Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients.
BACKGROUND
Germline mutations of the AIP (aryl-hydrocarbon receptor interacting protein) gene are associated with a predisposition to pituitary adenomas. Such mutations are found in about half of patients with familial acromegaly, but penetrance is incomplete.


OBJECTIVE
We studied the prevalence of germline AIP mutations in a large cohort of patients with apparently sporadic pituitary adenomas.


METHODS
A total of 443 patients with pituitary adenomas of all histotypes, who had no familial history of pituitary adenomas or multiple endocrine neoplasia and who were examined at Bicêtre University Hospital, a tertiary referral center, between 2007 and 2010, were enrolled in this prospective study.


METHODS
The entire coding sequence of the AIP gene was screened for germline mutations. A subgroup of patients were screened for large deletions or duplications of the AIP and MEN1 genes by multiplex ligation-dependent probe amplification.


RESULTS
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. This is the first report of an AIP mutation leading to a truncated protein in a patient with Cushing's disease. Patients with AIP mutation were younger at diagnosis (24.1 vs. 42.8 yr) and had predominantly macroadenoma (12 of 16). No mutations were found in patients diagnosed after age 40 yr, whereas the prevalence before this age was 7.2% (16 of 222). Studies of seven of the AIP-mutated patients' families showed that one asymptomatic parent carried the same mutation in each case.


CONCLUSIONS
This large prospective cohort study confirms the very low prevalence of germline AIP mutations in patients with apparently sporadic pituitary adenomas. We propose to limit AIP testing to patients diagnosed before age 40 yr with apparently sporadic large pituitary adenomas, especially GH- or PRL-secreting adenomas.
Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, F-94275 Le Kremlin-Bicêtre, France.
Laure
L
Cazabat
Jérôme
J
Bouligand
Sylvie
S
Salenave
Michèle
M
Bernier
Stephan
S
Gaillard
Fabrice
F
Parker
Jacques
J
Young
Anne
A
Guiochon-Mantel
Philippe
P
Chanson
D049913:ACTH-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000172:Acromegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D005260:Female; D005602:France; D056726:Genetic Association Studies; D006785:Hospitals, University; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D012727:Sex Characteristics; D047368:Tumor Burden; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein