Chapter 535. Adrenal Excess

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.

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.

Epidemiology and Associated Disorders

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 tumors, and medullary carcinoma of the thyroid.29,30

Clinical Findings and Diagnosis

Central obesity, “moon facies,” hirsutism, and facial flushing are seen in over 80% of adults with Cushing syndrome. Striae, hypertension, muscular weakness, back pain, “buffalo hump” fat distribution, psychological disturbances, acne, and easy bruising are also very commonly described (35–80%). However, these are the signs and features of advanced Cushing disease. When annual photographs of such patients are available, it is often apparent that these features can take 5 years or longer to develop. Thus, the classic “cushingoid appearance” is not the initial picture in the child with Cushing syndrome. The earliest, most reliable indicators of hypercortisolism in children are weight gain and growth arrest3 (Table 535-1). Cumulative data from three large studies of pediatric Cushing disease identified weight gain at presentation in 91/97 cases and growth failure in 82/95 cases.3-5 Thus, any overweight child who stops growing should be evaluated for Cushing syndrome. Glucocorticoids suppress growth by increasing hypothalamic secretion of somatostatin, suppressing growth hormone and insulin-like growth factor 1 production, and by acting directly on the epiphyses to inhibit sulfation of cartilage, inhibit mineralization, and inhibit cell proliferation. By contrast, children with simple dietary obesity often grow more rapidly and are tall for their age. The obesity of Cushing disease in children is initially generalized rather than centripetal, and a “buffalo hump” is evidence of long standing disease. Psychological disturbances, especially compulsive overachieving behavior, are seen in about 40% of children and adolescents with Cushing disease3 and are distinctly different from the depression typically seen in adults.6 Emotional lability has been described in approximately 30% of cases.5 There can be a substantial degree of bone loss and undermineralization in these patients.3,7,8 It is likely that Cushing disease is generally regarded as a disease of young adults because the diagnosis was missed, rather than absent, during adolescence. Rarely, Cushing syndrome caused by adrenal carcinoma or the ectopic ACTH syndrome can produce a rapid fulminant course.

Concentrations of plasma ACTH and cortisol may not be elevated in the morning but may be mildly elevated in the afternoon and evening. This loss of the diurnal rhythm is usually the first laboratory finding of Cushing disease. Plasma cortisol obtained at midnight from a sleeping patient should be less than 2 μg/dL; higher values suggest Cushing disease.31-35 By contrast, the values for ACTH and cortisol are typically extremely high in the ectopic ACTH syndrome, whereas cortisol is elevated but ACTH suppressed in adrenal tumors and in multinodular adrenal hyperplasia (Table 535-2). Adrenal adenomas almost always secrete cortisol with minimal secretion of mineralocorticoids or sex steroids. By contrast, adrenal carcinomas tend to secrete both cortisol and androgens and are often associated with progressive virilization.23,24

Petrosal sinus sampling is widely used to distinguish pituitary Cushing disease from the ectopic ACTH syndrome in adults. The smaller vascular bed in children increases the risk of this procedure, but inferior petrosal venous sampling can be used in adolescents to localize pituitary adenomas before surgery.36 Unlike patients with Cushing disease, adults and children with the ectopic ACTH syndrome frequently have hypokalemic alkalosis, presumably because the extremely high levels of ACTH stimulate the production of DOC by the adrenal fasciculata and may also stimulate the adrenal glomerulosa in the absence of hyperreninemia.20 The 24-hour urinary free cortisol assists in the diagnosis; several collections should be taken and compared to normal ranges adjusted for size and age, as obese children have higher cortisol secretion rates.

