Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families

Adrian F Daly, Jean-François Vanbellinghen, Sok Kean Khoo, Marie-Lise Jaffrain-Rea, Luciana A Naves, Mirtha A Guitelman, Arnaud Murat, Philippe Emy, Anne-Paule Gimenez-Roqueplo, Guido Tamburrano, Gérald Raverot, Anne Barlier, Wouter De Herder, Alfred Penfornis, Enrica Ciccarelli, Bruno Estour, Pierre Lecomte, Blandine Gatta, Olivier Chabre, María Isabel Sabaté, Xavier Bertagna, Natalia Garcia Basavilbaso, Graciela Stalldecker, Annamaria Colao, Piero Ferolla, Jean-Louis Wémeau, Philippe Caron, Jean-Louis Sadoul, Adriana Oneto, Françoise Archambeaud, Alain Calender, Olga Sinilnikova, Carmen Fajardo Montañana, Francesco Cavagnini, Vaclav Hana, Angela Solano, Dreanina Delettieres, Douglas C Luccio-Camelo, Armando Basso, Vincent Rohmer, Thierry Brue, Vincent Bours, Bin Tean Teh, Albert Beckers
Journal of Clinical Endocrinology and Metabolism 2007, 92 (5): 1891-6

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.

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