Pediatrics

Cushing syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Cushing Syndrome? What are the typical findings for this disease?

Cushing Syndrome (CS) is a multi-system disorder resulting from prolonged exposure to excess glucocorticoids. The most common cause of CS in children is exogenous glucocorticoid use, or iatrogenic Cushing syndrome.

The etiology of endogenous CS may be subdivided into ACTH-dependent versus ACTH-independent CS. The cause of ACTH-dependent CS is either overproduction of ACTH from the pituitary, ectopic production, or rarely excess production of CRH. The most common cause of endogenous CS in children is overproduction of ACTH from a pituitary adenoma, which is termed Cushing's disease (CD). Ectopic sources of ACTH include small cell carcinoma of the lungs, carcinoid tumors in the bronchus, pancreas, or thymus, medullary carcinomas of the thyroid, pheochromocytomas, and other neuroendocrine tumors. These tumors may also, rarely, produce CRH.

The adrenals may also be the cause of excess cortisol production (termed ACTH-independent CS) and account for approximately 15% of all cases in childhood. Bilateral hyperplasia, bilateral nodular adrenal disease, adrenal carcinoma, or adrenal adenomas can all cause excess production of cortisol, which is secreted autonomously.

Bilateral adrenal nodular diseases that are rare causes of CS include primary pigmented adrenocortical nodular disease (PPNAD) usually associated with Carney complex, massive macronodular adrenal hyperplasia (MMAD), and bilateral macronodular adrenal hyperplasia as seen in McCune Albright syndrome.

Clinical Presentation

The most common symptom is weight gain, which is often also the inital manifestation.

In children, growth failure is the most reliable sign, especially when combined with continuing weight gain.

Other features of CS include violaceous skin striae, easy bruising, hirsutism, acne, facial plethora, delayed sexual development, and amenorrhea. In children who are pubertal, they may present with signs of virilization.

What other disease/condition shares some of these symptoms?

Differential Diagnosis for elevated UFC:

-physical and emotional stress

-obesity

-depression

-pregnancy

-alcoholism

-anorexia

-narcotic withdrawal

-anxiety

-malnutrition

-high water intake

What caused this disease to develop at this time?

A tumor producing ACTH in the pituitary (most commonly) or elsewhere (rarely).

Adrenal tumors or adrenocortical hyperplasia

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Confirmation of diagnosis: Signs and symptoms of CS must be present before proceeding with an evaluation. Use of exogenous glucocorticoids and conditions that can cause mild elevation of cortisol levels, such as anorexia, alcoholism, depression, and obesity, must be investigated.

  • Documentation of hypercortisolism: screening tests to confirm elevated cortisol levels

    • Urinary free cortisol (UFC) is the most cost-effective and most convenient test to obtain as an outpatient. 24-hour collection for urine creatinine should be performed at the same time, and urinary free cortisol should be corrected for body surface area (normal 24-hr UFC<70 ug/m2/day). UFCs should be obtained on multiple occasions.

    • low dose dexamethasone suppression test: 1mg dexamethasone at 11pm, and measure serum cortisol at 8am the following morning. The level should be <1.8ug/dl. It is more expensive than UFC, but is useful in patients in whom urinary collection is difficult. Note that dexamethasone is metabolized by the cytochrome P450 enzyme, and levels are affected by other medications that interact with this enzyme.

    • midnight serum cortisol level: this test assumes a normal sleep cycle, and is not useful in an outpatient setting. Normal cortisol levels should be <4.4 ug/dl in children, or <7.5 ug/gl in adolescents or adults.

    • midnight salivary cortisol level: correlates well with serum cortisol, and is a convenient test to use in an outpatient setting. A value >0.13 ug/dl is abnormal, and is highly sensitive and specific for CS. Samples should be collected on multiple occasions.

  • Pseudo-Cushing versus Cushing syndrome

    • combined dexamethasone-CRH test: low dose dexamethasone (0.5mg adjusted for body weight in children<70kg) is administered every 6 hours for 8 doses. This is followed by administration of 1ug/kg of ovine-CRH 2 hours after the last dose of dexamethasone. Measurements of ACTH and cortisol are obtained at baseline and every 15 minutes for 1 hour after administration of CRH. Patients with a normal response will have cortisol levels <1.4ug/dL 15 minutes after CRH administration.

  • Distinguish the source: ACTH-dependent versus ACTH-independent

    • measurement of ACTH: levels<5ng/dL indicates ACTH-independent CS, while levels of ACTH>20 imply ACTH-dependent CS. These levels should be repeated on multiple occasions due to the variability of ACTH secretion, as well as its instability after collection. If the source is confirmed to be ACTH-independent, then the next step is imaging. Values inbetween are not definitive, and should prompt further testing (see below).

