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DR DINA EL GAYAR
PROFESSOR OF CHEMICAL PATHOLOGY
CAIRO UNIVERSITY
Definition
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Multipleendocrine neoplasia syndrome is defined as
a disorder with neoplasms in two or more different
hormonal tissues in several members of a family.
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It is inherited as an autosomal dominant trait.
Although rare, MEN1 is the most common MEN syndrome
with prevalence of 220 per 100,000 .
Reported age range of 581 years
MEN1 GENE
On chromosome 11q13
Consists of 10 exons that span 9 kb and encode a 610 amino acid protein called MENIN
Mutations: Germline & Somatic
Menin acts as a tumor suppressor, involved in cell functions such as copying and
repairing DNA and regulating the activity of other genes.
When mutations inactivate both copies of the MEN1 gene, Menin is no longer available
to control cell growth and division. It occurs in selected endocrine tissues leading to the
classic MEN1 phenotype
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The syndrome is characterized by:
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1. Hyperparathyroid 95% due to hyperplasia of the four glands
2. Enteropancreatic tumors 50% of patients functional or non funcional
3. Anterior pituitary adenomas 20-25%,
4. Adrenal adenomas 30%
5. Thyroid nodules 10%
Hyperparathyroid
The first manifestation of MEN TYPE 1
85% of patients Hyperparathyroid
15% of patients insulinoma or a prolactinoma
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Second most common manifestation of MEN1,
30% are malignant
Estimated penetrance of 50%.
They tend to occur in parallel with hyperparathyroidism.
Tumors secrete peptide hormones that cause specific clinical
syndromes.
A. Gastrinomas
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Most common enteropancreatic tumors in MEN1 patients
Result in the Zollinger-Ellison syndrome (ZES).
The robust acid production may cause; Esophagitis, Duodenal
ulcers throughout the duodenum, Ulcers (which is commonly
refractory to conservative therapy such as antacids) and Diarrhea.
Occurs in > of MEN1 pts with small carcinoid-like tumors in
the duodenal wall or, less often, by pancreatic islet cell tumors.
There may be > one gastrin-producing tumor, making localization
difficult.
Diagnosis
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Elevated basal gastrin levels in the serum [generally >115 pmol/L
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Second most common enteropancreatic tumors in MEN
Diagnosis
Hypoglycemia after a short fast
Inappropriate elevation of serum insulin and C-peptide
levels.
Large insulinomas may be identified by CT or MRI
scanning.
Intraoperative ultrasonography. Selective hepatic vein
sampling for insulin
C . Glucagonoma
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seen occasionally in MEN1,
a syndrome of , hyperglycemia, skin rash ( necrolytic migratory
erythema),anorexia, glossitis, anemia, depression
glucagon level is double fold elevated
D.VIPomas
(1%) secrete VIP and cause profuse watery diarrhea,
hypokalemia, and achlorhydria
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These tumors can exhibit aggressive behavior and local invasiveness
that makes them difficult to resect.
1 Prolactinomas
Most common
serum prolactin levels >200 g/L
serum prolactin levels <200 g/L may be due to a prolactin-secreting
neoplasm or to compression of the pituitary stalk by a different type of
pituitary tumor.
2 Acromegaly
due to excessive GH production is the second most common syndrome
caused by pituitary tumors in MEN1.
.
3. Cushing's disease:
It is caused by
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ACTH-producing pituitary tumors
or
Ectopic production of ACTH or CRH(islet cell or
carcinoid tumors or adrenal adenomas).
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in about 37% of patients with MEN 1
MEN1 germline mutation testing may be recommended in individuals with an atypical MEN1
phenotype
Individuals who are found to have a MEN1 germline mutation should be screened regularly (e.g. on an
annual basis) for development of MEN1-associated tumors.
If a coding region MEN1 mutation is not identified, then testing for partial or whole-gene deletion, or
haplotype analysis of the MEN1 locus, or analysis of other genes should be considered
N.B.
Relatives of a patient with a known MEN1 mutation should be offered MEN1 germline mutation analysis
before biochemical and radiological screening tests for the detection of MEN1 tumors, so as to avoid the
burden of undergoing multiple tests involving different modalities and to reduce financial costs .
MEN Type 2(Sipple's Syndrome)
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It is inherited as an autosomal dominant trait.
prevalence of 1-10 per 100,000 .
The International RET Mutation Consortium has proposed three
phenotypic subtypes of MEN-2
MEN-2 (1) MTC, pheochromocytoma, and hyperparathyroidism
MEN-2 (2) MTC and pheochromocytoma
MEN-2 (3) MTC and hyperparathyroidism
ret protooncogene (RET) mutation.
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This gene provides instructions for producing a protein that
is involved in signaling within cells. Mutations in the RET
gene overactivate the protein's signaling function, which
can trigger cell growth and division in the absence of
signals from outside the cell. This unchecked cell division
can lead to the formation of tumors in endocrine glands
and other tissues.
Their first-degree relatives may have specific RET
mutation.
Patients may present with:
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1. Medullary thyroid carcinoma (> 90%);it starts by hyperplasia of the
calcitonin producing cells which is a precursor of MCT multicentric
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stimulation test basal and stimulated plasma calcitonin (CT)
Serum calcium level every two y and PTH levels screen for hyperparathyroidism.
Imaging Studies
If calcitonin levels are elevated at either baseline or with provocative
testing, evaluate the chest and abdomen for metastatic disease.
Perform CT scanning or MRI for imaging of the adrenals.
MEN Type 3
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Familial, autosomal dominant multiglandular syndrome that is caused by a
mutation of the ret protooncogene (RET) on chromosome 10.
1. Mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue
2. Marfan-like habitus (75%),
3. Adrenal pheochromocytomas (60%) rarely malignant and often bilateral
4. Medullary thyroid carcinoma (80%).
5. Intestinal ganglioneuromas
6. Skeletal abnormalities (87%)
7. Delayed puberty (43%).
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Medullary thyroid carcinoma is aggressive and presents early in
life. Therefore, infants having a parent with MEN 3 receive
genetic screening; those carrying the RET mutation undergo a
prophylactic total thyroidectomy by age 6 months.
Indviduals at risk of MEN 2
and MEN 3 Negativ
e
Screen for RET mutation
Positive
Unilateral
Bilateral
Adrenalrectomy
Adrenalectomy
Biochemical check
MEN 4 (MEN X syndrome)