Chapter 30: Cushing Syndrome

INTRODUCTION

Cushing syndrome (CS) is characterized by increased circulating glucocorticoid concentrations. It is very rare in childhood and adolescence, with the most common cause of CS being iatrogenic, owing to chronic or excessive administration of exogenous glucocorticoids in the form of topical, inhaled, or oral corticosteroids for the treatment of many non-endocrine diseases, including pulmonary, autoimmune, dermatologic, hematologic, and neoplastic disorders.^1,2 The overall incidence of CS is approximately 2 to 5 new cases per million people per year and only 10% of these cases occur in children. There is a female-to-male predominance, which decreases with younger age and may even lead to a male-to-female predominance in infants and young toddlers.^3,4

CS in childhood and adolescence can be classified into adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent. Causes can be further classified according to the age of onset (At-A-Glance). These conditions are discussed below.

CUSHING SYNDROME: CLASSIFICATION

ACTH-Dependent Cushing Syndrome/Cushing Disease

ACTH-dependent Cushing disease (CD) is characterized by hypercortisolism caused by an ACTH-secreting corticotroph adenoma. It is the most common cause of CS beyond the age of 7 years and accounts for 75% to 80% of all cases.⁵ To date, no genetic defects have been consistently associated with childhood corticotropinomas; they only rarely occur in the familial setting, and most commonly in the context of multiple endocrine neoplasia type 1 (MEN1) and rarely due to aryl hydrocarbon receptor-interacting protein (AIP) mutations.⁶ ACTH secretion occurs in a semi-autonomous manner, maintaining some feedback of the HPA axis.

The pituitary tumor is almost always a microadenoma, usually of a diameter of 3 mm or less; however, macroadenomas have been reported very rarely and the tumor might even invade the cavernous sinus. Pituitary macroadenoma may also be an early manifestation of MEN1.^3,7,8

Ectopic ACTH production in children and adolescents occurs less frequently than in adults. Sources of ectopic ACTH secretion include small cell carcinoma of the lung, carcinoid tumors in the bronchus and other neuroendocrine tumors, especially those of the pancreas and gut carcinoids or thymus, medullary carcinomas of the thyroid, and pheochromocytomas. Rarely, ACTH overproduction by the pituitary may be the result of increased corticotropin-releasing hormone (CRH) secretion by the hypothalamus or by an ectopic CRH source.⁹

ACTH-Independent Cushing Syndrome

ACTH-independent CS accounts for up to 15% of cases of CS in children older than 7 years, but as many as 50% of cases of CS in younger children. Adrenocortical lesions leading to ACTH-independent CS include the common, isolated and sporadic, solitary cortisol-producing adenoma, the rare adrenocortical cancer, and a spectrum of bilateral adrenocortical hyperplasias (BAHs).

Adrenocortical Tumors ([ACTs] Adenoma or Carcinoma)

Adrenocortical neoplasms account for 0.3% to 0.4% of all childhood tumors. However, there is ...