AIP variants were detected in 3% of the 127 patients, comprising four of 48 patients with acromegaly (8%), 0 of 43 with prolactinomas, 0 of the 20 patients with non-functioning adenomas, 0 of 15 with corticotroph adenomas and 0 of one with a thyrotroph adenomas.
AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas.
Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age.
This unique disturbance of the cAMP-PDE pathway observed in the majority of <i>AIP</i>-mutation positive adenomas could contribute to their well-described poor response to somatostatin analogs and may support a role in tumorigenesis.
In addition, we summarize the clinical features of IFS families with AIP mutations: The adenomas are diagnosed at a young age and are larger than in IFS patients without AIP mutations or in sporadic somatotropinomas, indicating more aggressive disease.
No significant difference was observed in AIP mRNA expression between tumors with low or high AIP protein expression suggesting post-transcriptional regulation. miR-34a was highly expressed in low AIP protein samples compared high AIP protein adenomas and miR-34a levels were inversely correlated with response to SSA therapy. miR-34a inhibited the luciferase-AIP-3'UTR construct, suggesting that miR-34a binds to AIP-3'UTR.
AIP mutations were detected in 16 (3.6%) of the 443 patients, comprising six of 148 patients with acromegaly (4.1%), six of 132 patients with prolactinomas (4.5%), one of 113 patients with nonfunctioning adenomas (0.9%), three of 44 patients with corticotropic adenomas (6.8%), and none of the six patients with thyrotropic adenomas.
Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors.
Patients with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are characterized by young-onset somatotroph or lactotroph macroadenomas, while in the other, larger group of FIPA patients with typically adult-onset disease and more varied adenoma types, no causative gene(s) has been identified.
AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur.