Clinical Information

Carney complex (CNC) is an autosomal dominant disorder caused by heterozygous germline  inactivating variants in the PRKAR1A gene. This condition has also been designated by the following acronyms: NAME (nevi, atrial myxomas, ephelides) and LAMB (lentigines, atrial myxoma, blue nevi). CNC is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors, and schwannomas. The most common presenting feature of CNC is unusual skin pigmentation, including brown skin spots called lentigines or blue-black moles called blue nevi. Myxomas are noncancerous (benign) tumors that can occur in the heart (cardiac myxoma), skin, breast, and other internal organs. Cardiac myxomas can occur at a young age and may block blood flow through the heart, causing serious complications or sudden death. Approximately 25% of affected individuals will develop primary pigmented nodular adrenocortical disease (PPNAD), which can lead to development of Cushing syndrome. Large-cell calcifying Sertoli cell tumors occur in most affected male patients and may develop in the first decade of life in about one third of cases. Multiple thyroid nodules are present in as many as 75% of affected individuals. Pituitary adenomas resulting in clinically evident acromegaly occur in approximately 10% of adults with CNC. Another 10% of affected individuals have psammomatous melanotic schwannomas, which are typically benign but may be malignant.(1-4)

PRKAR1A encodes for cyclic AMP-dependent protein kinase type I-alpha regulatory subunit. PRKAR1A functions as a canonical tumor-suppressor gene, with biallelic inactivation in tumors resulting in constitutive activation of protein kinase A. Approximately 70% of individuals with a diagnosis of CNC have an affected parent, while approximately 30% have a de novo disease-causing variant. CNC is a highly penetrant disorder, with approximately 95% of those with a disease-causing PRKAR1A variant developing disease by age 50 years. The proportion of probands with a disease-causing variant detectable by sequence analysis is approximately 60% but can be higher (approximately 80%) in individuals presenting with Cushing syndrome caused by PPNAD.(4)

While the majority of reported disease-causing PRKAR1A gene variants are associated with CNC, this gene is also associated with an autosomal dominant condition called acrodysostosis-1 with hormone resistance. This condition is characterized by multiple hormone resistance, short stature, brachycephaly, and short broad hands with short metacarpals and phalanges, among other features. This phenotype results from disease-causing PRKAR1A variants in one of the protein’s cyclic AMP-binding domains and has a different mechanism of disease than CNC.(5)