MEN 1 SYNDROME

Presentors :-Dr sai krishna PGY2

Dr Hemanth PGY1
 INTRODUCTION
• Multiple Endocrine Neoplasia is also known as Wermer’s syndrome.
• It is characterised by the presence of tumors involving two or more
endocrine glands.
• There are four types of MEN syndromes
1. MEN 1
2. MEN 2
3. MEN 3
4. MEN 4
 PREVALENCE
• MEN 1 Syndrome is common among the four types of MEN
syndromes
• This disorder occurs at any age group ranging from 5-81 years
• Usually the clinical and biochemical manifestations develop from 5th
decade
 PATHOLOGY
• The MEN 1 gene is located on chromosome 11q13 which consists of
10 exons
• This MEN1 gene encodes for a 610 amino acid protein called menin
• Menin regulates transcription , genome stability , cell division, and
proliferation.
• The pathophysiology of MEN 1 follows KNUDSON two hit hypothesis
with tumor suppressor role for menin
 KNUDSON 2 HIT HYPOTHESIS
• Inheritance of germline MEN1 mutation(FIRST HIT) predisposes an
individual to develop a tumor
• This is followed by somatic mutation(SECOND HIT) which may be
either point mutation or more commonly a deletion leading to LOH
(loss of heterozygosity) in the tumor DNA
• These germline mutations of MEN 1 gene are scattered throughout
the coding regions and splice sites
• There is no correlation between location of MEN 1 mutations and
clinical manifestations
 FEATURES OF MEN 1 IN ADULTS
• PARATHYROID
Adenoma
• PANCREATICO DUODENAL
Gastrinoma
Insulinoma
non functioning tumors
glucagonoma VIPoma
• PITUITARY (ANTERIOR)
Prolactinoma
others(non functioning ,Growth hormone+prolactin,ACTH , thyrotropin)
 FEATURES OF MEN 1 IN ADULTS
• FOREGUT CARCINOID
Thymic carcinoid
bronchial carcinoid
Gastric enterochromaffin like tumor
• ADRENAL
cortex(non functional functioning and cancer)
Medulla (Pheochromocytoma)
NON ENDOCRINE FEATURES OF MEN 1
• Angiofibroma
• Collagenoma
• Lipoma
• Leiomyoma
• Meningioma
• Barrets esophagus
• Angiofibroma
• Malignant melanoma
MEN 2A- Medullary thyroid carcinoma
- pheochromocytoma
-parathyroid adenoma
MEN 2B / MEN3 -Medullary thyroid carcinoma
-pheochromocytoma
-Mucosal neuromas, marfanoid habitus,megacolon,
-medullated corneal nerve fibres
MEN 4- Pituitary tumors,
-parathyroid adenoma
- Testicular cancer
- neuro endocrine cervical cancer
MULTIPLE ENDOCRINE AND OTHER
ORGAN NEOPLASIA(MEON)
• Hyperparathyoidism jaw tumor
• Carney complex
• Von hippel lindau disease
• Neurofibromatosis
• Cowdens syndrome
• Mccune Albright syndrome
PARATHYROID TUMORS
• Hyperparathyroidism is the most common manifestation of MEN1
• It is seen in members of the MEN 1 Syndrome families as early as 8
years of age and by 40 yrs of age almost 95% of the MEN 1 carriers
show hyperparathyroidism
• MEN 1 accounts for 1-3% in all cases of primary hyperparathyroidism
• HPT in MEN 1 is usually asymptomatic
PARATHYROID TUMORS
• Clinical features:-
hypercalcemia
urolithiasis
muscular skeletal complaints
weakness
alteration of mental status
• These features are similar to those with other forms of primary Hyper
parathyroidism .
