外周性性早熟患儿的病因及预后随访

目的：探讨外周性性早熟的病因及预后。方法：应用简化的促性腺激素释放激素（GnRH）激发试验测定卵泡刺激素（FSH）及黄体生成素（LH）、雌二醇（E2）水平,并采用B超检查及骨龄检测等方法对125例外周性性早熟患儿进行病因诊断。随访病例102例,随访时间3个月至7.5年。结果：125例患儿的病因分布为：摄入外源性性激素80例,卵巢囊肿11例,McCune Albright 综合征11例,先天性肾上腺皮质增生症（CAH）5例,卵巢畸胎瘤、男性化肾上腺肿瘤、女性化肾上腺肿瘤、垂体柄肿瘤各1例,另有14例患儿病因尚不能确定。预后：摄入外源性性激素者随访72例,均在1～6个月性征消退;11例卵巢囊肿患儿中,8例1~4个月性征自行消退,但其中1例2年3个月后转为中枢性性早熟;1例囊肿切除术后性征消退;卵巢畸胎瘤者术后性征消退;McCune Albright 综合征及CAH者治疗后临床症状减轻,7例转为中枢性性早熟;2例肾上腺肿瘤术后性征消退;1例垂体柄肿瘤术后1年死亡。结论：外周性性早熟病因多样,详细的病史、体检、辅助检查有助于早期明确诊断,不同病因预后不同。     

Tamoxifen improved final height prediction in a girl with McCune-Albright syndrome: patient report and literature review

McCune-Albright syndrome (MAS) is characterized by gonadotropin-independent precocious puberty, café-au-lait spots on the skin and polyostotic fibrous dysplasia of bones. Treatment of precocious puberty (PP) in MAS should be considered in patients with poor predicted adult height (PAH). Treatment of gonadotropin-independent PP in MAS with ketoconazole, cyproterone acetate or testolactone, an aromatase inhibitor, does not appear to be always effective in slowing bon. maturation. We report here a Thai girl with MAS who received tamoxifen, one of the selective estrogen receptor modulators, for the management of advanced puberty and rapid bone maturation. Her pubertal progression, vaginal bleeding, growth rate and PAH improved during treatment with tamoxifen despite persistently elevated serum estradiol levels and an enlarged ovarian cyst.     

A Case of Atypical McCune-Albright Syndrome with Vaginal Bleeding

Background

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.

Conclusion

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.     

Recurrent ovarian cyst and mutation of the Gsα gene in ovarian cyst fluid cells: what is the link with McCune-Albright syndrome?*

Isolated peripheral precocious puberty due to recurrent ovarian cysts evokes a McCune-Albright syndrome (MAS). This syndrome associates endocrine dysfunction such as precocious puberty, polyostotic fibrous dysplasia, and ‘’café-au-lait“ skin lesions. We report the case of a 3-y-old girl who presented with peripheral puberty with extremely elevated oestradiol level, low LH and FSH levels, and an ovarian cyst that quickly resolved. Skeletal X-rays were normal and she had no café-au-lait spots. GnRH analogue treatment was ineffective. A second ovarian cyst appeared and was completely drained under ultrasonographic guidance. Molecular biological analysis performed on fluid cells revealed the Arg201→His mutation of the Gsa gene described in MAS. Percutaneous aspiration of simple ovarian cyst to detect‘’MAS” mutation is of interest in the diagnosis of recurrent ovarian cyst.     

