What is the diagnostic approach for Cushing's (Cushing's syndrome) syndrome in pediatric patients?

Diagnostic Approach for Cushing's Syndrome in Pediatric Patients

The diagnosis of Cushing's syndrome in pediatric patients requires a stepwise approach starting with clinical suspicion based on growth failure with concurrent weight gain, followed by confirmation of hypercortisolism using multiple screening tests including late-night salivary cortisol, 24-hour urinary free cortisol, and overnight dexamethasone suppression test. 1, 2, 3

Clinical Presentation and Initial Suspicion

• Lack of height gain concomitant with weight gain is the most common presentation of Cushing's syndrome in children, making it somewhat easier to detect compared to adults 1
• Growth failure with continued weight gain is a key discriminating feature between simple obesity and Cushing's syndrome in prepubertal children 2, 4
• The Pediatric Endocrine Society recommends screening only when weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity 5
• Other clinical features may include hirsutism, purple striae, proximal muscle weakness, and hypertension (present in 47% of pediatric patients) 6, 7

First-Line Screening Tests

• Late-night salivary cortisol (LNSC): At least 2-3 tests should be performed with sensitivity of 95% and specificity of 100% 2, 5
• 24-hour urinary free cortisol (UFC): Collect at least 2 samples with diagnostic cut-off >193 nmol/24h (>70 μg/m²), sensitivity 89%, and specificity 100% 2, 5
• Overnight 1-mg dexamethasone suppression test (DST): Normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight 1, 5
• A midnight cortisol value of ≥4.4 μg/dL has been shown to confirm diagnosis with 99% sensitivity and 100% specificity in children 4

Determining the Cause of Hypercortisolism

• Measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 2, 5
  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L): Suggests ACTH-dependent Cushing's syndrome
  • Low/undetectable ACTH: Indicates ACTH-independent Cushing's syndrome
• In children over age 6, Cushing's disease (pituitary adenoma) is the most common cause of Cushing's syndrome, while adrenal causes are more common in younger children 1, 3
• High-dose dexamethasone suppression test: Suppression of morning cortisol levels >20% identifies almost all patients with pituitary tumors (sensitivity: 97.5%; specificity: 100%) 4
• CRH stimulation test: Useful for ACTH-dependent Cushing's syndrome with sensitivity of 74-100% 2, 3

Imaging Studies

• Pituitary MRI scan for ACTH-dependent Cushing's syndrome, with adenoma detection sensitivity of 63% and specificity of 92% 2, 3
• Adrenal imaging for ACTH-independent cases 5, 6

Special Considerations in Pediatric Patients

• The Dex-CRH test is not useful in children 1
• Inferior petrosal sinus sampling (IPSS) has a more limited role in children compared to adults but can be valuable in equivocal cases 1, 5
• Genetic testing should be considered in cases with family history or signs suggestive of genetic syndromes (MEN1, RET, AIP, PRKAR1A, CDKN1B, DICER1, SDHx, and CABLES1) 1, 3
• Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1, 3

Diagnostic Algorithm

1. Establish clinical suspicion based on growth failure with weight gain 2, 4
2. Rule out exogenous glucocorticoid use 5
3. Perform multiple screening tests (LNSC, UFC, overnight DST) 2, 5
4. If screening tests are abnormal, measure plasma ACTH 5
5. For ACTH-dependent cases:
   • Perform high-dose dexamethasone suppression test and CRH stimulation test 3, 4
   • Obtain pituitary MRI 2, 3
   • Consider IPSS in equivocal cases 1, 5
6. For ACTH-independent cases, proceed with adrenal imaging 5, 6

Pitfalls and Caveats

• Severe obesity, uncontrolled diabetes, and other pseudo-Cushing's states can cause false-positive results 5
• Consider cyclic Cushing's syndrome in cases with inconsistent results 5
• Test results in children may not match standard diagnostic criteria derived from adult studies 7
• Early diagnosis remains challenging but is critical to prevent long-term adverse health outcomes from prolonged hypercortisolism 1, 7