Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort

Abstract

Aim: To study the prevalence of germline mutations of the aryl-hydrocarbon receptor interacting protein (AIP) gene in a large cohort of patients seen in the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), UK, with apparently sporadic pituitary adenomas, who were either diagnosed or had relevant clinical manifestations by the age of 40 years. Patients: We prospectively investigated all patients who were seen at Oxford University Hospital, OCDEM, and a tertiary referral centre, between 2012 and 2013, and presented with pituitary tumours under the age of 40 years and with no family history: a total of 127 patients were enrolled in the study. Methods: Leukocyte-origin genomic DNA underwent sequence analysis of exons 1-6 and the flanking intronic regions of the AIP gene (NM_003977.2), with dosage analysis by multiplex ligation-dependent probe amplification. Results: 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. Definite pathogenetic mutations were seen in 2/4 variants, comprising 4.2% of patients with acromegaly. Conclusions: This prospective cohort study suggests a relatively low prevalence of AIP gene mutations in young patients with apparently sporadic pituitary adenomas presenting to a tertiary pituitary UK centre. Those with somatotroph macroadenomas have a higher rate of AIP mutation. These findings should inform discussion of genetic testing guidelines.

Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma

“…The prevalence of GNAS mutations were comparable with the previous report of Japanese acromegalic patients [18]. On the other hand, although it has been reported that AIP mutations in sporadic Japanese patients with somatotropinoma may be extremely rare [19], our cohort study showed a comparable prevalence of AIP mutations (4.9%) to that of European patients [19][20][21]. In addition, our results suggest that the prevalence of GPR101 mutation is rare in Japanese patients.…”

The genetic background of acromegaly

“…AIP mutations can also be identified in sporadic acromegaly cases [6, 37–41]. Considering patients without any age limitations, only about 4% of the apparently sporadic patients will harbor a germline AIP mutation [40].…”

Prevalence of AIP mutations in a series of Turkish acromegalic patients: are synonymous AIP mutations relevant?

“…In sporadic acromegaly, overall AIP mutation prevalence was reported as 3.1-16 % [10][11][12]26]. In selected acromegalic populations such as patients diagnosed with a macroadenoma before the age of 30, the ratio is reported as 2.3 or 13.3 % in different studies [18,27] or patients diagnosed before the age 40 as 4 % [28] or patients with resistance to SSA as 4 % [24]. These studies were carried out in patients from different regions of Europe.…”