Pubertal development in patients with McCune-Albright syndrome or pseudohypoparathyroidism

Gain or loss of function mutations of the GNAS1 gene lead to McCune-Albright syndrome (MAS) or pseudohypoparathyroidism Ia (PHP-Ia), respectively. Patients with MAS, caused by a post-zygotic missense mutation leading to constitutive activation of Gs alpha, suffer from gonadotropin-independent precocious puberty, and delayed or incomplete sexual development and reproductive dysfunction is found in women with PHP-Ia, an inherited disorder caused by deficient expression or function of the Gs alpha protein. In females with MAS, 50% developed precocious puberty by the age of 4 years, the remaining between 4 and 8 years. Peripheral precocious puberty is often atypical and characterized by alternate periods of rapid progression and regression of pubertal development; menstrual bleeding may occur before breast development. Ovarian cyst growth and regression is often described as a sign of ovarian follicle hyperactivation. Notwithstanding this clinical heterogeneity, a subset of patients with MAS develop relentlessly progressive precocious puberty ultimately resulting in premature epiphyseal fusion and reduced adult stature. Long-term information on reproductive function has been obtained in females: some patients had regular menses without ovarian cysts on pelvic US scan, whereas others were oligomenorrheic and showed recurrent ovarian cysts. In males with MAS, precocious puberty occurred in three patients between 4 and 9 years of age. In one patient, long-term follow-up demonstrated normal plasma testosterone and gonadotropin values at the age of 17 years. On testicular sonography, multiple hyperechogeneic spots were found in both testicles (snow-storm appearance). Female patients with PHP-Ia were oligomenorrheic or amenorrheic; more than half had delayed or incomplete sexual development, They were mildly hypoestrogenic with normal to slightly elevated serum gonadotropin levels. These clinical and biochemical findings indicate partial resistance of the theca and granulosa cells of the ovary to gonadotropins due to deficient Gs alpha activity. Responsiveness might be sufficient to promote some degree of follicular development and steroid secretion, but insufficient to induce ovulation     

McCune-Albright syndrome associated with pituitary microadenoma: patient report

McCune-Albright syndrome (MAS) is a rare disorder characterized by the classic triad of precocious puberty, polyostotic fibrous dysplasia and café-au-lait spots. Additional endocrine abnormalities may also be present, including hyperthyroidism, growth hormone excess and hyperprolactinemia. The most commonly encountered endocrine dysfunction is gonadal hyperfunction. Gonadotropin-independent precocious puberty is typically the initial manifestation of MAS in girls. Ovarian cysts may be detected on pelvic ultrasound. Our patient was also found to have pituitary microadenoma, evidenced by dynamic magnetic resonance imaging.     

Effective aromatase inhibition by anastrozole in a patient with gonadotropin-independent precocious puberty in McCune-Albright syndrome

Testolactone is used to treat conditions with excessive estrogen synthesis, e.g. gonadotropin-independent precocious puberty in McCune-Albright syndrome (MAS). Unfortunately, daily treatment with testolactone requires 3 to 4 doses (10-20 tablets) and even at these doses it is sometimes ineffective. We treated a patient with MAS (café-au-lait spots; thelarche at age 2- 6/12 yr; menarche at 5- 5/12 yr; accelerated bone age [BA 10 yr]) with the highly selective aromatase inhibitor anastrozole (1 mg once per day). Tamoxifen 1 mg/kg per day was added for 1 year but was discontinued when an ovarian cyst developed with markedly elevated estradiol levels. Estradiol levels returned to normal after resuming anastrozole-only treatment and accelerated BA progressed only 6 months during 2 1/2 years of treatment. The potent estrogen suppressive action and simple dosage regimen of anastrozole suggest it may be advantageous compared to other aromatase inhibitors such as testolactone or anti-estrogens.     

Isosexual Precocious Puberty in Girls

ABSTRACT. This paper reviews the clinical findings, pituitary gonadotrophin reserve and plasma oestradiol, neurological findings and pelvic ultrasound appearance in 47 girls with precocious puberty starting before the age of 7 years. Of the 39 girls who had air encephalograms or cranial CT scans, 19 showed intracranial abnormalities (hamartomas 11; hydrocephalus 5; optic glioma 2; arachnoid cyst 1). There was no significant difference in the peak serum luteinizing hormone and follicle-stimulating hormone responses to intravenous gonadotrophin stimulating hormone in girls with and without intracranial lesions. Pelvic ultrasound examination showed development of the ovaries, uterus, and vagina similar to that seen in normal puberty. Treatment with cyproterone acetate (50-100 mg/day) in 26 girls resulted in arrest of breast development and suppression of menstruation, but a definite effect on growth was not documented.     

