Discovery of the Carney complex

In 1984, the adrenal pathologic findings in 4 Mayo Clinic cases of Cushing syndrome led to characterization of a unique disorder termed primary pigmented nodular adrenal disease (PPNAD). A literature review showed that the condition had occurred in 2 families. In 1 family, 2 siblings were affected and a third sibling without Cushing syndrome died of cardiac myxoma.

To test the hypothesis that a connection existed between PPNAD and cardiac myxoma, J. Aidan Carney, M.D., Ph.D, emeritus member of the Department of Laboratory Medicine and Pathology at Mayo Clinic, searched Mayo Clinic files and the world literature for patients with both conditions.

Dr. Carney recalls: "I noted in a Swiss report that 2 siblings with PPNAD had other disorders. One, aged 35 years, also had an eyelid fibroma and became hemiparetic 4 years after adrenalectomy. The other, aged 37 years, was thought to have neurofibromatosis because of skin fibromas.

"There was another odd finding in the family: a third sibling without Cushing syndrome or skin lesions died of left atrial myxoma at age 4 years. It seemed remarkable to haply find 2 disorders, a manifestly rare adrenal disorder, PPNAD, and another rare condition, cardiac myxoma—and possibly a third, neurofibromatosis—in a sibship and there not be a connection between them."

Dr. Carney continues: "But to entertain this hypothesis seriously, it was necessary to find at least 1 patient with PPNAD and cardiac myxoma. The 4 Mayo Clinic patients and the 19 patients with PPNAD identified in the literature were obvious candidates for the combination, but none had cardiac myxoma.

"Review of records of 131 Mayo Clinic patients who had undergone bilateral or subtotal adrenalectomy for Cushing syndrome up to 1982 showed that none had cardiac myxoma, either. I tried another search approach: I reviewed the approximately 500 reported cases of cardiac myxoma and the 51 patients with cardiac myxoma operation at Mayo Clinic up to 1981, seeking cases that also featured Cushing syndrome. There were none.

"Up to that time, 29 additional Mayo Clinic patients had died of or with cardiac myxoma as an autopsy finding; none had Cushing syndrome. Review of pathologic diagnoses in these cases revealed 1 case with multiple cortical (adrenal) adenomas. The gross description of the glands was 'there are multiple cortical nodules in both adrenals. These are of a yellowish color, but contain some brown and black dots.'

"The bilaterality and color of the nodules were reminiscent of PPNAD. However, there was no mention of cytoplasmic pigment or the bizarre cytologic features typical of PPNAD. Apparently, the lesions were small, standard adenomas.

"In a desperate effort to complete what had been a time-consuming and psychically draining experience before finally abandoning the search, I reviewed the adrenal microscopic slides in the 29 autopsy cases. The slides arrived for study on April 24, 1982. What emotion I felt as I looked at those of the case of multiple cortical adenomas. The patient had PPNAD! At that instant, the PPNAD-cardiac myxoma combination assumed a reality for me. It never crossed my mind for a moment that the concurrence of the 2 conditions might have been simply the chance occurrence of 2 rare disorders in the same patient."

Dr. Carney reports: "It was surely not accidental that the cardiac myxoma in the case had been attached in the left atrium at the junction of septum and posterior wall, not the fossa ovalis, the usual site for sporadic neoplasm. Cushing syndrome was not mentioned in the autopsy clinical abstract, which was surprising. PPNAD had been functional in all the cases I had identified up to then.

"The incongruity was partially explained when I found Crooke hyaline change in corticotroph cells, a telltale sign of hypercortisolemia. The clinical record was a revelation. I went through it with mounting excitement and almost disbelief. The medical resident who initially saw the patient noted an unusual skin finding: 'deeply pigmented moles cover most of body.' The finding was repeated elsewhere in the report:

• 'Pale, tranquil with numerous nevi also (on) mouth/lips'
• 'She looks pale, somewhat puffy, numerous pigmented nevi'
• 'Many pigmented moles'
• 'Myxomatous mammary fibroadenoma'

"As I read these observations, I had the eerie feeling that I was reading the description of an unrecognized syndrome. It seemed almost impossible, statistically, that all the patients' conditions—PPNAD, unusually situated or multiple cardiac myxomas, numerous pigmented moles, and a myxomatous mammary fibroadenoma—could be encountered together in the particular circumstances in which they had been found and the events be unconnected. They must all be related. They must constitute a syndrome."

Carney complex

Dr. Carney's discovery led to further studies that documented what is termed Carney complex. The syndrome is characterized by:

Characteristics of Carney complex

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• Spotty skin pigmentation (pigmented lentigines and blue nevi on the face, including eyelids, vermilion lip borders, conjunctivae, and sclera)
• Myxomas (cardiac, cutaneous, and mammary)
• Testicular large-cell calcifying Sertoli cell tumors
• Growth hormone-secreting pituitary adenomas
• Psammomatous melanotic schwannomas

The hypercortisolism in individuals with PPNAD is caused by multiple, pigmented, autonomously functioning adrenocortical nodules.

Patients with PPNAD may present with the typical signs and symptoms of hypercortisolism, including:

• Central weight gain
• Hyperglycemia
• Proximal muscle weakness
• Purple-red abdominal striae
• Hypertension
• Menstrual cycle disturbance

However, the patients tend to be young (<30 years) and may have:

• Mild or severe signs and symptoms related to hypercortisolism
• Marked osteoporosis, presumably due to chronic mild hypercortisolism
• Cyclic disease

Baseline hormonal evaluation documents:

• Increased cortisol levels in blood and urine
• Suppressed corticotrophin
• Suppressed serum dehydroepiandrosterone sulfate
• A paradoxical increase in urinary free cortisol with dexamethasone suppression testing

Approximately half of patients with PPNAD prove to have Carney complex. Thus far, mutations in 2 genes have been associated with the disorder: PRKAR1A and PDE11A. However, because some families with Carney complex do not have mutations in 1 of these 2 genes, studies are ongoing to identify additional loci.

In most familial cases, Carney complex appears to be autosomal dominant in inheritance. Germline mutations in PRKAR1A also may be present in patients with isolated PPNAD.