I first learned of this condition in 1990 during my fellowship training in endocrinology at The Johns Hopkins Hospital. I
From the desk of Lewis S. Blevins Jr. M.D. – I first learned of this condition in 1990 during my fellowship training in endocrinology at The Johns Hopkins Hospital. It was during those early years that I learned as much as possible about pituitary and adrenal disorders, as well as most other endocrine disorders, for I knew I wanted to be a pituitary specialist who also treated patients with adrenal diseases. Now, 35 years later, I have finally seen my first patient with this condition!
A 66-year-old woman was referred for evaluation of hypercortisolism. Symptoms and signs included some loss of muscle mass in her arms and legs, depression, anxiety, and osteopenia. She did not appear Cushingoid on examination. Her 24-hour urine corticoids were elevated, measuring 83.5 mcg and 48.8 mcg. She had an abnormal dexamethasone-suppressed cortisol that measured 3.1 mcg/dL. She failed the test three times. ACTH levels ranged from 6 to 19 pg/mL. The DHEA-S level was low-normal, measuring 40 mcg/dL. Her adrenal CT scan showed modular enlargement of the left adrenal gland and an otherwise normal-appearing right adrenal gland. These scans are shown below. She underwent a resection of the left adrenal gland as it was the abnormal finding on CT. Pathology showed typical features of primary pigmented nodular adrenocortical disease. PPNAD is one of the relatively unusual yet distinct forms of micronodular adrenal hyperplasia. This condition was first described by Carney in 1984.
Figure 1. The arrow points to a relatively normal appearing right adrenal gland.
About 90% of patients with this condition have what is often described as the Carney Complex, characterized by spotty pigmentation of the skin. And especially around the central parts of the face and the lips, myxomas of the skin and breast, atrial and ventricular myxomas in the heart, and either unilateral or bilateral adrenal nodular disease. Other associated conditions can include thyroid tumors, growth, hormone-secreting pituitary tumors, calcified Sertoli cell tumors, and ovarian cysts.
Symptoms and signs may be related to some of the conditions mentioned above, but many are directly related to hypercortisolism itself. They are variable because cortisol production differs in degrees of severity between patients. Furthermore, there are probably genetic factors that lead to susceptibility to the manifestations of diabetes and hypertension, etc. A preponderance of patients will have osteopenia or osteoporosis. Many children present with growth failure but an increase in weight.
While many patients present in childhood, the average age of affected patients is approximately 22, with a range of one to 61 years. I suppose that my patient is probably one of only a few people who present in the seventh decade of life. About two-thirds of cases are familial, and one-third are sporadic, meaning there are no affected relatives. The PRKAR1α gene is mutated in about 75% of patients. Other mutations have been described.
As in my patient, the hypercortisolism is classified as ACTH-independent, meaning that the adrenals are producing cortisol on their own, rather than being regulated by the hypothalamic-pituitary unit. In fact, the hypothalamus and the pituitary are usually suppressed by the cortisol production, and the ACTH level is generally low or low normal. The DHEA-S level falls since ACTH levels are low, as it is a marker of overall adrenal activity as regulated by the pituitary gland. The degree of hypercortisolism can be best described as mild to moderate and is rarely severe. Some patients have cyclical or periodic disease. This can make the diagnosis difficult because urine cortisol levels can vary from being normal to elevated.
Figure 2. The arrow points to one of the nodules on the left adrenal gland. While this nodule is a little atypical and large for the condition, it is the abnormality that led to the adrenal surgery that proved the underlying diagnosis.
Most patients have a paradoxical response to dexamethasone, where cortisol levels increase instead of decreasing as they would in normal people who are treated with dexamethasone. One has to wonder whether this is a situation where hypercortisolism fuels itself. The hyperplastic nodules of the adrenal glands are usually small, and the unaffected adrenal cortex between them is typically atrophic, indicating that it has been suppressed due to low ACTH levels.
Unilateral or bilateral adrenalectomy is the treatment of choice. As with most hyperplasias, if I observe that one adrenal gland appears to be more affected than the other, as in my patient, I tend to recommend removal of the one that looks abnormal. It is imperative to perform cardiac echocardiography in patients found to have PPNAD, as the myxomas in the heart can lead to cardiac dysfunction or embolic events that can cause strokes.
I presented the most extreme biochemical features seen in my patient during her investigations. In fact, she had a few normal urine cortisol levels, and at times it appeared that she had mild autonomous cortisol secretion, MACS, rather than hypercortisolism. Her case serves as an example that patients with mild disease can truly have important pathology, and so they need treatment. This particular patient was seen by physicians from different specialties at several major medical centers, who did not possess the depth of knowledge required to establish a diagnosis and treatment plan. Sometimes, those second and third opinions are useful.
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