Partial benefit of anastrozole in the long-term treatment of precocious puberty in McCune-Albright syndrome

We report a long-term follow-up on the use of anastrozole in the treatment of peripheral precocious puberty (PP) in McCune-Albright syndrome (MAS). A girl, age 3 years and 9 months, was diagnosed with MAS due to PP, café-au-lait spots, and polyostotic fibrous dysplasia. Serum estradiol was elevated, and gonadotropins were suppressed. Pelvic ultrasound showed an enlarged uterus and a follicle cyst (13 mm) in the left ovary. Bone scintigraphy showed osteogenic lesions on the skull, humerus, tibia, and acetabulum. Bone age was 3 years and 5 months at the chronological age of 3 years. After 36 months of treatment with anastrozole (1 mg/day), there was suppression of breast growth, normalization of growth velocity and serum estradiol, and disappearance of ovarian cysts. However, there was increase in uterine volume, advancement of bone age, and two episodes of vaginal bleeding (18th and 24th months). This report shows the partial benefit of anastrozole in the treatment of peripheral PP of girls with MAS.     

Effects of leuprolide in the treatment of central precocious puberty

Leuprolide acetate (D-Leu6 des-Gly-NH2(10), Pro-ethylamide9), a synthetic non-apeptide analog of naturally occurring gonadotropin releasing hormone, was used to treat 62 children with central precocious puberty. Sex steroid levels (testosterone in boys and estradiol in girls) were suppressed during treatment lasting from 3.5 to 24.9 months. Basal follicle-stimulating hormone values and both luteinizing hormone and follicle-stimulating hormone peak responses to stimulation by luteinizing hormone releasing hormone were also suppressed, although basal luteinizing hormone values did not differ. Linear growth rate and the rate of bone age advancement decreased during leuprolide therapy. Side effects were minimal. The long-term safety of this treatment has not yet been established; however, leuprolide appears to be an effective long-term therapy for central precocious puberty.     

Growth hormone secretory dynamics in children with precocious puberty

We investigated whether an increase in growth hormone secretion contributed to the growth spurt in children with precocious puberty by measuring the 24-hour profile of serum growth hormone in 51 patients with central precocious puberty. Girls with central precocious puberty had significantly greater mean 24-hour levels of growth hormone in comparison with normal prepubertal girls (5.1 +/- 0.5 SEM vs 3.4 +/- 0.3 ng/mL, P less than 0.005). Mean 24-hour growth hormone levels did not differ significantly between boys with central precocious puberty and normal prepubertal boys (4.4 +/- 1.2 vs 3.0 +/- 0.4 ng/mL). Serum somatomedin C levels were significantly correlated with mean 24-hour growth hormone levels in the girls only. Height age advancement (expressed as height age/chronologic age) was significantly correlated with mean 24-hour growth hormone levels in both boys and girls with central precocious puberty. We conclude that spontaneous 24-hour growth hormone secretion in girls with precocious puberty is greater than that of normal prepubertal girls and may mediate at least in part the increased growth rate in this disorder.     

Somatomedin-C in accelerated growth of children with precocious puberty

To assess the role of somatomedin-C as a possible mediator of the growth spurt in children with central precocious puberty, we compared Sm-C levels in 40 children with central precocious puberty, 87 age-matched normal children, and 110 normal pubertal controls. Somatomedin C levels were significantly elevated for age in the children with precocious puberty (P less than 0.01), and were similar to the levels observed during normal puberty. The patients with precocious puberty were given the luteinizing hormone releasing hormone analogue D-Trp6-Pro9-NEt-LHRH (LHRHa) for 6 months. Treatment caused a significant decrease in secondary sexual characteristics, growth rate, plasma gonadotropins, sex steroids (estradiol in the girls and testosterone in the boys), and Sm-C levels. Growth during LHRHa treatment returned to the age-appropriate rate, whereas plasma Sm-C levels, although lower than pretreatment levels, remained significantly elevated for age (P less than 0.002). In addition, growth rates before and during treatment did not correlate with the plasma somatomedin C levels, nor did the decreases in growth rate during LHRHa therapy correlate with the decreases in somatomedin C levels. Growth rates did correlate significantly, however, with plasma estradiol levels in the girls (P less than 0.0005) and with plasma testosterone levels in the boys (P less than 0.025). We conclude that the growth spurt in children with precocious puberty cannot be explained by the plasma level of somatomedin C.     

