What are the diagnostic tests for Cushing's (Cushing's syndrome) syndrome in children?

Diagnostic Testing for Cushing's Syndrome in Children

The diagnostic approach for Cushing's syndrome in children should follow a stepwise algorithm starting with screening tests, followed by tests to determine the cause of hypercortisolism, with referral to specialized pediatric endocrinology centers for optimal management.

Clinical Suspicion and Initial Screening

• Screen for Cushing's syndrome in children with unexplained weight gain combined with either decreased height standard deviation score or reduced height velocity, as this combination has high sensitivity and specificity for Cushing's syndrome 1, 2
• First rule out exogenous glucocorticoid use (oral, injections, inhalers, topical) as this is the most common cause of Cushing's syndrome 1
• In children with clinical suspicion, perform multiple first-line screening tests 1, 2:

First-Line Screening Tests

• Late-night salivary cortisol (LNSC): Perform at least 2-3 tests (sensitivity 95%, specificity 100%) 1, 2
• 24-hour urinary free cortisol (UFC): Collect at least 2-3 samples with diagnostic cut-off >193 nmol/24h (>70 μg/m²) (sensitivity 89%, specificity 100%) 1
• Overnight dexamethasone suppression test (DST): Normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after dexamethasone administration 1
• Midnight serum cortisol: A value ≥4.4 μg/dL has 99% sensitivity and 100% specificity for diagnosing Cushing's syndrome in children 3

Determining the Cause of Hypercortisolism

• Measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 1:

  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L): ACTH-dependent Cushing's syndrome
  • Low/undetectable ACTH: ACTH-independent Cushing's syndrome

• Important epidemiological considerations 1:

  • In children over age 6, Cushing's disease (pituitary adenoma) is the most common cause (75-80% of cases)
  • In children under age 6, adrenal causes are more common
  • Boys have more aggressive disease with higher BMI, shorter height, and higher ACTH levels than girls

Confirmatory Testing

For ACTH-dependent Cushing's syndrome:

• High-dose dexamethasone suppression test: Suppression of morning cortisol >20% identifies pituitary tumors with 97.5% sensitivity and 100% specificity 3, 4
• CRH stimulation test: Identifies 80% of patients with Cushing's disease 4
• Pituitary MRI: Sensitivity of 63% and specificity of 92% for adenoma detection 1

For equivocal cases:

• Inferior petrosal sinus sampling (IPSS): Has more limited role in children compared to adults but valuable in equivocal cases 1
• The Dex-CRH test is not useful in children 1

Special Considerations

• Microadenomas account for 98% of pituitary causes in children, with adenoma diameter frequently ≤2 mm 1
• Macroadenomas are rare in children (2-5% vs. 10% in adults) 1
• Consider genetic testing in cases with family history or signs suggestive of genetic syndromes 2

Pitfalls to Avoid

• False positives can occur in severe obesity, uncontrolled diabetes, and other pseudo-Cushing's states 1
• The Dex-CRH test, which is useful in adults, should not be used in children 1
• Growth failure may not be a reliable indicator in post-pubertal adolescents 1
• Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise to avoid diagnostic and management errors 1

Management Implications

• Early diagnosis is critical to prevent long-term adverse health outcomes from prolonged hypercortisolism 1
• After successful treatment, adrenal function typically recovers within approximately 12 months 1
• Evaluation for growth hormone deficiency should be done 3-6 months postoperatively 1