Brief

in

Cushing Syndrome
Jason Klein, MD, Patricia Vuguin, MD, MSc, Sharon Hyman, MD
Department of Pediatric Endocrinology, Cohen Children’s Medical Center of New York, New Hyde Park, NY

AUTHOR DISCLOSURE Drs Klein, Vuguin, Cushing syndrome (CS) is a state of glucocorticoid excess in which there is loss of
and Hyman have disclosed no financial
the normal hypothalamic-pituitary-adrenal feedback axis. First described in 1912
relationships relevant to this article. This
commentary does not contain discussion by American neurosurgeon Dr Harvey Williams Cushing in reference to a 23-year-
of unapproved/investigative use of old patient with obesity, hirsutism, and amenorrhea, CS has since been recog-
a commercial product/device.
nized as a rare, yet serious and significant, condition in the pediatric population.
Under normal circumstances, hypothalamic corticotropin-releasing hormone
(CRH) is delivered to the anterior pituitary via the portal circulation, resulting in
adrenocorticotropin hormone (ACTH) release from the anterior pituitary into the
systemic circulation. ACTH acts on the zona fasciculata of the adrenal cortex to
stimulate release of cortisol. The secretion of cortisol results in negative feedback,
downregulating production of both ACTH and CRH. Cortisol has metabolic and
cardiovascular effects. It plays an important role in hepatic glucose metabolism by
increasing gluconeogenesis and glycogenolysis, as well as affecting proteolysis
and lipolysis. In addition, it influences myocardial contractility, cardiac output,
and blood pressure. It also has a variety of effects on the immunologic and
inflammatory systems, musculoskeletal and connective tissue, and fluid and
electrolyte homeostasis, as well as neuropsychiatric, behavioral, gastrointestinal,
and developmental effects. In the general population, there are approximately 2 to
5 new cases per million per year of CS; only approximately 10% of these cases
occur in the pediatric population. Although adolescents with CS, similar to
adults, have a slight female to male predominance, this predilection goes away
in younger patients and may even be reversed in infants with CS.
Pediatric CS can be divided into 2 distinct categories: ACTH dependent and
ACTH independent (Table 1). The most common cause of CS is exogenous
administration of corticosteroids, which have become the first-line treatment of
multiple pediatric disorders. Although oral corticosteroids are generally implicated
in the development of CS, long-term use of inhaled and topical corticosteroids,
commonly used as treatment for asthma and atopic dermatitis, respectively, can also
result in CS. In addition, ACTH, used as treatment in certain seizure disorders, can
stimulate adrenal cortisol release, resulting in CS.
Cushing’s Syndrome in Children and When exogenous causes of CS have been ruled out based on a careful history,
Adolescents: Presentation, Diagnosis, and
endogenous causes should be sought. In children older than 5 years, Cushing
Therapy. Magiakou MA, Mastorakos G,
Oldfield EH, et al. N Engl J Med. 1994;331 disease (hypercortisolism resulting from oversecretion of pituitary ACTH from
(10):629–636 a corticotroph adenoma) is the most common cause of CS. In contrast, infants are
The Diagnosis of Cushing’s Syndrome: An most likely to have a primary adrenal condition, such as an adrenocortical tumor
Endocrine Society Clinical Practice (adenoma or carcinoma). Although adrenocortical tumors are fairly rare in the
Guideline. Nieman LK, Biller BM, Findling JW,
pediatric age group, comprising only approximately 0.6% of childhood tumors,
et al. J Clin Endocrinol Metab. 2008;93
(5):1526–1540 upward of one-third manifest with signs and symptoms of CS. Nearly all are
unilateral (90% to 98%) and more than 70% are malignant. Most unilateral
Cushing Syndrome in Pediatrics. Stratakis
CA. Endocrinol Metab Clin N Am. 2012;41 adrenal tumors are sporadic, but they may be part of a genetic syndrome, such as
(4):793–803 Beckwith-Wiedemann syndrome or Li-Fraumeni syndrome.

