Cushing Syndrome (Adrenal Excess)
Cushing Syndrome (Adrenal Excess): Excerpt from The 5-Minute Pediatric Consult
J. Nina Ham, MDLorraine E. Levitt Katz, MD
Cushing Syndrome - BASICS
Cushing Syndrome - description
Cushing syndrome is a state of excess cortisol secretion by the adrenal cortex. This may be associated with excess production of other adrenal hormones, such as androgens and mineralocorticoids.
Cushing Syndrome - epidemiology
- Cushing disease: Female > Male
- Adrenocortical carcinoma: Female > Male
- Cushing disease: Most common cause of endogenous Cushing syndrome, accounting for 80% of Cushing syndrome in adults and children >7 years of age
- Adrenal tumor: Adrenocortical carcinomas account for >50% of Cushing syndrome in children <7 years of age. These tumors are less common in adults and children >7 years of age.
Cushing Syndrome - incidence
- 0.1–0.5/1,000,000 new pediatric cases per year
- 10 times more common in adults
Cushing Syndrome - pathophysiology
- Cushing disease: Pituitary ACTH oversecretion, usually due to pituitary adenoma, with resultant bilateral adrenal hyperplasia
- Adrenal tumors
- Adrenal adenomas: Benign tumors that secrete mainly cortisol
- Adrenal cortical carcinomas: Usually large, rapidly growing tumors, which produce a variety of hormones including cortisol and androgens
- Ectopic ACTH production: A rare cause of Cushing syndrome in pediatrics. Small cell carcinoma, pheochromocytomas, medullary thyroid carcinoma, and carcinoid tumors can all secrete ectopic ACTH.
- Exogenous steroids: Iatrogenic Cushing syndrome is the most common cause in pediatrics. Cushing syndrome can be caused by chronic systemic, topical, or intranasal steroid, or ACTH use.
Cushing Syndrome - DIAGNOSIS
Cushing Syndrome - signs & symptoms
Cushing Syndrome - history
- Weight gain, gradual onset
- Weakness and fatigue
- Emotional or mental changes
- Use of oral, topical, inhaled, or intranasal steroids
Cushing Syndrome - physical exam
- Growth arrest: Most consistent finding
- Obesity: Cervicodorsal fat; localized (e.g., moon facies, truncal obesity)
- Thin skin with striae, facial plethora: Sign of cortisol excess
- Hirsutism, acne: Sex hormone effect
- Pubertal arrest/menstrual disorders: Common finding
- Hypertension: Mineralocorticoid effect
- Bruising: Capillary friability
- Hyperpigmentation: ACTH effect
- Virilization/feminization: Sex hormone effect
Cushing Syndrome - tests
Cushing Syndrome - lab
- Diagnostic tests:
- Midnight salivary cortisol level >0.35 mcg/dL. Patients are instructed to collect saliva by chewing a commercially available cotton swab at midnight. This provides a convenient, 1st-line diagnostic test. Establishes hypercortisolism, but positive results should be confirmed with urine-free cortisol level.
- Urinary 24-hour free cortisol >90 mcg/24 hours. Correct for creatinine and surface area. 2 or 3 separate collections are preferable. Establishes the diagnosis of hypercortisolism
- Urinary 24-hour 17-hydroxysteroids >6 mg/g creatinine. Establishes the diagnosis of hypercortisolism
- Overnight dexamethasone suppression test (15 mcg/kg): Screening only; 8:00 a.m. plasma cortisol >5 mcg/L suggests hypercortisolism, but can be falsely negative.
- Loss of diurnal variation of plasma cortisol in older children: Normally, the 11:00 p.m. cortisol is <50% of the 8:00 a.m. value. The majority of patients with Cushing syndrome have mean elevated plasma cortisol, without diurnal variation.
- Differentiate causes:
- Random ACTH level: Cushing disease (increased ACTH with increased cortisol level), adrenal tumor (low ACTH and increased cortisol)
- Androgen levels: Often high in adrenocortical carcinoma. Androgen levels are low in benign, cortisol-secreting adenomas.
- Dexamethasone-suppression tests. Low-dose dexamethasone (30 mcg/kg/d) divided q6h PO for 2 days, followed by high-dose (120 mcg/kg/d) divided q6h PO for 2 days. Collect 24-hour urine for cortisol and 17-hydroxysteroids throughout. Non-Cushing states usually suppress urinefree cortisol and 17-hydroxysteroids to 50–90% of baseline values after low dose. Majority of pituitary tumors are suppressible after high dose. Adrenal source: Hypercortisolism will not suppress.
Cushing Syndrome - imaging
Tumor location:
- Abdominal CT/MRI will demonstrate adrenal carcinoma, adrenal adenomas, or bilateral hyperplasia/nodules resulting from Cushing disease.
- Abdominal ultrasound may be useful as initial imaging for adrenal tumor.
- Pituitary MRI with gadolinium may demonstrate a pituitary adenoma.
- Cavernous sinus sampling for ACTH: Utility in lateralizing pituitary microadenoma in pediatric patients may be limited.
