A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics

BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.     

婴儿期生长情况对青春期性发育的影响研究

目的 探讨婴儿期快速生长对青春期性发育的影响,对预防未来青春期提早发育提供依据。方法 选择2004年1月-2005年1月在温州市儿童医院及本院体检的198例生长过快的婴儿为观察组,另选择175名正常婴儿为对照组。根据出现月经初潮/遗精的时间点,把观察组分成性早熟组和正常发育组。采用Spearman相关性分析观察组婴儿1周岁的身高Δ值、体重Δ值与青春期性早熟的相关性。结果 观察组婴儿1周岁的身高Δ值、体重Δ值均显著大于对照组,差异有统计学意义(t＝2.085,2.146,P＜0.05);观察组儿童的身高、体重、体脂、骨龄值均显著大于对照组儿童,观察组儿童的T、E2、FSH、LH水平均显著高于对照组儿童,差异均有统计学意义(P＜0.05)。对照组无性早熟患儿。观察组、早熟组和正常组的男女比例对比,差异无统计学意义(P＞0.05)。早熟组身高、体重、体脂、骨龄值均显著大于正常组,早熟组T、E2、FSH、LH水平均显著高于正常组,差异有统计学意义(P＜0.05)。观察组婴儿1周岁的身高Δ值、体重Δ值与青春期性早熟呈正相关(r=0.816,0.872,P<0.001)。结论 婴儿期快速生长可造成儿童青春期前肥胖和体脂过度,使青春期早发。控制婴儿期过快生长对预防未来青春期提早发育有重要意义。     

Evaluation of pubertal and pathological gynaecomastia in children: A single-center experience

Gynaecomastia in adolescents is a benign glandular proliferation of the male breast. Secondary causes of gynaecomastia in adolescents are relatively rare and may result from a wide variety of rare pathological conditions. Among these, klinefelter syndrome, complete androgen resistance, adrenal tumours and oestrogen-secreting testicular tumours, hypogonadism, hyperthyroidism, kidney disease and medications play a role in aetiology. The aim of our study is to review the demographic characteristics, hormone profile, aetiological characteristics of paediatric gynaecomastia patients admitted to a single center and to determine the frequency of pathological gynaecomastia. Forty-three male patients with gynaecomastia who applied to the paediatric endocrinology outpatient clinic were included in our study. Demographic characteristics, physical examination findings, hormone profile, breast ultrasonography and karyotype results of the patients were recorded. There were 43 male patients in our study. Thirty-six (83.7%) of the patients were pubertal gynaecomastia, 7 (16.2%) were pathological gynaecomastia. Three of the patients with pathological gynaecomastia were prepubertal gynaecomastia, 2 had klinefelter syndrome, 1 had hypergonadotropic hypogonadism after acute lymphoblastic leukaemia treatment and 1 had gynaecomastia after spirololactone use. Careful evaluation of patients with gynaecomastia is especially important in detecting pathological types. We reported the rare prepubertal gynaecomastia and klinefelter frequency in our study.     