For the dexamethasone suppression test, children should be hospitalized, and 2 days of baseline data should be obtained. Low dose dexamethasone (20 μg/kg/d, up to a maximum of 2 mg) is given, divided into equal doses given every 6 hours for 2 days followed by high dose dexamethasone (80 μg/kg/d) for 2 days. Values for ACTH and cortisol are obtained at 8 am and 8 pm (or midnight), and 24 hour urine collections for 17OHS, free cortisol, and creatinine (to monitor the completeness of the collection) should be obtained on each of the 6 days of the test. Measurements of either urinary free cortisol or 17OHCS are equally reliable if the laboratory has established good pediatric standards. Because of the episodic secretion of ACTH, the 8 am and 8 pm blood values should be drawn in triplicate at 8:00, 8:15, and 8:30. In patients who do not have Cushing syndrome, cortisol, ACTH, and urinary steroids will be suppressed readily by low dose dexamethasone. Patients with adrenal adenoma, adrenal carcinoma, or the ectopic ACTH syndrome will have values relatively insensitive to both low and high dose dexamethasone. Patients with Cushing disease classically respond with a suppression of ACTH, cortisol, and urinary steroids during the high dose treatment but not during the low dose treatment. However, some children, especially those early in the course of their illness, may exhibit partial suppression in response to low dose dexamethasone. Thus, if the low dose that is given exceeds 20 μg/kg/d or if the assays used are insufficiently sensitive to distinguish partial from complete suppression, false negative tests may result. The diagnosis of Cushing disease can be considerably more difficult to establish in children than in adults.

Treatment

Treatment of Cushing syndrome depends upon the etiology of elevated corticosteroids. Tumors require surgical resection and corticosteroid replacement therapy for adrenal insufficiency pending recovery of normal adrenal function (see Chapter 536). Treatment of Cushing disease is focused on identification and removal of the source of increased ACTH. Among adults, over 90% of Cushing patients undergoing transsphenoidal surgery have identifiable pituitary microadenomas.6,9 These tumors are generally 2 to 10 mm in diameter, are not encapsulated, have ill defined boundaries, and are frequently detectable with a contrast enhanced pituitary MRI. These tumors are often identifiable only by minor differences in their appearance and texture from surrounding tissue, and thus, the frequency of surgical cure is correlated with the technical skill of the surgeon. About 80% to 85% of children and adolescents with Cushing disease have surgically identifiable microadenomas.3,10,11 Removal of the tumor is usually curative, but 20% of “cured” patients suffer relapse of their Cushing disease within about 5 years, so the net cure rate is 65% to 75%.3-5,12,13 Transsphenoidal surgery is the best initial approach, but alternative approaches may be necessary in younger children without aerated sphenoid sinuses. Control of hypercortisolemia is important in the perioperative period. Careful monitoring for recovery of the hypothalamic-pituitary-adrenal axis is necessary over several months, as stress responses may be diminished despite normal basal cortisol values. Short-term consequences of transsphenoidal surgery include transient diabetes insipidus and cerebrospinal fluid rhinorrhea.4,5,14 Persistent hypopituitarism is rare, but the effects of hypercortisolism on growth hormone secretion may last for 1 to 2 years after treatment, and growth hormone deficiency can occur even in those children who have not received irradiation.4,5,14 Final height may be reduced by 1.5 to 2.0 SD by the long-term hypercortisolism.3,15 Treatment with growth hormone may ameliorate this growth loss in patients with GH insufficiency.16,17

