A 42-year-old woman presents with progressive weight gain over 18 months, predominantly in the face and upper back. She reports easy bruising, proximal muscle weakness, and amenorrhea for 6 months. On examination: BP 158/96 mmHg, central obesity with supraclavicular fullness, purple striae on abdomen, and proximal lower limb weakness (grade 4/5). 24-hour urinary free cortisol is 320 µg/day (normal <50). Low-dose dexamethasone suppression test (LDDST) shows cortisol 28 µg/dL after 8 mg dexamethasone. High-dose dexamethasone suppression test (HDDST) shows cortisol suppression to 8 µg/dL. MRI pituitary shows a 6 mm hypodense lesion in the anterior pituitary. What is the most likely diagnosis?

Explanation

## Diagnostic Approach to Cushing Syndrome **Key Point:** The combination of elevated 24-hour UFC, failure of suppression at low-dose dexamethasone (LDDST), and **suppression at high-dose dexamethasone (HDDST)** with a visible pituitary adenoma on MRI is diagnostic of **Cushing disease** (pituitary-dependent). ### Interpretation of Dexamethasone Suppression Tests | Test | Cushing Disease | Ectopic ACTH | Primary Adrenal | Normal | |------|-----------------|--------------|-----------------|--------| | **LDDST (8 mg)** | No suppression | No suppression | No suppression | Suppresses | | **HDDST (8 mg)** | **Suppresses** | No suppression | No suppression | Suppresses | | **Pituitary MRI** | Adenoma visible | Normal | Normal | Normal | **High-Yield:** HDDST suppression (cortisol <50% of baseline) distinguishes pituitary-dependent (Cushing disease) from ectopic ACTH and primary adrenal causes. The 6 mm pituitary lesion on MRI confirms the source. ### Clinical Features Supporting Cushing Disease 1. **Classic presentation:** Central obesity, supraclavicular fullness, proximal myopathy, purple striae, hypertension, amenorrhea 2. **Biochemical profile:** Markedly elevated UFC (320 µg/day) 3. **Dexamethasone response:** Pituitary tumor retains some sensitivity to glucocorticoid feedback → suppresses at high dose 4. **Imaging:** Small pituitary adenoma (6 mm) consistent with microadenoma **Clinical Pearl:** Cushing disease accounts for ~70% of endogenous Cushing syndrome. Pituitary microadenomas (<10 mm) may not always be visible on standard MRI; if clinical suspicion is high and imaging is negative, inferior petrosal sinus sampling (IPSS) is the gold standard to confirm pituitary source. ### Why HDDST Suppression Occurs in Cushing Disease Pituitary corticotroph adenomas retain partial responsiveness to negative feedback. At the higher dexamethasone dose (8 mg), sufficient glucocorticoid effect accumulates to suppress ACTH and cortisol production. Ectopic ACTH-secreting tumors (e.g., small cell lung cancer) are autonomous and do not suppress at any dexamethasone dose.