Carney complex and McCune Albright syndrome: an overview of clinical manifestations and human molecular genetics

Abstract

Endocrine neoplasia syndromes feature a wide spectrum of benign and malignant tumors of endocrine and non-endocrine organs associated with other clinical manifestations. This study outlines the main clinical features, genetic basis, and molecular mechanisms behind two multiple endocrine neoplasia syndromes that share quite a bit of similarities, but one can be inherited whereas the other is always sporadic, Carney complex (CNC) and McCune-Albright (MAS), respectively. Spotty skin pigmentation, cardiac and other myxomas, and different types of endocrine tumors and other characterize Carney complex, which is caused largely by inactivating Protein kinase A, regulatory subunit, type I, Alpha (PRKAR1A) gene mutations. The main features of McCune-Albright are fibrous dysplasia of bone (FD), café-au-lait macules and precocious puberty; the disease is caused by activating mutations in the Guanine Nucleotide-binding protein, Alpha-stimulating activity polypeptide (GNAS) gene which are always somatic. We review the clinical manifestations of the two syndromes and provide an update on their molecular genetics.

Keywords: Carney complex; Endocrine neoplasia; GNAS; McCune–Albright; PRKAR1A.

Figure 1

Molecular mechanisms in Carney complex (CNC) and McCune-Albright syndrome (MAS): Receptor activation (ligand binding) makes Gsα to exchange GDP to GTP, Gsα is then freed from the β-γ dimer and activates adenyl cyclase (AC). Under normal conditions intrinsic turn off takes place through GTP-to-GDP exchange and Gsα gets inactivated. In McCune-Albright syndrome patients, GNAS mutations inhibit Gsa intrinsic turn off and leads to constant Gsa and AC activation. Activated AC produces cAMP, 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. Phosphorylated CREB and other downstream targets will activate the interacting pathways that control metabolism, growth or proliferation. PRKAR1A inactivating mutations in Carney complex patients will result in less binding of the catalytic to the regulatory subunits and excessive cAMP signaling. PDE8B and PDE11A mutations in patients with adrenal hyperplasias lead to less cAMP degradation and to excess cAMP signaling. Downstream effects of the excessive cAMP/PKA signaling in Carney complex patients include higher CREB phosphorylation, possible MAPK and Rb/E2F pathway activation among others, SMAD3 inactivation, and increased β-catenin nuclear localization (activation of the Wnt pathway) at least in adrenal lesions of patients with Carney complex.