Some patients lack an identifiable microadenoma, and some “cured” patients relapse. These patients may have a primary hypothalamic disorder, or the region of the pituitary responsible for ACTH-hypersecretion was not excised. Repeat transsphenoidal surgery is typically the first approach in managing nonresponsive or relapsed Cushing disease, especially if there is evidence of a distinct lesion or lateral hypersecretion of ACTH. Second-line approaches include hypophysectomy, gamma-knife irradiation, cyproheptidine, adrenalectomy, and drugs that inhibit adrenal function. All have significant disadvantages. Hypophysectomy will eliminate secretion of growth hormone, thyrotropin (TSH), and gonadotropins, causing growth failure, hypothyroidism, and failure to progress in puberty, respectively. Although hypothyroidism is easily treated with oral thyroxine, growth hormone deficiency requires very expensive replacement therapy. Sex steroid replacement can be used to achieve secondary sexual characteristics at the age of puberty, but gonadotropin replacement or pulsatile gonadotropin releasing hormone therapy will be needed to achieve fertility. Pituitary irradiation is not recommended in children; growth-hormone deficiency occurs in most cases, and additional endocrinopathies can occur with time,18 and the interval from radiotherapy to cure can be more than 1 year, requiring therapeutic blockage of hypercortisolemia to prevent the ongoing effects of Cushing disease on growth, weight, and bone mineralization. Large doses of radiation increase the risk of cerebral arteritis, leukoencephalopathy, leukemia, glial neoplasms, and tumors of the skull; stereotactic radiotherapy may reduce these potential effects, but few data exist yet in children. Cyproheptidine is rarely successful in pediatric Cushing disease and has unacceptable side effects (weight gain, irritability, hallucinations) with the needed doses.

Adrenalectomy is the preferred approach when 2 transsphenoidal procedures fail. Removal of the adrenal eliminates the physiologic feedback on the pituitary; in some adults, this results in the development of pituitary macroadenomas, producing very large quantities of ACTH. These can expand and impinge on the optic nerves and can produce sufficient preoptic melanocortin (POMC) to yield enough melanocyte stimulating hormone (MSH) to produce profound darkening of the skin (Nelson syndrome), but this is very rare in children. There is relatively little pediatric experience with ketoconazole and other drugs that inhibit steroidogenesis; these may be useful for short-term control of hypercortisolemia in selected patients.19

Most virilizing adrenal tumors are adrenal carcinomas producing both androgens and glucocorticoids; virilizing or feminizing adenomas are quite rare. Boys with virilizing tumors will have phallic enlargement, erections, pubic and axillary hair, increased muscle mass, deepening of the voice, acne, and scrotal thinning, but the testicular size will be prepubertal. Elevated concentrations of testosterone in young boys will increase irritability, rambunctiousness, hyperactivity, and rough play, but without evidence of libido. Diagnosis is based on hyperandrogenemia unsuppressable by glucocorticoids, and the treatment is surgical; all such tumors should be handled as if they are malignant, with care exerted not to cut the capsule and seed cells onto the peritoneum. The pathologic distinction between adrenal adenoma and carcinoma is difficult. Feminizing adrenal tumors are extremely rare in either sex. P450aro, the enzyme aromatizing androgenic precursors to estrogens, is not normally found in the adrenals but is found in peripheral tissues such as fat, and can be found in some adrenal malignancies. Feminizing adrenal tumors can be distinguished from true (central) precocious puberty in girls by the absence of increased circulating concentrations of gonadotropins and by a prepubertal response of luteinizing hormone in response to intravenous GnRH. In boys, such tumors will cause gynecomastia, which will resemble the benign gynecomastia that often accompanies puberty. However, as with virilizing adrenal tumors, testicular size and the gonadotropin response to GnRH testing will be prepubertal.

Conn syndrome, characterized by hypertension, polyuria, hypokalemic alkalosis, and low plasma renin activity due to an aldosterone producing adrenal adenoma is exquisitely rare in children. Diagnosis requires differentiation of primary aldosteronism from physiologic secondary hyperaldosteronism due to disorders such as renal tubular acidosis, treatment with diuretics, salt wasting nephritis, or hypovolemia due to nephrosis, ascites, or blood loss all cause physiologic secondary hyperaldosteronism.

Familial glucocorticoid resistance is a very rare disorder caused by mutations in the a-isoform of the glucocorticoid receptor. Decreased glucocorticoid action results in grossly elevated levels of ACTH, cortisol, and other adrenal steroids. Patients may present with fatigue, hypertension, and hypokalemic alkalosis, suggesting a mineralocorticoid excess syndrome, but may also have hyperandrogenism.37 Patients can have homozygous missense mutations38 or heterozygous gene deletions39 so that in each case some receptor activity remains such that there is only partial resistance to the action of glucocorticoids.