What is Cushing disease?

What is Cushing Disease?

Cushing disease is a rare endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma that leads to chronic hypercortisolism and represents the most common cause of endogenous Cushing's syndrome. 1

Pathophysiology

• The disease results from a benign monoclonal pituitary adenoma that secretes excessive ACTH, which in turn stimulates the adrenal glands to produce supraphysiological levels of cortisol 2
• Microadenomas (≤10 mm) account for 98% of cases in children and adolescents, with tumor diameters frequently ≤2 mm 1, 3
• Macroadenomas are uncommon, representing only 2-5% of pediatric cases and 10% of adult cases 1, 3

Epidemiology

• The incidence is approximately 0.5 new patients per million individuals per year 1, 3
• Cushing disease accounts for 75-80% of Cushing's syndrome cases in children/adolescents and 49-71% in adults 1, 3, 4
• There is a striking gender difference: 63% male predominance in pediatric patients (71% prepubertal) versus 79% female predominance in adults 1
• Boys with Cushing disease tend to have more aggressive disease with elevated BMI, shorter height, and higher plasma ACTH levels than girls 1

Clinical Manifestations

The chronic hypercortisolism produces characteristic features including:

• Metabolic effects: Weight gain, central obesity, moon face, dorsal and supraclavicular fat accumulation (buffalo hump), abdominal striae 4, 5
• Dermatologic changes: Facial plethora, hirsutism, fragile skin, easy bruising 4, 5
• Cardiovascular: Hypertension mimicking severe metabolic syndrome 4
• Endocrine/metabolic: Glucose abnormalities and diabetes 4
• Musculoskeletal: Muscle weakness, osteoporosis, and fractures (especially vertebral) 6
• Neuropsychiatric: Mood disorders, cognitive alterations 4, 6
• Reproductive: Menstrual irregularities 4

Pediatric-Specific Features

• Growth failure with subnormal growth velocity is a key distinguishing feature in prepubertal children 1
• The combination of unexplained weight gain with either growth rate deceleration or decrement in height centile has high sensitivity and specificity for Cushing syndrome in children 1
• Height standard deviation score (SDS) falls below the mean while BMI SDS rises above the mean for age and sex 1

Morbidity and Mortality Impact

• Cushing disease is associated with significantly increased morbidity and premature death due to cardiovascular disease, infections, and metabolic complications 5, 7, 6
• Long-term quality of life is notably worse for patients with Cushing disease compared to those with adrenal causes of Cushing's syndrome 1
• Critical caveat: Even after correction of hypercortisolism, many comorbidities may persist, particularly increased cardiovascular risk, visceral adiposity, glucose intolerance, hypertension, dyslipidemia, atherosclerosis, and cognitive/mood alterations 6
• Diagnosis is often delayed for years due to lack of awareness of the insidious, progressive disease process and testing complexity 1

Distinction from Other Forms of Cushing's Syndrome

Cushing disease specifically refers to the pituitary-dependent form and must be distinguished from:

• Ectopic ACTH syndrome: ACTH produced by non-pituitary tumors (e.g., thymic tumors account for up to 2% of cases) 4
• Adrenal Cushing's syndrome: Direct cortisol overproduction by adrenal tumors or hyperplasia (ACTH-independent) 3, 8
• Exogenous Cushing's syndrome: Iatrogenic from chronic glucocorticoid administration 4