AROMATASE DEFICIENCY IN MALE AND FEMALE SIBLINGS CAUSED BY A NOVEL MUTATION AND THE PHYSIOLOGICAL-ROLE OF ESTROGENS
AROMATASE DEFICIENCY IN MALE AND FEMALE SIBLINGS CAUSED BY A NOVEL MUTATION AND THE PHYSIOLOGICAL-ROLE OF ESTROGENS
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DOI：
10.1210/jc.80.12.3689
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发表时间：
1995-12-01
影响因子：
5.8
通讯作者：
QIN, K
中科院分区：
文献类型：
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作者：
MORISHIMA, A;GRUMBACH, MM;QIN, K
芳香酶复合物催化多种组织（包括卵巢、睾丸、胎盘、脑和脂肪组织）中雄激素转化为雌激素。仅分离出一个编码芳香酶P450（CYP 19）的人类基因;组织特异性调节部分由替代启动子以组织特异性方式控制。我们报告了一个新的突变在CYP 19基因在一个妹妹和弟弟。28岁的XX先证者，从婴儿期开始随访，表现出最近定义的芳香化酶缺乏综合征的主要特征。她出生时患有非肾上腺性女性假两性畸形，并接受了外生殖器修复术，包括阴蒂切除术。在青春期时，她出现了进行性男性化体征、青春期失败（无雌激素作用体征）、高促性腺激素性性腺功能减退症、盆腔超声检查显示多囊卵巢和身材高大。血浆睾酮、雄烯二酮和17-羟孕酮的基础浓度升高，而血浆雌二醇较低。多囊卵巢囊肿液中雄烯二酮和睾酮与雌二醇和雌酮的比例明显异常。激素替代治疗导致乳房发育，月经，卵巢囊肿的解决，并抑制FSH和LH值的升高。她的成年身高为177.6 cm（+2.5 SD）。她唯一的兄弟姐妹，XY男性，在24岁时进行了研究。在两次妊娠期间，母亲表现出进行性男性化的迹象，产后退化。兄弟的身高为204 cm（+3.7 SD），骨骼比例为阉人，体重为135.1 kg（+2.1 SD）。他性成熟，患有巨睾丸症。睾酮（2015 ng/dL）、5 α-二氢睾酮（125 ng/dL）和雄烯二酮（335 ng/dL）的血浆浓度升高;雌二醇和雌酮水平低于7 pg/mL。血浆FSH和LH浓度超过平均值的3倍。血浆PRL低，血清胰岛素样生长因子I和GH结合蛋白正常。骨龄为14岁，实足年龄为24 3/12岁。手腕处出现明显的骨质疏松。腰椎（松质骨）和桡骨远端（皮质骨）的骨矿物质密度测定指数与骨质疏松症一致;桡骨远端比年龄和性别匹配的正常男性的平均值低-4.7 SD;骨转换指数增加。检测到高胰岛素血症、血清总胆固醇和低密度脂蛋白胆固醇升高、甘油三酯和高密度脂蛋白胆固醇降低。对来自姐妹和兄弟的转化淋巴母细胞的基因组DNA的分析表明，CYP 19基因的外显子IX的碱基对1123（C->T）处存在纯合的单碱基变化，这导致在位置375（R375 C）处半胱氨酸代替精氨酸。在这一血缘家系中，双亲为专性杂合子。突变互补DNA的表达表明，R375 C突变的芳香酶活性为野生型酶的0.2%。受影响的24岁的弟弟，在儿童时期生长正常，身材高大，男性第二性征正常，大睾丸症，骨质疏松症，血浆FSH，LH和雄激素值升高，但雌二醇和雌酮浓度低于7 pg/mL。此外，还检测到高胰岛素血症和血脂异常。兄妹的性心理取向与其表型性别相适应。这些观察结果与以下解释一致：1）雌激素对正常骨骼成熟和比例是必不可少的（但不是线性增长），增加和维持骨矿物质密度和质量，以及控制骨转换率; 2）雌激素在男性性类固醇-促性腺激素反馈机制中具有重要作用，即使面对高循环睾酮; 3）成年男性中缺乏雌激素似乎与高胰岛素血症和血脂异常有关; 4）胎盘芳香化酶在保护女性胎儿免于胎儿男性化和孕妇免于男性化中具有关键作用。研究结果再次表明，胚泡，胎儿和胎盘中的雌激素合成对于正常的胚胎和胎儿发育并不重要，并加强了胎盘雌激素在孕妇生理学中没有重要作用的概念。
The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue. Only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. We report a novel mutation in the CYP19 gene in a sister and brother. The 28-yr-old XX proband, followed since infancy, exhibited the cardinal features of the aromatase deficiency syndrome as recently defined. She had nonadrenal female pseudohermaphrodism at birth and underwent repair of the external genitalia, including a clitorectomy. At the age of puberty, she developed progressive signs of virilization, pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism, polycystic ovaries on pelvic sonography, and tall stature. The basal concentrations of plasma testosterone, androstenedione, and 17-hydroxyprogesterone were elevated, whereas plasma estradiol was low. Cyst fluid from the polycystic ovaries had a strikingly abnormal ratio of androstenedione and testosterone to estradiol and estrone. Hormone replacement therapy led to breast development, menses, resolution of ovarian cysts, and suppression of the elevated FSH and LH values. Her adult height is 177.6 cm (+2.5 SD).Her only sibling, an XY male, was studied at 24 yr of age. During both pregnancies, the mother exhibited signs of progressive virilization that regressed postpartum The