Cushing Disease and Cushing Syndrome

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Basics

Description

  • Cushing syndrome is defined as excessive glucocorticoid exposure from exogenous (steroid medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.).
  • Exogenous intake of steroids is the primary cause of Cushing syndrome.
  • Cushing disease—the most common cause of primary Cushing syndrome—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 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 (refer to the “Alert” section in this chapter for further information).

Epidemiology

Incidence
Endogenous causes of Cushing syndrome are extremely rare. They are estimated at around 8 cases per U.S. million population.

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

Etiology and Pathophysiology

  • General population
    • Exogenous glucocorticoids
    • 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, bronchial carcinoid)
      • 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
    • Adrenal causes
    • ACTH-independent adrenal hyperplasia

Genetics
  • Multiple endocrine neoplasia (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

  • Preponderance in women: female/male: 3–8/1 for Cushing disease, 4–5/1 for adrenal causes
  • 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

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Basics

Description

  • Cushing syndrome is defined as excessive glucocorticoid exposure from exogenous (steroid medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.).
  • Exogenous intake of steroids is the primary cause of Cushing syndrome.
  • Cushing disease—the most common cause of primary Cushing syndrome—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 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 (refer to the “Alert” section in this chapter for further information).

Epidemiology

Incidence
Endogenous causes of Cushing syndrome are extremely rare. They are estimated at around 8 cases per U.S. million population.

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

Etiology and Pathophysiology

  • General population
    • Exogenous glucocorticoids
    • 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, bronchial carcinoid)
      • 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
    • Adrenal causes
    • ACTH-independent adrenal hyperplasia

Genetics
  • Multiple endocrine neoplasia (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

  • Preponderance in women: female/male: 3–8/1 for Cushing disease, 4–5/1 for adrenal causes
  • 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

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