Cushing syndrome is the clinical manifestation of excess glucocorticoid. Along with the well-known manifestations in adults, affected children have attenuated linear growth.49 Indeed, growth arrest may be the only clear clinical sign of Cushing syndrome. Interestingly, often these children tend to be highly responsible and obsessive about schoolwork, housework, and hobbies. Multiple factors50,51 and 52 contribute to linear growth arrest. These range from direct inhibition of cell proliferation to inhibition of growth hormone release.

The abnormal glucose tolerance associated with hypercortisolism is attributable to increased gluconeogenesis. Ecchymosis secondary to increased capillary fragility, hypertrichosis resembling that seen in states of malnutrition, and muscle weakness and fatigue all appear to be related to increased protein catabolism. The hypertension is caused by increased vascular reactivity to vasoconstrictive factors,53 increased plasma renin substrate,53 cortisol overload,54 and increased mineralocorticoid production.55 Hyperpigmentation is seen in those patients with elevated plasma ACTH levels. Concomitant androgen excess is responsible for hirsutism or virilization, the latter of which suggests a tumor.

The most common cause of Cushing syndrome in children is pharmacologic glucocorticoid therapy. Attenuation of linear growth occurs at all doses that exceed the normal replacement range of 10 to 20 mg/m² per day cortisol, or the equivalent.52 The syndrome can occur after use of topical corticoids, depending on the steroid and the dose. Some individuals are hyperre-active to glucocorticoids, and become cushingoid on normal replacement doses.56 High doses of some synthetic progestins can cause cushingoid state.56a

Cushing disease is hyperadrenocortisolism secondary to excessive secretion of pituitary ACTH, which results in bilateral adrenal hyperplasia (see Chap. 75). In children, as in adults, it is usually caused by a pituitary microadenoma (Fig. 83-3). It may have an autoimmune basis.57 Hyperfunctioning adrenocortical tumors occur three times more frequently in girls than in boys. Cushing syndrome secondary to ACTH production by nonen-docrine tumors is very rare in the pediatric population. ACTH-independent, primary bilateral adrenal hyperplasia may be caused by McCune-Albright syndrome variants.58 Adrenocortical micronodular dysplasia causing Cushing syndrome is primarily a disorder of young girls. It may be familial, associated with multiple endocrine neoplasia-type I,59 or myxoid and other tumors,60,61 or it can occur as an autoimmune disease.49 In some cases, hormonogenesis is periodic, and in others it is estrogen-61 or food-dependent.62