Preoperative Diagnostic Evaluation of Children With Cushing’s Syndrome
By Stephen W. Bickler, Thomas J. McMahon, John R. Campbell, Scott Mandel, Joseph H. Piatt, and Marvin W. Harrison Portland, Oregon
. Recent advances in biochemical and imaging studies have improved the diagnostic accuracy of Cushing’s syn- drome. To better define roles for these studies in children, the authors reviewed their experience with this rare group of patients. Fifteen children, aged 11 weeks to 17 years, were treated for noniatrogenic Cushing’s syndrome over a 33-year period. All children presented with signs of hypercortisolism. Nineteen different diagnostic tests were used, reflecting changes in how these patients are evaluated. Pathological diagnoses were adrenal cortical carcinoma (3), primary adre- nocortical nodular dysplasia (PAND) (2), and pituitary ad- enoma (10). Children with adrenal cortical carcinoma pre- sented with an adrenal mass and at a younger age (mean, 22.3 months). Key diagnostic features of patients with PAND were a low plasma adrenocorticotrophin hormone (ACTH) and no suppression with high-dose dexamethasone. Chil- dren with a pituitary cause of Cushing’s syndrome presented at an older age (mean, 15.7 years) and were diagnosed using a combination of high-dose dexamethasone testing, simulta- neous inferior petrosal sinus sampling, and/ or ovine cortico- trophin-releasing hormone stimulation test. A strategy for the diagnosis of Cushing’s syndrome in children is presented. Copyright & 1994 by W.B. Saunders Company
INDEX WORDS: Cushing’s syndrome; hypercortisolism.
A’ LTHOUGH the clinical features of hypercorti- solism in children were described long before Cushing’s description in 1932 of a patient with a pituitary adenoma, it was his seminal work that was critical to the understanding of the syndrome that now bears his name.1,2 Since then, the spectrum of what is now called Cushing’s syndrome has expanded considerably. Understanding of the normal hypotha- lamic-pituitary-adrenal axis has improved, and bio- chemical analysis and imaging studies can now facili- tate more specific diagnosis in these patients. Recent advances, including reliable adrenocorticotrophin hor- mone (ACTH) assays, the ovine corticotropin- releasing hormone (o-CRH) stimulation test,3-5 petro- sal sinus sampling,6 and magnetic resonance imaging (MRI) have improved the diagnostic accuracy and altered the algorithm for defining the etiology of Cushing’s syndrome. Roles for these studies have not been clearly defined for pediatric patients. This report reviews our experience with the diagnostic evaluation of patients with Cushing’s syndrome.
MATERIALS AND METHODS
A record review was done for all patients aged 0 to 18 years treated at the Oregon Health Sciences University from 1960 to
1993, whose diagnosis was noniatrogenic Cushing’s syndrome. Data were collected regarding presenting symptoms, diagnostic tests, and surgical management.
RESULTS
Fifteen children with Cushing’s syndrome were identified: one was treated in the first decade (1960 to 1970), three in the next decade (1970-1980), and 11 were treated between 1980 and 1993. There were no cases of ACTH-producing tumors.
Signs and Symptoms
The age, gender, and presenting signs and symp- toms of children with Cushing’s syndrome are summa- rized in Table 1. All children presented with physical signs of hypercortisolism. The most common physical findings are highlighted in Table 1. Associated medi- cal conditions were uncommon. One patient with adrenal cortical carcinoma also had hemihypertro- phy; another patient with Cushing’s disease was later diagnosed as having papillary adenocarcinoma of the thyroid; a third patient with Cushing’s disease has multiple endocrine neoplasia I syndrome.
Biochemical Studies
Biochemical studies used in the evaluation of children with Cushing’s syndrome are shown in Table 2. Hypercortisolism was confirmed using a combina- tion of elevated serum cortisol, elevated 24-hour excretion of urinary-free cortisol (UFC) and 17- hydroxycorticosteroids (17-OHCS), and a low-dose dexamethasone suppression test (DST). The key diagnostic feature of patients with primary adrenocor- tical nodular dysplasia (PAND) was low-baseline ACTH levels ie, all AM baseline ACTH measure- ments were <2.5 (normal, 20 to 100 pg/mL), and no suppression of serum or urinary steroids by low- or
From the Divisions of Pediatric Surgery and Neurosurgery, Depart- ments of Surgery and Pediatrics, School of Medicine, Oregon Health Sciences University, Portland, OR.
Presented at the 26th Annual Meeting of the Pacific Association of Pediatric Surgeons, Cairns, Queensland, Australia, May 9-14, 1993.
