Carney complex: an update

Abstract

Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by pigmented lesions of the skin and mucosa, cardiac, cutaneous and other myxomas and multiple endocrine tumors. The disease is caused by inactivating mutations or large deletions of the PRKAR1A gene located at 17q22-24 coding for the regulatory subunit type I alpha of protein kinase A (PKA) gene. Most recently, components of the complex have been associated with defects of other PKA subunits, such as the catalytic subunits PRKACA (adrenal hyperplasia) and PRKACB (pigmented spots, myxomas, pituitary adenomas). In this report, we review CNC, its clinical features, diagnosis, treatment and molecular etiology, including PRKAR1A mutations and the newest on PRKACA and PRKACB defects especially as they pertain to adrenal tumors and Cushing's syndrome.

Figure 1

Figure 1A, B, C: Manifestation of Carney Complex. Characteristic distribution of the lentigines on the eyelids (A), the vermillion border of the lips and the cheeks (B), and the ears, including the ear canal (C) in patients with CNC; such typical pigmentation on the face is only present in less than one third of the patients but it is rather diagnostic when present. D: a pigmented macule (arrow) on the outer canthus of a patient with CNC who had minimal other pigmentation; inner or outer canthal pigmentation such as the one shown here is only seen in CNC and Peutz-Jeghers syndrome making it diagnostic for these two conditions. E: Nipple myxoma in a female patient with CNC. F: Ear myxoma complicated by chronic infection and tissue overgrowth in a toddler with CNC. G and H: Large myxoma (circled) between the left atrium and ventricle detected by echocardiography in an adolescent with CNC (G) who had surgery immediately thereafter, and a much smaller myxoma (arrow) of the left ventricle originating from the cardiac diaphragm detected by cardiac MRI in an older patient with CNC (H); this myxoma was followed by serial echocardiogram and has yet to be operated, as it is not growing and poses no immediate risks. J: 5x magnification hematoxylin and eosin staining of the adrenal gland of a patient with CNC: the characteristic nodules of PPNAD are shown by the arrows; the overall size of the gland is normal and the nodules may not be visible by imaging studies.

Figure 2. cAMP pathway activation

Receptor activation (ligand binding) makes Ga to exchange GDP to GTP, Ga is then freed from the Gβ-Gγ dimer and activates adenyl cyclase (AC). Activated AC produces cAMP from ATP, cAMP causes dissociation of the inactive protein kinase A (PKA) tetramer and then the catalytic subunits are freed to mediate serine-threonine phosphorylation of target molecules, including CREB. PRKAR1A inactivating mutations in Carney complex patients will result in less binding of the catalytic to the regulatory subunits and excessive cAMP signaling.