2nd Department of Internal Medicine, Semmelweis University, Szentkirályi u. 46, Budapest, H-1088, Hungary.
Hungarian Academy of Sciences and Semmelweis University "Lendület" Hereditary Endocrine Tumours Research Group, Budapest, Hungary.
BMC Med Genet. 2018 Mar 6;19(1):37. doi: 10.1186/s12881-018-0552-6.
Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue-specific, or generalized partial insensitivity to glucocorticoids.
A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone. 24 h urinary cortisol was increased, but a normal midnight serum cortisol was detected suggesting a maintained circadian rhythm. Plasma dehydroepiandrosterone-sulfate and androstendione levels were also elevated. Repeated plasma ACTH measurements indicated slightly elevated or normal values. Bone mineral density was normal. All laboratory results confirmed the diagnosis of glucocorticoid resistance. Genetic counseling followed by Sanger sequencing of the coding region of the gene encoding human glucocorticoid receptor was performed and a missense mutation (Arg714Gln, R714Q) in a heterozygous form was detected. Following family screening, the same mutation was found in her clinically-healthy 35-year-old sister who had no fertility problems.This variant was not detected in more than 60 patients and controls tested either for glucocorticoid resistance or Cushing's syndrome in our Laboratory and it was absent in Exome Variant Server, HumanGene Mutation Database and ExAC databases.
Our case fulfils the diagnostic criteria of glucocorticoid resistance, also named Chrousos syndrome. The glucocorticoid receptor gene mutation detected in our patient has been already reported in a 2-year-old child with hypoglycaemia, hypokalaemia, hypertension and premature puberty. These distinct phenotypes may suggest that other factors may modify the functional consequences of the R714Q variant of GR.
糖皮质激素抵抗是一种罕见的、散发性或家族性疾病，由糖皮质激素受体 (GR) 编码基因突变引起。临床上表现为局部、组织特异性或全身糖皮质激素部分不敏感引起的症状。
一位 31 岁女性因不孕症在塞梅尔维斯大学第二医学系内分泌科就诊。在实验室检查中，观察到血清和唾液皮质醇升高，给予 1mg 地塞米松后未能抑制。24 小时尿皮质醇增加，但午夜血清皮质醇正常，提示昼夜节律维持。血浆脱氢表雄酮硫酸酯和雄烯二酮水平也升高。重复的血浆 ACTH 测量表明值略高或正常。骨密度正常。所有实验室结果均证实为糖皮质激素抵抗。随后进行遗传咨询，对编码人类糖皮质激素受体的基因编码区进行 Sanger 测序，发现杂合形式的错义突变（Arg714Gln，R714Q）。在家族筛查中，她 35 岁的临床健康妹妹也发现了同样的突变，她没有生育问题。在我们实验室检测的糖皮质激素抵抗或库欣综合征的 60 多个患者和对照中未发现该突变，在 Exome Variant Server、HumanGene Mutation Database 和 ExAC 数据库中也未发现该突变。
我们的病例符合糖皮质激素抵抗的诊断标准，也称为 Chrousos 综合征。在我们的患者中检测到的糖皮质激素受体基因突变已在一名 2 岁低血糖、低钾血症、高血压和性早熟的儿童中报道。这些不同的表型可能表明其他因素可能会改变 GR 的 R714Q 变体的功能后果。
