++
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 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