Address reprint requests to Marvin W. Harrison, MD, Professor of Surgery and Pediatrics, Division of Pediatric Surgery, L223, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201.
| Adrenal Cortical Carcinoma (n = 3) | Primary Adrenocortical Nodular Dysplasia (n = 2) | Pituitary Adenoma (n = 10) | Total (n = 15) | |
|---|---|---|---|---|
| Mean age | 22.3 mo | 8.1 yr | 15.7 yr | |
| Range | 13-37 mo | 11.8 mo-7 yr | ||
| Male | 1 | 1 | 6 | 8 |
| Female | 2 | 1 | 4 | 7 |
| Moon facies | 3 | 2 | 10 | 15 |
| Obesity | 3 | 1 | 10 | 14 |
| Acne | 3 | 1 | 8 | 12 |
| Longitudinal growth failure | 0 | 2 | 9 | 11 |
| Buffalo hump | 2 | 0 | 7 | 9 |
| Hirsutism | 3 | 0 | 6 | 9 |
| Plethora | 1 | 1 | 7 | 9 |
| Hypertension | 3 | 0 | 4 | 7 |
| Stria | 0 | 1 | 5 | 6 |
| Skin hyperpigmentation | 0 | 0 | 4 | 4 |
| Renal stones | 0 | 1 | 1 | 2 |
high-dose dexamethasone. Of the 10 patients with the diagnosis of Cushing’s disease, only four of nine were found to have elevated baseline serum ACTH levels; one patient’s ACTH levels were in the high-normal range. In eight of nine patients, low-dose dexametha- sone did not suppress the serum cortisol; in three, suppression was not achieved with high-dose dexa- methasone. For the latter three patients, Cushing’s disease was confirmed by simultaneous inferior petro- sal sinus sampling and/or o-CRH stimulation tests.
Radiological Studies
A summary of radiological studies used to localize the anatomic cause of Cushing’s syndrome is shown in Table 3. For children with adrenal cortical carcinoma, the adrenal masses were demonstrated by computed tomography (CT) or intravenous pyelography. In one
patient with adrenal cortical carcinoma, abdominal ultrasonography and venography showed tumor exten- sion into the inferior vena cava. Both patients with PAND had abdominal CT; onc scan had normal findings, and the other showed only slightly enlarged adrenal glands. Petrosal sinus sampling confirmed the diagnosis of Cushing’s disease in two of the three patients for whom it was done. A CT scan of the head showed a pituitary lesion in three of five patients; both patients who had MRI were found to have pituitary adenomas. Only one of six patients who had skull films was noted to have an abnormality of the sella turcica.
Surgical Management
Fourteen of the 15 patients underwent surgery to treat the Cushing’s syndrome. The exception was a patient treated with external radiation to the pituitary in 1975. The remaining nine patients with Cushing’s disease had transsphenoidal adenomectomy (7), transsphenoidal hemihypophysectomy (1), or bilat- eral adrenalectomy (1). The patient who had hemihy- pophysectomy initially underwent transsphenoidal pituitary exploration, which showed a probable left- sided adenoma. Postoperatively, repeat petrosal si- nus sampling suggested left-sided ACTH production. Subsequently the patient underwent left hemihy- pophysectomy. Of the three children with adrenal cortical carcinoma, two underwent adrenalectomy, and one had en bloc adrenalectomy and nephrec- tomy. Both children with PAND had bilateral adrenal- ectomies. A transabdominal approach was used for all children who underwent adrenalectomy.
DISCUSSION
The diagnosis and surgical management of children with Cushing’s syndrome is challenging. Although accurate preoperative diagnosis should be possible in
| Serum | Elevated Urine Excretion (24 h) | Suppression With Dexamethasone | |||||
|---|---|---|---|---|---|---|---|
| Elevated Cortisol* | Elevated ACTHt | Low ACTH# | UFC§ | 17-OHCS| | Low Dose'l | High Dose# | |
| Adrenal cortical carcinoma (n = 3) | 2/2 | 1/2 | 0/2 | 0/0 | 3/3 | 0/0 | 0/0 |
| Primary adrenocortical nodular dysplasia (n = 2) | 2/2 | 0/2 | 2/2 | 2/2 | 2/2 | 0/2 | 0/2 |
| Pituitary adenoma (n = 10) | 5/10 | 4/9 | 0/9 | 6/6 | 6/6 | 1/9 | 6/9 |
*AM serum/cortisol > 21 µg/dL.
tAM serum ACTH > 100 pg/mL.
AM serum ACTH < 20 pg/mL.
