罕见中枢性性早熟同患分泌绒毛膜促性腺激素的颅内生殖细胞肿瘤女性患儿1例研究报告

目的　报告１例中枢性性早熟（central precocious puberty,CPP）女性患儿同患分泌绒毛膜促性腺激素（HCG）的颅内生殖细胞肿瘤（intracranial germ cell tumor,IGCT）资料,为临床CPP的精准诊治提供理论指导。方法　总结2020年12月首次就诊于中山大学附属第一医院的1例CPP同患分泌HCG的IGCT女性患儿临床资料,并进行文献复习。结果　该例患儿7岁3月龄时出现乳房发育伴生长加速;8岁2月龄于当地诊断CPP,同时发现血β-HCG升高（56.45～20.70 IU/L）;8岁9月龄于中山大学附属第一医院就诊示血和脑脊液β-HCG均升高（分别为40.03 IU/L,103.22 IU/L）、甲胎蛋白（AFP）正常。经头颅鞍区脊髓核磁共振成像（MRI）、头颅CT、胸腺CT/MRI、腹部/盆腔B超等检查,确诊为分泌HCG的颅内非生殖细胞瘤性生殖细胞肿瘤（右侧基底节豆状核）、中枢性性早熟、松果体囊肿。予联合化疗连同促性腺激素释放激素（GnRHa）治疗CPP,后化疗不敏感,转脑科医院治疗,予松果体病变手术病理为中枢神经细胞瘤。结论　该例CPP女性患儿同患分泌HCG的IGCT为国际首例报告;其CPP的发生与该肿瘤分泌的HCG无关,与该肿瘤和松果体病变导致的中枢神经系统病变可能有关;血β-HCG及AFP检测应纳入性早熟的诊断流程的基本筛查项目。女性CPP（甚至＞6岁发病）即使无中枢神经系统异常临床表现,头颅（垂体）MRI/CT检查也是必要的。     

4岁内儿童性早熟57例

目的探讨4岁内儿童性早熟的病因、诊断要点,研究简易的促性腺激素释放激素(GnRH)激发试验的可行性。方法对57例<4岁性早熟患儿的临床资料进行回顾性分析。57例均行GnRH激发试验,对中枢性与部分中枢性组患儿的LH值进行秩和检验。结果本组男3例,女54例。外周性性早熟36例(63.1%);中枢性性早熟(CPP)4例;部分性CPP17例。CPP促黄体生成素(LH)升高为甚,50%峰值落在60~90min,部分性CPP促卵泡生成素(FSH)升高为甚,84.2%峰值落在90~120 min;CPP与部分性CPP 30、60、90、120 min LH比较有显著差异(P均<0.01)。结论<4岁儿童性早熟以女性发病为主,多为外周性性早熟。GnRH激发试验对病因分类很必需,应在0、60、120 min测LH、FSH,以明确CPP和部分性CPP。     

儿童下丘脑综合征19例临床分析

目的探讨儿童下丘脑综合征的病因及临床特点。方法收集下丘脑综合征病例19例,对其病因、首发症状及临床特点等进行分析。结果 19例患儿均存在不同程度的下丘脑功能紊乱及下丘脑—垂体—靶腺轴功能的异常。8例患儿经垂体核磁检查确诊为颅内肿瘤,其中生殖细胞瘤6例,颅咽管瘤、下丘脑错构瘤各1例;病毒性脑炎、幼年型黄色肉芽肿病(全身型)各1例,9例病因不明。在下丘脑综合征的首发症状中,多饮、多尿和摄食障碍位居前2位。结论颅内肿瘤为小儿下丘脑综合征的重要原因,其中生殖细胞瘤可能是第1位的原因。多饮多尿,摄食障碍为下丘脑综合征重要的首发症状。对中枢性尿崩症患儿、摄食障碍患儿和不明原因的下丘脑综合征患儿均应长期进行随访,定期进行垂体核磁增强扫描,以期发现随时可能出现的颅内肿瘤。     

