Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation

Abstract

Carney complex is a multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous, and neural tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex is inherited as an autosomal dominant trait and may simultaneously involve multiple endocrine glands, as in the classic multiple endocrine neoplasia syndromes 1 and 2. Carney complex also has some similarities to McCuneAlbright syndrome, a sporadic condition that is also characterized by multiple endocrine and nonendocrine tumors. Carney complex shares skin abnormalities and some nonendocrine tumors with the lentiginoses and certain of the hamartomatoses, particularly Peutz-Jeghers syndrome, with which it shares mucosal lentiginosis and an unusual gonadal tumor, large-cell calcifying Sertoli cell tumor. Careful clinical analysis has enabled positional cloning 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 1alpha 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 associated 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 differences between patients with PRKAR1A mutations and those without. This article summarizes the clinical manifestations of Carney complex from a worldwide collection 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.

Newly Diagnosed Carney Complex in 3 Young Adults with Primary Adrenal Cushing Syndrome – A Case Series and Review of the Literature

“…Apart from controlling hypercortisolemia and its deleterious effects, screening for other manifestations of CNC may be lifesaving. These include cardiac myxomas (11) that are responsible for 50% of the mortality from CNC (2,12). In addition, tumors of the gonads, pituitary gland, peripheral nervous system, and other organs may develop and should be followed-up.…”

“…Among the endocrine manifestations of CNC, Cushing syndrome (CS) is the most common, evolving from a distinct type of adrenal hyperplasia-primary pigmented nodular adrenocortical disease (PPNAD) (2). In addition, patients with CNC are more prone to pituitary hypersecretion of growth hormone (GH), due to hyperplasia or adenoma.…”

“…In addition, patients with CNC are more prone to pituitary hypersecretion of growth hormone (GH), due to hyperplasia or adenoma. Gonadal neoplasms may also develop as part of CNC, including large cell calcify-ing Sertoli cell tumors of the testes, and ovarian benign cystadenomas or ovarian cancer (2). Thyroid nodules are observed in three fourths of the cases, with a variable histologic picture ranging from follicular hyperplasia to malignancy.…”

Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

“…This increased PKA activity is attributed to Prkar1a haploinsufficiency. 2 Various mouse models have been developed to study CNC disease. Constitutive homozygous deletion of Prkar1a from conception causes embryonic lethality.…”

“…1 CNC patients have substantially decreased life-span with B60% of deaths due to heart-related morbidities and the remainder due to post-operative complications or malignant disease. 2 Carney complex disease shares similarities with the McCune-Albright syndrome (MAS), particularly paradoxical responses to endocrine signals; accordingly, mutations of genes involved in cyclic nucleotide (e.g., cAMP, cGMP) mediated signalling are implicated in both syndromes. 3 Notably, two thirds of patients with Carney complex syndrome have heterozygous mutations in the Prkar1a gene (chromosome 17q24), which encodes the regulatory subunit RIa (PRKAR1a) of cAMP-dependent protein kinase A (PKA).…”