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DEFINITION

This article provides an overview of multiple endocrine neoplasia syndromes, including their definition, types, characteristics, and associated genetic abnormalities. It discusses the prevalence, clinical syndromes, molecular diagnosis, and the value of genetic information in managing these autosomal dominant syndromes. The article also suggests screening approaches and highlights the importance of gene testing in reducing morbidity and mortality.

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DEFINITION

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  1. MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES • 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

  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%)

  6. Clinical syndromes of familial primary hyperparathyroidism Multiple Endocrine Neoplasia Type 1 (MEN1) Multiple Endocrine Neoplasia Type 2A (MEN2A) 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)

  7. 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

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

  9. ONE DECADE FOLLOWING THE CLONING OF THE MEN1 GENE 1336 mutations and 24 polymorphisms MUTATIONS (in 1091 families) POLYMORPHISMS • 12 in the coding regions • 9 in the introns • 3 in untranslated regions Useful for segregation analysis if MEN1 mutation is not found • >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 Adapted from: JCEM 92:3389, 2007; Hum Mutat 29:22, 2008

  10. 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: • A first degree relative with a major endocrine tumor • Age of onset less than 30 yr • Multiple pancreatic tumors • Parathyroid hyperplasia Adapted from: JCEM 92:3389, 2007; Exp Clin Endocrinol Diabetes 115:509, 2007; Hum Mutat 29:22, 2008

  11. 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: • In children by the first decade • Asymptomatic gene carriers are closely followed • 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

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

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

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

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

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

  17. SCHEMATIC REPRESENTATION OF THE RET TYROSINE KINASE RECEPTOR

  18. ALL THE MEN2 VARIANTS ARE CAUSED BY RET GERMLINE MUTATION • Stratification riskaccording 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/FMTClower risk; operated on at a later stage

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

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

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

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

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

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