Description

• Cushing syndrome is defined as excessive glucocorticoid exposure from exogenous (steroid medications) or less commonly from endogenous sources (pituitary, adrenal, pulmonary, etc.).
• Cushing disease is glucocorticoid excess due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor.
• System(s) affected: endocrine/metabolic, musculoskeletal, skin/exocrine, cardiovascular; neuropsychiatric

Pediatric Considerations

• Rare in infancy and childhood
• Cushing disease accounts for approximately 75% of all cases of Cushing syndrome in children >7 years.
  • Rarely, Cushing disease (ACTH-producing pituitary adenoma) can be the initial manifestation of multiple endocrine neoplasia (MEN) type 1 in pediatric patients.
• In children <7 years, adrenal causes of Cushing syndrome (adenoma, carcinoma, or bilateral hyperplasia) are more common.
• The most common presenting symptom is lack of growth and weight gain.

Pregnancy Considerations

• Pregnancy may exacerbate the disease.
• Cortisol levels increase in normal pregnancy.

Epidemiology

Incidence
U.S. endogenous causes of Cushing syndrome are rare—around 8 cases per million population.

Prevalence
2–5% prevalence reported in difficult-to-control diabetics with obesity and hypertension (HTN)

Etiology and Pathophysiology

• Exogenous
  • Prolonged glucocorticoid use (most commonly in chronic disorders like asthma, chronic obstructive pulmonary disease, etc.)
• Endogenous glucocorticoid secretion
  • Endogenous ACTH–dependent hypercortisolism: 80–85%
    • ACTH-secreting pituitary tumor (Cushing disease): ~75%
    • Ectopic ACTH production (e.g., small cell carcinoma of lung, neuroendocrine tumors of the lung, or rarely thyroid, thymus, and pancreas)
  • Endogenous ACTH–independent hypercortisolism: ~15–20%
    • Adrenal adenoma
    • Adrenal carcinoma
• Pediatric/adolescent
  • Adrenal hyperplasia secondary to McCune-Albright syndrome: mean age 1.2 years
  • Adrenocortical tumors: mean age 4.5 years
  • Ectopic ACTH syndrome: mean age 10.1 years
  • Primary pigmented nodular adrenocortical disease: mean age 13.0 years
  • Cushing disease: mean age 14.1 years
• Pregnancy
  • Pituitary-dependent Cushing syndrome
  • Adrenal causes
  • ACTH-independent adrenal hyperplasia

Genetics

• MEN
• Carney complex (an inherited multiple neoplasia syndrome)
• McCune-Albright syndrome (mutation of GNAS1 gene)
• Familial isolated pituitary adenomas (mutations in the aryl hydrocarbon receptor–interacting protein gene)
• Activating somatic mutations of the USP8 (ubiquitin-specific protease 8) gene are found in a large proportion of Cushing disease cases. Presence of USP8 mutation in pituitary tumors is linked to higher incidence of tumor recurrence after transsphenoidal surgery.

Risk Factors

Prolonged use of corticosteroids

General Prevention

Avoid corticosteroid exposure, when possible.

Commonly Associated Conditions

Psychiatric disorders, diabetes, HTN, hypokalemia, infections, dyslipidemia, osteoporosis, and poor physical fitness