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 TABLE 1. Categories of Pediatric Cushing Syndrome
ACTH-DEPENDENT CUSHING SYNDROME ACTH-INDEPENDENT CUSHING SYNDROME

Exogenous ACTH use Exogenous corticosteroid use

Cushing disease (ACTH-secreting pituitary adenoma) Adrenocortical tumor
Ectopic ACTH syndrome (ACTH-secreting disease from nonpituitary site) Bilateral primary adrenocortical hyperplasia
PPNAD or Carney complex
Massive macronodular adrenal hyperplasia
McCune-Albright SYNDROME
CRH hypersecretion (adult case reports only)

ACTH¼adrenocorticotropin hormone; CRH¼corticotropin-releasing hormone; PPNDAD¼primary pigmented nodular adrenocortical disease.

Rarer causes of ACTH-independent CS include primary especially elevation of diastolic blood pressure, occurs in
pigmented nodular adrenocortical disease, a condition char- approximately half of pediatric patients with CS.
acterized by bilateral nodular adrenals. Primary pigmented The initial step in making the diagnosis of CS is confirm-
nodular adrenocortical disease is associated with atypical or ing the presence of elevated cortisol levels (hypercortisolism)
cyclical CS and is the most frequent presentation of Carney in 2 separate measurements. Screening tests, particularly
complex in children and adolescents, characterized by skin when in conjunction with each other, have a high sensitivity
pigmentary abnormalities, myxomas, endocrine tumors or and sensitivity for detecting CS. Twenty-four-hour urine
overactivity, and schwannomas. Massive macronodular ad-
renal hyperplasia is rare and associated with extremely large
adrenals and multiple cortisol-producing adenomatous nod-
TABLE 2. Signs and Symptoms of Cushing
ules. McCune-Albright syndrome, a triad of precocious pu-
Syndrome
berty, cafe-au-lait spots, and polyostotic fibrous dysplasia, can
result in continually activated, ACTH-independent cortisol PATIENTS AT
release. SIGN OR SYMPTOM PRESENTATION, %
In ACTH-dependent CS, ectopic ACTH release by cer- Weight gain 90
tain tumors, such as squamous cell carcinoma of the lung
Growth failure 83
and neuroendocrine masses, is an infrequent cause of CS,
Hirsutism or acne 78
representing only approximately 1% of cases of pediatric CS.
The classic signs and symptoms of CS (Table 2) tend to be Amenorrhea and delay puberty 78
insidious in development and are not always all present. By Generalized for centripetal obesity (buffalo 75
far, the most common presentation in pediatrics is growth hump or moon facies)
failure in association with excessive weight gain, present in Osteopenia 70
nearly 90% of cases. Review of growth curves in the pre- Violaceous striae (may be hyperpigmented 60
ceding years is a crucial step in the workup of CS. Because when ACTH level is elevated)
exogenous obesity is associated with tall stature and robust Hypertension 50
growth velocity, evaluation for CS should be considered in
Headaches 25
any patient with poor growth velocity with increased weight
Plethora and skin bruising 25
gain. Hirsutism and acne are common, as well as irregular
menses in adolescent girls. Buffalo hump, from an increased Compulsive behaviors and emotional 20
lability (depression)
dorsocervical fat pad, and/or moon facies may be seen in
three-quarters of patients. Osteopenia tends to be subclinical Muscle weakness 12
and is likely underdiagnosed, although bone mineral density ACTH¼adrenocorticotropin hormone.
is regained after adequate treatment of CS. Hypertension,

