Frequency and incidence of Carney complex manifestations: A prospective multicenter study with a three-year follow-up

Carney complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome, described in 1985 by J. Aidan Carney (1). The diagnostic criteria include dermatologic manifestations (spotty skin pigmentation with typical periorificial distribution [known as lentigines], cutaneous myxomas), cardiac myxoma, primary pigmented nodular adrenal disease (PPNAD) causing adrenal Cushing, acromegaly due to growth hormone (GH)-producing pituitary adenoma, breast myxomatosis and breast ductal adenoma, large cell calcified Sertoli cell tumors (LCCSCT), thyroid carcinoma or multiple nodules, psammomatous melanotic schwannoma (PMS) and osteochondromyxoma (2). The diagnosis is based on the presence of 2 or more manifestations. In addition, other endocrine manifestations suggestive of CNC include hyperprolactinemia, elevated IGF-I concentrations or inadequate GH suppression following an oral glucose tolerance test, or paradoxical GH responses to thyrotropin releasing hormone (TRH) stimulation in the absence of clinical acromegaly, blue nevi, or a single thyroid nodule. Non-endocrine manifestations possibly associated with CNC have been described, such as cardiomyopathy, colonic polyps, bronchogenic cysts, hepatocellular adenoma and carcinoma, colonic or gastric carcinomas, retroperitoneal fibrous histiocytomas and pancreatic tumors (2, 3). Approximately 30% of cases are sporadic and the remaining 70% are dominantly inherited (2). The causal gene for CNC was identified in 2000 as the tumor suppressor gene PRKAR1A, located at 17q22-24 and encoding for the regulatory subunit type 1 alpha of the protein kinase A (4, 5). Affected patients harbor a germline heterozygous PRKAR1A alteration, more often a mutation rather than an intragenic deletion, with large deletions being rarely observed.