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Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma - results from a large patient cohort.Dénes, J; Swords, F; Rattenberry, E; Stals, K; Owens, M; Cranston, T; Xekouki, P; Moran, L; Kumar, A; Wassif, C; et al. (2014-12-12)Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. Objective: To study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: University hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL. Outcome: Genetic screening and clinical characteristics. Results: Eleven germline mutations (5 SDHB, 1 SDHC, 1 SDHD, 2 VHL and 2 MEN1) and four variants of unknown significance (2 SDHA, a SDHB, and a SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in 3 pituitary adenomas and LOH at the MEN1 locus in 2 pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, while mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.