Neonatal Complete Generalized Glucocorticoid Resistance and Growth Hormone Deficiency Caused by a Novel Homozygous Mutation in Helix 12 of the Ligand Binding Domain of the Glucocorticoid Receptor Gene (NR3C1)
Neonatal Complete Generalized Glucocorticoid Resistance and Growth Hormone Deficiency Caused by a Novel Homozygous Mutation in Helix 12 of the Ligand Binding Domain of the Glucocorticoid Receptor Gene (NR3C1)
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DOI：
10.1210/jc.2009-1003
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发表时间：
2010-01-01
影响因子：
5.8
通讯作者：
Batch, Jennifer A.
中科院分区：
文献类型：
--
作者：
McMahon, Sarah K.;Pretorius, Carel J.;Batch, Jennifer A.
内容：糖皮质激素抵抗是一种罕见的遗传性疾病，其特征是对皮质醇信号的敏感性降低，随后下丘脑-垂体-肾上腺轴过度活化。目的：目的是确认患者糖皮质激素抵抗的诊断，确定地塞米松对皮质醇和ACTH水平的抑制程度，并确定潜在的遗传异常和功能后果的突变。病人和方法：病人提出的第一天的生活与深刻的低血糖症。初始皮质醇水平适当升高;然而，发现患者皮质醇和ACTH水平持续升高。婴儿的皮肤晒得黝黑，高血压严重，喂养时容易疲劳。在2300 h时进行一系列口服地塞米松抑制试验，剂量从0.125 mg递增至12 mg。糖皮质激素受体基因的测序与糖皮质激素受体的功能研究沿着进行。GH分泌进行了评估与精氨酸胰高血糖素刺激test.Results：皮质醇和ACTH水平没有抑制剂量高达12毫克地塞米松。在糖皮质激素受体配体结合域的氨基酸位置773处发现A2-bp缺失。证明完全缺乏地塞米松结合和体外生物学效应。GH刺激试验与GH缺乏症一致。结论：糖皮质激素受体基因配体结合区纯合突变导致糖皮质激素受体功能失活，糖皮质激素抵抗明显，生化GH缺乏症。（临床内分泌代谢杂志95：297-302，2010）
Context: Glucocorticoid resistance is a rare genetic condition characterized by reduced sensitivity to cortisol signaling and subsequent hyperactivation of the hypothalamic-pituitary-adrenal axis.Objective: The objective was to confirm the diagnosis of glucocorticoid resistance in the patient, to determine the degree of suppression of cortisol and ACTH levels in response to dexamethasone, and to determine the underlying genetic abnormality and functional consequences of the mutation.Patient and Methods: The patient presented on the first day of life with profound hypoglycemia. Initial cortisol levels were appropriately elevated; however, the patient was found to have persistently elevated levels of both cortisol and ACTH. The baby developed a tanned appearance and severe hypertension and fatigued easily with feeding. Serial oral dexamethasone suppression tests were performed with doses escalating from 0.125 mg to 12 mg dexamethasone given at 2300 h. Sequencing of the glucocorticoid receptor gene was performed along with functional studies of the glucocorticoid receptor. GH secretion was assessed with an arginine glucagon stimulation test.Results: Cortisol and ACTH levels did not suppress with doses of upto 12 mg dexamethasone. A2-bp deletion was found at amino acid position 773 of the glucocorticoid receptor ligand binding domain. A complete lack of dexamethasone binding and in vitro biological effect was demonstrated. GH stimulation testing was consistent with GH deficiency.Conclusion: The homozygous mutation in the ligand-binding domain of the glucocorticoid receptor gene resulted in a functionally inactive glucocorticoid receptor and apparent complete glucocorticoid resistance with biochemical GH deficiency. (J Clin Endocrinol Metab 95: 297-302, 2010)