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目的了解不同初治年龄对先天性肾上腺皮质增生症(CAH)患儿身高、骨龄、性早熟等方面的影响。方法将1982～2004年在上海新华医院和上海市儿科医学研究所内分泌、遗传代谢病专科诊治的32例CAH患儿(年龄:女≥8岁,男≥9岁),按初治年龄分为≤3岁组(14例)和>3岁组(18例),观察两组间末次复诊时骨龄与身高龄之差、性早熟例数及男女患儿发生性早熟的不同。结果14例初治年龄≤3岁患儿末次复诊时骨龄与身高龄之差[(3.0±2.0)岁]与18例>3岁组[(4.6±1.6)岁]比较差异有显著性(P<0.05),初治年龄>3岁组发生真性性早熟(9例)与≤3岁组(2例)比较差异有显著性(χ2=4.453,P<0.05)。男性患儿发生真性性早熟(9例)与女性患儿(2例)比较差异有显著性(χ2=4.794,P<0.05)。结论CAH患儿≤3岁得到诊治者其预测终身高较>3岁方诊治者明显改善,其性早熟发生率明显减少,男性CAH患儿较女性CAH患儿更易发生性早熟。     

儿童性早熟药物治疗进展

性早熟包括中枢性性早熟(CPP)和外周性性早熟(PPP)2种.1个月缓释型促性腺激素释放激素类似物(GnRHa)是CPP的标准治疗药物,较长时间缓释型GnRHa的疗效与1个月缓释型相近,而有较好的发展前景;重组人生长激素(rhGH)或氧雄龙不推荐常规用于接受GnRHa治疗的CPP患儿.PPP的治疗要根据性别、病因、药物机制等个体化,确切疗效需要更多中心观察;继发性CPP需联合应用GnRHa.     

周围性性早熟36例临床分析

目的分析儿童周围性性早熟病因和临床表现,以进一步提高对本病的认识。方法对2000-01—2007-03在浙江诸暨市人民医院住院诊治的36例(男9例,女27例)周围性性早熟儿童的病因、临床状况和实验室数据进行回顾统计分析。结果周围性性早熟患儿的年龄从3.2～10.0岁,中位数为4.3岁。最常见症状是乳晕等色素沉着,占88.9%;乳房增大,占80.6%;其次分别是外阴分泌物增多(22.2%)和阴蒂/阴茎增大(19.4%)。异性性早熟最多见于先天性肾上腺皮质增生症女孩(3例)和外源性性激素摄入的男孩(3例)。病因分析发现,性腺异常(占38.9%)是最常见原因,包括12例自主性孤立性卵巢囊肿,1例卵巢支持细胞瘤,1例睾丸肿瘤。先天性肾上腺皮质增生症是男性患儿中最常见原因。外源性性激素摄入6例(占16.7%)是第3位病因。MeCune-Albright综合征1例。病因不明7例。结论周围性性早熟在儿童内分泌疾病中并不少见,多见于女孩,详细的病史、体检、实验室和影像学检查对周围性性早熟的诊断和治疗非常重要。     

