CONTEXT: An association between germline aryl hydrocarbon receptor-interacting 
protein (AIP) gene mutations and pituitary adenomas was recently shown.
OBJECTIVE: The objective of the study was to assess the frequency of AIP gene 
mutations in a large cohort of patients with familial isolated pituitary adenoma 
(FIPA).
DESIGN: This was a multicenter, international, collaborative study.
SETTING: The study was conducted in 34 university endocrinology and genetics 
departments in nine countries.
PATIENTS: Affected members from each FIPA family were studied. Relatives of 
patients with AIP mutations underwent AIP sequence analysis.
MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations 
were the main outcome measures.
INTERVENTION: There was no intervention.
RESULTS: Seventy-three FIPA families were identified, with 156 patients with 
pituitary adenomas; the FIPA cohort was evenly divided between families with 
homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 
germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, 
Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described 
previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a 
younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative 
subjects. Somatotropinomas predominated among FIPA families with AIP mutations, 
but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting 
adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those 
with familial somatotropinomas were negative for AIP mutations.
CONCLUSIONS: AIP mutations, of which nine new mutations have been described 
here, occur in approximately 15% of FIPA families. Although pituitary tumors 
occurring in association with AIP mutations are predominantly somatotropinomas, 
other tumor types are also seen. Further study of the impact of AIP mutations on 
protein expression and activity is necessary to elucidate their role in 
pituitary tumorigenesis in FIPA.