Cushing Disease and Cushing Syndrome

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Basics

Description

  • Clinical abnormalities associated with chronic exposure to excessive amounts of cortisol (the major adrenocorticoid)
  • Cushing syndrome is defined as excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor. Exogenous intake of steroids is the primary cause of Cushing syndrome.
  • Cushing disease is defined as glucocorticoid excess due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor, the most common cause of primary Cushing syndrome.
  • 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.
  • In children <7 years, adrenal causes of Cushing syndrome (adenoma, carcinoma, or bilateral hyperplasia) are more common.
  • Most common presenting symptom is lack of growth consistent with the weight gain.
Pregnancy Considerations
  • Pregnancy may exacerbate disease.
  • Cortisol levels increase in normal pregnancy states.

Epidemiology

Incidence
Uncommon: 0.7 to 2.4/1 million per year

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

Etiology and Pathophysiology

  • Syndrome: excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor
  • Disease: pituitary tumor causing excess ACTH (corticotropin)
  • General population
    • Exogenous glucocorticoids
    • Endogenous ACTH–dependent hypercortisolism: 80–85%
      • ACTH-secreting pituitary tumor: 75%
      • Ectopic ACTH production (e.g., small cell carcinoma of lung, bronchial carcinoid): 20%
    • Endogenous ACTH–independent hypercortisolism: 15–20%
      • Adrenal adenoma
      • Adrenal carcinoma
      • Macronodular or micronodular hyperplasia
  • 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: 33%
    • Adrenal causes: 40–50%
    • ACTH-independent adrenal hyperplasia: 3%

Genetics
  • Multiple endocrine neoplasia
  • 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)

Risk Factors

  • Prevalent sex: female > male (3:1)
  • Most often occurs between the ages of 25 and 40 years
  • Prolonged use of corticosteroids

General Prevention

Avoid corticosteroid exposure, when possible.

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