What are the diagnostic criteria for Cushing's syndrome?

Diagnostic Criteria for Cushing's Syndrome

The diagnosis of Cushing's syndrome requires a three-step approach: clinical suspicion, biochemical confirmation of hypercortisolism, and determination of etiology, with no single test being 100% accurate. 1, 2

Clinical Suspicion

• In children and adolescents, screening is recommended only when weight gain is inexplicable AND combined with either decreased height standard deviation score or decreased height velocity 1, 2
• Growth failure sensitively discriminates simple obesity from Cushing's syndrome in prepubertal children but is unreliable in post-pubertal children who should be assessed according to adult guidelines 1
• Clinical features include unusual fat distribution (face, neck, trunk), skin changes (plethora, acne, hirsutism, livid striae, easy bruising), and signs of protein catabolism (thinned skin, osteoporotic fractures, proximal myopathy) 3

Biochemical Confirmation of Hypercortisolism

The diagnosis usually includes three tests, none with 100% diagnostic accuracy:

• Late-night salivary cortisol (LNSC): First-line screening test with sensitivity of 95% and specificity of 100%; at least 2-3 samples should be collected 2, 4
• 24-hour urinary free cortisol (UFC): Diagnostic cut-off >193 nmol/24h (>70 μg/m²), sensitivity 89%, specificity 100%; at least 2-3 collections recommended to evaluate variability 1, 2
• Dexamethasone suppression testing:
  • Overnight 1-mg test: Normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight 4, 5
  • Low-dose dexamethasone suppression test (LDDST): Diagnostic cut-off ≥50 nmol/L (≥1.8 μg/dL), sensitivity 95%, specificity 80% 2, 6
• Serum cortisol circadian rhythm study: Midnight diagnostic cut-off ≥50 nmol/L (≥1.8 μg/dL), sensitivity 100%, specificity 60% 1, 2

Determining Etiology of Cushing's Syndrome

After confirming hypercortisolism, the next step is to determine its cause:

• Morning plasma ACTH level: Diagnostic cut-off >1.1 pmol/L (>5 ng/L)
  • Normal/elevated ACTH suggests ACTH-dependent Cushing's syndrome (pituitary or ectopic source)
  • Low/undetectable ACTH indicates ACTH-independent Cushing's syndrome (adrenal cause) 2, 4
• CRH stimulation test: For ACTH-dependent Cushing's syndrome, sensitivity 74-100% 2, 7
• Pituitary MRI scan: For ACTH-dependent Cushing's syndrome, adenoma detection sensitivity 63%, specificity 92% 2, 4
• Bilateral inferior petrosal sinus sampling (IPSS): Should not be used to diagnose hypercortisolism but is valuable for differentiating between pituitary and ectopic sources of ACTH 1, 4

Special Considerations

• Exogenous glucocorticoids must be eliminated before biochemical testing 1, 6
• In children over age 6, Cushing's disease (pituitary adenoma) is the most common cause (75-80% of cases), while adrenal causes are more common in younger children 1, 4
• False positives can occur with "pseudo-Cushing's states" including severe obesity, uncontrolled diabetes, depression, and alcoholism 1, 8
• The combined LDDST-CRH (Dex-CRH) test or desmopressin test may help distinguish between ACTH-dependent Cushing's syndrome and pseudo-Cushing's states 1, 8
• Genetic testing should be considered in cases with family history or signs suggestive of genetic syndromes 4

Pitfalls to Avoid

• Relying on a single test for diagnosis (at least two abnormal results are typically required) 2, 6
• Testing patients with low pre-test probability (common symptoms like hypertension or weight gain alone do not justify biochemical testing) 3
• Failing to repeat tests when results are equivocal 1, 6
• Not considering cyclic Cushing's syndrome, where dynamic testing should be preceded by confirmatory tests to document active phase 1