Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia - Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene
Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia - Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene
复制标题
DOI：
10.1172/jci119284
复制
发表时间：
1997-03-15
影响因子：
15.9
通讯作者：
Strauss, JF
中科院分区：
文献类型：
--
作者：
Fujieda, K;Tajima, T;Strauss, JF
先天性类脂质肾上腺增生（类脂质CAH）是CAH的最严重形式，其中所有性腺和肾上腺皮质类固醇的合成明显受损。我们在这里报告了对两个不相关的日本家族的46，XX例患有脂类CAH并表现出自发青春期的受试者的临床、内分泌和分子分析。表型为46，XX核型的女婴在新生儿时被诊断为类脂CAH，其临床病史包括发育不良、色素沉着过度、低钠血症、高钾血症、血清皮质醇和尿17-羟皮质类固醇和17-酮类固醇的低基础值。这些患者对糖皮质激素和9 α-氟氢可的松治疗有反应。自发性乳房初长分别在10岁和11岁时与血清雌二醇水平升高相关。阴毛在12岁11个月的年龄在一个主题和初潮是在12岁的年龄在两种情况下。两名受试者均报告周期性月经出血，随后发生多囊卵巢。为了研究这些患者类固醇代谢损伤的分子基础，我们用PCR和直接DNA序列分析对星星基因进行了鉴定。DNA序列分析显示，一名患者是外显子7中Gln 258 Stop突变的纯合子，另一名患者是Gln 258 Stop突变和另一个等位基因中密码子238处单个A缺失的复合杂合子，导致移码，这使得星星蛋白无功能。这些发现表明，卵巢类固醇合成可以在一定程度上通过青春期时，星星基因产物是无活性的。这与早期发病的睾丸和肾上腺皮质类固醇生成严重缺陷形成鲜明对比，这是这种疾病的特征。
Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9 alpha-fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.