Precocious puberty caused by a suprasellar arachnoid cyst. Analysis of 6 cases

The authors report 6 cases (4 girls and 2 boys) with central precocious puberty associated with a suprasellar arachnoid cyst. Precocious puberty is rarely the presenting sign of arachnoid cysts. It was characterized by early onset, patent symptoms and frequent association (3 of 6 cases) with growth hormone deficiency. The latter represents a further risk of short stature. Evolution of precocious puberty varied from one case to another, without any relation with the quality of control of the arachnoid cyst and associated hydrocephalus. Half-yearly follow-up of height and bone age allowed for deciding a suppressive treatment of precocious puberty and a substitutive growth hormone therapy when needed.     

McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age

Gonadal hyperfunction is the most frequent endocrine dysfunction in females with McCune-Albright syndrome (MAS). Peripheral precocious puberty is usually the first MAS manifestation in children, characterized by episodes of hypersecretion of estrogens with a consequent reduction in gonadotropin secretion. Little is known about the course of this endocrine disease in adolescence and during young adult life. The aim of this study was to evaluate ovarian function in 10 females with MAS (age 11.4-20.1 years) to detect the persistence of autonomous ovarian hyperfunction throughout and following adolescence, after at least 1 year wash out of any treatment for precocious puberty. LH, FSH, estradiol, prolactin, androgen secretion, ovarian and breast sonography in luteal and follicular phases of some menstrual cycles were evaluated. We demonstrated the persistence of some ovarian autonomy, documented by hyperestrogenism and/or low or absent gonadotropin secretion and/or ovarian cysts.     

Advanced bone age as an indicator facilitates the diagnosis of precocious puberty

Objective

Diagnosis of central precocious puberty has always been challenging in clinical practice. As an important method in the diagnosis of central precocious puberty, luteinizing hormone-releasing hormone stimulation test is complex and time-consuming. In many cases, clinical traits are inconsistent with luteinizing hormone-releasing hormone stimulation test results, therefore not reliable for diagnosis. In this study, the authors intended to find an indicator that predicts the results of the luteinizing hormone-releasing hormone stimulation test among subjects with early pubertal signs.

The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing hormone releasing hormone analogue therapy

Between 1979 and 1983, 129 children (95 girls) with precocious puberty were referred to the National Institutes of Health and received treatment for at least 6 months with the long-acting LHRH analogue D-Trp6-Pro9-NEt-LHRH. The majority (107 of 129) of the children had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis in association with hypothalamic hamartomas (24 of 107) or other central nervous system lesions (21 of 107), or idiopathic precocious puberty (62 of 107). Hypothalamic hamartomas or other central nervous system lesions were a frequent cause of central precocious puberty in girls (27 of 87), but idiopathic precocious puberty was still the most frequent diagnosis (63%). Idiopathic precocious puberty was uncommon in boys (6%). The patients with peripheral precocious puberty included six girls with McCune-Albright syndrome and six boys with familial male precocious puberty. These children had peripheral sex steroid secretion in the absence of hypothalamic-pituitary-gonadal axis maturation. The children with combined peripheral and central precocious puberty included nine children with congenital adrenal hyperplasia and one girl with a virilizing adrenal tumor. In the patients with central precocious puberty or combined peripheral and central precocious puberty, LHRHa therapy caused suppression of gonadotropin and sex steroid levels (P less than 0.001), stabilization or regression of secondary sexual characteristics, and decreases in growth rate and in the rate of bone age maturation (P less than 0.005). Patients with peripheral precocious puberty, however, had no significant change in gonadotropin or sex steroid levels, growth rate, or the rate of bone age maturation, and no improvement in secondary sexual characteristics. Thus, LHRHa is an effective treatment of central precocious puberty and combined peripheral and central precocious puberty, but is ineffective in the therapy of peripheral precocious puberty.     

