Al Argan Reem, Saskin Avi, Yang Ji Wei, D'Agostino Maria Daniela, Rivera Juan
Division of Endocrinology and Metabolism, Department of Medicine, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
Department of Human Genetics, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
Endocr J. 2018 Nov 29;65(11):1139-1146. doi: 10.1507/endocrj.EJ18-0135. Epub 2018 Aug 30.
Glucocorticoid resistance syndrome (GRS) is a rare genetic disorder caused by inactivating mutations of the NR3C1 gene which encodes the glucocorticoid receptor. The phenotypic spectrum is broad but typically include symptoms of adrenal insufficiency, mineralocorticoid excess and hyperandrogenism. We report a new case associated with a novel NR3C1 mutation. A 55-year-old woman with lifelong history of low body weight, hyperandrogenism and anxiety was seen at the endocrine clinic after left adrenalectomy and salpingoophorectomy for lesions suspicious of ovarian cancer and adrenal metastasis. The tumors turned out to be a 3.5 cm benign ovarian serous adenofibroma and a 3.5 cm multinodular adrenal mass. She complained of worsened fatigue and inability to recover weight lost with surgery. Pre-operative serum and urinary cortisol were elevated, but she had no stigma of Cushing's syndrome. Plasma ACTH was elevated and a 1-mcg cosyntropin stimulation test was normal. Her fatigue persisted over ensuing years and ACTH-dependent hypercortisolemia remained stable. Low dose oral dexamethasone failed to suppress endogenous cortisol. A pituitary MRI was normal but revealed incidental brain aneurysms. Bone densitometry showed profound osteoporosis. On the bases of this contradictory clinical picture, glucocorticoid resistance syndrome (GRS) was suspected. Using next generation sequencing technology, a novel heterozygous pathogenic variant in the NR3C1 gene was detected. We speculate that vascular malformations and profound osteoporosis, findings associated to cortisol excess, reflect in our patient a variable tissue sensitivity to glucocorticoids. In conclusion, in patients with clinically unexpected ACTH-dependent hypercortisolemia, primary glucocorticoid resistance (GRS) should be considered.
糖皮质激素抵抗综合征（GRS）是一种罕见的遗传性疾病，由编码糖皮质激素受体的NR3C1基因失活突变引起。其表型谱广泛，但通常包括肾上腺功能不全、盐皮质激素过多和高雄激素血症的症状。我们报告了一例与新的NR3C1突变相关的病例。一名55岁女性，有终生体重偏低、高雄激素血症和焦虑病史，因怀疑卵巢癌和肾上腺转移灶而接受左肾上腺切除术和输卵管卵巢切除术后在内分泌诊所就诊。结果发现肿瘤是一个3.5厘米的良性卵巢浆液性腺纤维瘤和一个3.5厘米的多结节肾上腺肿块。她抱怨疲劳加重，术后体重减轻后无法恢复。术前血清和尿皮质醇升高，但她没有库欣综合征的体征。血浆促肾上腺皮质激素（ACTH）升高，1微克促肾上腺皮质激素刺激试验正常。在接下来的几年里，她的疲劳持续存在，ACTH依赖性高皮质醇血症保持稳定。低剂量口服地塞米松未能抑制内源性皮质醇。垂体磁共振成像（MRI）正常，但发现了偶然的脑动脉瘤。骨密度测定显示严重骨质疏松。基于这种矛盾的临床表现，怀疑为糖皮质激素抵抗综合征（GRS）。使用下一代测序技术，在NR3C1基因中检测到一个新的杂合致病性变异。我们推测，血管畸形和严重骨质疏松，这些与皮质醇过多相关的发现，在我们的患者中反映了对糖皮质激素的可变组织敏感性。总之，对于临床上出现意外的ACTH依赖性高皮质醇血症患者，应考虑原发性糖皮质激素抵抗（GRS）。
