SUN-447 Screening of Genetic Alterations in Patients with Giant Prolactinomas

Prolactinomas are the most common pituitary adenomas. The majority occurs sporadically in women at childbearing age. Only 5% have a genetic etiology usually in the context of MEN1 syndrome, Carney Complex or McCune-Albright Syndrome. Mutations of the AIP gene (aryl hydrocarbon receptor interacting protein) are also associated with familial cases of pituitary adenomas, however with low penetrance (20-23%) (1). Specific characteristics of pituitary adenomas, as the size of the tumor, age of onset and the existence of multiples cases in the same family, may predict a genetic origin. Giant prolactinomas are the largest prolactinomas and contrasting with micro and macroprolactinomas they are found mainly in young males. We wondered whether these tumors have a genetic etiology. With this purpose in mind, we studied four male patients, aged 26 to 42 years who presented pituitary adenomas (>4 cm in diameter) with prolactin levels above 4000 ng/ml (normal 10-21 ng/ml). Diagnosis of large pituitary adenomas in young males, from the same small community, pointed to a possible common genetic origin. After extraction of peripheral blood DNA, samples were analyzed by Next Generation Sequencing (NGS) and using the TruSightCancer Gene Set (Illumina) methodology. Investigation of significant deletions and/or duplications was performed using the MLPA (Multiplex ligation-dependent probe amplification) technique. No mutation in the MEN1 gene was detected. A mutation of the AIP gene c.47G>A expecting to lead to a substitution of arginine by histidine at position 16 (p.Arg16His) of the aryl hydrocarbon receptor interacting protein, was identified in two patients. Both inherited the mutation from their fathers. The mutation was not found in other members of their families. The prolactin level in one of the affected fathers was 240 ng/ml and the CT scan showed a microprolactinoma of 6 mm. No pituitary alterations were found in the other progenitor harboring the mutation. This variant of the gene AIP (p.Arg16His) is described in a database of 1000 Genomes and ExAC with an allelic frequency in the European population of 0.3%. Insilico analysis and the information available in the literature as well as in databases are not concordant regarding the pathogenicity of this alteration in AIP gene. However, the familial segregation study in our patients is in favor of its pathogenicity. In conclusion, the variant of the AIP gene identified in the present study may be associated with giant prolactinomas. 1)Hernández-Ramírez LC et al.; International FIPA Consortium. Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab 2015;100:E1242-4. 2) Aflorei ED et al.; In vivo bioassay to test the pathogenicity of missense human AIP variants. J Med Genet 2018;0:1-8. Doi:10.1136/jmedgenet-2017-105191