MEN1 Disease Occurring Before 21 Years Old: A 160-Patient Cohort Study From the Groupe d'étude des Tumeurs EndocrinesThe Journal of Clinical Endocrinology & Metabolism


P. Goudet, A. Dalac, M. Le Bras, C. Cardot-Bauters, P. Niccoli, N. Lévy-Bohbot, H. du Boullay, X. Bertagna, P. Ruszniewski, F. Borson-Chazot, B. Vergès, J. L. Sadoul, F. Ménégaux, A. Tabarin, J. M. Kühn, P. d'Anella, O. Chabre, S. Christin-Maitre, G. Cadiot, C. Binquet, B. Delemer
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MEN1 disease occurring before 21 years old. A 160patient cohort study from the GTE (Groupe d’étude des Tumeurs Endocrines).

P. Goudet1, A. Dalac2, A. Le Bras 3, C. Cardot-Bauters4, P. Niccoli5,

N. Lévy-Bohbot2, H. du Boullay6, X. Bertagna7, P. Ruszniewski8,

F. Borson-Chazot9, B. Vergès10, JL. Sadoul11, F. Ménégaux12, A. Tabarin13,

JM. Kühn14, P. d’Anella15, O. Chabre16, S. Christin-Maitre17, G. Cadiot18,

C. Binquet19, B. Delemer2 1: Centre Hospitalier Universitaire de Dijon, Endocrine Surgery, Dijon, France; INSERM U866, Dijon,

France; University of Burgundy, Dijon, France. 2: Service d’Endocrinologie et Maladies Métaboliques,

Centre Hospitalier Universitaire, Hôpital Robert Debré, Reims, France, 3: Clinique d’Endocrinologie,

Centre Hospitalier Universitaire, Nantes, France, 4: Service de Médecine Interne et Endocrinologie,

Clinique Marc Linquette, Centre Hospitalier Régional et Universitaire, Lille, France, 5: Service d’Oncologie

Médicale, Institut Paoli-Calmettes, APHM, Université Aix-Marseille, Marseille, France, 6: Service d’Endocrinologie, Centre Hospitalier de Chambéry, Chambéry, France, 7: Département d’Endocrinologie, Hôpital Cochin, Université Paris Descartes, Paris, France, 8: Service de

Gastroentérologie-pancréatologie, APHP, Hôpital Beaujon et Université Paris 7 Denis Diderot, Clichy,

France, 9: Fédération d’Endocrinologie, Hospice Civils de Lyon et Université Lyon 1. Groupement

Hospitalier Est. Lyon, France, 10: Service d’Endocrinologie, Diabète et Maladies métaboliques, Centre

Hospitalier Universitaire de Dijon, Hôpital du Bocage, Dijon, France, 11: Département d’Endocrinologie,

Hopital de l’Archet, Nice, France, 12: Service de Chirurgie Générale, Viscérale et Endocrinienne,

Groupement Hospitalier Universitaire Est, Hôpital de la Pitié, Paris, France, 13: Service d’Endocrinologie,

Centre Hospitalier Universitaire, Hôpital du Haut Levêque, Pessac, France, 14: Département d’Endocrinologie, Hôpital Universitaire de Rouen. Rouen, France, 15: Service d’Endocrinologie, Centre

Hospitalier d’Avignon, Avignon, France, 16: Service d’Endocrinologie, Diabète et Maladies métaboliques,

Centre Hospitalier Universitaire de Grenoble, Hôpital Michalon, Grenoble, France, 17 : Service d’Endocrinologie, Centre Hôpitalier Universitaire. Hôpital St-Antoine, Paris, France, 18: Service d’HépatoGastro-Entérologie et de Cancérologie Digestive, Centre Hospitalier Universitaire, Hôpital Robert Debré,

Reims, France, 19: INSERM, CIC1432, Dijon, France; Centre Hospitalier Universitaire de Dijon, CIC, module épidémiologie clinique / essais cliniques, Dijon, France; INSERM U866, Dijon, France. Key items: multiple endocrine neoplasia, young patients, screening, surgery.

Background: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case-reports.

Objective: Improve knowledge of MEN1 natural history before 21 years old.

Methods:Descriptionof first symptomsoccurringbefore 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a groupof 160 patients extracted from the “Grouped’étude des Tumeurs Endocrines”

MEN1 cohort.

Results: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), non-secreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%) and malignant thymic-NET in one (1%). Hyperparathyrodismwas the first lesion in 90 cases (56%). The

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.

Copyright © 2015 by the Endocrine Society

Received September 26, 2014. Accepted January 9, 2015.


O R I G I N A L A R T I C L E doi: 10.1210/jc.2014-3659 J Clin Endocrinol Metab 1

The Endocrine Society. Downloaded from by [${individualUser.displayName}] on 16 March 2015. at 11:48 For personal use only. No other uses without permission. . All rights reserved. first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n9, 16%), hyperparathyroidism (n38, 31%), gastrinoma (n1, 33%), NSPT (n5, 36%), and all cases of insulinoma, adrenal tumors and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases.

Conclusions: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidismwas the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is aninherited disease that predisposes carriers to primary hyperparathyroidism (pHPT), endocrine enteropancreatic tumors, pituitary adenomas, adrenal and thymic/bronchial neuroendocrine tumors (th-NET/br-NET).

MEN1 disease may display various clinical associations, and the criteria for diagnosiswere established first inGubbio (Italy) and then regularly updated (1–4). MEN1 disease is usually described as an autosomal dominant cancer syndrome with a very progressive but finally high penetrance during the lifespan (2, 5, 6). TheMEN1 gene located on chromosome 11q13 is considered as tumor suppressor, given the loss of heterozygoty (LOH) in MEN1related tumors DNA (7, 8).MEN1 gene encodes menin, a 610 amino acid protein expressed in all tissues tested (9, 10). Menin interacts with a large number of intracellular molecules, including transcriptional factors, cytoskeletal components, and proteins involved in the control of DNA replication (9–12). Because of its lowandprogressive penetrance, MEN1 disease has been poorly studied during childhood and adolescence. Only case-reports are available (1, 13–22). This lack of data prompted us to carry out a new study focused on young MEN1 patients belonging to the GTE cohort (Groupe d’étude des Tumeurs Endocrines) and presenting any clinical symptoms, and/or biological and/or imaging changes before the age of 21. The aims of this study were to describe the natural history of