§ 24-h urinary free cortisol > 60 mg/m2.
|17-OHCS > 5 mg/24 h.
fSuppression with low-dose dexamethasone < 50% baseline average.
Suppression with high-dose dexamethasone < 10% baseline average.
| Petrosal Sinus Sampling* | CT of the Headt | CT of the Abdomen | IVP+ | MR of the Headt | Digital Subtraction Angiogramt | Skull X-rayll | |
|---|---|---|---|---|---|---|---|
| Adrenal cortical carcinoma (n = 3) | 0/0 | 0/1 | 2/2$ | 1/1 | 0/0 | 0/0 | 0/0 |
| Primary adrenocortical nodular dysplasia (n = 2) | 0/1 | 0/0 | 1/2š | 0/0 | 0/0 | 0/0 | 0/0 |
| Pituitary Adenoma (n = 10) | 2/3 | 3/5 | 0/0 | 0/0 | 2/2 | 1/1 | 1/6 |
NOTE. Numbers indicate positive studies per number of studies performed.
*Inferior petrosal sinus ACTH/peripheral blood ACTH > 2.
+Pituitary adenoma.
Adrenal mass.
§ Bilateral adrenal enlargement.
||Abnormalities in sella turcica.
all cases, the roles of recently developed diagnostic studies are only beginning to be defined. Authors of several recent reviews7-10 have suggested roles for the new diagnostic tests. In our series, 18 different diagnostic tests were used to define the cause of Cushing’s syndrome. This indicates the changes that have occurred in the evaluation of this disease over the past 33 years. An average of seven tests (range, three to nine) were performed for each patient. Clearly, a strategy for diagnosis based on the sensitiv- ity and specificity of diagnostic tests is needed.
Complete differential diagnosis is the first step toward accurate diagnosis of Cushing’s syndrome in children. The clinical entities known to cause Cushing’s syndrome in children are listed in Table 4. Traditionally, causes of Cushing’s syndrome have been divided into ACTH-dependent and ACTH- independent states. In infants, adrenal tumors are the most frequent cause of Cushing’s syndrome.11-13 Most often, patients are identified because of virilization and signs of hypercortisolism. After the seventh year of life, Cushing’s syndrome is predominantly the result of pituitary adenomas. This pattern was demon- strated in our series. PAND occurs almost exclusively in children and young adults.14-17 With this disorder, cortisol is autonomously secreted from hyperplastic adrenocortical nodules. Cutaneous hyperpigmenta- tion and pituitary abnormalities are absent, and patients have low plasma levels of ACTH. PAND has also been described as a component of several syn-
Table 4. Causes of Cushing’s Syndrome in Infants and Children
ACTH-dependent states Pituitary adenoma (Cushing’s disease)
Ectopic hormone production by tumor ACTH secreting
CRF secreting
ACTH-independent (primary adrenal states)
Adrenal cortical adenoma
Adrenal cortical carcinoma
Primary adrenocortical nodular dysplasia
dromes. Carney’s complex is characterized by cardiac and cutaneous myxomas, mammary myxoid fibroad- enomas, spotty mucocutaneous pigmentation, pri- mary pigmented adrenal cortical disease, large cell calcifying Sertoli cell tumors of the testis, growth hormone-secreting pituitary adenomas, and psam- momatous melanotic schwannomas.18 Cushing’s syn- drome has also been associated with the McCune- Albright syndrome. This syndrome describes the association of sexual precocity, skin pigmentation, and polyostotic fibrous dysplasia with various endo- crine disorders.19 Ectopic production of ACTH or corticotrophin-releasing hormone (CRH) by tumors is rare in children. Wilms’ tumor and tumors of the neural tissue, thymus, or pancreas are the most common sources of ectopic ACTH in children.20,21 There has been no reported case of ectopic CRH secretion in a child.
The diagnosis of Cushing’s syndrome is based on the demonstration of excess unregulated cortisol secretion, and abnormal feedback regulation of the hypothalamic-pituitary axis. The first is achieved by measuring urinary glucocorticoids, the second by means of dynamic stimulation and suppression tests.
Because the circadian rhythm of cortisol secretion is lost in Cushing’s syndrome, random serum cortisol levels are of limited value. Twenty-four-hour urinary excretion of cortisol and its metabolites is a more accurate method to demonstrate excess cortisol pro- duction because it measures integrated cortisol secre- tion. UFC has a false-negative rate of 5% to 6%, and false-positive rates of 1% for individuals of normal weight and 5% for obese patients.22 Urinary 17- OHCS excretion is principally a measure of cortisol and the cortisone metabolites tetra-hydrocortisol and tetra-hydrocortisone. A false-negative rate of 11% and a false-positive rate of 27% were recently re- ported when using 17-OCHS to diagnose Cushing’s syndrome.22 From these studies, it appears that 17- OHCS as a single screening test for Cushing’s syn-
drome is unwarranted. We collect urine for both UFC and 17-OHCS, especially for younger children sus- pected of having adrenal cortical carcinoma, because urinary 17-OHCS may be markedly elevated in such patients.
