OVERVIEW: What every practitioner needs to know

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

Cushing syndrome or pathologic cortisol excess is a rare condition in the pediatric population. Nevertheless, with increasing rates of simple obesity among children and adolescents, referrals for evaluation of excess cortisol levels are also rising. In this regard, it is important to remember that Cushing syndrome carries a high morbidity and mortality, due at least in part to the delay in establishing its diagnosis. Cushing syndrome should be strongly suspected in patients with weight gain associated with growth failure and rounded facies. The initial work-up should include assessments of hypothalamic-pituitary-adrenal axis function. Cushing disease is excess cortisol caused by a pituitary tumor, usually a microadenoma.

Clinical Findings

In the pediatric population, weight gain, growth failure, and rounded facies are the most common clinical findings. Auxologic data are extremely important in the diagnosis of pediatric Cushing syndrome. Case series suggest an elevated body mass index (BMI) in nearly all cases, with a mean BMI standard deviation score (SDS) of approximately +2.3. In contrast to adults, pediatric patients have stunted growth with a mean height SDS of approximately –1.8.

Other common clinical features include hirsutism, acne, striae, plethora, fatigue, psychological disturbances, hypertension, and proximal muscle weakness. It is interesting to note that muscle weakness and mental symptoms are thought to be less common than in adults with Cushing syndrome. Declining school performance is unusual. Indeed rather than depression, compulsive overachieving behavior has been noted. Preliminary biochemical work-up may reveal elevated blood glucose and hypokalemia.

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What other disease/condition shares some of these symptoms?

Simple obesity, surreptitious glucocorticoid use, hypopituitarism associated with growth hormone deficiency and hypothyroidism are important differential diagnosis considerations. Patients with simple obesity can be ruled out clinically as they usually present with increased height velocity and not growth failure. Hypothyroidism can be identified with thyroid-stimulating hormone (TSH) and free T4 levels. Growth hormone deficiency can be evaluated by specific growth hormone stimulation testing.

What caused this disease to develop at this time?

Cushing disease is most often caused by pituitary microadenomas. The underlying cause is essentially unknown and therefore it is difficult to predict when this tumor may develop.

Confirming the diagnosis

The first step is to confirm hypercortisolism. This is done by the following tests:

Urinary free cortisol (24-hour urine collection × 3): Levels consistently within the normal range make pathologic cortisol excess unlikely.

Low-dose dexamethasone suppression test: This is usually performed by administering dexamethasone 0.5 mg every 6 hours by mouth in children weighing more than 40 kg. For children weighing less than 40 kg, a dexamethasone dose of 30 µg/kg/d is suggested. Serum cortisol levels are measured at 4 hours, 24 hours, and 48 hours. Normal individuals will suppress to less than 5 µg/dL. Alternatively an overnight 1-mg dexamethasone suppression test may be done in which dexamethasone is taken at midnight and serum cortisol and adrenocorticotropic hormone (ACTH) are measured at 8 AM. Using the 5 µg/dL level, one can expect approximately 90%-95% sensitivity. Using a cutoff of 1.8 µg/dL, the sensitivity of this test is 100%.

Serum cortisol circadian rhythm assessment: This requires the child to be admitted and serum cortisol is measured at 9 AM, 6 PM, and 12 AM. In normal children, serum cortisol levels at midnight should be 5 µg/dL. Salivary cortisol tests are used in adults to assess the circadian rhythm, but normative data are lacking in children.

Once pathologic cortisol excess has been documented, the next step is to measure ACTH. If ACTH is detectable (normal range usually 10-50 ng/L), an ACTH-dependent cause is strongly suspected, and the most common cause of this is Cushing disease. Ectopic Cushing syndrome also causes ACTH-dependent cortisol excess but is exceedingly rare. Other causes of cortisol excess have undetectable ACTH levels.

The next step is localization of the responsible lesion. The most common cause of Cushing disease is a pituitary microadenoma. If this is suspected based on the previously described biochemical tests, dedicated pituitary imaging should be performed by magnetic resonance imaging (MRI). If MRI is not feasible, computed tomography (CT) can be performed, although it is a less sensitive modality.

Most disease-causing adenomas are microadenomas measuring less than 5 mm and are hypodense and nonenhancing after gadolinium. However, concordance of findings on MRI with those at pituitary surgery is approximately 50%. Therefore, further invasive studies, namely bilateral inferior petrosal sinus sampling (BIPSS), may be required.