Pelvic ultrasonography in normal girls and in girls with pubertal precocity

This prospective study sought to evaluate the role of pelvic ultrasonography in differentiating between various types of pubertal precocity. A control group of 117 normal girls (aged 1.1-15.6) was studied and compared with 87 girls with premature sexual maturation (aged 1.1-9.2y). Of these patients 19 had central precocious puberty (CPP), 48 had isolated premature thelarche (IPT) and 20 had premature adrenarche (IPA) Pelvic ultrasound variables evaluated were: (i) uterus: longitudinal diameter (uterine length), cross-sectional area (CSA) and fundo-cervical ratio; and (ii) ovaries: volume and morphology. Ovarian morphology was subdivided in 6 different appearances: solid, microcystic, paucicystic, multicystic, macrocystic, and major isolated cyst. In normal control girls, uterine length and CSA increased with age, although no cut-off values could be defined between different age ranges, and they were correlated with breast stage; fundo-cervical ratio was stable through childhood and increased after age 9. Ovarian volume was significantly greater in pubertal girls with breast stage 2 than in those with only pubic and/or axillary hair. There was a clear predominance of solid ovarian appearances in the age range 2-7, with the multicystic appearance being seen only after age 7, a minority being macrocystic. After age 10 all the different patterns were observed, and after age 13 the frequency of a macrocystic pattern increased. Significantly more mature ovarian appearances were observed in subjects with breast development compared with those without, independently of the presence of pubic hair. Patients with IPT had no significant differences in pelvic ultrasound measurements when compared with age-matched controls. All the different morphological ovarian appearances were observed in IPT, in contrast to age-matched controls, where only the less mature patterns (solid, micro- and paucicystic) were seen. Patients with CPP had significantly more mature patterns of ovarian morphology compared with age-matched controls, but did not differ from pubertal pre-menarcheal controls. Those patients with IPA differed from age-matched controls only in having significantly greater uterine length and CSA. Comparison of the pelvic ultrasound parameters between patient groups (IPT, CPP, IPA) and age-matched controls revealed significantly higher values in CPP for uterine length, uterine CSA and ovarian volume. Ovarian volume was also greater in IPT than in IPA. Ovarian morphology was significantly different in patients (IPT, CPP, IPA) compared with age-matched controls, but none of the ovarian morphological appearances was exclusive to a single condition. In conclusion: (i) pelvic ultrasound parameters increase progressively from birth to maturity, but no clear cut-off values can be established between age ranges; (ii) pelvic ultrasound variables reach adult values during puberty, with differences in the timing that may reflect geographical variations; (iii) the multicystic ovarian appearance occurs just before the onset of puberty; (iv) pelvic ultrasonography cannot always differentiate clearly between different disturbances of puberty and therefore cannot supersede other observations and investigations in the evaluation of pubertal disorders; and (v) in this study we propose a more detailed pelvic ultrasound terminology that can avoid apparent confusion in defining ovarian ultrasound appearance.     

Effect of central precocious puberty and gonadotropin-releasing hormone analogue treatment on peak bone mass and final height in females

To evaluate the effect of central precocious puberty (CPP) and its treatment with gonadotropin-releasing hormone (GnRH) analogues on final height and peak bone mass (PBM), we measured lumbar bone mineral density (BMD) in 23 girls at final height. Patients were distributed in two groups. Group 1: 14 patients with progressive CPP were treated with GnRH analogues; seven patients received buserelin (1600 μg/daily), subsequently switched to depot triptorelin (60 μg/kg/26–28 days); seven patients were treated with depot triptorelin (60 μg/kg/26–28 days); mean age of treatment was 6.2 years (range 2.7–7.8 years); the treatment was discontinued at the mean age of 10.1 years (range 8.7–11.3 years); final height was reached at the mean age 13.4 years (range 12.0–14.9 years). Group 2: 9 patients (mean age 6.5 years, range 4.8–7.7 years) with a slowly progressing variant of CPP were followed without treatment; final height was reached at the mean␣age␣13.6 years (range 12.5–14.8 years). Lumbar BMD (L₂-L₄ by dual energy X-ray␣absorptiometry) was measured in all patients at final height. In group 1, final height␣(158.9 ± 5.4 cm) was significantly greater than the pre-treatment predicted height (153.5 ± 7.2 cm, P < 0.001), but significantly lower than mid-parental height (163.2 ± 6.2 cm, P < 0.005). Subdividing the girls of group 1 according to the bone age at discontinuation of therapy (i.e. ≤11.5 years, n = 5, or ≥12.0 years, n = 9), the former patients had a final height significantly higher than the latter (163.7 ± 3.9 cm vs 156.5 ± 4.6 cm, P < 0.02). In group 2, final height (161.8 ± 4.6 cm) was similar to the pre-treatment predicted height (163.1 ± 6.2 cm, P = NS) and was not significantly different from mid-parental height (161.0 ± 5.9 cm). BMD values (group 1: 1.11 ± 0.14 g/cm², group 2: 1.22 ± 0.08 g/cm²) were not significantly different from those of a control group (1.18 ± 0.10 g/cm²; n = 20, age 16.3–20.5 years) and the patients' mothers (group 1: 1.16 ± 0.07 g/cm², n = 11, age 32.9–45.1 years; group 2: 1.20 ± 0.08 g/cm², n = 7, age 33.5–46.5 years). In group 1, the girls who stopped therapy at a bone age ≤11.5 years had significantly higher BMD (1.22 ± 0.10 g/cm²) compared to those who discontinued therapy at a bone age ≥12.0 years (1.04 ± 0.12 g/cm², P < 0.05). Conclusion In girls with progressive CPP, long-term treatment with GnRH analogues improves final height. A subset of patients with CPP does not require treatment because good statural outcome (slowly progressing variant). In CPP, the abnormal onset of puberty and the long-term GnRH analogue treatment do not impair the achievement of PBM. In GnRH treated patients, the discontinuation of therapy at an appropriate bone age for pubertal onset may improve both final height and PBM. Received: 5 June 1997 / Accepted in revised form 21 November 1997     