Cushing Syndrome - differencial diagnosis
- Cushing disease: Pituitary ACTH oversecretion
- Adrenal tumors:
- Adrenal adenomas
- Adrenal cortical carcinomas
- Exogenous glucocorticoid treatment
Cushing Syndrome - TREATMENT
Cushing Syndrome - general measures
- Cushing disease:
- Transsphenoidal pituitary surgery: 70–80% success, may be less in some series, perioperative glucocorticoid replacement required, postoperative complications can include transient diabetes insipidus and, rarely, hypopituitarism or permanent diabetes insipidus
- Pituitary radiation: 6–18 months for effect: Remission in 45–85% of individuals. Remission rate improved if combined with o,p′ -DDD. Hypopituitarism is the most common side effect.
- Bilateral adrenalectomy: Indicated in patients with bilateral micronodular disease or in patients with Cushing disease who fail surgery or radiotherapy. High rate of surgical complications. May result in Nelson syndrome: Pituitary adenoma growth and hyperpigmentation; long-term glucocorticoid and mineralocorticoid replacement may be needed.
- Drug therapy: Ketoconazole (inhibits multiple adrenal enzymes, o,p′DDD (adrenolytic agent), metyrapone (11-hydroxylase inhibitor), aminoglutethimide (20,22-desmolase inhibitor), trilostane (3β-hydroxysteroid dehydrogenase inhibitor), RU-486 (glucocorticoid receptor antagonist). Drug combinations may reduce individual doses and lessen side effects.
- Adrenal tumor:
- Aggressive surgical resection, chemotherapy for carcinoma: Cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), 5-fluorouracil (5-FU), methotrexate (MTX)
- Drug therapy to control hypercortisolism: o,p′DDD at high doses may lower 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
Cushing Syndrome - FOLLOW UP
Cushing Syndrome - prognosis
- 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 Syndrome - complications
- Growth arrest
- Obesity
- Pubertal arrest
- Glucose intolerance
- Osteoporosis
- Adrenal carcinomas: Metastatic spread
Cushing Syndrome - patient monitoring
- Acute glucocorticoid replacement: 10–12 mg/m2/d divided as b.i.d. to t.i.d. until recovery of hypothalamic/pituitary function (6–12 months). Parents should be taught to triple the dose for stress, fever, illness, or vomiting. Injectable hydrocortisone should be given for emergency use. Taper corticosteroid treatment gradually.
- Chronic glucocorticoid replacement: Patients treated with bilateral adrenalectomy or with o,p′DDD require life-long steroid replacement and stress dose steroids.
- Reassess 24-hour urinary cortisol/ketosteroid secretion during the 1st week after treatment and at 6 weeks.
- In the week after effective pituitary surgery, cortisol should be undetectable and ACTH <5 pg/mL, 24 hours after last hydrocortisone dose. Stimulation and suppression tests are performed 6 weeks after surgery (holding hydrocortisone dose).
- Frequent follow-up to monitor for recurrence. Monitor for cortisol withdrawal symptoms, hypopituitarism. Consider medical treatment for persistent hypercortisolism.
- Monitor growth carefully. Linear growth is often compromised in Cushing syndrome. Growth hormone deficiency can result from transsphenoidal surgery or pituitary irradiation.
- False-positive tests for hypercortisolism: stress, lack of suppression, depression, anorexia, primary glucocorticoid resistance
- False-negative tests: Incomplete urine collection, periodic or intermittent cortisol hypersecretion, slow metabolism of dexamethasone
- Aberrant renal metabolism
- Repeat if suspicion is strong.
Cushing Syndrome - bibliography
- Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: A consensus statement. J Clin Endocrinol Metab. 2003;88:5593–5602.
- Atkinson AB, Kennedy A, Wiggam M, et al. Long-term remission rates after pituitary surgery for Cushing’s disease. Clin Endocrinol. 2005;63(5):549–559.
- Batista D, Gennari M, Riar J, et al. An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease. J Clin Endocrinol Metab. 2006;91(1):221–224.
- Gomez MT, Malozowski S, Winterer J, et al. Urinary free cortisol values in normal children and adolescents. J Pediatr. 1991;118(2):256–258.
- Magiakou MA, Chrousos GP. Cushing’s syndrome in children and adolescents: Current diagnostic and therapeutic strategies. J Endocrinol Invest. 2002;25:181–194.
- Papanicolaou DA, Yanovski JA, Cutler GB Jr, et al. A single midnight serum cortisol measurement distinguishes Cushing’s syndrome from pseudo-Cushing states. J Clin Endocrinol Metab. 1998;83(4):1163–1167.
- Putignano P, Toja P, Dubini A, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J Clin Endocrinol Metab. 2003;88(9):4153–4157.
- Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer. 2004;40(8):1117–1126.
- Savage MO, Scommegna S, Carroll PV, et al. Growth in disorders of adrenal hyperfunction. Horm Res. 2002;58(suppl 1):39–43.
- Yanovski JA, Cutler GB Jr, Chrousos GP, et al. The dexamethasone-suppressed corticotropin-releasing hormone stimulation test differentiates mild Cushing’s disease from normal physiology. J Clin Endocrinol Metab. 1998;83(2):348–352.
Cushing Syndrome - CODES
Cushing Syndrome - icd9
255.0 Cushing syndrome
Cushing Syndrome - FAQ
- Q: What clinical features help distinguish patients with pituitary Cushing disease from patients with adrenal tumors?
- A: Cushing syndrome and hyperpigmentation suggest an ACTH effect. Cushing syndrome and virilization suggest 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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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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