BACKGROUND Adrenal hypoplasia congenita (AHC) is an X-linked disorder that affects the adrenal cortex and hypothalamus-pituitary-gonadal axis (HPG), leading to primary adrenocortical insufficiency (PAI) and hypogonadotropic hypogonadism. AHC is caused by a mutation in the DAX-1 gene (NR0B1). More commonly, this disease is characterized by early-onset PAI, with symptoms in the first months of life. However, a less severe phenotype termed late-onset AHC has been described, as PAI signs and symptoms may begin in adolescence and adulthood. Here we describe a family report of a novel mutation within NR0B1 gene and variable reproductive phenotypes, including spontaneous fertility, in a very late-onset X-linked AHC kindred. CASE PRESENTATION Three affected maternal male relatives had confirmed PAI diagnosis between 30 y and at late 64 y. The X-linked pattern has made the endocrinology team to AHC suspicion. Regarding the HPG axis, all males presented a distinct degree of testosterone deficiency and fertility phenotypes, varying from a variable degree of hypogonadism, oligoasthenoteratozoospermia to spontaneous fertility. Interestingly, the other five maternal male relatives unexpectedly died during early adulthood, most likely due to undiagnosed PAI/adrenal crisis as the probable cause of their premature deaths. Sequencing analysis of the NR0B1 gene has shown a novel NR0B1 mutation (p.Tyr378Cys) that segregated in three AHC family members. CONCLUSIONS NR0B1 p.Tyr378Cys segregates in an AHC family with a variable degree of adrenal and gonadal phenotypes, and its hemizygous trait explains the disease in affected family members. We recommend that NR0B1 mutation carriers, even those that are allegedly asymptomatic, be carefully monitored while reinforcing education to prevent PAI and consider early sperm banking when spermatogenesis still viable.

中文翻译：

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在具有新的DAX-1 / NR0B1突变的成人发病X连锁的肾上腺功能不全的家庭中，自然繁殖力和生殖表型的变化谱。

背景技术先天性肾上腺皮质发育不全（AHC）是一种X连锁疾病，会影响肾上腺皮质和下丘脑-垂体-性腺轴（HPG），导致原发性肾上腺皮质功能不全（PAI）和促性腺激素性性腺功能减退。AHC由DAX-1基因（NR0B1）中的突变引起。更常见的是，这种疾病的特征是早发性PAI，并在生命的最初几个月出现症状。然而，由于PAI的体征和症状可能始于青春期和成年期，因此已描述了一种不太严重的表型，称为晚期发作AHC。在这里，我们描述了一个非常晚发病的X连锁AHC亲属的NR0B1基因内新突变和可变生殖表型（包括自发生育力）的家族报告。病例介绍三名受影响的产妇男性亲属在30 y至64 y后期确诊为PAI。X连锁模式已使内分泌团队对AHC产生怀疑。关于HPG轴，所有男性都表现出不同程度的睾丸激素缺乏和生育表型，从可变程度的性腺机能减退，少精症，少精症到自发生育。有趣的是，其他五个产妇男性亲属在成年早期意外死亡，很可能是由于未诊断为PAI /肾上腺危机而导致其过早死亡。NR0B1基因的测序分析显示了一个新的NR0B1突变（p.Tyr378Cys），该突变分离在三个AHC家族成员中。结论NR0B1 p.Tyr378Cys在一个具有不同程度的肾上腺和性腺表型的AHC家庭中分离，并且其半合子性状解释了该​​疾病在受影响的家庭成员中的发生。我们建议使用NR0B1突变携带者，