Ovarian cysts in precocious puberty

We describe a 7-year-old girl with precocious puberty in whom a single large cyst (5 cm) and several small cysts (8-10 mm) in the single remaining ovary were detected by the ultrasound examination. Endocrinological examinations confirmed the diagnosis of central precocious puberty. Pathologic findings after the removal of the cystic lesions revealed that the large cyst was derived from degenerated follicular cysts and the small cysts were identical to follicular cysts: all were considered to have been formed by gonadotropin stimulation. In general, surgical removal of an ovarian follicular cyst in central precocious puberty is inappropriate. However, in this unusual patient who had a degenerated large cyst, surgery seemed to be appropriate because of a previously removed teratoma in the contralateral ovary.     

Laparoscopic management of ovarian cysts in peripheral precocious puberty of McCune-Albright syndrome

Ovarian cysts are common in peripheral precocious puberty in McCune-Albright syndrome (MAS). The clinical course of these cysts is unpredictable due to episodes of hyperestrogenism typical of MAS ovarian hyperfunction. In persistent and recurrent large ovarian cysts with sustained estrogen hypersecretion and relevant clinical disturbances (increased linear growth and bone age maturation, vaginal bleeding and psychological disturbances) treatment is mandatory. Experimental courses of estrogen-blocking drugs may have insufficient or nil therapeutic effects. In these cases and when molecular analysis is required to obtain MAS diagnosis as in isolated peripheral precocious puberty, surgery is the option. Laparoscopy minimizes surgical aggression and facilitates obtaining tissue samples for molecular analysis, and sometimes relieves hyperestrogenism with the excision of hyperactive ovarian areas. It can be conducted with trans-umbilical laparoscopic ovarian cystectomy (TULOC) before 3 years of age and with traditional techniques afterwards.     

Hypothyroidism-associated testicular enlargement: is it a form of precocious puberty or not? A case report

In children with untreated hypothyroidism, the onset of puberty is usually delayed, but gonadotropin-independent precocious puberty may occur in children with severe hypothyroidism of long duration. The association of hypothyroidism, delayed bone age and gonadotropin-independent precocious puberty is defined as Van Wyk Grumbach syndrome (VWGS). VWGS has been described mostly in girls, and only seldom in boys. The manifestation of VWGS in boys is only testicular enlargement without substantial Leydig cell stimulation or testosterone secretion. We report a case of testicular enlargement due to obvious hypothyroidism secondary to autoimmune thyroiditis in a boy who presented with obesity. With this case report, we would like to emphasize that VWGS is not a real gonadotropin- independent precocious puberty in boys as it is in girls. Additionally, we would like to emphasize that delayed bone age is a special discriminating feature for differentiation of VWGS from the other causes of precocious puberty.     

Studies of gonadotrophin pulsatility and pelvic ultrasound examinations distinguish between isolated premature thelarche and central precocious puberty

We have studied the pulsatile secretion of gonadotrophins at night and made ovarian ultrasound examinations in three girls with central precocious puberty and three with isolated premature thelarche. The three girls with precocious puberty had well-defined pulsatile secretion of LH and FSH with LH predominating, as would be expected in normal puberty. Pulsatile secretion of gonadotrophins was also seen in girls with premature thelarche but the pattern was reversed. In girls with precocious puberty, large multicystic ovaries and large uteri were seen on ultrasound examination, whereas girls with isolated premature thelarche had small uteri and ovaries with less than four cysts up to 15 mm in diameter. These data provide the key to understanding the aetiology of isolated premature thelarche.Abbreviations GnRH gonadotrophin releasing hormone - LH luteinising hormone - FSH Follicle stimulating hormone - SDS standard deviation score