伴性早熟的儿童生殖细胞瘤临床特点及血清和脑脊液β-hcG测定对肿瘤定位诊断的价值

目的 分析伴性早熟的儿童生殖细胞瘤的临床特点,评估血清和脑脊液人绒毛膜促性腺激素β亚单位(β-hcG)检测对肿瘤定位诊断的意义.方法 2005年1月至2009年12月在中山大学附属第一医院儿科内分泌专科就诊,经病理诊断证实为分泌hcG生殖细胞瘤的男童12例,年龄(7.3±1.8)岁(4.2～10.2岁),按肿瘤部位分为颅内组和颅外组,接受治疗前同时检测血清及脑脊液β-hcG,另5位性别年龄与颅外组匹配的非生殖细胞瘤儿童作为脑脊液β-hcG枪测对照组.总结临床特点并比较颅内与颅外组血睾酮、血清和脑脊液β-hcG水平的差异.结果 12例患儿血睾酮10.43(1.70～254.00)μg/L,11例睾丸容积＞4 ml,但促性腺激素释放激素(LHRH)激发试验呈抑制状态.6例有乳房发育.颅内组与颅外组血β-hcG水平分别为63.75(8.50～309.50)IU/L、59.00(25.10～71.77)IU/L,两者差异无统计学意义(P=0.644).血β-hcG水平与年龄、肿瘤部位、病程无相关.颅内组脑脊液β-hcG水平[488.99(17.30～1048.53)IU/L]远高于颅外组[1.20(1.20～1.50)IU/L](P=0.009),后者与对照组比较差异无统计学意义.结论 男孩分泌hcG的生殖细胞瘤主要表现为外周性性早熟,或睾丸发育与LHRH激发值水平不相符合,并可伴乳房发育.联合检测血清和脑脊液β-hcG可协助肿瘤的定位诊断.     

对中枢性(真性)性早熟诊断和治疗的建议

性早熟是儿科常见的发育异常 ,为规范中枢性 (真性 )性早熟的诊断和治疗 ,中华医学会儿科学分会内分泌遗传代谢学组对此进行了专题讨论 ,提出以下建议供参考。一、定义性早熟是指女孩在 8岁前 ,男孩在 9岁前呈现第二性征(见附 )。中枢性性早熟 (CPP)是指由于下丘脑提前分泌促性腺激素释放激素 (GnRH) ,激活了性腺轴 ,使垂体分泌促性腺激素以致性腺发育 ,从而导致的内、外生殖器发育和第二性征呈现。CPP重要特征是以上过程呈进行性直至生殖系统成熟。CPP又称为GnRH依赖性性早熟。二、病因中枢性性早熟病因分两大类 :(1 )中枢神经系统器…     

促性腺激素释放激素类似物在儿童中枢性性早熟中的应用

促性腺激素释放激素(GnRH)依赖性性早熟/中枢性性早熟(GDPP/CPP)是儿科内分泌系统的常见病之一,促性腺激素释放激素类似物(GnRHa)是国际上治疗CPP的主要药物,其通过抑制下丘脑-垂体-性腺轴的活动和性激素分泌,减缓CPP患儿骨龄进展、改善成年身高。在临床实践中,仍需要不断探索GnRHa治疗的获益人群,探讨GnRHa的最佳治疗方案,不断完善GnRHa长期疗效和安全性证据。     

性早熟伴肿瘤24例临床分析

目的探讨性早熟伴肿瘤患儿的临床特征。方法对住院的24例性早熟伴肿瘤患儿的临床资料进行统计分析。结果男女伴肿瘤性早熟占同性别性早熟的比例分别为12.93%及0.50%;以周围性性早熟（PPP）为表现的肿瘤患儿术后转变为中枢性性早熟（CPP）后其骨龄（BA）显著提前,黄体生成素（LH）、卵泡刺激素（FSH）基础值及GnRH激发试验峰值均明显升高。结论性早熟患儿中男性性早熟伴肿瘤的发生率高于女性,以周围性性早熟为表现的肿瘤患儿术后可转变为中枢性性早熟。     

Precocious puberty

Puberty occurring before the age of 8 years in girls and 9 years in boys is considered precocious. The numerous causes of precocity can be classified as central or peripheral. Central or true precocious puberty (CPP) is due to premature activation of the hypothalamopituitary-gonadal axis and is isosexual. Peripheral or pseudoprecocious puberty (PPP) results from the production of sex steroids independent of the H-P-G axis and may be isosexual or heterosexual. CPP is the most common form of precocity involving more than 50% of children and is much more common in girls than boys. CPP is more common between 4 and 8 years. A peak serum LH levels >10 iu/1 following GnRH stimulation is the absolute evidence of CPP. Serum IGF-I levels are predictive of the outcome. Availability of CT and MRI has helped to determine the cause of CPP in most cases. Hypothalamic hamartoma is the most common tumour causing CPP especially in boys. Adrenal causes, particularly CAH, are the commonest cause of PPP in boys whereas ovarian causes are more likely in girls. Long acting GnRH analogues provide a safe and effective form of treatment of CPP.     