Dynamic tests of the hypothalamic pituitary axis are the next major modality for diagnosing hypercor- tisolism. Dexamethasone suppresses ACTH release by the pituitary but is not detected with cortisol assays. The low-dose DST can be used as a confirma- tory study for hypercortisolism, but it may not be necessary if Cushing’s syndrome is strongly suggested by clinical examination and if UFC is markedly clevated. Measurements of plasma cortisol are typi- cally used. Suppression with low-dose dexametha- sone is defined as a decrease in cortisol levels to less than 10% of the baseline values. The 48-hour version of this test has been reported as having a true-positive rate of 97% to 100%.23 Recently, Cronin et al reported a false-positive rate of 12.5% in adults, using 1 mg of dexamethasone at midnight and taking serum cortisol measurements from 8 AM to 10 AM; their false-negative rate was 2%.24 Drugs that induce liver enzymes (eg, phenytoin, rifampin, and phenobarbi- tone) increase the clearance rate of dexamethasone, and consequently lower plasma levels, which results in higher false-positive rates.
After confirmation of Cushing’s syndrome, investi- gation should be directed toward establishing the precise cause of increased cortisol release, ie, ACTH- independent or ACTH-dependent. The introduction of reliable ACTH assays has greatly facilitated the diagnosis of Cushing’s syndrome.22 With sensitive assays, patients with Cushing’s disease or ectopic ACTH production can be shown to have plasma ACTH levels in either the high-normal range or the elevated range. In contrast, patients with Cushing’s syndrome related to a primary adrenal cause have extremely low or undetectable levels of ACTH. In our laboratory, using radioimmunoassays, we are able to detect levels as low as 2 pg/mL.
Distinguishing between a pituitary source and an ectopic source of ACTH is a difficult problem; this usually requires a combination of biochemical and imaging studies. The high-dose DST is a valuable first step. We prefer the 8-mg overnight DST performed on an outpatient basis. In a study of 76 patients with Cushing’s disease, Tyrell et al found this test to have a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%.25
The o-CRH stimulation test has become a powerful tool for investigating suspected cases of Cushing’s syndrome, but currently it is available only for experi-
mental use. CRH is released by the hypothalamus and is the most potent stimulator of pituitary ACTH secretion. This 41 amino acid peptide from the ovine hypothalamus was first characterized in 1981.26 It was later shown to stimulate ACTH secretion in subjects with Cushing’s syndrome.27 The o-CRH test is per- formed by intravenous administration of 1 µg/kg or 100 µg of CRH, with measurement of cortisol and ACTH every 15 minutes for 2 to 3 hours. Circulating ACTH and cortisol are elevated after CRH infusion in normal subjects. In patients with Cushing’s disease, the response is exaggerated. Typically, patients with ectopic ACTH production have no response to CRH. Few studies have compared the usefulness of CRH and DST. Ninety percent of patients with Cushing’s disease will have a cortisol response to CRH.10 Conversely, responsiveness to CRH almost always excludes ectopic ACTH production. Patients who have no response to CRH and in whom high-dose dexamethasone fails to suppress cortisol are likely to have ectopic ACTH production or a primary adrenal cause.
Radiological studies are essential in determining the cause of Cushing’s syndrome. CT, MRI of the pituitary, and simultaneous bilateral inferior petrosal sinus samplings are useful in diagnosing a pituitary cause. For younger children, abdominal CT should demonstrate adrenal tumors. CT is also of value in identifying an ectopic source of ACTH production. Because of the small size of some ACTH-secreting tumors, images at 1-cm intervals or less are necessary. MRI is more sensitive than CT for detecting pituitary tumors. MRI has a demonstrated sensitivity of 77% for the detection of pituitary adenomas in Cushing’s disease; CT’s sensitivity is only 47%.9 Because of the higher false-positive rate of MRI in detecting pitu- itary adenomas, we continue to prefer CT, and tend to rely more on petrosal sinus sampling to lateralize the pituitary adenoma. Positive findings from CT and MRI must be interpreted in conjunction with bio- chemical data.
