Basics
Description
Cushing syndrome is a multisystem disorder resulting from prolonged exposure to excess glucocorticoids.
- Characterized by growth deceleration, truncal obesity, characteristic skin changes, muscle weakness, and hypertension
- Most common cause in childhood is exogenous administration of glucocorticoids.
- Endogenous Cushing syndrome may be caused by ACTH-secreting tumor of the pituitary gland (Cushing disease), ectopic secretion of ACTH, or ACTH-independent secretion of glucocorticoids by the adrenal glands.
- Accurate diagnosis and classification of Cushing syndrome in children is crucial to guide appropriate therapeutic intervention.
- In endogenous Cushing syndrome, the hypothalamic-pituitary-adrenal axis has lost its ability for self-regulation due to excessive secretion of either ACTH or cortisol and loss of the negative feedback function.
- Diagnostic tests help to distinguish the cause of this disorder.
- Key differences in the diagnosis and management of Cushing syndrome exist between children and adults.
Epidemiology
- The overall incidence of Cushing syndrome is approximately 2-5 new cases per million people per year. Only approximately 10% of the new cases each year occur in children.
- In older children with Cushing syndrome, there is a female-to-male predominance, whereas in younger children there may be a male predominance.
- Exogenous Cushing syndrome caused by chronic administration of glucocorticoids (by any route) or, more rarely, by administration of ACTH (for example, for infantile seizures) is the most common cause of this syndrome in children.
- The pituitary-dependent form (Cushing disease) accounts for more than 80% of all cases of Cushing syndrome in children older than 7 years of age.
Etiology
- Adrenal sources of Cushing syndrome:
- In very young children, adrenal sources of Cushing syndrome are the most common causes of the condition.
- 10-15% of all the cases of Cushing syndrome in childhood are due to ACTH-independent Cushing syndrome from unregulated secretion of cortisol from the adrenal glands.
- Adrenocortical neoplasms
- Often malignant in young children.
- Primary pigmented nodular adrenocortical nodular disease (PPNAD)
- PPNAD is a genetic disorder often associated with Carney complex and related to mutations of the PRKAR1A gene.
- Cushing syndrome in PPNAD may be cyclical and difficult to diagnose.
- Isolated micronodular adrenocortical disease (iMAD)
- If no PRKAR1A mutations are found or if the patient does not have Carney complex, and Cushing syndrome is due to bilateral adrenal hyperplasia without massive enlargement of the adrenal glands on imaging, then, the most likely diagnosis is iMAD.
- Like in PPNAD, Cushing syndrome in iMAD can be difficult to diagnose due to an often atypical and/or cyclical clinical course.
- Massive macronodular adrenal hyperplasia (MMAD)
- Another form of ACTH-independent bilateral adrenal disease seen (rarely) in children
- Easier to diagnose due to massive enlargement of the adrenal glands on imaging studies
- Adrenal hyperplasia and/or adenomas can also be seen in the McCune Albright and Beckwith-Wiedemann syndromes, usually in the infantile period.
- Ectopic ACTH production accounts for less than 1% of the cases of Cushing syndrome in children and may be due to a variety of neuroendocrine (NE) tumors.
- NE tumors include carcinoid tumors in the lungs, pancreas (and other locations in the gastrointestinal tract), or thymus; medullary carcinomas of the thyroid; and pheochromocytomas, as well as small cell carcinoma of the lungs that may be seen rarely in adolescents.
- Other causes of ectopic ACTH secretion include infantile neuroblastomas (and related tumors) and paraneoplastic syndromes in all ages.
- Corticotropin-releasing hormone (CRH) secretion by an ectopic CRH-producing source, typically an NE tumor such as the ones producing ectopically ACTH, is an extremely rare cause of Cushing syndrome in children.
- Exogenous steroids: Iatrogenic Cushing syndrome is the most common cause in pediatrics. Cushing syndrome can be caused by chronic systemic, topical, or intranasal steroid use, or ACTH use.
Diagnosis
History
- The most common presenting symptom of the syndrome in childhood is weight gain accompanied by poor linear growth.
- Additional pertinent features in the history of presenting illness often include headaches, hypertension, weakness, hirsutism, irregular menses, and delayed puberty.
