GENETICS OF ENDOCRINE DISEASE Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation

Carney complex is a multiple neoplasia syndrome featuring car-diac, endocrine, cutaneous, and neural tumors, as well as a va-riety of pigmented lesions of the skin and mucosae. Carney com-plex is inherited as an autosomal dominant trait and may simultaneously involve multiple endocrine glands, as in the clas-sic multiple endocrine neoplasia syndromes 1 and 2. Carney complex also has some similarities to McCuneAlbright syn-drome, a sporadic condition that is also characterized by mul-tiple endocrine and nonendocrine tumors. Carney complex shares skin abnormalities and some nonendocrine tumors with thelentiginosesandcertainof thehamartomatoses,particularly Peutz-Jeghers syndrome, with which it shares mucosal lentigi-nosis and an unusual gonadal tumor, large-cell calcifying Sertoli cell tumor. Careful clinical analysis has enabled positional clon-ing efforts to identify two chromosomal loci harboring potential candidate genes for Carney complex. Most recently, at the 17q22–24 locus, the tumor suppressor gene PRKAR1A, coding for the type 1 regulatory subunit of PKA, was found to be mutated in approximately half of the known Carney complex kindreds. PRKAR1A acts a classic tumor suppressor gene as demonstrated by loss of heterozygosity at the 17q22–24 locus in tumors asso-ciated with the complex. The second locus, at chromosome 2p16, to which most (but not all) of the remaining kindreds map, is also involved in the molecular pathogenesis of Carney complex tumors, as demonstrated by multiple genetic changes at this locus, including loss of heterozygosity and copy number gain. Despite the known genetic heterogeneity in the disease, clinical analysis has not detected any corresponding phenotypic differ-ences between patients with PRKAR1A mutations and those without. This article summarizes the clinical manifestations o