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 cardiac, endocrin e, cutaneous, and neural tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex is inherited as an autosomal domina nt trait and may simultaneously involve multiple endocrine glands, as in th e classic multiple endocrine neoplasia syndromes 1 and 2. Carney complex al so has some similarities to McCuneAlbright syndrome, a sporadic condition t hat is also characterized by multiple endocrine and nonendocrine tumors. Ca rney complex shares skin abnormalities and some nonendocrine tumors with th e lentiginoses and certain of the hamartomatoses, particularly Peutz-Jegher s syndrome, with which it shares mucosal lentiginosis and an unusual gonada l tumor, large-cell calcifying Sertoli cell tumor. Careful clinical analysi s has enabled positional cloning efforts to identify two chromosomal loci h arboring potential candidate genes for Carney complex. Most recently, at th e 17q22-24 locus, the tumor suppressor gene PRKAR1A, coding for the type 1 a regulatory subunit of PKA, was found to be mutated in approximately half of the known Carney complex kindreds. PRKAR1A acts a classic tumor suppress or gene as demonstrated by loss of heterozygosity at the 17q22-24 locus in tumors associated with the complex. The second locus, at chromosome 2p16, t o 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 an d copy number gain. Despite the known genetic heterogeneity in the disease, clinical analysis has not detected any corresponding phenotypic difference s between patients with PRKAR1A mutations and those without. This article s ummarizes the clinical manifestations of Carney complex from a worldwide co llection of affected patients and also presents revised diagnostic criteria for Carney complex. In light of the recent identification of mutations in the PRKAR1A gene, an estimate of penetrance and recommendations for genetic screening are provided.