Simultaneous bilateral inferior petrosal sinus sam- pling allows confirmation of pituitary ACTH secre- tion as well as lateralization of the tumor within the pituitary fossa. Because ectopic ACTH production is so rare in children, the primary role of petrosal sinus sampling is to assist the neurosurgeon in planning transsphenoidal exploration. Preoperative localiza- tion allows selective transsphenoidal adenomectomy, which is the favored procedure in Cushing’s disease.28 A ratio of inferior petrosal sinus ACTH levels to peripheral vein ACTH levels of greater than 2 is necessary to diagnosis Cushing’s disease with confi-
Confirm Hypercortisolism: 24 hr. UFC 17-OHCS +/- Low Dose DST
Children Less Than Seven Years
CT Adrenals
Serum ACTH, and High Dose DST
No Dominant Adrenal Mass -PAND vs. other etiology
Dominant Adrenal Mass -adenoma -adenocarcinoma
Adrenalectomy
Normal to Elevated ACTH (ACTH Dependant)
Low to Undetectable ACTH, and No Suppression w/ High Dose DST (ACTH Independant)
Primary Adrenal Etiology
No Suppression w/ High Dose DST
Suppression w/ High Dose DST
CT Adrenals
Ectopic ACTH Source
No Dominant Adrenal Mass -PAND
Dominant Adrenal Mass -adenoma -adenomacarcinoma
Confirm w/ -Patrosal Sinus Sempling OCRH SEim Test
Pituitary ACTH Source
Extensive Search for Source of ACTH -selective venous sampling -full body Imaging
Transphenoidal Exploration
Bilateral Adrenalectomy
Unilateral Adrenalectomy
dence.10 Accurate positioning of the catheter is criti- cal. Physical size constraints limit inferior petrosal sinus sampling to older children.
Figure 1 is an algorithm for evaluating children with suspected Cushing’s syndrome, and Table 5 summarizes the expected outcome of diagnostic tests. Because no test for Cushing’s syndrome has 100% specificity or sensitivity, the algorithm is intended to serve only as a contemporary general guideline. Hypercortisolism is confirmed using a 24-hour urine collection test for UFC and 17-OHCS. If Cushing’s syndrome is still questionable, the 24-hour urine collection test is repeated, and a low-dose DST performed. For children under 7 years of age with an adrenal mass demonstrated by CT, the workup is complete, and surgical exploration is appropriate. For the remaining patients, an attempt is made to determine if the hypercortisolism is ACTH-depen- dent (pituitary adenoma or ectopic ACTH). Serum ACTH is measured, and a high-dose DST is per- formed on an outpatient basis. An elevated or high- normal ACTH level and suppression of serum corti-
sol with high-dose dexamethasone is suggestive of a pituitary cause. The o-CRH stimulation test, petrosal sinus sampling, and imaging studies of the sella should be used as confirmatory tests. The rare cases of suspected ectopic ACTH production require addi- tional studies such as full-body imaging and selective venous sampling to identify the site of ACTH produc- tion. A low serum ACTH level with no suppression of cortisol by high-dose dexamethasone is suggestive of a primary adrenal cause. Children with adenoma or adenocarcinoma, determined by abdominal imaging, should undergo unilateral adrenalectomy. Children whose diagnostic workup shows PAND should un- dergo bilateral adrenalectomy.
We conclude the following: (1) accurate preopera- tive diagnosis should be possible in all children with Cushing’s syndrome, using a limited number of bio- chemical and imaging studies, (2) the diagnosis of children with Cushing’s syndrome continues to evolve, and (3) prospective studies are needed to define the sensitivity and specificity of diagnostic tests in pediat- ric patients.
| UFC & 17-OHCS | Low-Dose DST* | High-Dose DSTŤ | Abdominal CT | Pituitary MRI | Petrosal Sinus Sampling | |
|---|---|---|---|---|---|---|
| Adrenal cortical carcinoma | f | No | No | Unilateral mass | - | NA |
| Primary adrenocortical | 1 | No | No | Normal or minimally enlarged | - | NA |
| nodular dysplasia | ||||||
| Pituitary adenoma | 1 | No | <50% of baseline | Mild bilateral enlargement | +/- | + ☒ |
| Ectopic ACTH | 1 | No | No | Enlarged or normal | - | - |
*This test is performed on an outpatient basis by administering 25 ug/kg, up to a maximum dose of 1 mg, at midnight, and by measuring cortisol levels at 8 AM.
tThis test is performed by administering 8 mg/1.73 m2 (up to 8 mg dexamethasone) orally at 11 PM. Suppression of morning plasma cortisol <50% of baseline is indicative of Cushing’s disease.
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