SUN-476 - A Case of Discordant Clinical and Biochemical Findings in Cushing'S Syndrome

Background: Cushing’s syndrome results from prolonged glucocorticoid exposure. Development of persistent hypercortisolaemic features despite hypocortisolemia is rare. It can be attributed to glucocorticoid receptor (GR) hypersensitivity. We report one such case.

Case Presentation: A 28-year-old woman with a history of bronchial asthma presented with progressive facial puffiness, weight gain, and violaceous striae over a year. She had received a short course of oral steroids for an asthma exacerbation one year earlier, which was discontinued after improvement, with no subsequent glucocorticoid exposure. Examination revealed moon facies, buffalo hump, easy bruising, acneiform eruptions, and centripetal obesity, without virilization or hyperpigmentation. Biochemical evaluation demonstrated low 24-hour urinary free cortisol with suppressed ACTH levels, and CECT of the abdomen was normal. In the setting of persistent Cushingoid features despite hypocortisolaemia, GR hypersensitivity was suspected.

Discussion: Iatrogenic Cushing syndrome was ruled out based on history, with no glucocorticoid exposure in the preceding year. Endogenous ACTH-dependent and ACTH-independent causes are associated with hypercortisolemia. In this case, persistently low serum and urinary cortisol levels, low ACTH, and normal adrenal imaging ruled out pituitary, ectopic, adrenal, and intermittent Cushing syndrome.
A literature review identified only a few similar cases, highlighting the rarity of this presentation. In such cases, persistent Cushingoid features in the setting of hypocortisolaemia have been attributed to GR hypersensitivity, resulting in exaggerated tissue responses despite low cortisol levels. This is thought to result from increased receptor sensitivity or post-receptor signal amplification rather than excess hormone production.
In collaboration with the endocrinology team, the patient was treated with mifepristone, a combined progesterone and glucocorticoid receptor antagonist, at a dose of 10 mg/kg/day, with subsequent improvement in clinical symptoms.

Conclusion: GR hypersensitivity represents a rare mechanism by which patients may develop classical Cushingoid features despite biochemical hypocortisolaemia. In such cases, Cushing’s syndrome should not be excluded solely based on low cortisol levels when clinical features are strongly suggestive. Given this receptor hypersensitivity, strict caution is warranted when using glucocorticoids, as even low-dose exposure via the inhaled or topical route may precipitate hypercortisolemic features.

Reference: Al-Shoumer, K. A., Hafez, M. F., & Doi, S. A. (2008). A case of hypocortisolemic clinical Cushing's syndrome. Annals of Saudi medicine, 28(2), 124–127. https://doi.org/10.5144/0256-4947.2008.124

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