1. DEFINITION A case or a family with hormone-secreting or hormone- producing neoplasia in multiple tissue types It encompasses several types of etiology, varying from two coincidental tumors to complex patterns of tumor types. Certain patterns of tumor types recur reproducibly among unrelated cases or among unrelated families MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

2. SIX MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES AND THEIR MAIN CHARACTERISTICS

3. Endocrine Tumors Expressed in Multiple Endocrine Neoplasia Types 1 and 2

4. MEN1-Related Endocrine Tumors And Their Prevalence Parathyroid Adenomas (90%) GEP Gastrinoma (40%) Insulinoma (10%) Others (VIPoma, PPoma, SSoma, Glucagonoma) (2%) Non-functioning (20%) Anterior Pituitary Functioning: PRLoma (20%) GH-, GH/PRL-, TSH-, ACTH-secreting, or Non-functioning (17%) Foregut Carcinoids Thymic (2%) Bronchial (2%) Gastric (ECLoma) (10%) Adrenal Gland Non-functioning (20%)

5. MEN1-Related Non-Endocrine Tumors And Their Prevalence Cutaneous Tumors Lipomas (30%) Facial angiofibromas (85%) Collagenomas (70%) Central Nervous System Meningiomas (5%) Ependymomas (1%) Others Leyomiomas (10%)

7. Familial Hypocalciuric Hypercalcemia (FHH)/Neonatal Severe Hyperparathyroidism (NSHPT)/Neonatal Hyperparathyroidism (NHPT)/Autosomal Dominant Moderate Hyperparathyroidism (ADMH) Hyperparathyroidism- Jaw Tumors (HPT-JT) Familial Isolated Primary Hyperparathyroidism (FIHPT) Multiple Endocrine Neoplasia Type 2A (MEN2A) Multiple Endocrine Neoplasia Type 1 (MEN1) Clinical syndromes of familial primary hyperparathyroidism

8. MOLECULAR DIAGNOSIS CAN NOW BE INCORPORATED INTO THE MANAGEMENT OF PATIENTS WITH THESE AUTOSOMAL DOMINANT SYNDROMES however VALUE OF GENETIC INFORMATION IN THE CONTEXT OF CLINICAL SCREENING AND EARLY SURGERY VARIES AMONG THESE DISORDERS

9. Inactivating HRPT2 /oncusuppressor 1q25-q31HPT-JT/607393 Inactivating CaSR 3q13.3-q21FHH-NSHPT/NHPT 145980-239200 Atypical inactivating CaSR 3q13.3-q21 ADMH/601199 Inactivating for MEN1, HRPT2, and CaSR genes MEN1 /oncosuppressor, HRPT2 /oncosuppressor, CaSR and still unknown genes 11q13, 1q25-q31, 3q13.3-q21/2p13.3-14, and still unknown loci FIHPT/145000 Activating RET /proto-oncogene 10q11.1MEN2A/171400 Inactivating MEN1 /oncosuppressor 11q13MEN1/131100 Type of germline mutation Gene/activity Chromosomal localization Syndrome/OMIM#° Chromosomal localization and genetic defects underlying each familial form of hereditary hyperparathyroidism Gene Mutation (%) 90 98 10-18 100 N.R. 60

10. ONE DECADE FOLLOWING THE CLONING OF THE MEN1 GENE 1336 mutations and 24 polymorphisms MUTATIONS (in 1091 families) POLYMORPHISMS Adapted from: JCEM 92:3389, 2007; Hum Mutat 29:22, 2008 >70% lead to truncated forms of menin 4% are large deletions Four occur frequently No genotype/phenotype correlations Therefore the screening becomes time consuming, arduous and expensive 12 in the coding regions 9 in the introns 3 in untranslated regions Useful for segregation analysis if MEN1 mutation is not found

11. CHARACTERISTICS OF THE MUTATED MEN1 CASES Sporadic cases: 6-10% had MEN1 mutations Familial cases: 90-94% had MEN1 mutations A mutation is most likely when one typical endocrine tumor and at least one of the following is present: 1. A first degree relative with a major endocrine tumor 2. Age of onset less than 30 yr 3. Multiple pancreatic tumors 4. Parathyroid hyperplasia Adapted from: JCEM 92:3389, 2007; Exp Clin Endocrinol Diabetes 115:509, 2007; Hum Mutat 29:22, 2008

12. CAN GENE TESTING DECREASE THE MORBIDITY AND MORTALITY ASSOCIATED WITH MEN1? Asymptomatic gene carriers will NOT be treated with prophylactic or early surgery Familial screening: 1.In children by the first decade 2.Asymptomatic gene carriers are closely followed 3.A negative test precludes from periodic screening The identification of MEN1 mutations is of help in clinical management of patients and their families and in life-planning decisions of affected patients

13. J Clin Endocrinol Metab, September 2012, 97(9):2990–3011

14. Basis for a diagnosis of MEN1 in individuals Adapted from: JCEM 97:2990, 2012

15. Suggested biochemical and radiological screening in individuals at high risk of developing MEN1 Adapted from: JCEM 97:2990, 2012

16. An approach to screening in MEN1 Adapted from: JCEM 97:2990, 2012

17. MEN syndromes and their characteristic tumors and associated genetic abnormalities Adapted from: JCEM 97:2990, 2012

18. SCHEMATIC REPRESENTATION OF THE RET TYROSINE KINASE RECEPTOR

19. ALL THE MEN2 VARIANTS ARE CAUSED BY RET GERMLINE MUTATION Stratification risk according to RET mutation codons 883, 918, 922 (exons 15, 16) MEN2B highest risk for aggressive MTC; operated on within the first 6 months codons 611, 618, 620, 634 (exons 10, 11) MEN2A/FMTC intermediate risk; thyroidectomy performed before the age of 5 yr. codons 609, 768, 790, 791 804, 891 (exons 10, 13, 14, 15) MEN2A/FMTC lower risk; operated on at a later stage

20. American Thyroid Association risk level and timing of prophylactic thyroidectomy in MEN2A* Adapted from: Surgery 148:1302, 2010

21. Recommendations for screening procedures and time of prophylactic thyroidectomy.* Adapted from: Best Practice and Research Clinical Endocrinology and Metabolism 24:371, 2010

22. Graphic representation of the nuclear interactions of p27 Adapted from: Neuroendocrinology 2010

23. Clinical and molecular characteristics of the identified CDKN1B/p27 variants Adapted from: Neuroendocrinology 2010

24. Organizzazione del Centro di Riferimento T.E.E. della Regione Toscana nell’Ambito dell’A.O.U.C. Rapporti costanti con i pazienti ed i familiari per follow-up e risposta dei test genetici SOD Patologia Chirurgica Reparto di Degenza SOD Medicina Interna 2 Front line Ambulatorio Day Hospital Laboratorio