory states that the high concentrations of TSH are sufficient to cause activation of the FSH receptor and produce gonadal enlargement. Thyroid replacement therapy results in a resolution of all signs and symptoms. For this reason, conservative management of the ovarian masses is advocated. Our case is unique as this girl did not have breast development or multicystic ovaries (as the other cases in the literature). This may be due to an early recognition and relatively low TSH levels in comparison to other cases.     

Sertoli Cell Tumor Causing Precocious Puberty in a Girl with Peutz-Jeghers Syndrome

Distinctive ovarian and cervical tumors are associated with Peutz-Jeghers syndrome (PJS). The most common gynecological tumors in this syndrome are adenoma malignum of the uterine cervix and ovarian sex cord tumor, particularly sex cord tumor with annular tubules (SCTAT). Other kinds of ovarian tumors have been rarely reported in association of PJS, including Sertoli cell tumors. We report a case of a 4.5-year-old girl with PJS who presented with isosexual precocious puberty (IPP) due to ovarian lipid-rich Sertoli cell tumor. In addition to estrinizing effect of the tumor, the patient had decidual reaction secondary to tumor-derived progesterone secretion. The literature on gonadal tumors in PJS is reviewed, including one previous report of ovarian lipid-rich Sertoli cell tumor associated with this syndrome.     

Giant multilocular sex cord tumor with annular tubules associated with precocious puberty

We report a case of sex cord tumor with annular tubules featuring a giant multilocular cyst, grossly similar to cystadenoma, in the ovary of an 8.5 year old girl. Estrogen-related symptoms, including precocious puberty and irregular uterine bleeding, immediately improved after tumor resection.     

Dysgerminoma of the ovary with precocious puberty: A case report

Ovarian dysgerminoma is usually hormonally inert, but when it contains syncytiotrophoblastic giant cells or undergoes malignant transformation, the level of estradiol might be elevated. A 6-year-old girl contracted ovarian dysgerminoma with precocious puberty, and her levels of β-human chorionic gondaotropin, α-fetoprotein and estradiol were high. After resection of the tumor, levels of tumor markers became normal and precocious puberty disappeared. We report this unusual type of dysgerminoma with a brief review of the literature.     

Dysgerminoma of the ovary with precocious puberty: a case report.

Ovarian dysgerminoma is usually hormonally inert, but when it contains syncytiotrophoblastic giant cells or undergoes malignant transformation, the level of estradiol might be elevated. A 6-year-old girl contracted ovarian dysgerminoma with precocious puberty, and her levels of beta-human chorionic gondaotropin, alpha-fetoprotein and estradiol were high. After resection of the tumor, levels of tumor markers became normal and precocious puberty disappeared. We report this unusual type of dysgerminoma with a brief review of the literature.     

Precocious puberty

Precocious puberty is an early sexual maturation before the age of 8 in case of girls and 9 in boys. There are two types: isosexual precocious puberty--characteristic are appropriate for the child's genetic and gonadal sex; and heterosexual precocious puberty--sexual characteristic are inappropriate for the genetic sex (feminizing syndrome in boys or virilizing syndrome in girls). Precocious puberty is an important problem in childhood gynecology pediatrics, endocrinology and psychology.     

The genetic origin of Klinefelter syndrome and its effect on spermatogenesis

Klinefelter syndrome is the most prevalent chromosome abnormality and genetic cause of azoospermia in males. The availability of assisted reproductive technology (ART) has allowed men with Klinefelter syndrome to father their own genetic offspring. When providing ART to men with Klinefelter syndrome, it is important to be able to counsel them properly on both the chance of finding sperm and the potential effects on their offspring. The aim of this review is twofold: [1] to describe the genetic etiology of Klinefelter syndrome and [2] to describe how spermatogenesis occurs in men with Klinefelter syndrome and the consequences this has for children born from men with Klinefelter syndrome.     

