• Cushing disease—pituitary ACTH oversecretion, usually due to pituitary adenoma, with resultant bilateral adrenal hyperplasia.
  • Adrenal tumors
  • Adrenal adenomas—secrete mainly cortisol
  • Adrenal cortical carcinomas—usually large, rapidly growing tumors, which produce a variety of hormones including cortisol and androgens.

• Incidence
  • 0.1 to 0.5 new pediatric cases per million population/year
  • Ten times more common in adults
• Gender
  • Cushing disease—female predominance
  • Adrenocortical carcinoma—female predominance
• Age
  • Cushing disease—accounts for 80% of Cushing syndrome in adults and children greater than 7 years of age.
  • Adrenal tumor—adrenocortical carcinomas account for more than 50% of Cushing syndrome in children less than age 7.
• These tumors are less common in adults and children older than 7 years of age.

• Cushing syndrome:
  • Growth arrest
  • Obesity
  • Pubertal arrest
  • Glucose intolerance
  • Osteoporosis
  • Adrenal carcinomas—metastatic spread

• The prognosis for cure is good with Cushing disease and adrenal adenoma.
• The prognosis for adrenal carcinoma is poor because of the frequency of micrometastases and high recurrence rate.

• Cushing disease
  • Pituitary ACTH oversecretion
• Adrenal tumors
  • Adrenal adenomas
  • Adrenal cortical carcinomas
• Exogenous glucocorticoid treatment

• Weight gain, gradual onset
• Weakness and fatigue

Question: What emotional/mental changes are seen?
Significance: Cortisol exceess can cause emotional changes.

Finding: Growth arrest
Significance: Most consistent finding

Finding: Obesity
Significance: Cervicodorsal fat (localized: moon facies, truncal obesity)

Finding: Thin skin with striae, facial plethora
Significance: Sign of cortisol excess

Finding: Hirsutism, acne
Significance: Sex hormone effect

Finding: Pubertal arrest/menstrual disorders
Significance: Common finding

Finding: Hypertension
Significance: Mineralocorticoid effect

Finding: Bruising
Significance: Capillary friability

Finding: Hyperpigmentation
Significance: ACTH effect

Finding: Virilization/feminization
Significance: Sex hormone effect

Test: Urinary 24-h free cortisol greater than 90 gg/24 h (preferred test). Correct for creatinine and surface area. Two or three separate collections are preferable.
Significance: Establishes the diagnosis of hypercortisolism.

Test: Urinary 24-h 17-hydroxysteroids greater than 6 mg/g creatinine
Significance: Establishes the diagnosis of hypercortisolism

Test: Overnight dexamethasone suppression test (15 gg/kg)
Significance: Screening only; 8:00 A.M. plasma cortisol ³5 µg/L, suspect hypercortisolism

Test: Loss of diurnal variation of plasma cortisol in older children.
Significance: Normally, the 11:00 P.M. cortisol is less than 50% of 8:00 A.M. value. The majority of patients with Cushing syndrome have mean elevated plasma cortisol, without diurnal variation.

Test: ACTH levels
Significance: Cushing disease: increased ACTH with hypercortisolism. Adrenal tumor: low ACTH and hypercortisolism.

Test: Androgen levels
Significance: Often high in adrenocortical carcinoma. These patients are often virilized. Androgen levels are low in benign cortisol secreting adenomas.

Test: Dexamethasone suppression tests. Low dose (30 gg/kg/day) divided q6h P0 ×2 days, followed by high dose (120 ltg/kg/day) divided q6h P0 ×2 days. A 24-h urine collection for cortisol and 17-hydroxysteroids throughout.
Significance: Non-Cushing states usually suppress urinary-free cortisol and 17 hydroxysteroids to 50% to 90% of baseline values after low dose.

Test: Pituitary MRI with gadoliniurn
Significance: May demonstrate a pituitary adenoma

Test: Abdominal CT/MRI
Significance: Will demonstrate adrenal carcinoma, adrenal adenomas, or bilateral hyperplasia/nodules resulting from Cushing disease.

Test: Cavernous sinus sampling for ACTH
Significance: Will help to lateralize pituitary microadenomas

• Transphenoidal pituitary surgery
  • 70% to 80% success, may be less in some series
  • Perioperative glucocorticoid replacement required
• Pituitary radiation—6 to 18 months for effect
  • Remission in 45% to 85% of individuals
  • Remission rate improved if combined with o,p'DDD
• Bilateral adrenalectomy
  • High rate of surgical complications
  • May result in Nelson syndrome—pituitary adenoma growth and hyperpigmentation, long-term glucocorticoid and mineralocorticoid replacement.
• Drug therapy
  • Ketoconazole—inhibits multiple adrenal enzymes
  • o,p'DDD—adrenolytic agent
  • Metyrapone—11-hydroxylase inhibitor
  • Aminoglutethimide—20,22 desmolase inhibitor
  • Trilostane—3 B-hydroxysteroid dehydrogenase inhibitor
  • RU 486—Glucocorticoid receptor antagonist
  • Drug combinations may lower individual doses and lessen side effects
• Adrenal tumors
  • Aggressive surgical resection
  • Chemotherapy for carcinoma: Cytoxan, Adriamycin, 5FU, MTX
• Drug therapy to control hypercortisolism
  • o,p'DDD at high doses—may improve recurrence risk in patients with complete tumor resection. In those with residual or recurrent disease, it may improve hypercortisolism, but not survival
• Glucocorticoid and possibly mineralocorticoid replacement.

• Chronic glucocorticoid replacement 10 to 12 mg/m²/day divided as b.i.d. to t.i.d. until recovery of hypothalamic/pituitary function (6–12 months). Triple for stress; fever illness, vomiting. Injectable hydrocortisone for emergency use taper corticosteroid treatment gradually.
• Reassess 24-h urinary cortisol/ketosteroid secretion during the first week after treatment and at 6 weeks.
• In the week after effective pituitary surgery, cortisol should be undetectable and ACTH less than 5 pg/mL, 24 hours after last hydrocortisone dose. Stimulation and suppression tests are performed 6 weeks post-surgery (holding hydrocortisone dose).
• Frequent follow-up to monitor for recurrence. Monitor for cortisol withdrawal symptoms, hypopituitarism. Consider medical treatment for persistent hypercortisolism.

• False-positive tests for hypercortisolism
  • Stress—lack of suppression
  • Depression
  • Anorexia
  • Primary glucocorticoid resistance
• False-negative tests
  • Incomplete urine collection
  • Periodic hormonogenesis
  • Slow metabolism of dexamethasone
• Aberrant renal metabolism
• Repeat if suspicion is strong

Q: What clinical features help distinguish patients with pituitary Cushing disease from patients with adrenal tumors?
A: Cushing syndrome and hyperpigmentation suggests an ACTH effect. Cushing syndrome and virilization suggests adrenal carcinoma.

Q: What physical characteristics most clearly differentiate children with exogenous obesity from those with Cushing Syndrome?
A: Exogenous obesity is associated with robust linear growth while Cushing Syndrome is associated with growth failure.

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Gomez MT, Malozowski S, Winterer J, Vamvakopoulos C, Chrousos GP. Urinary free cortisol values in normal children and adolescents. J Pediatr 1991;118(2):256–258.

Magiakou MA, Mastorakos G, Oldfield EH, et al. Cushing’s syndrome in children and adolescents: presentation, diagnosis, and therapy. N Engl J Med 1994;331:629–636.

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