MEN 1 HYPERPARATHYROID VS
SPORADIC HYPER PARATHYROID
• Early onset i.e 25y versus 55y
• No gender predilection i.e 1:1 versus 3:1 female to male ratio
• Unlike solitary adenoma in sporadic ,enlargement of 3 to 4
Parathyroid glands in highly asymmetric fashion is present in MEN 1
• Even successful subtotal parathyroidectomy is followed by recurrent
hyperparathyroidism in half of MEN 1
• Hyperparathyroid in MEN1 never progresses to parathyroid carcinoma
Pancreatico-duodenal neuro endocrine tumors
• It is the second most common endocrine manifestation of MEN 1
syndrome
• It is seen in Almost 60% of MEN 1 patients
• Silent pancreatico duodenal macroadenoma may be recognised at
surgery or autopsy in nearly 100% of MEN 1 patients older than 40
years
• These are multiple and can over secrete various hormones and these
can become malignant and undergo metastasis
• The frequency of peptide immuno staining in MEN 1 shows
35% glucagon
25%Insulin
5% pancreatic polypeptide, and
10% no hormone
• Early studies shows hyperplastic process and budding of islets since
from Ducts (nesidiblastosis) but now considered not specific
• Now multifocal microadenoma due to a monoclonal or oligo clonal
process is considered in its Pathogenesis
 Gastrinoma
• It is the most common cause of severe symptoms and Signs in MEN 1
• The symptoms and signs reflects two processes
• malignancy and
• Gastrin induction of excessive acid secretion by stomach
• These are found in about 40% of adults with MEN 1
• Among all patients of ZES (Zollinger-Ellison) MEN 1 is found to be in
about 25%
 Gastrinoma
Clinical features:-abdominal pain ,
burning sensation in epigastrium,
diarrhea
• Gastrinoma in MEN 1 occurs at earlier onset i.e around 10 years
earlier
• It is multi focal tumor with small multiple and intraduodenal but the
prognosis is similar to that in sporadic cases
 INSULINOMA
• It is the 2nd most common hormone secreting pancreaticoduodenal
neuro endocrine tumor in MEN 1
• It occurs in about 10% among those with MEN 1 and coincidentally
MEN 1 also accounts approximately 10% of all patients with
insulinoma
• Diagnostic criteria is same in MEN 1 and sporadic cases i.e
Glucopenic symptoms ,
fasting hypoglycemia ,
high insulin and
c-peptide levels are present
 VIPoma
• It is a diarrheal syndrome caused due to over secretion of vaso active
intestinal peptide
• It is originated from neoplastic D2 cells usually from body or tail of
pancreas
• It is termed as WDHA /Pancreatic cholera
watery diarrhoea
hypokalemia
achlorhydria
 VIPoma
• It is usually sporadic and may rarely present in MEN 1
• Half of VIPoma causes hypercalcemia due to co-secreting PTH related
peptides
• These are malignant large and are metastatic at presentation
 Glucagonoma
• These are mostly sporadic pancreatic endocrine tumors
• It is rare in MEN 1
• But one 3rd of Pancreatico duodenal tumors in MEN 1 stain for
glucagon
• These are usually large and are metastatic at presentation
 Glucagonoma
• Clinical features :-
• Hall mark feature is Necrolytic migratory erythema –rash present over
groin and perineum (due to elevated glucagon levels and ?Zinc
deficiency)
• Other features include weight loss ,
• abdominal pain
• diabetes
• stomatitis,
• glossitis , chelitis ,neuropsychiatric symptoms
 Pancreatico duodenal tumors
• Other ectopic hormone that are over secreted by pancreatico
duodenal neuroendocrine tumors in MEN 1 includes
ACTH
PTH-related peptide
somatostatin
Calcitonin.
 Pituitary tumors
• Anterior pituitary tumor occurs in about 1/3rd of MEN 1 patients
• MEN 1 accounts for less than 5% in pituitary tumors
• The hypersecretion of hormones are similar to non M1 pituitary
tumors that is 60% prolactin hormone
15% growth hormone
25% Non secreting
5% ACTH
 Pituitary tumors
• Mass Effect in MEN 1 is the principal problem since tumor has been
larger and lesser responsive to the treatment
• These tumors occur early in MEN 1 and occasionally it may be the
first recognized feature
• Prolactinoma-It is most common pituitary tumor in MEN 1 and
• It is 3rd most common endocrine tumor in MEN 1 after parathyroid
tumors and gastrinoma
 Pituitary tumors
• Excess Growth hormone from tumors is secreted is by two
mechanisms
1.Inactivating of both the alleles of MEN 1 Gene
2.Excessive secretion of GHRH(Growth Hormone Releasing Hormone)
by pancreatic islet or carcinoid tumor
• Hypercortisolism in MEN 1 can be caused by pituitary tumor
secreting ACTH and by ectopic production of ACTH by a carcinoid or
an islet tumor and ectopic production of CRH or adrenal tumor
Primary adrenocortical hyperfunction
• One or both adrenal glands are enlarged in about 40% of MEN 1
patients
• These are generally clinically silent and are usually discovered during
pancreatic imaging and it rarely behaves as a neoplasm
• MEN 1 cases have been identified occasionally with hypercortisolism
hyperaldosteronism
• Adrenocortical tumors are more often found to be malignant in MEN
1 than in sporadic cases
 Foregut carcinoid
• Forgut carcinoid tumors are recognised in 5 to 15% of MEN 1 patients
• These unlike sporadic carcinoid tumors which are derived from mid
gut and hindgut , are primarily derived from foregut that is from the
thymus bronchus stomach
• These differs from sporadic carcinoid in gender predilection.
• Thymic carcinoid is found mainly in male patients and bronchial
carcinoid is found mainly in female patients
 Foregut carcinoid
• The average age of carcinoid detection in MEN 1 is 45 years
• Thymic carcinoid in MEN 1 is usually found at in advanced stage with
large invasive mass
• It is more malignant than bronchial carcinoid in MEN 1
• mostly these are considered clinically silent but may rarely
oversecrete hormones like ACTH ,GHRH,serotonin and histamine.
Gastric carcinoid
• Gastric carcinoid has been recognized more recently in MEN 1
• It is tumor of Enterochromaffin like cells
• These are large tumors that secrete hormones like serotonin
histamine in MEN 1
• It is present in 15% of MEN 1 patients and are incidentally recognised
during endoscopy
REFERENCES
• HARRISON’S PRINCIPLES OF INTERNAL MEDICINE 21ST EDITION
• WILLIAMS ENDOCRINOLOGY 14TH EDITION
THANK YOU