Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

Adrian F Daly , Maria A Tichomirowa , Patrick Petrossians , Elina Heliövaara , Marie-Lise Jaffrain-Rea , Anne A. Barlier (1) , Luciana A Naves , Tapani Ebeling , Auli Karhu , Antti Raappana , Laure Cazabat , Ernesto de Menis , Carmen Fajardo Montañana , Gerald Raverot , Robert J Weil , Timo Sane , Dominique Maiter (2) , Sebastian Neggers , Maria Yaneva , Antoine Tabarin , Elisa Verrua , Eija Eloranta , Arnaud Murat , Outi Vierimaa , Pasi I Salmela , Philippe Emy , Rodrigo A Toledo (3) , Maria Isabel Sabaté , Chiara Villa (4, 5) , Marc Popelier (6) , Roberto Salvatori , Juliet Jennings , Angel Ferrandez Longás , José Ignacio Labarta Aizpún , Marianthi Georgitsi , Ralf Paschke (7) , Cristina Ronchi , Matti Valimaki , Carola Saloranta , Wouter de Herder , Renato Cozzi , Mirtha Guitelman , Flavia Magri , Maria Stefania Lagonigro , Georges Halaby , Vinciane Corman , Marie-Thérèse Hagelstein , Jean-François Vanbellinghen , Gustavo Barcelos Barra , Anne-Paule Gimenez-Roqueplo , Fergus J Cameron , Françoise Borson-Chazot , Ian Holdaway , Sergio P A Toledo , Günter K Stalla , Anna Spada , Sabina Zacharieva , Jerome Bertherat (8) , Thierry Brue (1) , Vincent Bours , Philippe Chanson (9, 10) , Lauri A Aaltonen , Albert Beckers

1 CRN2M - Centre de recherche en neurobiologie - neurophysiologie de Marseille
2 Endocrinology
3 Endocrine Genetics Unit (LIM-25), Endocrinology, Department of Internal Medicine
4 U894 - Centre de Psychiatrie et Neurosciences
5 Department of neuropathology
6 Pharmacologie Endocrinienne
7 Department for Internal Medicine, Endocrinology and Nephrology
8 Pôle Endocrinologie-Diabétologie Adultes-Enfants
9 Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique
10 Service d'Endocrinologie et Maladies de la reproduction

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Domaines: Biochimie [q-bio.BM]

Adrian F Daly, Maria A Tichomirowa, Patrick Petrossians, Elina Heliövaara, Marie-Lise Jaffrain-Rea, et al.. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.. Journal of Clinical Endocrinology and Metabolism, 2010, 95 (11), pp.E373-83. ⟨10.1210/jc.2009-2556⟩. ⟨hal-00625303⟩