    • High-dose dexamethasone suppression test (modified Liddle's test): This test helps distinguish between CD and ectopic ACTH-producing tumors, since CD patients will have suppression of cortisol to <5 ug/dL, while those with ectopic tumors will not suppress more than 50% of the baseline cortisol value. The test involves high dose dexamethasone (8mg, or weight adjusted for those <70kg) given at 11pm, and plasma cortisol is measured the following morning at 9am. This test should not be performed prior to confirmation of hypercortisolism, since normal patients will also have suppression of cortisol levels after dexamethasone. 85% of CD patients show suppression, while <10% of patients with ectopic ACTH tumors show suppression.

    • CRH test: This test is another way to distinguish between CD and ectopic ACTH-producing tumors. CRH (100 ug) is administered intravenously, and ACTH and cortisol are measured at 15 minute intervals for one hour. Patients with CD have an increase in cortisol from baseline by 20%, and an increase in ACTH by 35% at 30 and 45 minutes. 85% of patients with CD respond with an increase in cortisol and ACTH, while 95% of patients with ectopic ACTH production do not respond with increased levels.

    • Combined CRH/high dose dexamethasone test: increases the sensitivity and specificity of both tests

    • IPSS: bilateral inferior petrosal sinus sampling (IPSS) may be needed to help distinguish between a pituitary microadenoma and an ectopic source of ACTH, as pituitary imaging may be normal. ACTH concentrations are measured at baseline and after 3, 5, and 10 minutes post-CRH administration. Patients with an ectopic source of ACTH do not have a gradient between petrosal sinus samples and peripheral ACTH values, whereas those with a pituitary microadenoma will have at least a two-fold gradient as compared with the periphery. Note, however, that the patient must be hypercortisolemic, and assumes a normal venous drainage from the pituitary.

  • Once the source is confirmed by laboratory testing, imaging should be obtained, with the exception of IPSS, which should be obtained only if the pituitary MRI is normal, as it is an invasive test.

  • Adrenal sources of excess cortisol, cortisol-producing adenomas and, rarely, bilateral hyperplasias, cause ACTH-independent CS. In these patients:

    • ACTH levels are typically low or undetectable

    • 8am cortisol levels in response to low dose dexamethasone (1mg dexamethasone administered at 11pm) fail to suppress <1.8 ug/dl

    • 9am cortisol levels in response to high-dose dexamethasone (8mg administered at 11pm) fail to suppress

    • Urinary levels of cortisol (UFCs) or 17-hydroxysteroids (17-OHs) fail to suppress during Liddle's test

    • The CRH test remains "flat": there is no response to CRH in both ACTH (which is steadily low or undetectable during the test) or cortisol (which remains steadily elevated during the test).

Would imaging studies be helpful? If so, which ones?

  • Evaluation for suspected CD:

    • pituitary MRI with gadolinium contrast, performed with thin sections and high resolution. The majority of tumors will be hypoenhancing microadenomas.

  • Evaluation for suspected adrenal source:

    • CT is preferable to MRI for evaluation of the adrenal glands as the source of hypercortisolism. The adrenal glands in patients with CD may appear enlarged and nodular, due to ACTH-driven bilateral hyperplasia, whereas adrenal adenomas are small, usually less than 5 cm, and are unilateral. PPNAD features normal or small-appearing adrenal glands on imaging, despite histologic abnormalities, while MMAD features massive enlargement of both glands visible on CT or MRI.

    • Ultrasound of the adrenal glands may be performed, although it is less sensitive and more inaccurate when compared with CT or MRI.

  • Evaluation for suspected ectopic source:

    • CT or MRI of the chest, abdomen, and pelvis may be useful when localizing an ectopic ACTH source.

    • Octreotide scan: uses radio-labelling to help localize an ectopic ACTH source.

    • Venous sampling: to evaluate suspected for elevated ACTH levels, once imaging suggests a source.

Confirming the diagnosis

See Figure 1 for clinical decision algorithm.

Figure 1.

Diagnostic Algorithm

If you are able to confirm that the patient has Cushing syndrome, what treatment should be initiated?

  • ACTH-secreting pituitary adenoma (Please see chapter on Cushing Disease for more information)

    • treatment of choice is transphenoidal surgery (TSS), which offers a success rate of 90% in an experienced center.

    • pituitary radiation is an option for treatment following a failed TSS, and offers up to 80% remission rate.