No Activating Mutations of FSH Receptor in Four Children with Ovarian Juvenile Granulosa Cell Tumors and the Association of These Tumors with Central Precocious Puberty

Study ObjectiveThe stimulation of the follicle-stimulating hormone receptor (FSHR) by circulating FSH or some activating mutations of the FSHR may play a causal role in the development of granulosa cell tumors of ovaries.Study designWe evaluated four patients with ovarian juvenile granulosa cell tumors (age range, 2.4 to 7.2; median, 2.9 years) and five healthy pubertal girls (age range, 16 to 18.5; median, 16.8 years) for activating mutations in exon 10 of the FSHR. The patients were followed and evaluated clinically. Genomic DNA was extracted from the peripheral blood. Exon10 of the FSHR was evaluated for mutations.ResultsAll four patients presented with signs of precocious puberty. One patient, who had markedly accelerated growth velocity and advanced bone age, developed central precocious puberty after the removal of her tumor. Another patient was diagnosed to have a left ovarian cyst without tumor recurrence approximately 3.3 years after the removal of the tumor. Activating mutations were not found, but previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in three of four patients and in three of five controls. The follow-up period of these four patients ranged from 4.5 to 8.8 years, with a median value of 6.7 years.ConclusionsWe did not find any activating mutation in exon 10 of the FSHR in our patients, and one patient developed precocious puberty after removal of her tumor. The development of ovarian tumors in these patients may have been caused by mutations at other exons of the FSHR and G protein subunits, so the association noted between central precocious puberty and granulosa cell tumors might not be coincidental.     

Hyperprolactinaemia in a patient with the McCune-Albright Syndrome

A patient is presented with the syndrome of polyostotic fibrous dysplasia and precocious puberty (McCune-Albright Syndrome). In adult life she developed hyperprolactinaemia with galactorrhoea and amenorrhoea; there was also evidence of excessive secretion of growth hormone.     

Proteus syndrome: a possible case associated to precocious puberty.

We report a boy with possible Proteus syndrome and precocious puberty. This appears to be the first report of this association.     

中国城市儿童性早熟现状的调查研究

目的对国内城市儿童性早熟现状进行调查,为制定有效的预防策略,并推动儿童性早熟的临床规范化和个性化治疗提供理论依据。方法 2014年3月至12月在全国范围内开展"中国城市儿童性早熟现状调研"活动。调研共收集来自全国10余省市的2 687份问卷,其中1 714份问卷纳入统计分析。结果调查人群大多分布在全国10个主要省市,包括北京、上海、重庆、江苏、湖北等;调查患儿以女童为主,其男女比例约1∶16。诊断为中枢性性早熟的患者占75.79%(1 299/1 714);调查中初次诊断为中枢性性早熟患者占88.91%(1 524/1 714)。调查患者的骨龄为(10.00±1.77)岁,高于实际年龄(8.29±1.60)岁,差异有统计学意义(P0.001);初次诊断为CPP的患者的骨龄为(10.11±1.70)岁,高于实际年龄(8.35±1.57)岁,差异均有统计学意义(P0.001)。结论国内城市儿童性早熟就诊患者的年龄偏大,为防止患者就诊时已错过最佳的干预和治疗时机,应引起对疾病筛查的高度重视,做到早发现、早诊断和早治疗。     

Do Most 7- to 8-Year-Old Girls with Early Puberty Require Extensive Investigation and Treatment?

Study ObjectiveTo investigate the etiology, progression, and treatment of precocious puberty in 7- to 8-year-old girls with breast development. Additionally, we evaluated the value of diagnostic tests in differentiating rapidly progressive precocious puberty (RP-PP) and slowly progressive precocious puberty (SP-PP) in these girls.DesignAmbispective cohort study.SettingSingle-center, pediatric endocrinology unit.ParticipantsGirls with breast development between the ages of 7 and 8 years and assessed between July 2016 and July 2018.InterventionsCollected of clinical data and followed-up for 2 to 3 years. Girls were divided into RP-PP and SP-PP groups.Main Outcome MeasuresDescribed the etiology, rate of progression of puberty, and proportion intervened and compared the results of auxiliary examinations between the groups.ResultsA total of 212 girls were enrolled, of which 211 (99.53%) were diagnosed with central precocious puberty (CPP) and 1 with peripheral precocious puberty (PPP). Hypophysis magnetic resonance imaging revealed that none had pathological brain lesions requiring surgical intervention. A total of 95 girls (44.81%) developed RP-PP, and 117 girls (55.19%) developed SP-PP. A total of 31 girls (14.62%) with RP-PP received treatment due to deteriorated predicting adult height. As compared with the SP-PP group, the RP-PP group showed more advanced bone age (BA), a higher level of basal luteinizing hormone (LH), and larger ovarian volume and uterine volumes. Receiver operating characteristic analyses revealed that BA was the best at identifying girls with RP-PP.ConclusionThe majority of girls with breast development between the ages of 7-8 years do not need treatment. BA is a useful preliminary test for identifying girls with RP-PP who are more likely to require treatment.     

