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This version published online on January 23, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2513
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Submitted on November 15, 2006
Accepted on January 12, 2007

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, and Albert Beckers*

Departments of Endocrinology (A.F.D., A.B.) and Molecular Genetics (J-F.V.B., V.B.), Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium.; Laboratory of Cancer Genetics (S-K.K, B-T.T.), and Laboratory of Germline Modification and Cytogenetics (S.K.K.), Van Andel Research Institute, Grand Rapids, Michigan 49503, U.S.A.; Department of Experimental Medicine (M-L.J-R.), University of L'Aquila, and Neuromed, Istituto di Ricovero e Cura a Carattere Scientifico, 86077 Pozzili, Italy.; Division of Endocrinology (L.A.N.), University of Brasilia, Brasilia, Brazil.; Neuroscience Institute (M.A.G., A.Ba.), and TCba Salguero Laboratory (A.O., D.D. A.S.), Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina., Department of Endocrinology (A.M.), Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France., Department of Endocrinology (P.E.), Centre Hospitalier Regional, 45032 Orléans, France.; Department of Genetics (A-P.G-R.), Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université René Descartes-Paris 5 and INSERM U772, Collège de France, Paris, France.; Department of Clinical Science (G.T.), Endocrine Section, University of Rome La Sapienza, 00100 Rome, Italy.; Departments of Endocrinology (G.R.) and Human Genetics (A.Ca., O.S.), Centre Hospitalier Universitaire de Lyon, 69495 Lyon, France.; Laboratoire de Biochimie Biologie Moléculaire (A.B.), Centre Hospitalier Universitaire Conception, 13385 Marseille, France.; Section of Endocrinology (W.D.H.), Department of Internal Medicine, Erasmus Medical Centre, 3015 GD Rotterdam, Netherlands.; Department of Endocrinology (A.P.), Centre Hospitalier Universitaire de Besançon, 25030 Besançon, France.; Division of Endocrinology and Metabolism (E.C.), Department of Internal Medicine, University of Turin, 10100 Turin, Italy.; Department of Endocrinology (B.E.), Centre Hospitalier Universitaire de Saint Etienne, 42055 Saint Etienne, France.; Unit of Endocrinology (P.L.), Centre Hospitalier Régional Universitaire Tours, 37044 Tours Cedex 9, France.; Department of Endocrinology (B.G.), Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut Lévéque, 33604 Pessac, France.; Department of Endocrinology (O.C.), Centre Hospitalier Universitaire Grenoble, 38043 Grenoble, France.; Austral University Hospital (M.I.S., N.G.B.), Avenida Pte Peron 1500, Buenos Aires, Argentina.; Department of Endocrine and Metabolic Disease (X.B.), Centre Hospitalier d'Université Cochin, 75014 Paris, France.; Pirovano General Acute Hospital (G.S.), Avenida Monroe 3551, Buenos Aires, Argentina.; Department of Molecular and Clinical Endocrinology and Oncology (A.Co.), University "Federico II", 80131 Naples, Italy.; Department of Internal Medicine and Endocrine Sciences (P.F.), University of Perugia, 06100, Perugia, Italy.; Endocrinological Clinic Marc Linquette (J-L.W.), Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.; Department of Endocrinology and Metabolic Disorders (P.C.), University Hospital Rangueil, 31403 Toulouse Cedex, France.; Department of Endocrinology and Metabolic Diseases (J-L.S.), Centre Hospitalier Universitaire de Nice, 06202 Nice Cedex 3, France.; Departments of Internal Medicine and Endocrinology (F.A.), Hôpital du Cluzeau, 87042 Limoges, France.; Department of Endocrinology (C.F.M.), Hospital de la Ribera, 46600 Alzira, Valencia, Spain.; Department of Endocrinology (F.C.), Ospedale San Luca, Istituto Auxologico Italian, IRCCS, Milan, Italy.; Third Department of Medicine (V.H.), First Medical Faculty, Charles University, 128 02 Prague 2, Czech Republic.; Division of Endocrinology (D-C.L-C), Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil 21949-590.; Department of Endocrinology (V.R.), Centre Hospitalier Universitaire de Angers, 49033 Angers, France; Laboratoire Interactions Cellulaires Neuroendocriniennes (T.B.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 6544, Institut Fédératif Jean Roche, Faculté de Médecine, Université de la Méditerranée, 13284 Marseille Cedex 7, France

* To whom correspondence should be addressed. E-mail: albert.beckers{at}chu.ulg.ac.be.

Context: An association between germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations and pituitary adenomas was recently demonstrated.

Objective: Assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).

Design: Multicenter, international, collaborative study

Setting: Thirty-four University endocrinology and genetics departments in nine countries

Patients: Affected members from each FIPA family. Relatives of patients with AIP mutations underwent AIP sequence analysis.

Outcome Measure: Presence/absence and description of AIP gene mutations.

Intervention: None

Results: 73 FIPA families identified with 156 patients with pituitary adenomas; FIPA cohort evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families harbored 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 versus mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed growth hormone/prolactin-secreting tumors, prolactinomas and non-secreting 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. While 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.
Key words: Pituitary • adenoma • familial • AIP • dioxin




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