What causes Cushing syndrome?

Causes of Cushing Syndrome

Cushing syndrome is primarily caused by prolonged exposure to excess cortisol, with the most common cause being exogenous glucocorticoid use, followed by ACTH-secreting pituitary adenomas (Cushing disease), ectopic ACTH-producing tumors, and adrenal tumors. 1, 2

Etiological Classification

1. Exogenous Causes (Most Common)

• Iatrogenic glucocorticoid administration: Long-term treatment with glucocorticoids (>7.5 mg prednisone daily) 3
• Routes: oral, injectable, topical, inhaled

2. Endogenous Causes

ACTH-Dependent Cushing Syndrome (80-85% of endogenous cases)

1. Cushing Disease (60-70% of endogenous cases) 1, 2

   • Caused by ACTH-secreting pituitary adenoma
   • Microadenomas (<10mm) account for 98% of cases in children and adolescents 4
   • Shows male predominance in prepubertal children (71%), contrasting with female predominance (79%) in adults 4

2. Ectopic ACTH Syndrome (10-15% of endogenous cases) 1

   • Sources:
     • Poorly differentiated endocrine tumors (small cell lung cancer)
     • Well-differentiated endocrine tumors (bronchial carcinoids, thymic carcinoids)
     • Medullary thyroid carcinoma
     • Gastroenteropancreatic neuroendocrine tumors
     • Pheochromocytoma
   • Associated with severe hypercortisolism and hypokalemia (in up to 57% of cases) 1

ACTH-Independent Cushing Syndrome (15-20% of endogenous cases)

1. Adrenal Adenoma 3

   • Benign tumor causing autonomous cortisol production

2. Adrenal Carcinoma 3

   • Malignant tumor with poor prognosis
   • Can produce multiple hormones

3. Bilateral Adrenal Hyperplasia 3

   • Macronodular or micronodular forms
   • Autonomous cortisol production

Pathophysiology

Cushing syndrome results from disruption of the hypothalamic-pituitary-adrenal axis:

1. Normal Physiology: Cortisol secretion is regulated by ACTH from the pituitary, which is controlled by CRH from the hypothalamus, with negative feedback by cortisol 1

2. Pathological Mechanisms:

   • In Cushing disease: Pituitary adenoma produces ACTH that is relatively resistant to negative feedback 5
   • In ectopic ACTH syndrome: Tumors produce ACTH independent of normal regulatory mechanisms 6
   • In adrenal causes: Autonomous cortisol production bypasses pituitary control 6

3. Molecular Mechanism: In pituitary adenomas, pasireotide (a medical treatment) works by binding to somatostatin receptors (particularly SSTR5, which is overexpressed in corticotroph tumor cells), inhibiting ACTH secretion and consequently reducing cortisol production 7

Epidemiology

• Incidence of endogenous Cushing syndrome: 2-8 cases per million people annually 2
• Cushing disease accounts for 75-80% of pediatric Cushing syndrome cases 4
• Mean age at presentation in children: 12.3 ± 3.5 years (range 5.7-17.8) 4
• Gender distribution varies by age:
  • Overall male predominance in children (63%)
  • Female predominance in adults (79%) 4

Clinical Implications

Prolonged hypercortisolism leads to significant morbidity affecting multiple systems:

• Metabolic: Hyperglycemia, insulin resistance, visceral obesity
• Cardiovascular: Hypertension (70-90% of patients) 1
• Musculoskeletal: Muscle atrophy, proximal weakness, osteoporosis
• Dermatologic: Purple striae, easy bruising, facial plethora
• Neuropsychiatric: Mood disorders, cognitive changes
• Immune: Increased susceptibility to infections

Early identification and treatment are essential as mortality and morbidity are significantly increased in untreated cases 8.

Key Diagnostic Considerations

Diagnosis involves:

1. Excluding exogenous glucocorticoid use
2. Confirming hypercortisolism with screening tests:
   • 24-hour urinary free cortisol
   • Late-night salivary cortisol
   • Overnight 1-mg dexamethasone suppression test 1
3. Determining ACTH dependence/independence
4. Localizing the source through imaging (pituitary MRI, adrenal CT, etc.) 6

Children with unexplained weight gain combined with either growth rate deceleration or height centile decrement should be investigated for Cushing syndrome 4.