Carney complex (CNC) was described in 1985 as “the complex of myxomas, spotty pigmentation, and endocrine overactivity” (1). The most frequent manifestations of CNC are lentiginosis, myxomas, and ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is a unique cause of adrenal Cushing syndrome in which bilateral pigmented micronodules are typically visible at macroscopic examination in the adrenal cortex. It is mostly the investigation of this rare type of adrenal tumors that led to the identification of CNC by Dr. J. A. Carney at the Mayo Clinic (2). Since the first description of CNC, an autosomal dominant inheritance was postulated. In 2000, the identification of the CNC1 gene (PRKAR1A), located at 17q22-24, was reported by Stratakis and colleagues (3) at the National Institutes of Health. This gene encodes the regulatory subunit 1A of the protein kinase A, a central component of the cAMP signaling pathway. Because cAMP signaling is activated by various molecular and cellular defects in endocrine tumors, it appeared quickly that the identification of CNC1 was a major step for the understanding of endocrine tumorigenesis. Germline PRKAR1A mutations are heterozygous inactivating mutations. Allelic loss of the wild-type allele is frequently observed in tumors from CNC patients. Therefore, PRKAR1A is considered as a tumor suppressor gene. So far only PPNAD, which is a typical benign secreting tumor with a very slow growth, has been reported in adrenal tumors of CNC patients. In this issue of the JCEM, two cases of adrenocortical cancer (ACC) are reported in CNC patients with germline PRKAR1A mutations. The paper by Anselmo et al. (20) describes a large Azorean family with at least 10 CNC patients and a germline heterozygous PRKAR1A point mutation (S147G). The index case was a 28-yr-old female who presented with a right 12-cm ACC with liver metastasis arising in the background of bilateral PPNAD. Clinical and hormonal investigations showed cortisol and androgen excess. Three other family members presented with PPNAD and a typical paradoxical increased cortisol secretion after dexamethasone suppression test. The other frequent CNC manifestation in this family was lentiginosis (facial pigmented macules typically located on the lips and eyelids in CNC). The paper by Morin et al. (21) describes a 22-yr-old female with cardiac myxoma and lentiginosis. Her mother also suffered from cardiac myxoma at age 23 and had lentiginosis. A germline heterozygous PRKAR1A mutation that creates a premature stop codon in exon 2 of the gene (p.Lys32Argfs*12) was found in the index case. Mutant PRKAR1A mRNA with a premature stop codon are usually degraded by a mechanism of nonsense-mediated mRNA decay, inactivating the mutant allele. This applies to the majority (about 80%) of the PRKAR1A mutations that have been reported (4). This 22-yr-old female patient was diagnosed with a cortisoland androgen-secreting 8.5-cm tumor of the left adrenal that was removed by laparoscopy. Pigmented micronodules typical of PPNAD were observed at pathological examination in the adrenal adjacent to the ACC. Three months after surgery, local recurrence was observed. The patient was then reoperated and treated with mitotane. Twenty-nine months later, liver and pulmonary metastasis were progressing.