What is the diagnostic approach for cyclic Cushing's syndrome?

Diagnostic Approach for Cyclic Cushing's Syndrome

Multiple, periodic, sequential late-night salivary cortisol (LNSC) measurements are the most effective diagnostic tool for cyclic Cushing's syndrome, as they can detect episodes of cortisol excess interspersed with normal cortisol secretion periods. 1

Definition and Characteristics

Cyclic Cushing's syndrome is characterized by:

• Repeated episodes of cortisol excess alternating with periods of normal cortisol secretion
• Cycles occurring regularly or irregularly with intercyclic phases ranging from days to years
• Formal diagnosis requires demonstration of three peaks and two troughs of cortisol production 2
• Most commonly originates from pituitary corticotroph adenomas (54%), followed by ectopic ACTH-producing tumors (26%) and adrenal tumors (11%) 2

Clinical Presentation

• Most patients show clinical signs of Cushing's syndrome that may be:
  • Fluctuating (appearing and disappearing)
  • Permanent (persistent despite biochemical fluctuations)
• Some patients may have no clinical signs despite biochemical evidence
• The combination of weight gain with decreased height velocity is particularly important in children and adolescents 1

Diagnostic Algorithm

Step 1: Initial Screening

• Collect multiple LNSC samples over time (at least 2-3 measurements) 1

  • LNSC is particularly useful for longitudinal surveillance of cyclic Cushing's syndrome
  • Samples should be collected at usual bedtime
  • Sensitivity >90% when properly collected

• Perform 24-hour urinary free cortisol (UFC) collections (at least 2-3 samples) 1

  • Be aware that UFC may be normal or only mildly elevated in cyclic Cushing's syndrome 3
  • Ensure complete collections with appropriate total volumes

• Overnight 1-mg dexamethasone suppression test (DST) 1

  • May give false negative/positive results due to spontaneous fluctuations in cortisol

Step 2: Monitoring for Cyclicity

• Implement frequent measurements of LNSC over weeks to months 1, 2
  • This is the most reliable and convenient screening tool for suspected cyclic Cushing's syndrome
  • Document at least three peaks and two troughs to confirm diagnosis 2
  • Mass spectrometry methods are preferred over immunoassays for better sensitivity 1

Step 3: Determine ACTH Dependency

Once cyclic hypercortisolism is confirmed:

• Measure plasma ACTH levels 1
  • Low ACTH: ACTH-independent (likely adrenal source)
  • Normal/high ACTH: ACTH-dependent (pituitary or ectopic source)

Step 4: Localization Studies

Based on ACTH status:

• ACTH-dependent:

  • Pituitary MRI
  • If MRI is negative or equivocal, inferior petrosal sinus sampling (IPSS) with CRH or desmopressin stimulation 1
  • For suspected ectopic source: whole-body CT and specific biochemical testing for carcinoids/neuroendocrine tumors 2

• ACTH-independent:

  • Adrenal CT or MRI 1

Important Considerations and Pitfalls

• Timing is critical: Biochemical tests may be normal if performed during periods of normal cortisol secretion 2
• False negatives: A single normal UFC or LNSC does not exclude cyclic Cushing's syndrome 3
• Test interpretation challenges: Cortisol stimulation or suppression tests may give spurious results due to spontaneous fluctuations 2
• Assay methods matter: Mass spectrometry provides better sensitivity than immunoassays for LNSC 1
• Potential interference: Medications, disrupted sleep cycles, and improper sample collection can affect test results 1
• Diagnostic persistence: Repeated testing over time is essential when clinical suspicion remains high despite initial normal results 3

Special Considerations in Children

• Growth failure combined with weight gain is a highly specific indicator of Cushing's syndrome in prepubertal children 1
• In post-pubertal adolescents, adult diagnostic criteria should be applied 1
• Microadenomas (≤2 mm) are the most common cause of Cushing's disease in children and adolescents 1

By following this structured diagnostic approach with emphasis on multiple, sequential LNSC measurements, clinicians can effectively diagnose cyclic Cushing's syndrome despite its challenging presentation and fluctuating biochemical profile.