A 38-year-old woman presents with progressive proximal muscle weakness, easy bruising, and amenorrhea for 6 months. Clinical examination reveals central obesity, purple striae, and hypertension (160/95 mmHg). Laboratory investigations show elevated 24-hour urinary free cortisol and suppressed ACTH. Which of the following is NOT a typical feature of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome?

Explanation

## Understanding ACTH-Independent Cushing Syndrome ### Clinical Context The patient presents with classic Cushing syndrome features (proximal weakness, striae, central obesity, hypertension, amenorrhea) with suppressed ACTH, indicating an ACTH-independent (primary adrenal) cause. ### Key Features of ACTH-Independent Cushing Syndrome **Key Point:** ACTH-independent Cushing syndrome results from primary adrenal pathology (adenoma, carcinoma, or bilateral hyperplasia) with autonomous cortisol secretion and suppressed pituitary ACTH. | Feature | ACTH-Independent | ACTH-Dependent | |---------|------------------|----------------| | Plasma ACTH | Low/suppressed | Elevated | | 24h UFC | Elevated | Elevated | | Adrenal imaging | Unilateral adenoma or bilateral hyperplasia | Normal or hyperplastic | | Hyperpigmentation | Absent (low ACTH) | Present (high ACTH stimulates melanocytes) | | Dexamethasone suppression | No suppression at high dose | Suppression at high dose (pituitary) | ### Why Hyperpigmentation is NOT a Feature **High-Yield:** Hyperpigmentation (darkening of skin and mucous membranes) occurs in ACTH-dependent Cushing syndrome (Cushing disease or ectopic ACTH) because elevated ACTH stimulates melanocytes via melanocyte-stimulating hormone (MSH) — both are derived from pro-opiomelanocortin (POMC). **Clinical Pearl:** In ACTH-independent Cushing syndrome, ACTH levels are suppressed, so there is no stimulus for melanin production. Hyperpigmentation is therefore absent and is a useful clinical discriminator. ### Typical Features Present in This Case 1. **Suppressed ACTH** — confirms primary adrenal disease 2. **Elevated 24-hour UFC** — demonstrates autonomous cortisol excess 3. **Bilateral adrenal hyperplasia** — common cause of ACTH-independent disease (primary bilateral adrenal hyperplasia or PBAH) 4. **Absent hyperpigmentation** — distinguishes from ACTH-dependent causes **Mnemonic:** ACTH-I (ACTH-Independent) = **No ACTH, No pigmentation** — remember the suppressed ACTH means no MSH-driven melanin synthesis. ### Differential Diagnosis of ACTH-Independent Cushing - **Adrenal adenoma** (most common, ~40% of ACTH-independent cases) — unilateral - **Adrenal carcinoma** — unilateral, aggressive - **Primary bilateral adrenal hyperplasia (PBAH)** — bilateral, rare - **Ectopic CRH secretion** — rare, from non-pituitary tumors [cite:Harrison 21e Ch 375]