Clinical expression of precocious pubertal development in girls

The paediatric endocrinologist is frequently asked whether pubertal development in a girl is normal, early or too early (precocious). This review will cover all clinical expression of premature development of puberty: central precocious puberty (neurogenic, secondary, and idiopathic) where treatment with GnRHa is considered, early puberty, partial puberty or pubertal variants and peripheral or pseudo precocious puberty related to an antonomous hypersecretion of estrogens by the ovaries. A special attention should be paid also to the role of environmental disruptors in the development of peripheral precocious puberty. GnRHa treatment should be considered only when evidence of central activation of the gonadotropic axis is proved by the LHRH-test.     

Pubertal disorders in inv dup(15) syndrome

Duplication of chromosome 15 (inv dup[15] chromosome) is the most common supernumerary marker chromosome in humans. Inv dup(15) chromosomes are commonly associated with mental retardation ,epilepsy ,behavioral problems and structural malformations. Ten patients (4 male ,6 female) were detected with inv dup(15) syndrome. At clinical follow-up three girls showed pubertal disorders: two with central precocious puberty and one with ovarian dysgenesis. As has already been found in other patients with chromosome 15p abnormalities ,we believe that gynecological disorder is an important clinical finding also in patients with inv dup(15) syndrome. We report the first data of a systematic endocrinological study on inv dup(15) syndrome which suggest that endocrine investigation in these patients is both warranted and useful. Moreover ,our observations confirm that a karyotype analysis in patients in whom precocious puberty is associated with mental retardation is mandatory.     

Pubertal disorders in inv dup(15) syndrome.

Duplication of chromosome 15 (inv dup[15] chromosome) is the most common supernumerary marker chromosome in humans. Inv dup(15) chromosomes are commonly associated with mental retardation, epilepsy, behavioral problems and structural malformations. Ten patients (4 male, 6 female) were detected with inv dup(15) syndrome. At clinical follow-up three girls showed pubertal disorders: two with central precocious puberty and one with ovarian dysgenesis. As has already been found in other patients with chromosome 15p abnormalities, we believe that gynecological disorder is an important clinical finding also in patients with inv dup(15) syndrome. We report the first data of a systematic endocrinological study on inv dup(15) syndrome which suggest that endocrine investigation in these patients is both warranted and useful. Moreover, our observations confirm that a karyotype analysis in patients in whom precocious puberty is associated with mental retardation is mandatory.     

A case of mosaic Klinefelter syndrome associated with isodicentric Yp

We describe a case of mosaic Klinefelter syndrome demonstrating an isodicentric Y chromosome. A 70-year-old man visited our outpatient clinic complaining of dysuria resulting from atrophy of the penis. His height was 170 cm and his weight was 60 kg. A serum hormonal analysis revealed hypergonadotropic hypogonadism. A chromosomal analysis with fluorescence in situ hybridization revealed four cell lines in which the karyotypes were 47,XXY, 46,XY, 46,XX and 47,XX,idic(Y) (q11.2). To the best of our knowledge this is the first case of mosaic Klinefelter syndrome bearing an isodicentric Y chromosome. The origin of the isodicentric Y is discussed.     

Adult height of patients with classical congenital adrenal hyperplasia.

BACKGROUND AND PURPOSE: Data on factors that affect the final height of patients with classical congenital adrenal hyperplasia (CAH) are limited. This study investigated the factors that can affect height outcome of patients with classical CAH. METHODS: A retrospective study of 44 patients (16 males, 28 females) with classical CAH who had attained the adult height without gonadotropin-releasing hormone analog therapy was conducted. Adult height standard deviation scores (AHSDS) and target height standard deviation scores (THSDS) were determined. The impact of type, gender, control of disease activity or occurrence of precocious puberty on height was analyzed. RESULTS: The difference between AHSDS and THSDS of the 44 patients was -0.7 +/- 1.0 and was greatest in simple-virilizing males (-1.1 standard deviation score [SDS]). However, no significant differences in height outcomes were identified between genders and types. The differences between AHSDS and THSDS of patients with good control of disease activity or normal puberty were -0.3 SDS and -0.4 SDS, respectively, which were better height outcomes than those of the other groups (p < 0.05). CONCLUSIONS: Classical CAH can lead to reduced adult height. Good control of disease activity and the prevention of the occurrence of precocious puberty is important to achieving normal adult height outcome.