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Requests for reprints should be addressed to Nilay Desai, MD, Division of Endocrinology, T15-060, Health Sciences Center, Stony Brook University, Stony Brook, NY 11794
Cushing’s syndrome is a constellation of signs and symptoms due to glucocorticoid excess. Most commonly it results from chronic glucocorticoid therapy. The main cause of spontaneous Cushing’s syndrome (60-70% of cases), also known as Cushing’s disease, is a pituitary adenoma secreting adrenocorticotropic hormone. Fifteen to 20% of cases of Cushing’s syndrome are due to ectopic adrenocorticotropic hormone secretion from nonpituitary tumors, whereas 10% of cases are due to glucocorticoid production from adrenal tumors.
Rare causes of Cushing’s syndrome include corticotrophin-releasing hormone (CRH)-producing tumors, bilateral macronodular adrenal hyperplasia, and primary pigmented nodular disease. Total white blood cell count is usually normal in Cushing’s syndrome with low eosinophil and lymphocyte counts, although granulocytes may be mildly increased.
Herein we report a case of Cushing’s syndrome due to bilateral adrenal adenoma initially presenting only as persistent leukocytosis.
Case report
A 30-year-old white woman presented to her primary care physician in August 2003 for fatigue of 1 month’s duration. She had an elevated white blood cell count (14.4 × 109/L) and was found to have urinary tract infection and an ear infection for which she was treated with antibiotics. Since leukocytosis persisted even after treatment, she was referred to the hematology service in September 2003. Her past medical history was significant for polycystic ovary syndrome, frequent vaginal yeast infections, recurrent urinary tract infections, and left axillary sebaceous cyst infections. HIV and diabetes mellitus were ruled out by appropriate testing in the past. She had been taking metformin for approximately 1 year for polycystic ovary syndrome. Her family history included familial adenomatous polyposis of the colon in her father and brother. Her mother died at age 19 from Hodgkin’s disease.
During hematological evaluation, her white blood cell count was 19.2 × 109/L with normal differentiation; hemoglobin and hematocrit were 16.2 g/dL and 48.9%, respectively. She denied any symptoms except persistent fatigue, and her physical examination was unremarkable. On further testing, blood glucose was 84 mg/dL, serum Na 140 mmol/L, and K 4.4 mmol/L. Blood and urine cultures, chest radiograph, and purified protein derivative test were negative. Her bone marrow aspiration and biopsy revealed no evidence of any hematological problem. Computed tomography (CT) scans of the chest and abdomen revealed a heterogeneous solid nodule in each adrenal gland. Her random serum cortisol levels were 26.2 microg/dL (11 am) and 22.3 microg/dL (4 pm). She was then referred to the endocrinology service in November 2003.
At presentation to the endocrinology service, she complained of persistent fatigue as well as new symptoms of abdominal cramping, bloating, and weight gain. On examination, blood pressure was 140/90, and heart rate was 96 beats per minute. She had a round face, acne, hirsutism, and pink abdominal striae. There were no bruises or dorso- cervical fat pad. Following the administration of 1 mg dexamethasone at 11 pm, serum cortisol was 24.7 μg/dL the following morning. Other test results are shown in the Table.
Random adrenocorticotropic hormone level was 2 pg/mL, and simultaneous serum cortisol was 39.8 μg/dL, consistent with an adrenocorticotropic hormone-independent cause of hypercortisolism. Magnetic resonance imaging study of the abdomen showed bilateral adrenal nodules, 2 × 3 × 2.5 cm on the left and 2 × 1.9 × 1.6 cm on the right (Figure 1). Both adrenal nodules demonstrated <50% signal drop on the out-of-phase images, consistent with bilateral adrenal adenomas. On iodocholesterol scanning, abnormal radiotracer uptake was seen in both adrenal glands, consistent with bilateral functioning adrenal cortical adenoma
The patient underwent laparoscopic bilateral adrenalectomy in April 2004. Surgical pathology showed bilateral adrenal adenoma with atrophy of attached cortex, consistent with suppression of adrenocorticotropic hormone. There were no features of malignancy (Figure 3). Both nodules were well circumscribed and yellow/tan in color. Postoperative baseline serum cortisol level was undetectable, suggesting cure of Cushing’s syndrome. By June 2004, her white blood cell count returned to normal.
Figure 3Hematoxylin-and-eosin-stained tissue sections of left adrenal gland (A) and right adrenal gland (B) demonstrate bilateral tumor nodules and atrophic non-tumorous adrenal tissue (50×).
This case is unique, as the patient presented only with persistent leukocytosis (with normal differential count). She initially denied common symptoms of Cushing’s syndrome except chronic fatigue and frequent infection. She had no stigmata of Cushing’s syndrome on initial clinical examination. She developed classic features of Cushing’s syndrome later on during her evaluation for bilateral adrenal masses.
Bilateral functioning adrenal adenomas are very rare. Only 25 cases have been reported since 1977.
There are several forms of adrenocorticotropic hormone-dependent and -independent bilateral adrenal hyperplasia. Simple adrenocortical hyperplasia due to Cushing’s disease (adrenocorticotropic hormone-dependent) is the most common. On histology, there is equal hyperplasia of clear cells of the zona fasciculata and compact cells of the zona reticularis.
Abnormal adrenal expression of receptors for a variety of hormones (like gastric inhibitory peptide) can lead to adrenocorticotropic hormone-independent bilateral macronodular adrenal hyperplasia (AIMAH)
Cortisol- producing primary adrenal adenomas are usually single, unilateral and encapsulated. It is usually associated with suppressed adrenocorticotropic hormone levels leading to atrophy of the adjacent non-nodular area and uninvolved gland.
Surgical specimens in this case showed bilateral, well-circumscribed yellow/tan nodules arising from the parenchyma with atrophy of attached cortex. This is consistent with bilateral adrenal adenomas. Primary pigmented nodular adrenocortical disease is another rare cause of bilateral adrenal hyperplasia. It is an autosomal dominant disease of young age. It is associated with the Carney complex-cardiac, cutaneous, and mammary myxomas, spotty facial skin pigmentation, testicular tumors, acromegaly, Schwannomas, and thyroid nodules.
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