Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene
Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene
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DOI：
10.1210/jc.86.9.4068
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发表时间：
2001-09-01
影响因子：
5.8
通讯作者：
Mendonca, BB
中科院分区：
文献类型：
--
作者：
Domenice, S;Latronico, AC;Mendonca, BB
原发性肾上腺功能不全在儿童年龄是一种罕见的情况，它与性早熟发展的联系也非常罕见。我们报告一位患有DAX1基因突变的两岁巴西男童，他的第一个临床表现是同性促性腺激素非依赖性性早熟。他出现阴毛，阴茎和睾丸增大，骨龄增大。睾酮水平升高，而基础和促性腺激素释放激素刺激的促黄体生成素水平符合青春期前的模式。慢性促性腺激素释放激素激动剂治疗没有降低T水平，支持促性腺激素非依赖性性早熟的诊断。在对黄体生成素受体基因第11外显子测序正常后，排除了中毒。在3岁时，他出现了严重的原发性肾上腺皮质功能不全的临床和激素特征。通过直接测序分析了DAX1基因的全部编码区。在DAX-1基因第1外显子430和431之间插入G核苷酸，导致DAX-1新的移码突变和71位提前终止密码子。令人惊讶的是，类固醇替代治疗导致睾丸大小和T水平明显下降至青春期前范围。这些发现表明，肾上腺功能不全导致的慢性ACTH水平过高可能刺激间质细胞，并导致一些DAX1基因突变的男孩发生促性腺激素非依赖性性早熟。
Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.