Stratakis C A, Vottero A, Brodie A, Kirschner L S, DeAtkine D, Lu Q, Yue W, Mitsiades C S, Flor A W, Chrousos G P
Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Clin Endocrinol Metab. 1998 Apr;83(4):1348-57. doi: 10.1210/jcem.83.4.4697.
Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or gynecomastia, and affected females had isosexual precocity and/or macromastia. The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old sister had precocious puberty, and their father and paternal grandmother had peripubertal gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adrenal steroid hormones were determined before and after the administration of corticotropin and/or hCG. Aromatase activity was determined by [3H]delta4-androstenedione to [3H]estrone conversion by cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphocytes and was detected by immunohistochemistry and/or Western analysis. Linkage was examined with a polymorphism of the aromatase (P450arom) gene. The P450arom messenger ribonucleic acid was analyzed by rapid amplification of complementary DNA (cDNA) ends, ribonuclease protection assay, and RT-PCR. hCG testing demonstrated a high rate of conversion of delta4-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a GnRH analog, which successfully delayed skeletal and pubertal development in both children. Markedly increased aromatase activity was found in the patients' fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom polymorphism segregated with the disease in the family. A new 5'-splice variant was present in the patients' P450arom messenger ribonucleic acid, thus identifying yet another first exon of this gene, which appears to be aberrantly expressed in this family. In conclusion, a family with the aromatase excess syndrome is described, in which the condition was inherited in an autosomal dominant manner, led to feminizing manifestations in both sexes, and was associated with the aberrant utilization of a novel transcript of the P450arom gene.
已有报道称，腺体外芳香化作用增强是家族性男性乳房发育症的病因。我们研究了一个以常染色体显性方式遗传的芳香化酶过多症家族，其中受影响的男性有异性性早熟和/或男性乳房发育，受影响的女性有同性性早熟和/或巨乳症。先证者是一名患有男性乳房发育症的9岁男孩。他7.5岁的妹妹有性早熟，他们的父亲和祖母分别有青春期前后的男性乳房发育症和巨乳症。在注射促肾上腺皮质激素和/或人绒毛膜促性腺激素前后，测定血清性腺和肾上腺类固醇激素浓度。通过培养的皮肤成纤维细胞和/或爱泼斯坦-巴尔病毒转化的淋巴细胞将[3H]δ4-雄烯二酮转化为[3H]雌酮来测定芳香化酶活性，并通过免疫组织化学和/或蛋白质印迹分析进行检测。用芳香化酶（P450arom）基因的多态性进行连锁分析。通过互补DNA（cDNA）末端的快速扩增、核糖核酸酶保护试验和逆转录聚合酶链反应（RT-PCR）分析P450arom信使核糖核酸。人绒毛膜促性腺激素检测显示，先证者及其父亲体内δ4-雄烯二酮向雌酮以及睾酮向雌二醇的转化率很高。对先证者及其妹妹开始用一种芳香化酶抑制剂（睾内酯）和一种促性腺激素释放激素类似物进行治疗，成功地延缓了两个孩子的骨骼和青春期发育。在患者的成纤维细胞和爱泼斯坦-巴尔病毒转化的淋巴细胞中发现芳香化酶活性明显增加。P450arom多态性在该家族中与疾病共分离。患者的P450arom信使核糖核酸中存在一种新的5'-剪接变体，从而确定了该基因的另一个第一外显子，该外显子在这个家族中似乎异常表达。总之，本文描述了一个芳香化酶过多综合征家族，该病以常染色体显性方式遗传，导致两性出现女性化表现，并与P450arom基因一种新转录本的异常利用有关。