Isosexual precocious puberty

Isosexual precocious puberty refers to the appearance of phenotypically appropriate secondary sexual characteristics before age 8 years in girls and before 9 years in boys. Isosexual precocity may be categorized into several subgroups depending upon etiology and clinical course: true and complete isosexual precocity refers to early activation of the intact hypothalamic-pituitary-gonadal axis; pseudo-isosexual precocity is due to sex steroid production which is independent of hypothalamic-pituitary regulation; incomplete forms of isosexual precocity include premature thelarche and premature adrenarche. Etiologic, diagnostic and therapeutic considerations are discussed.     

Gonadotropin releasing hormone-independent precocious puberty in a 5 year-old girl with suprasellar germ cell tumor secreting beta-hCG and alpha-fetoprotein.

A 5 year-old girl presented with typical features of isosexual precocity with breast and pubic hair development (Tanner stage 3) and menarche, following a few months history of hirsutism of the back and thighs. Stimulation testing revealed GnRH-independent precocious puberty, tertiary hypothyroidism, hyperprolactinemia and mild testosteronemia. The ovaries in ultrasound examination were prepubertal. Tumor markers beta-hCG and AFP were markedly elevated and a 2.5 x 1.5 cm suprasellar germ cell tumor (GCT) was visualized by MRI. Combined chemotherapy followed by radiotherapy resulted in normalization of pubertal features along with estrogen and marker levels. Our observations support the possibility of hCG-dependent precocious puberty (PP) in girls caused by suprasellar hCG-secreting tumor. We emphasize the need of diagnostic management of hCG-dependent PP not only in boys, but also in girls, especially when they present even slight features of androgenization. We hypothesize that the rarity of isosexual PP in girls with hCG-secreting suprasellar GCT results not only from the lower occurrence of these tumors in girls than in boys, but above all from a rare simultaneous concomitant incidence of both high tumor aromatase activity and hCG secreting potency.     

Sexual precocity: clinical profile and laboratory evaluation

Fifteen children (8 boys and 7 girls) with sexual precocity were evaluated. Idiopathic precocious puberty was the most frequent diagnosis in girls (71·4%), whereas it was uncommon in boys (25%). Hydrocephalus and hypothalamic hamartoma were other causes of central precocity. Congenital adrenal hyperplasia (CAH) was a frequent (50%) cause of precocity in boys.     

Management of central isosexual precocity: diagnosis, treatment, outcome

The diagnosis of central isosexual precocity, a condition much more common in girls than in boys, is currently viewed as a spectrum of disorders between isolated premature thelarche and borderline early puberty. In some countries, a trend may be seen toward onset of puberty at earlier ages. Integration of the clinical findings with bone age, pelvic echography, and hormonal data as well as follow-up ascertainment of progression of development is critical to define which patients should be proposed for therapy. The use of long-acting forms of gonadotropin-releasing hormone (GnRH) agonists may not be indicated in slowly progressive variants or borderline early puberty because they do not affect final height. Preservation of height potential is particularly obvious in precocious puberty starting at young ages. In some selected patients, associated growth hormone therapy may increase adult height but further studies are warranted. The psychosocial and behavioral correlates of precocious puberty are an important and under investigated area.     

Sexual precocity: sex incidence and aetiology.

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.     

Sexual precocity: sex incidence and aetiology

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.     

Causes and Types of Precocious Puberty in North-West Iran

Objective

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.

Methods

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.

Findings

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.

Conclusion

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.     

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.