Etiology

The most common cause of Cushing syndrome is prolonged exogenous administration of glucocorticoid hormones, especially at the high doses used to treat lymphoproliferative disorders. This rarely represents a diagnostic challenge, but management of hyperglycemia, hypertension, weight gain, linear growth retardation, and osteoporosis often complicates therapy with corticosteroids.

Endogenous Cushing syndrome is most often caused in infants by a functioning adrenocortical tumor (Chapter 573). Patients with these tumors often exhibit signs of hypercortisolism along with signs of hypersecretion of other steroids such as androgens, estrogens, and aldosterone.

Although extremely rare in infants, the most common etiology of endogenous Cushing syndrome in children older than 7 yr of age is Cushing disease, in which excessive ACTH secreted by a pituitary adenoma causes bilateral adrenal hyperplasia. Such adenomas are often too small to detect by imaging techniques and are termed microadenomas. They consist principally of chromophobe cells and frequently show positive immunostaining for ACTH and its precursor, pro-opiomelanocortin (POMC).

ACTH-dependent Cushing syndrome may also result from ectopic production of ACTH, although this is uncommon in children. Ectopic ACTH secretion in children has been associated with islet cell carcinoma of the pancreas, neuroblastoma or ganglioneuroblastoma, hemangiopericytoma, Wilms tumor, and thymic carcinoid. Hypertension is more common in the ectopic ACTH syndrome than in other forms of Cushing syndrome, because very high cortisol levels may overwhelm 11β-hydroxysteroid dehydrogenase in the kidney (Chapter 568) and thus have an enhanced mineralocorticoid (salt-retaining) effect.

Several syndromes are associated with the development of multiple autonomously hyperfunctioning nodules of adrenocortical tissue, rather than single adenomas or carcinomas (which are discussed in Chapter 573). Primary pigmented nodular adrenocortical disease (PPNAD) is a distinctive form of ACTH-independent Cushing syndrome. It may occur as an isolated event or, more commonly, as a familial disorder with other manifestations. The adrenal glands are small and have characteristic multiple, small (<4 mm in diameter), pigmented (black) nodules containing large cells with cytoplasm and lipofuscin; there is cortical atrophy between the nodules. This adrenal disorder occurs as a component of Carney complex,