406 Pediatrics in Review

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collection for free cortisol has been used since the 1970s, For ACTH-dependent pituitary adenomas, transsphenoi-
with levels greater than 90 mg/24 h (via radioimmunoassay) dal resection by an experienced neurosurgeon is the treat-
consistent with hypercortisolism, although ensuring ad- ment of choice. A successful cure rate is 80% to 90% on the
equate collection is difficult and cumbersome. Because first surgery, with decreasing rates of cure on subsequent
CS is associated with loss of the normal diurnal pattern attempts. Surgical complications, such as diabetes insipidus,
of cortisol secretion, abnormally elevated levels of cortisol syndrome of inappropriate antidiuretic hormone secretion,
should be expected around midnight, the time of the normal panhypopituitarism, bleeding, and pituitary apoplexy, are rare
nadir. A midnight salivary cortisol sample has a near 100% but can occur. For a unilateral adrenal mass, single adrenal-
sensitivity and 96% specificity for CS when the level is ectomy has a nearly 100% cure rate; a few require adjunctive
greater than 0.13 mg/dL (3.6 nmol/L). An overnight low-dose chemotherapy. With the bilateral nature of nodular disease,
dexamethasone suppression test (1 mg given orally between which fortunately is rare, both adrenal glands may have to be
11 PM and midnight) should normally result in a low 8 AM removed to ensure cure. In cases of surgical failure or ectopic
cortisol level the next morning; a cortisol level greater than ACTH secretion without a localized source, some pharma-
1.8 mg/dL (49.7 nmol/L) despite dexamethasone suppres- cotherapeutic options exist; mitotane, for example, inhibits
sion has a 95% sensitivity for CS but a lower specificity of the production of corticosteroids by blocking essential en-
approximately 80%. zymes and destroying adrenocortical cells.
Once elevated cortisol levels have been confirmed, the Once treatment for CS has been started and glucocorti-
next step in diagnosis is to determine whether the hyper- coid levels suddenly decrease, affected patients are at risk for
cortisolism is under hormonal control from ACTH secre- adrenal crisis if replacement glucocorticoid therapy at stress
tion. This is best accomplished with a plasma ACTH sample doses (approximately 3 times daily maintenance in 3 to 4 di-
drawn between 11 PM and 1 AM: a level greater than 23 pg/mL vided oral doses) is not started. This regimen can subsequently
(5 pmol/L) in a patient with hypercortisolism confirms be weaned to maintenance level (6 to 9 mg/m2 daily in 2 to 3
ACTH dependency. By comparison, patients with primary divided oral doses), followed by an ACTH-stimulation test
adrenal CS tend to have virtually undetectable ACTH levels to assess the integrity of the hypothalamic-pituitary-adrenal
(<5 pg/mL [1 pmol/L]), and those with ectopic ACTH axis.
syndrome have levels elevated upward of 100 times normal.
After biochemical confirmation of CS, imaging plays an COMMENT: Our authors note that the most common cause
important role in the next steps of management. In patients of CS is the administration of exogenous steroids. With
with laboratory findings consistent with ACTH-dependent a prevalence of close to 10% among children in the United
CS or Cushing disease, contrast-enhanced magnetic reso- States, asthma is the most common diagnosis for which our
nance imaging of the pituitary should be performed, looking patients receive corticosteroids, both orally and inhaled. The
for a corticotroph microadenoma. In the absence of an obvious Centers for Disease Control and Prevention has reported
pituitary mass on imaging, inferior petrosal sinus sampling that although the prevalence of asthma has increased since
may be necessary to localize and lateralize a small micro- the turn of this century, health care visits for asthma per 100
adenoma. For investigation of ACTH-independent CS from persons with asthma have decreased in primary care set-
a primary adrenal tumor or bilateral nodular adrenal disease, tings, and asthma is disproportionately prevalent among
adrenal computed tomography is the imaging study of children who are least likely to have ongoing medical care.
choice. Adrenal carcinomas tend to be large at diagnosis, Episodic visits for emergency treatment, with the possibility
whereas adrenocortical adenomas are typically smaller of additional courses of rescue steroids without consistent
than 5 cm in diameter; both tend to be unilateral but rarely monitoring, are not the way to prevent glucocorticoid
are bilateral. Imaging for the workup of ectopic ACTH toxicity.
syndrome may include computed tomography, magnetic
resonance imaging, positron emission tomography, and/ – Henry M. Adam, MD
or octreotide scanning. Editor, In Brief

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 Cushing Syndrome
Jason Klein, Patricia Vuguin and Sharon Hyman
Pediatrics in Review 2014;35;405
DOI: 10.1542/pir.35-9-405

Updated Information & including high resolution figures, can be found at:
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 Cushing Syndrome
Jason Klein, Patricia Vuguin and Sharon Hyman
Pediatrics in Review 2014;35;405
DOI: 10.1542/pir.35-9-405

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/35/9/405

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