A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom).
A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom).
复制标题
DOI：
10.1210/jcem.78.6.8200927
复制
发表时间：
1994-06
期刊：
影响因子：
--
通讯作者：
F. Conte;M. Grumbach;Y. Ito;C. Fisher;E. Simpson
中科院分区：
文献类型：
--
作者：
F. Conte;M. Grumbach;Y. Ito;C. Fisher;E. Simpson
我们报告了一个46，XX女性由于CYP 19（P450 arom）基因的分子缺陷引起的芳香化酶缺乏症的新综合征的特征。在出生时，病人提出了非肾上腺形式的女性假两性畸形。在17个月大时，剖腹手术显示正常的雌性内部生殖器结构;卵巢的组织学外观正常。FSH浓度在9.4 ng/mL LER 869时显著升高，雌酮和雌二醇水平无法检测到（< 37 pmol/L）。到14岁时，她没有表现出乳房发育。阴蒂增大到4 x 2厘米，阴毛为坦纳IV期。睾酮的血浆浓度升高至3294 pmol/L，雄烯二酮也升高至9951 pmol/L。血浆雌二醇水平低于37 pmol/L。促肾上腺皮质激素和地塞米松试验表明睾酮和雄烯二酮的非肾上腺来源。血浆促性腺激素水平在去势范围内。盆腔超声和磁共振成像显示双侧多个4至6厘米的卵巢囊肿。尽管增加循环雄激素和阴蒂生长，骨龄为10岁，在实足年龄14 2/12岁。雌激素替代治疗导致生长突增、乳房发育、月经初潮、促性腺激素水平抑制和囊肿消退。临床表现提示P450 arom缺乏症。对卵巢成纤维细胞基因组DNA的分析表明，P450 arom基因编码区有两个单碱基变化，一个在外显子10的1303个碱基对（C-T），R435 C，另一个在外显子10的1310个碱基对（G-A），C437 Y。分子遗传学研究表明，患者是这些突变的复合杂合子。这些突变的表达表明，R435 C突变具有野生型P450 arom酶活性的1.1%，而C437 Y突变没有活性。该综合征的主要特征是P450 arom缺乏的结果：1）该综合征的胎儿男性化可归因于C19类固醇向雌激素的胎盘转化缺陷，导致雌性胎儿暴露于过量的睾酮; 2）青春期失败，轻度男性化，多囊卵巢，FSH和LH对卵巢的过度刺激是卵巢不能将睾酮和雄烯二酮芳香化为雌激素的结果; 3）骨龄显著延迟至14 2/12岁，这支持了雌激素与雄激素相反是青春期驱动骨骼成熟的主要性类固醇的观点。家族性P450 arom缺乏症虽然罕见，但可能比以前怀疑的更常见。（400字处截断摘要）
We report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (< 37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris had enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. The cardinal features of this syndrome are a consequence of P450arom deficiency: 1) the fetal masculinization in this syndrome can be ascribed to defective placental conversion of C19 steroids to estrogens, leading to exposure of the female fetus to excessive amounts of testosterone; 2) the pubertal failure, mild virilization, multicystic ovaries, and hyperstimulation of the ovaries by FSH and LH are the result of the inability of the ovary to aromatize testosterone and androstenedione to estrogens; and 3) the striking delay in bone age at 14 2/12 yr supports the notion that estrogens, in contrast to androgens, are the major sex steroid driving skeletal maturation during puberty. Familial P450arom deficiency, although rare, may be more common than previously suspected.(ABSTRACT TRUNCATED AT 400 WORDS)