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Early signs of glucocorticoid excess include increased appetite,
weight gain, and growth arrest without a concomitant delay in bone
age. Chronic glucocorticoid excess in children results in typical
Cushingoid facies, but the “buffalo hump” and
centripetal distribution of body fat that are characteristic of
adult Cushing disease are seen only in long standing disease. Mineralocorticoid
excess is characterized by hypertension, but patients receiving
very low sodium diets (eg, the newborn) will not be hypertensive,
as mineralocorticoids increase blood pressure primarily by retaining
sodium and thus increasing intravascular volume. Moderate hypersecretion
of adrenal androgens is characterized by mild signs of virilization;
substantial hypersecretion of adrenal androgens is characterized
by accelerated growth, increased bone age, increased muscle mass,
acne, hirsutism, and deepening of the voice.
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Cushing syndrome describes any form of glucocorticoid
excess; Cushing disease designates hypercortisolism
due to pituitary overproduction of corticotropin (ACTH). The related
disorder caused by ACTH of nonpituitary origin is called the ectopic
ACTH syndrome. Other causes of Cushing syndrome include
adrenal adenoma, adrenal carcinoma, and multinodular adrenal hyperplasia.
These disorders are distinct from iatrogenic Cushing syndrome, which
is the clinical constellation resulting from administration of supraphysiologic
quantities of ACTH or glucocorticoids.
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Epidemiology
and Associated Disorders
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In adults and children over 7 years of age, the most common cause
of Cushing syndrome is true Cushing disease (adrenal hyperplasia
due to hypersecretion of pituitary ACTH).1 About 25% of
patients referred for Cushing disease are children; thus, pediatric
Cushing disease is more common than generally recognized. Many patients
first seen as adults actually experience the onset of symptoms in
childhood or adolescence. Boys are more frequently affected than
girls in the prepubertal period, although the sex ratios are equal
during adolescence, and women have a higher incidence of Cushing disease
in adulthood.2Adrenal tumors, especially
adrenal carcinomas, cause most cases of Cushing syndrome in children
less than 7 years old3-21 (eTable 535.1).
These tumors are more common in girls22 and may be associated
with bodily hemihypertrophy as part of the Beckwith-Wiedemann syndrome,
or with germline mutations or loss-of-heterozygocity of the tumor
suppressor gene p53 as in the Li-Fraumeni syndrome.23-25 The ectopic
ACTH syndrome is commonly seen in adults with oat cell
carcinoma of the lung, carcinoid tumors, pancreatic islet cell carcinoma, and
thymoma. Ectopic ACTH syndrome is rare in children; associated tumors
include neuroblastoma, pheochromocytoma, and islet cell carcinoma
of the pancreas.20ACTH independent multinodular
adrenal hyperplasia, also called primary pigmented adrenocorticoid
disease (PPNAD), is a rare entity characterized by hypersecretion
of cortisol and adrenal androgens.26-29 It is seen in all
age groups, more frequently in females. It is usually seen as part
of the “Carney complex” (a form of multiple endocrine
neoplasia), consisting of pigmented lentigines and blue nevi on
the face, lips, and conjunctiva, and a variety of tumors including
schwannomas and atrial myxomas, and, occasionally, GH-secreting
pituitary adenomas, Leydig cell tumors, calcifying Sertoli cell ...