    • bilateral adrenlectomy may be used as a third-line option, however, Nelson syndrome may develop in up to 15% of patients with CD treated with adrenalectomy. The features of Nelson syndrome include hyperpigmentation, elevated ACTH levels, and enlargement of the pituitary tumor.

  • Adrenal adenoma

    • CT imaging can often help distinguish between adrenal adenoma vs carcinoma, however, the diagnosis is often made at the time of surgery.

      • Precontrast Hounsfield units (HU) are helpful in differentiating a benign adenoma from a malignant carcinoma. Typically, lipid-rich adenomas have a HU measurement of less than 10, although some adenomas that do not contain large amounts of lipid can have higher HU measurements. Adenomas tend to have a smooth, round, and homogeneous density and measure less than 4 cm. In contrast, adrenal carcinomas and metastases have readings of greater than 20 HUs, have irregular shapes, may display tumor calcifications, appear inhomogeneous, and typically measure greater than 4 cm.

    • surgical resection is the treatment of choice, which can often be done laparascopically.

  • Adrenal carcinomas

    • surgical resection may be an option for less advanced stages

    • mitotane, an adrenocytolytic agent, can be used as adjuvant therapy, or in cases where surgical resection is not an option.

    • chemotherapeutic agents: cisplatin, 5-flourouracil, suramin, doxorubicin, etoposide

    • pharmacotherapeutic treatment for hypercortisolism: glucocorticoid antagonists and steroid synthesis inhibitors (See Table I.)

    • radiotherapy

  • Bilateral adrenalnodular disease

    • bilateral total adrenalectomy is the treatment of choice for bilateral micro or macronodular disease (i.e. PPNAD, MMAD)

  • Ectopic ACTH source

    • surgical resection is the treatment of choice when the source of ACTH production is localized

    • pharmacotherapy to block production of cortisol should be used when the source can not be localized (See Table I.)

    • bilateral adrenalectomy is another option in those patients who fail pharmacotherapy and in whom the source of the ACTH production can not be localized after multiple attempts.

Table I.

Medical treatment of Cortisol Excess
Medication Initial dose Maximum dose Adverse effects
Ketoconazole (Nizoral) 200 mg bid 1200 mg Nausea, vomiting, abdominal pain, weakness, hypothyroidism, gynecomastia, hepatotoxicity and hypertriglyceridemia
Metyrapone (Metopirone) 250 mg qid 6000 mg Headache, alopecia,hirsutism, acne, nausea, abdominal discomfort, hypertension, weakness, andleucopenia
Mitotane (Lyzodren) 500 mg tid 9000 mg Nausea, vomiting, anorexia, diarrhea, ataxia, confusion, skin rash, and hepatotoxicity
Aminoglutethimide (Cytadren) 250 mg qid 2000 mg/d Lethargy, nausea,anorexia, hypothyroidism, somnolence

What are the adverse effects associated with each treatment option?

Pharmacotherapy:

-ketoconazole: common side effects include headache and GI side effects. Liver function should be monitored, as the drug can also cause hepatotoxicity.

-mitotane: can cause hypertension and GI side effects. The dose should be monitored with serum levels 14 days after initiation of treatment. Glucocorticoid replacement is required at higher doses once adrenal insufficiency is achieved.

-aminoglutethamide: no longer available in the U.S.

-metyrapone: hirsutism in women, along with salt retention and hypertension

Bilateral Adrenalectomy:

-patients will require lifelong glucocorticoid and mineralocorticoid replacement. In addition, they will require stress doses of glucocorticoids immediately postoperatively, and when in situtations such as surgical procedures, febrile illness, etc.

-in patients with CD, Nelson syndrome can occur in up to 15% of patients, and may cause rapid enlargement of the pituitary tumor due to lack of negative feedback. The growth of the tumor may result in compression symptoms related to nearby structures.

TSS:

-patients will require glucocorticoid replacement in stress doses immediately post-operatively, and in replacement doses (12-15 mg/m2/day bid or tid) afterwards, while hypothalamic pituitary adrenal axis is recovering. The patient should be monitored every few months, and an assessment of adrenal function should be performed using a high dose ACTH stimulation test.

What are the possible outcomes of Cushing Syndrome?

In patients with CD treated with TSS, successful resection of a pituitary tumor occurs in over 90% of cases in an experienced medical center and with an experienced neurosurgeon. In cases where a reoperation is required, the success rate is approximately 60%. Treatment failures are usually associated with a large macroadenoma or a tumor that is invading the cavernous sinus. Pituitary irradiation has a success rate of up to 80%, but is often associated with hypopituitarism.