height of the brother was 204 cm (+3.7 SD) with eunuchoid skeletal proportions, and the weight was 135.1 kg (+2.1 SD). He was sexually fully mature and had macroorchidism. The plasma concentrations of testosterone (2015 ng/dL), 5 alpha-dihydrotestosterone (125 ng/dL), and androstenedione (335 ng/dL) were elevated; estradiol and estrone levels were less than 7 pg/mL. Plasma FSH and LH concentrations were more than 3 times the mean value. Plasma PRL was low; serum insulin-like growth factor I and GH-binding protein were normal. The bone age was 14 yr at a chronological age of 24 3/12 yr. Striking osteopenia was noted at the wrist. Bone mineral densitometric indexes of the lumbar spine (cancellous bone) and distal radius (cortical bone) were consistent with osteoporosis; the distal radius was -4.7 SD below the mean value for age- and sex-matched normal men; indexes of bone turnover were increased. Hyperinsulinemia, increased serum total and low density lipoprotein cholesterol, and triglycerides and decreased high density lipoprotein cholesterol were detected.Analysis of genomic DNA in transformed lymphoblasts from both the sister and brother indicated a homozygous single base change at base pair 1123 (C-->T) in exon IX of the CYP19 gene, a highly conserved region, that results in a cysteine instead of an arginine at position 375 (R375C). The parents are obligate heterozygotes in this consanguineous pedigree. Expression of the mutant complementary DNA showed that the R375C mutation had 0.2% the aromatase activity of the wild-type enzyme.The clinical features in the affected female were similar to those described previously due to generalized aromatase deficiency. The affected 24-yr-old brother, who grew normally during childhood, has tall stature, normal male secondary sex characteristics, macroorchidism, osteoporosis, elevated plasma FSH, LH, and androgen values, but estradiol and estrone concentrations below 7 pg/mL. In addition, hyperinsulinism and an abnormal blood lipid profile were detected. The psychosexual orientation of both brother and sister was appropriate for their phenotypic sex. These observations are consistent with the following interpretations: 1) estrogens are essential for normal skeletal maturation and proportions (but not linear growth) in men as in women, the accretion and maintenance of bone mineral density and mass, and the control of the rate of bone turnover; 2) estrogens have a significant role in the sex steroid-gonadotropin feedback mechanism in the male, even in the face of high circulating testosterone; 3) deficient estrogens in the adult male appear to be associated with hyperinsulinemia and abnormal plasma lipids; 4) and placental aromatase has a critical role in protecting the female fetus from fetal masculinization and the pregnant woman from virilization. The findings suggest again that estrogen synthesis in the blastocyst, fetus, and placenta is not essential for normal embryonic and fetal development and reinforce the concept that placental estrogen has no essential role in the physiology of the pregnant woman.