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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
SIX MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES
AND THEIR MAIN CHARACTERISTICS
Endocrine Tumors Expressed in Multiple Endocrine
Neoplasia Types 1 and 2
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%)
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%)
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)
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
Chromosomal localization and genetic defects underlying
each familial form of hereditary hyperparathyroidism
Syndrome/OMIM#°
Gene Mutation
(%)
Chromosomal
localization
Gene/activity
Type of germline
mutation
MEN1/131100
90
11q13
MEN1/oncosuppressor
Inactivating
MEN2A/171400
98
10q11.1
RET/proto-oncogene
Activating
10-18
3q13.3-q21
CaSR
Inactivating
ADMH/601199
100
3q13.3-q21
CaSR
Atypical inactivating
HPT-JT/607393
60
1q25-q31
N.R.
11q13, 1q25-q31,
3q13.3-q21/2p13.3-14,
and still unknown loci
FHH-NSHPT/NHPT
145980-239200
FIHPT/145000
HRPT2/oncusuppressor
Inactivating
MEN1/oncosuppressor, Inactivating for MEN1,
HRPT2/oncosuppressor,
HRPT2, and CaSR
CaSR
genes
and still unknown genes
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
• >70% lead to truncated forms of menin
• 4% are large deletions
• Four occur frequently
• No genotype/phenotype correlations
Useful for segregation analysis
if MEN1 mutation is not found
Therefore the screening becomes time
consuming, arduous and expensive
Adapted from: JCEM 92:3389, 2007; Hum Mutat 29:22, 2008
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.
2.
3.
4.
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
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.
2.
3.
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
J Clin Endocrinol Metab, September 2012, 97(9):2990–3011
Basis for a diagnosis of MEN1 in individuals
Adapted from: JCEM 97:2990, 2012
Suggested biochemical and radiological screening
in individuals at high risk of developing MEN1
Adapted from: JCEM 97:2990, 2012
An approach to screening in MEN1
Adapted from: JCEM 97:2990, 2012
MEN syndromes and their characteristic tumors and
associated genetic abnormalities
Adapted from: JCEM 97:2990, 2012
SCHEMATIC REPRESENTATION
OF THE RET TYROSINE KINASE RECEPTOR
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
American Thyroid Association risk level and
timing of prophylactic thyroidectomy in MEN2A*
Adapted from: Surgery 148:1302, 2010
Recommendations for screening procedures and
time of prophylactic thyroidectomy.*
Adapted from: Best Practice and Research Clinical Endocrinology and Metabolism 24:371, 2010
Graphic representation of the nuclear interactions of p27
Adapted from: Neuroendocrinology 2010
Clinical and molecular characteristics of the identified
CDKN1B/p27 variants
Adapted from: Neuroendocrinology 2010
Organizzazione del Centro di Riferimento
T.E.E. della Regione Toscana nell’Ambito
dell’A.O.U.C.
Front line
Ambulatorio
Day Hospital
Laboratorio
SOD Patologia Chirurgica
Rapporti costanti con i
pazienti ed i familiari per
follow-up e risposta dei
test genetici
Reparto di Degenza
SOD Medicina Interna 2