Do single nucleotide polymorphisms in the AIP and MEN1 genes predispose individuals to the development of familial isolated pituitary adenomas?

Abstract

Pituitary adenomas (PA) are quite common and can occur in a familial setting such as MEN1 and Carney complex (CNC). Recently, germline mutations in the AIP gene have been found in 16% of all patients who were diagnosed with PA secreting GH. We here report a black family with non-MEN-1/CNC familial isolated PA in an attempt to identify predisposed individuals. Clinical characterization of such families may lead to the discovery of new genetic syndromes. A 55 yo black man was admitted to the UMMC with a 6 mo h/o recurrent headaches and diplopia. The patient denied any h/o renal calculi or MEN-1/CNC associated features in himself and his family members. MRI of the pituitary showed a 5.5×3.6×4cm sellar mass with suprasellar extension (Fig. 1,2). Biochemical testing revealed 2°AI, hypothyroidism, hypogonadism, and GH deficiency. Prolactin and alpha subunit were normal. After glucocorticoid and thyroid hormone replacement, he underwent TSS. Final pathology revealed a null cell PA with immunohistochemical results negative for anterior pituitary hormones. The index patient had a brother with a PA who presented similarly at the age of 50, and two cousins. To elucidate the pathogenesis of PA in this family and to help identify predisposed family members, we conducted a germline mutation analysis of the AIP and MEN1 genes in the index patient. No germline mutations in these genes were found but several SNPs (AIP: exon 2 + 5; MEN1: exon 9 + 10, 5' UTR). To our knowledge, this is the first black family reported with non-MEN1/CNC familial isolated PA. In at least 10% of patients with clinical features of MEN1, no germline mutations in the MEN1 gene are identified. Therefore, there is still a remote chance that our family has an atypical MEN1 variant. In contrast to patients reported with germline mutations in the AIP gene, our patient and family members had hormonally inactive PA and SNPs in the AIP and MEN1 gene. SNPs in various genes, here in the AIP and MEN1 gene, may increase the predisposition of individuals to develop certain tumors, and in the family reported here, PA.