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Aryl Hydrocarbon Receptor-Interacting Protein Gene Mutations in Familial Isolated Pituitary Adenomas: Analysis in 73 Families

Departments of Endocrinology (A.F.D., A.Be.) and Molecular Genetics (J.-F.V., V.B.), Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; Laboratory of Cancer Genetics (S.K.K., B.T.T., D.C.L.-C.), and Laboratory of Germline Modification and Cytogenetics (S.K.K.), Van Andel Research Institute, Grand Rapids, Michigan 49503; 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 70910-900; Neuroscience Institute (M.A.G., A.Bas.), and TCba Salguero Laboratory (A.O., D.D., A.S.), Faculty of Medicine, University of Buenos Aires, C117AE1 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 Institut National de la Santé et de la Recherche Médicale U772, Collège de France, 75908 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.Bar.), Centre Hospitalier Universitaire Conception, 13385 Marseille, France; Section of Endocrinology (W.D.H.), Department of Internal Medicine, Erasmus Medical Centre, 3015 GD Rotterdam, The 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.), B1629AHJ 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.), 1430 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 Italiano, Instituto di Ricovero e Cura a Carattere Scientifico, 20149 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; and 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

Address all correspondence and requests for reprints to: Albert Beckers, M.D., Ph.D., Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium. 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 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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