The risks of a TSS are related to problems with other pituitary hormones, including diabetes insipidus (DI), which is usually transient, as well as the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Additionally, central hypothyroidism, hypogonadism, and growth hormone deficiency can occur. Permanent pituitary dysfunction is rare. Other surgical risks include bleeding, infection, and pituitary apoplexy, while the mortality rate is very low at under 1%.

The risk of pituitary irradiation is primarily hypopituitarism, which can occur in more than 70% of patients, and is higher when surgery preceded irradiation. In patients treated with a bilateral adrenalectomy, treatment with glucocorticoid and mineralocorticoid replacement must be lifelong, and there is a risk of adrenal crisis secondary to adrenal insufficiency if treatment with stress dose steroids is not initiated promptly in times of high stress.

Furthermore, patients treated with a bilateral adrenalecomy for CD, there is a 15% risk of Nelson syndrome, which can involve growth of the pituitary tumor with subsequent compression of surrounding structures.

In patients with complications of hypercortisolemia, such as osteoporosis, improvement is generally seen in 6 months, although complete resolution does not occur. In patients with unilateral adrenal disease, the contralateral adrenal is almost always suppressed, and therefore, the patient will require replacement glucocorticoids until such as time as documented adrenal sufficiency occurs. Typically, this can occur on average between 6-18 months.

What causes this disease and how frequent is it?

The overall incidence of CS is approximately 2 to 5 new cases per million people per year. Of those cases, only 10% occur in children. There is a predominance of females, although in the youngest age groups, this predominance decreases.

The most common cause of CS is chronic glucocorticoid use, resulting in iatrogenic CS.

The most common cause of endogenous CS is secondary to CD, and 75% of all CS cases in children over the age of 7 are due to pituitary adenomas. In children under the age of 7, adrenal causes are more common. Ectopic ACTH tumors account for less than<10% of CS cases in children. Arenal adenomas account for 10-15% of cases, while bilateral adrenocortical disease accounts for 5-10% of cases.

How do these pathogens/genes/exposures cause the disease?

Known genetic causes of CS include PPNAD, MMAD, and bilateral macronodular adrenal hyperplasia.

PPNAD is usually associated with Carney complex, and is inherited in an autosomal dominant pattern.

MMAD is typically sporadic, and associated with aberrant expression of the GIP receptor in the adrenal glands.

In bilateral macronodular adrenal hyperplasia associated with McCune-Albright syndrome, a somatic mutation in a G protein leads to continuous activation, thereby leading to adrenal cortical hyperplasia.

What complications might you expect from the disease or treatment of the disease?

Untreated, CS has significant mobidity and mortality associated with it, with deaths being attributable to cardiovascular events, thromboembolic events, hypertensive complications, or infections.

CS due to CD is frequently curable, although secondary hormone deficiencies may result due to surgical complications or related to radiation. Treatment for adrenal disease with bilateral adrenalectomy carries with it risks of adrenal crisis if signs and symptoms of adrenal insufficiency are not noticed and managed immediately. Proper patient education can avoid this complication.

Ectopic ACTH tumors and adrenocortical carcinomas carry a poor prognosis, and pharmacologic treatment can be associated with significant side effects, as described above.

How can Cushing Syndrome be prevented?

There is no known prevention of Cushing Syndrome.

What is the evidence?

Batista, D.L, Riar, J, Keil, M, Stratakis, C.A. "Diagnostic tests for children who are referred for the investigation of Cushing syndrome". Pediatrics. vol. 120. 2007. pp. e575-586.

(Retrospective review of the diagnostic evaluation of 125 pediatric patients with CS.)

Magiakou, M, Mastorakos, G, Oldfield, EH, Gomez, MT, Doppman, JL, Cutler, GB. "Cushing’s Syndrome in Children and Adolescents: Presentation, diagnosis and therapy". N Engl J Med. vol. 331. 1994. pp. 629-636.

(Retrospective analysis of presentation, diagnosis, and treatment of 59 pediatric patients with CS.)

Stratakis, C, Kirschner, LS. "Clinical and Genetic Analysis of Primary Bilateral Adrenal Diseases (Micro- and Macronodular Disease) Leading to Cushing Syndrome". Horm Metab Res. vol. 30. 1998. pp. 456-463.

(Review of recent research on genetic causes of adrenal disease.)

Yanovski, JA, Cutler, GB, Chrousos, GP, Nieman, LK. "The dexamethasone-suppressed corticotropin-releasing hormone stimulation test differentiates mild Cushing's disease from normal physiology". JCEM. 1998. pp. 348-52.

(Comparison of 20 healthy adults to 20 surgically-proven patients with CD to evaluate utility of dexamethasone-suppressed corticotropin-releasing hormone stimulation test.)
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