ESE Young Investigator Award
Rossella Libé1,3, Anelia Horvath2, Amato Fratticci3, Delphine Vezzosi3, Joel Coste1, Marine Guillaud-Bataille1, Lionel Groussin1,3, Eric Clauser1, Marie Laure Raffin Sanson1,3, Xavier Bertagna1,3, Constantine Stratakis2 & Jérôme Bertherat1,3
Background: Cushing syndrome due to PPNAD is the main endocrine disorder of CNC, an autosomal dominant multiple neoplasia caused by germline inactivating mutations of the subunit type 1A (PRKAR1A) of the protein kinase A (PKA). In addition, germline inactivating mutations in the gene encoding phosphodiesterase 11A (PDE11A) have been identified in patients with PPNAD.
Aim of the study: To investigate the role of PDE11A genetic alterations in patients with CNC and PRKAR1A mutations.
Materials and methods: One hundred and fifty patients with CNC and PRKAR1A mutation (74 index cases) were investigated. PPNAD was the main endocrine manifestation: 104/150 (69.3%). DNA from 279 healthy volunteers examined to rule out endocrine tumors was also studied. Sequencing of the PDE11A4 20 coding-exons (323) was performed.
Results: In the CNC patients 38/150 (25.3%) PDE11A mutations were found: 31/38 missense and 7/38 nonsense mutations. In the controls 19/279 PDE11A4 missense mutations (6.8%) were observed but no nonsense mutations. The frequency of PDE11A4 mutations was significantly higher in CNC patients than in controls (χ2=29, P<0.00001). The frequency of PDE11A4 mutations was significantly higher in patients with PPNAD than in patients without PPNAD (30 vs 13%, χ2=5.3, P=0.025). There was a tendency for a younger age at diagnosis of Cushing syndrome in patients with PDE11A4 mutation. The frequency of PDE11A4 mutations was significantly higher in the male patients with testicular tumors (LCCSCT) than in patients without (47 vs 22%, χ2=5.5, P=0.025). No association was observed with cardiac myxoma, thyroid tumors, lentiginosis nor acromegaly.
Conclusions: The higher frequency of PDE11A mutations in CNC patients with PRKAR1A mutations and PPNAD or LCCSCT (compared to controls and CNC patients without these tumors) suggests a role of PDE11A in the genetic predisposition to adrenal Cushing syndrome and testicular tumors, as previously proposed. This suggests the possibility that PRKAR1A and PDE11A4 mutations act additively or even in synergy in CNC.