Diagnostic Workup for Pediatric Cushing's Syndrome
Initial Clinical Screening Criteria
Screen children for Cushing's syndrome ONLY when unexplained weight gain is combined with either declining height velocity or decreasing height standard deviation score (SDS)—this combination has high sensitivity and avoids unnecessary testing in simple obesity. 1
Key distinguishing features from common obesity include:
- Growth deceleration (subnormal growth velocity with height SDS below mean while BMI SDS rises above mean) 1
- Wide purple striae (though absence does not exclude diagnosis) 2
- Rounded facies with dorsocervical fat pad 3
- Hypertension 3
Important caveat: Not all children with Cushing's syndrome have obesity, and very few obese children actually have Cushing's syndrome—making the growth deceleration criterion critical for appropriate screening. 1
Biochemical Confirmation of Hypercortisolism
Perform 2-3 first-line screening tests simultaneously rather than relying on a single test, as no test has 100% diagnostic accuracy: 1, 4
The Three Essential Tests:
24-hour urinary free cortisol (UFC)
Late-night salivary cortisol (or sleeping midnight serum cortisol)
Overnight 1 mg dexamethasone suppression test
Critical first step: Eliminate all exogenous glucocorticoid exposure before any biochemical testing, as exogenous steroids are the most common cause of Cushing's syndrome in children. 1, 3
Determining Etiology After Confirming Hypercortisolism
Step 1: Measure Morning Plasma ACTH
Obtain morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes (sensitivity 80%, specificity 90%). 4
- ACTH-dependent (elevated/normal ACTH): Pituitary adenoma (Cushing's disease) or ectopic ACTH (extraordinarily rare in children <18 years) 5
- ACTH-independent (suppressed ACTH): Adrenal causes (tumors or primary pigmented nodular adrenocortical disease) 3
Step 2: Imaging Based on ACTH Results
For ACTH-dependent disease, obtain pituitary MRI (sensitivity 63%, specificity 92%). 4
Pediatric-specific considerations:
- Microadenomas account for 98% of pediatric Cushing's disease, with adenomas frequently ≤2 mm 1
- Pituitary adenomas in children are smaller and more difficult to visualize than in adults 5
- If lesion ≥10 mm on MRI, presume Cushing's disease (positive predictive value 90%) 4
For ACTH-independent disease, obtain adrenal imaging to identify adrenal tumors or bilateral adrenal disease. 6
Step 3: Additional Testing for Diagnostic Uncertainty
When pituitary MRI is negative or equivocal in ACTH-dependent disease:
- High-dose dexamethasone suppression test 3, 6
- Corticotropin-releasing hormone (CRH) stimulation test 3, 6
- Bilateral inferior petrosal sinus sampling (for differentiating pituitary from ectopic sources) 6
Pediatric-Specific Epidemiology
Cushing's disease (pituitary adenoma) causes 75-80% of pediatric Cushing's syndrome, making it the most common endogenous cause in children >5 years. 1
Notable differences from adults:
- Male predominance in children (63% overall, 71% prepubertal) versus female predominance in adults (79%) 1
- Boys tend to have more aggressive disease with higher BMI, shorter height, and higher ACTH levels 1
- Mean age at presentation is 12.3 ± 3.5 years 1
Referral and Management Principles
Refer all children with suspected endogenous Cushing's syndrome to tertiary care centers with experienced pediatric endocrinology and neurosurgery specialists. 4, 3, 5
The complexity of diagnosis (including challenging inpatient testing and difficult imaging localization) combined with the rarity of the condition necessitates specialized multidisciplinary care. 3, 5 Early recognition and treatment are essential to avoid multisystemic complications including vertebral compression fractures, hypertension, and mental health disorders. 3