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Clinical Characterization of Familial Isolated Pituitary Adenomas

Departments of Endocrinology (A.F.D., A.Ci., H.V.-S., A.B.) and Neurosurgery (A.S.), Centre Hospitalier Universitaire de Liège, 4000 Liège, Belgium; 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; Department of Endocrinology (V.R.), Centre Hospitalier Universitaire de Angers, 49033 Angers, France; Department of Clinical Science (G.T.), Endocrine Section, University of Rome La Sapienza, 00100 Rome, Italy; Department of Endocrinology (C.B.-C.), Centre Hospitalier Universitaire de Lyon, 69495 Lyon, France; Department of Endocrinology (B.E.), Centre Hospitalier Universitaire de Saint Etienne, 42055 Saint Etienne, France; Division of Endocrinology and Metabolism (E.C.), Department of Internal Medicine, University of Turin, 10100 Turin, Italy; Centre National de la Recherche Scientifique (T.B.), Université de la Méditerranée, 13926 Marseille, France; Department of Internal Medicine and Endocrine Sciences (P.F.), University of Perugia, 06100 Perugia, Italy; Department of Endocrinology (P.E.), Centre Hospitalier Regional, 45032 Orléans, France; Department of Molecular and Clinical Endocrinology and Oncology (A.Co.), University "Federico II", 80131 Naples, Italy; Department of Internal Medicine (E.D.M.), General Hospital, 31100 Treviso, Italy; Unité d’Endocrinologie, Diabétologie et Maladies Métaboliques Centre Hospitalier Régional Universitaire Tours (P.L.), 37044 Tours Cedex 9, France; Department of Endocrinology (F.P.), Centre Hospitalier Universitaire de Besançon, 25030 Besançon, France; Department of Endocrinology (B.D.), Centre Hospitalier Universitaire de Reims, 50192 Reims, France; Service d’Endocrinologie (J.B.), Hôpital Cochin et Institut National de la Santé et de la Recherche Médicale U567, Paris, France; Clinique Endocrinologique Marc Linquette (J.L.W.), Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France; Section of Endocrinology (W.D.H.), Department of Internal Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands; Department of Internal Medicine (B) and Endocrinology (F.A.), Hôpital du Cluzeau, 87042 Limoges, France; Department of Human Genetics (A.Ca.), Hôpital Edouard Heriot, Centre Hospitalier Universitaire de Lyon, 69437 Lyon, France; Department of Endocrinology (A.M.), Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France; and Department of Endocrinology (F.C.), Ospedale San Luca, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico, 20149 Milan, Italy

Address all correspondence and requests for reprints to: Prof. Albert Beckers, M.D., Ph.D., Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium. E-mail: albert.beckers{at}chu.ulg.ac.be.

Context: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC).

Objective: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA).

Design and Setting: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands.

Results: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases.

Conclusions: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing’s disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.

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