- Dermatologic features include facial flushing, striae (in older children and adolescents only), acne, bruising, and acanthosis nigricans.
- Fractures and/or kidney stones related to Cushing syndrome are also relatively frequent manifestations.
Physical Examination
- Check growth chart and document height velocity and weight change.
- Note fat distribution (characteristic central obesity, dorsocervical, subclavicular, and bitemporal fat pads).
- Skin examination
- Document striae (usually wide, violaceous) and acanthosis.
- Look for characteristic dermatologic features that may be associated with genetic forms of Cushing (caf © au lait spots for MAS, lentigines for Carney complex).
- Neurologic examination
- Check for proximal muscular weakness (typically not present in younger children) by having patient rise from a squatting position.
- Check visual fields and perform funduscopic examination.
- Document Tanner staging and note any discrepancy between pubic hair and gonadal or breast size (which may point to ACTH-dependent or independent causes of Cushing syndrome).
Diagnostic Tests & Interpretation
- Diagnostic tests: The first step in the diagnosis of Cushing syndrome is to document hypercortisolism.
- Screening
- 24-hour urine free cortisol excretion
- Low-dose dexamethasone test
- 1 mg dexamethasone (adjust for pediatric patients 15 mcg — weight [kg]; maximum dose 1 mg) PO at 11 p.m. Measure plasma cortisol at 8 a.m. next day.
- Circadian cortisol profile
- Measure serum or salivary cortisol at 8 a.m. and midnight.
- Confirmation: The following results are suspicious for Cushing syndrome:
- 24-hour urine free cortisol excretion above normal limits for assay (corrected for body surface area)
- Post low-dose dexamethasone 8 a.m. plasma cortisol >1.8 mcg/dL
- Blunted circadian rhythm: a single midnight cortisol value of >4.4 mcg/dL highly sensitive and specific for Cushing syndrome
- Differentiate causes:
- Measure plasma ACTH.
- If low ACTH (<29 pg/mL) = likely ACTH- independent but need to confirm with dexamethasone testing; only completely undetectable ACTH levels indicate undoubtedly an adrenal source of Cushing syndrome.
- Proceed with high-dose dexamethasone suppression test (adjust dexamethasone dose for weight 120 mcg — kg; max dose 8 mg).
- Lack of suppression in response to high-dose dexamethasone indicates that the likely diagnosis is adrenal tumor.
- If high ACTH (>29 pg/mL) = likely ACTH-independent
- Proceed with CRH testing (generally done by an endocrine specialist).
- CRH given at 1 mcg/kg and serial cortisol and ACTH levels are measured. The criterion for the diagnosis of the pituitary-dependent Cushing disease is a mean increase of 20% above baseline for cortisol values at 30-45 minutes and an increase in the mean corticotropin concentrations of at least 35% over basal value at 15-30 minutes after CRH administration.
- If CRH testing is negative: Likely diagnosis is ectopic ACTH production.
- If CRH testing is positive: consistent with Cushing disease
Imaging
- When Cushing disease (ACTH-secreting pituitary tumor) is suspected, pituitary magnetic resonance imaging (MRI) should be done in thin sections with high resolution with gadolinium.
- Computed tomography (CT) of the adrenal glands useful in the distinction between pituitary Cushing disease and adrenal causes of Cushing syndrome. MRI of the adrenal glands is less useful for the detection of PPNAD or iMAD, but may be used for the detection of MMAD, single large tumors, and cancer.
- Bilateral inferior petrosal sinus sampling (IPSS) is a catheterization study used to confirm the source of ACTH secretion in ACTH-dependent Cushing syndrome. IPSS needed only when the pituitary MRI is negative or tests are contradictory, but may be performed only if ACTH-dependent disease is confirmed and cortisol levels are consistently high.
Treatment
- The treatment of choice for Cushing disease is transsphenoidal surgery (TSS).
- In most specialized centers with experienced neurosurgeons, the success rate of the first TSS is close to, or even higher than, 85%.
- The treatment of choice for adrenal tumors is surgical resection, and if metastatic carcinoma, chemotherapy and radiation may be employed.
- Bilateral total adrenalectomy is usually the treatment of choice in PPNAD, iMAD, and MMAD.
