Department of Endocrinology, Leeds Centre for Diabetes & Endocrinology, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, LS9 7TF, UK.
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
Pituitary. 2017 Oct;20(5):585-593. doi: 10.1007/s11102-017-0822-x.
DAX-1 (NR0B1) is an orphan nuclear receptor, which plays a critical role in development and regulation of the adrenal gland and hypothalamo-pituitary-gonadal axis. Mutations in NR0B1 lead to adrenal hypoplasia congenita (AHC), hypogonadotropic hypogonadism (HH) and azoospermia in men. Presentation is typically with adrenal insufficiency (AI) during infancy or childhood. To date only eight cases/kindreds are reported to have presented in adulthood.
We describe two new cases of men with DAX-1 mutations who presented in adulthood and who were diagnosed at a large University Hospital.
Case 1 presented with AI at 19 years. At 38 years he was diagnosed with HH. Detailed history revealed a brother diagnosed with AI at a similar age. Sequencing of the DAX-1 (NR0B1) gene revealed a heterozygous c.775T > C substitution in exon 1, which changes codon 259 from serine to proline (p.Ser259Pro). Case 2 was diagnosed with AI at 30 years. Aged 37 years he presented with HH and azoospermia. He was treated with gonadotropin therapy but remained azoospermic. Testicular biopsy showed maturational arrest and hypospermatogenesis. Analysis of the NR0B1 gene showed a heterozygous c.836C > T substitution in exon 1, resulting in a change of codon 279 from proline to leucine (p.Pro279Leu). This change alters the structure of the repression helix domain of DAX-1 and affects protein complex interactions with NR5A family members.
We describe two missense mutations within the putative carboxyl-terminal ligand binding domain of DAX-1, presenting with AHC and HH in adulthood, from a single center. DAX-1 mutations may be more frequent in adults than previously recognized. We recommend testing for DAX-1 mutations in all adults with primary AI and HH or impaired fertility where the etiology is unclear.
DAX-1（NR0B1）是一种孤儿核受体，在肾上腺和下丘脑-垂体-性腺轴的发育和调节中起着关键作用。NR0B1 突变导致先天性肾上腺发育不全（AHC）、促性腺激素低下性性腺功能减退症（HH）和男性无精子症。临床表现通常为婴儿期或儿童期的肾上腺皮质功能不全（AI）。迄今为止，仅有 8 例/家系报告在成年期发病。
我们描述了 2 例新的 DAX-1 基因突变男性病例，他们在成年期出现并在一家大型大学医院被诊断。
病例 1 在 19 岁时出现 AI。38 岁时，他被诊断为 HH。详细病史显示，一名兄弟在类似年龄时被诊断为 AI。DAX-1（NR0B1）基因测序显示，1 号外显子存在 c.775T>C 杂合突变，导致 259 号密码子由丝氨酸变为脯氨酸（p.Ser259Pro）。病例 2 在 30 岁时被诊断为 AI。37 岁时，他出现 HH 和无精子症。他接受了促性腺激素治疗，但仍无精子症。睾丸活检显示成熟停滞和少精子症。NR0B1 基因分析显示 1 号外显子存在 c.836C>T 杂合突变，导致 279 号密码子由脯氨酸变为亮氨酸（p.Pro279Leu）。这种变化改变了 DAX-1 抑制螺旋结构域的结构，并影响与 NR5A 家族成员的蛋白复合物相互作用。
我们描述了单一中心的 2 例 DAX-1 假定羧基末端配体结合域内的错义突变，在成年时表现为 AHC 和 HH。DAX-1 突变在成年人中可能比以前认为的更为常见。我们建议对所有病因不明的原发性 AI 和 HH 或生育能力受损的成年患者进行 DAX-1 突变检测。