BIPSS: This study is useful for distinguishing ectopic ACTH syndrome from Cushing disease. In addition, in Cushing disease, it can help lateralize the pituitary lesion. In the pediatric population, ectopic ACTH syndrome is quite rare. Therefore, BIPSS is mainly used to try to lateralize the pituitary lesion.

In this study, ACTH is sampled from the inferior petrosal sinuses and compared with peripheral values before and after the administration of corticotropic-releasing hormone (CRH). Pre-CRH central to peripheral ACTH values greater than 2 and post-CRH central to peripheral ACTH values greater than 3 strongly suggest Cushing disease as opposed to ectopic ACTH syndrome. Interpetrosal sinus ACTH ratio greater than 1.4 helps to lateralize the lesion and has a concordance with surgical findings in 70%-79% of cases (when centrally located pituitary adenomas are excluded).

BIPSS should be performed at experienced centers. Some centers report improvements in cure rates after the introduction of BIPSS.

Ectopic ACTH syndrome is very rare in the pediatric population. If it is suspected, bronchial carcinoids are the most common cause and thin-cut CT of the chest is the next most appropriate imaging modality.

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

For patients with Cushing disease, the first choice for treatment is transsphenoidal adenomectomy (TSA). In patients with microadenomas, the rate of cure is between 85% and 98% in experienced surgical hands. Conversely, the cure rate for macroadenomas is much lower. Cure is usually assessed by measuring early morning cortisol levels within 1-3 days of surgery. Cure is suggested by plasma cortisol values less than 1.8 µg/dL. Of patients thought to be cured, approximately 20% experience a recurrence and will therefore require further treatment.

If TSA is not successful or if Cushing syndrome recurs, either a hypophysectomy can be performed or other modalities may be pursued. The options include external-beam radiation treatment (XRT) and bilateral adrenalectomy. Combined TSA and XRT is associated with an 80% cure rate. XRT, however, is often associated with progressive hypopituitarism, and large doses may be associated with cerebral arteritis, bony tumors of the skull, leukoencephalopathy, glial neoplasms, and leukemia.

When both TSA and XRT fail, bilateral adrenalectomy is performed. This treatment is associated with a complete lack of physiologic feedback on the pituitary by adrenal glucocorticoids, resulting in large pituitary tumors, and proopiomelanocortin can be oversecreted to an extent that it produces darkening of the skin, a phenomenon known as Nelson syndrome.

Medications that interrupt cortisol biosynthesis such as ketoconazole and metyrapone are potential short-term treatment options. Both have significant side effects and are not recommended for long-term treatment.

What are the adverse effects associated with each treatment option?

Immediately after TSH, surgical complications may include cerebrospinal fluid leak, bleeding, and infection and require prompt attention. There is often transient damage to the posterior pituitary and patients may experience diabetes insipidus or syndrome of inappropriate antidiuretic hormone, or both, over the course of 7-10 days after surgery. This situation will often resolve; however, in the interim patients’ serum sodium levels and fluid intake and output should be monitored carefully. Finally, postoperatively the patient will need to be on replacement doses of glucocorticoids.

The major long-term complication is the development of hypopituitarism, and appropriate endocrine screening must be done several weeks after surgery. It is particularly important to assess for adequacy of growth hormone secretion, given the adverse effects on growth that Cushing syndrome itself causes.

What causes this disease and how frequent is it?

Cushing disease is extremely rare and as such there is very little information about prevalence or incidence. The mean age of presentation in most series is 14 years of age and it is almost never seen before the age of 7 years. Although there is no predisposing exposure as such, Cushing disease can occur in patients with McCune-Albright syndrome.

How can Cushing disease be prevented?

Cushing disease cannot be prevented.

What is the evidence?

Chan, LF, Storr, HL, Grossman, AB. “Pediatric Cushing's syndrome: clinical features, diagnosis and treatment”. Arq Bras Endocrinol Metab. vol. 51. 2007. pp. 1261-71.

Shah, NS, George, J, Acharya, SV. “Cushing disease in children and adolescents: twenty years' experience in a tertiary care center in India”. Endocr Pract. vol. 17. 2011. pp. 369-76.

Savage, MO, Storr, HL, Chan, LF. “Diagnosis and treatment of pediatric Cushing's disease”. Pituitary. vol. 10. 2007. pp. 365-71.

Miller, WL, Sperling, MA. “The adrenal cortex”. Pediatric Endocrinology. 2002. pp. 385-438.