What are the characteristics of Cushing's syndrome?

Characteristics of Cushing's Syndrome

Cushing's syndrome is characterized by chronic excessive glucocorticoid exposure resulting in a constellation of distinctive clinical features including central obesity, moon face, dorsal and supraclavicular fat pads, wide violaceous striae, hirsutism, and proximal muscle weakness. 1, 2

Clinical Presentation

Physical Characteristics

• Central obesity with redistribution of fat, particularly in the face ("moon face"), dorsal region ("buffalo hump"), and supraclavicular fossae 2
• Wide (1-cm) violaceous striae, especially on the abdomen 2
• Hirsutism and facial plethora 2, 3
• Skin changes including thinning, easy bruising, and poor wound healing 3, 4
• Proximal muscle weakness due to protein catabolism 2, 4

Metabolic and Cardiovascular Features

• Hypertension (present in >80% of cases) 2, 3
• Glucose abnormalities ranging from impaired glucose tolerance to overt diabetes mellitus 2, 5
• Metabolic syndrome-like presentation with multiple cardiovascular risk factors 1, 3
• Dyslipidemia 3

Neuropsychiatric Manifestations

• Depression and mood disorders 2, 3
• Cognitive changes and memory impairment 3
• Sleep disturbances 4

Other Clinical Features

• Menstrual irregularities in women 1, 4
• Growth failure in children (height SDS below and BMI SDS above the mean for age and sex) 2
• Osteopenia and osteoporosis with increased fracture risk 6, 4
• Increased susceptibility to infections due to immunosuppression 6, 3

Epidemiology and Prevalence

• Cushing's syndrome is relatively uncommon with an estimated incidence of 2-8 cases per million people annually 3
• Prevalence among causes of hypertension is <0.1% 2
• Gender distribution varies by age: male predominance in prepubertal children (71%), female predominance in adults (79%) 2

Etiology

• Exogenous (iatrogenic) glucocorticoid use is the most common cause overall 3
• Endogenous causes include:
  • ACTH-dependent causes (80-85%):
    • Pituitary adenomas (Cushing's disease) - 60-70% of endogenous cases 3
    • Ectopic ACTH-secreting tumors (15%) 1, 4
  • ACTH-independent causes (15-20%):
    • Adrenal adenomas or carcinomas 4

Diagnostic Approach

Initial Screening Tests

• 24-hour urinary free cortisol measurement (multiple collections) 2, 7
• Late-night salivary cortisol test (most sensitive screening test) 7
• Overnight dexamethasone suppression test (1 mg) 2, 7

Confirmatory Tests

• Low-dose dexamethasone suppression test (0.5 mg every 6 hours for 48 hours) 2
• Measurement of plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes 4
• 24-hour urinary free cortisol excretion (preferably multiple measurements) 2

Imaging and Localization

• MRI of the pituitary for suspected Cushing's disease 3
• CT or MRI of abdomen/pelvis for suspected adrenal causes 2
• Bilateral inferior petrosal sinus sampling to differentiate pituitary from ectopic sources of ACTH 4

Treatment Considerations

• First-line treatment is surgical resection of the causative tumor 3
• Medical therapy options include:
  • Adrenal steroidogenesis inhibitors (ketoconazole is first-line medical therapy) 4
  • Glucocorticoid receptor antagonists (mifepristone) 5
• Radiation therapy or bilateral adrenalectomy for refractory cases 3

Clinical Pitfalls and Caveats

• Diagnosis can be challenging in mild or cyclic hypercortisolism 7
• Pseudo-Cushing states (depression, alcoholism, obesity) can mimic true Cushing's syndrome 7
• Exogenous glucocorticoid use must be excluded before biochemical testing 2
• Perioperative management requires special attention due to cardiovascular instability and potential adrenal insufficiency 8
• Untreated Cushing's syndrome is associated with significant morbidity and mortality, primarily from cardiovascular complications 6, 3