青春期的性生理特征及其卫生教育

了解青春期的生理变化特征及其卫生,对青少年身心的健康成长和良好心理素质的培养具有重要意义.文章通过对青春期性心理特征的分析,重点阐述了如何对青少年加强性心理与心理卫生的教育.     

Continuous exposure to dibromoacetic acid delays pubertal development and compromises sperm quality in the rat.

Previously our work on the haloacid by-products of drinking water disinfection focused on adult exposures. Herein we evaluate the consequence of continuous exposure to dibromoacetic acid (DBA) via drinking water through reproductive development into adulthood. An initial study in which offspring were exposed from gestation day (GD) 15 through adulthood revealed significant delays in preputial separation and vaginal opening, dose-related decreases in the fertility of cauda epididymal sperm, and dose-related diminutions in the sperm membrane protein SP22. Subsequent studies consisted of groups in which exposure ceased on postnatal day 21 (PND 21) versus adulthood. For each exposure, animals were evaluated after puberty (PND 56) as well as at adulthood (PND 120). Exposure to 4, 40, or 400 ppm DBA from GD 15 through PND 21 failed to result in any significant reproductive alterations. By contrast, continuous exposure until adulthood resulted in dose-related alterations consistent with those observed in the dose-finding study. Preputial separation and vaginal opening were delayed 4 and 3 days in males and females exposed to 400 ppm (76.3 mg/kg) DBA. This was associated with increased responsiveness of both the testis and ovary to hCG ex vivo; hCG-stimulated testosterone production by testicular parenchyma on PND 56 was increased at 4 ppm (0.6 mg/kg) DBA and higher. Finally, the quality of proximal cauda epididymal sperm was compromised by continuous exposure to DBA. The sperm membrane proteome was altered in a dose-related manner with SP22, and one of its charged variants, diminished at 40 ppm (3.6 mg/kg) DBA and higher. As more sensitive endpoints are evaluated, lower effect levels can be attributed to haloacid exposure. We are now extending our evaluations to epidemiology studies designed to evaluate sperm quality in men exposed to varying levels of disinfection by-products.     

中药早熟3号治疗阴虚火旺夹痰湿之性早熟

目的:观察早熟3号颗粒剂治疗阴虚火旺夹痰湿型女童特发性性早熟的疗效和安全性。方法:将292例中医证属阴虚火旺夹有痰湿型特发性性早熟的患儿按激发试验的结果分为真性性早熟组(144例)和部分性早熟组(148例),均予口服早熟3号颗粒剂进行治疗,治疗12月后,观察两组临床疗效,治疗前后症状、体征方面的改善情况,以及性激素(FSH、LH、E2)、子宫卵巢容积和骨龄身高增长情况等变化。结果:①总体疗效比较:真性性早熟组总有效率为91.7%,部分性性早熟组总有效率为97.3%(P>0.05);②中医证候疗效比较:真性性早熟组总有效率为96.5%,部分性性早熟组为98.6%,两组比较无显著差异(P<0.05);③治疗后两组骨龄增速均得到改善,与治疗前相比有显著差异(P<0.05),真性性早熟组较部分性性早熟组相比无显著差异(P>0.05);④治疗期间,真性性早熟组身高增长优于部分性性早熟组,两组骨龄与身高龄差值都较治疗前减小,但真性性早熟组优于部分性性早熟组(P<0.05);⑤治疗期间未见明显不良反应。结论:早熟3号颗粒剂治疗阴虚火旺夹有痰湿型女童性早熟有较好临床效果且较安全。