- Adrenalectomy may also be used in patients with refractory Cushing disease or with difficult-to-treat ectopic ACTH-dependent Cushing syndrome.
Complications
- After TSS, patients may have persistent disease or recurrence.
- Postoperative complications may include transient diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion, central hypothyroidism, growth hormone deficiency, hypogonadism, bleeding, infection (meningitis), and pituitary apoplexy.
- Patients who undergo bilateral adrenalectomy with Cushing disease must be aware of the potential of Nelson syndrome, characterized by increased pigmentation, elevated ACTH levels, and a growing pituitary ACTH-producing pituitary tumor.
Additional Treatment
- Pituitary irradiation following a failed TSS will lead to remission in approximately 80% of patients, although commonly results in hypopituitarism. Newer forms of stereotactic radiotherapy are now available as options for the treatment of Cushing syndrome, including proton beam and gamma knife.
- A number of medications are available to inhibit corticosteroid biosynthesis, although none of these agents are specifically approved for use in children. These pharmacotherapies include metyrapone and ketoconazole, which may be employed in cases of refractory Cushing or when bridging the patient to definitive therapy. In addition, dopamine receptor agonists such as pasireotide and cortisol receptor antagonists, such as mifepristone, are also under clinical investigation for use in children.
Ongoing Care
- Following TSS in Cushing disease, patients will be transiently adrenally insufficient while the hypothalamic-pituitary-adrenal axis is recovering.
- Stress doses of cortisol are necessary in the perioperative period.
- These should be weaned relatively rapidly to a physiologic replacement dose.
- The patient should be followed every few months, and the adrenocortical function should be periodically assessed with a 1-hour 250 mcg ACTH test. Most patients recover HPA function within 1 year after TSS.
- Following bilateral adrenalectomy, lifetime replacement glucocorticoids and mineralocorticoids, (fludrocortisone 0.1-0.3 mg daily) is required.
- All patients status post cure of Cushing need to be taught precautions for adrenal insufficiency, including emergency injection of hydrocortisone and medical alert bracelet.
Alert
- Falsely high urine free cortisol may be obtained because of stress, obesity, pregnancy, chronic exercise, depression, poor diabetes control, alcoholism, anorexia, narcotic withdrawal, anxiety, malnutrition, and high water intake. A combined dexamethasone-CRH test may help to differentiate pseudo-Cushing syndrome from true Cushing syndrome.
- Falsely low urine free cortisol may be present if inadequate collection or intermittent cortisol hypersecretion.
Additional Reading
- Batista DL, Oldfield EH, Keil MF, et al. Postoperative testing to predict recurrent Cushing disease in children. J Clin Endocrinol Metab. 2009;94(8):2757-2765. [View Abstract]
- Batista DL, Riar J, Keil M, et al. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007;120(3):e575-e586. [View Abstract]
- Lodish M, Dunn SV, Sinaii N, et al. Recovery of the hypothalamic-pituitary-adrenal axis in children and adolescents after surgical cure of Cushing's disease. J Clin Endocrinol Metab. 2012;97(5):1483-1491. [View Abstract]
- Stratakis CA. Cushing syndrome in pediatrics. Endocrinol Metab Clin North Am. 2012;41(4):793-803. [View Abstract]
Codes
ICD09
ICD10
- E24.9 Cushing's syndrome, unspecified
- E24.0 Pituitary-dependent Cushing's disease
- E24.2 Drug-induced Cushing's syndrome
- E24.3 Ectopic ACTH syndrome
- E24.8 Other Cushing's syndrome
SNOMED
- 47270006 Hypercortisolism (disorder)
- 190502001 Pituitary-dependent Cushing's disease (disorder)
- 41299009 Iatrogenic Cushing's disease
FAQ
- Q: What clinical clue is most useful to determine which children have obesity alone versus those with Cushing syndrome?
- A: Cushing syndrome is associated with growth failure, whereas obesity is associated with adequate linear growth.
- Q: Are most patients on lifetime glucocorticoid replacement after surgery for Cushing disease?
- A: No. The majority of patients recover their hypothalamic-pituitary-adrenal axis within 1 year of their TSS and can be weaned off glucocorticoids.