DEFINITION.

The MEN syndromes are a group of inherited diseases

resulting in proliferative lesions (hyperplasia, adenomas, and
carcinomas) of multiple endocrine organs.
Both are inherited in an autosomal dominant manner, but the
pattern of tumours differs.
Is characterized by the following;
Tumors occur at a younger age than sporadic tumors.
They arise in multiple endocrine organs, either synchronously
(at the same time) or metachronously (at different times).
Even in one organ, the tumors are often multifocal.
 The tumors are usually preceded by an asymptomatic stage of
hyperplasia involving the cell of origin. For example,
individuals with MEN-2 almost universally demonstrate C-cell
hyperplasia in the thyroid parenchyma adjacent to medullary
thyroid carcinomas.
These tumors are usually more aggressive and recur in a
higher proportion of cases than do similar sporadic endocrine
tumors.
Three types of MEN syndromes are recognized:

MEN type I (Wermers syndrome). MEN type I

consists of pituitary adenoma, parathyroid
hyperplasia or adenoma, and pancreatic islet cell
neoplasms, including gastrinoma. Peptic ulcers
also occur in these patients, probably related to
gastrin production (Zollinger-Ellison syndrome).
Adrenocortical adenomas rarely occur.
MEN type IIa (Sipple syndrome). MEN type IIa consists
of medullary carcinoma and parafollicular cell
hyperplasia of the thyroid and adrenal medullary
hyperplasia or pheochromocytoma (Figure 60-4).
Parathyroid hyperplasia or adenoma may also be present.
These patients do not have pancreatic islet cell
neoplasms or pituitary neoplasms and have no increased
incidence of peptic ulcer.

MEN type IIb. A subgroup of MEN type II has been

identified in which patients have mucocutaneous (tongue,
eyelids, bronchus, intestine) neuromas in addition to the
thyroid and adrenal neoplasms. This is sometimes also
called MEN type III.
 Is characterized by abnormalities in the pancreas, parathyroid
and pituitary glands.
Parathyroid primary hyperparathyroidism is found in 80
95% of the cases of MEN I. This is common in the age group
between 40-50 years. The parathyroid manifestations include
pituitary adenomas and hyperplasia.
Pituitary The most frequent anterior pituitary tumor
encountered in MEN-1 is a prolactinoma; some patients
develop acromegaly from somatotrophin-secreting tumors.
Pancreas: Endocrine tumors of the pancreas are a leading
cause of morbidity and mortality in persons with MEN-1. These
tumors are usually aggressive and often present with metastatic
disease.
MEN-1-associated pancreatic endocrine tumors are often
functional; however, because pancreatic polypeptide is the
most commonly secreted product, many tumors fail to produce
an endocrine hypersecretion syndrome.
Among those that do, Zollinger-Ellison syndrome (associated
with gastrinomas) and hypoglycemia and neurologic
manifestations (associated with insulinomas) are most
common.
It is now recognized that the spectrum of this disease
extends beyond the 3Ps. The duodenum is the most
common site of gastrinomas in individuals with MEN-1
(far in excess of the frequency of pancreatic gastrinomas),
and synchronous duodenal and pancreatic tumors may be
present in the same individual.
In addition, carcinoid tumors, thyroid and adrenocortical
adenomas, and lipomas are more frequent than in the
general population.
Epidemiology.
Age of onset of the syndrome is between 4 81 years of
age but the peak age is 40-50 years.
Men and women are both equally affected.
Pathogenesis.
MEN1 syndrome is caused by germline mutations
in the MEN1 tumor suppressor gene, which
encodes a protein called menin.
Menin is a component of several different
transcription factor complexes, which may either
promote or inhibit tumorigenesis.
This dichotomy in menin function is best
exemplified in the interactions of menin with two
oncogenic transcription factors JunD and the
mixed lineage leukemia (MLL) protein.
When menin partners with JunD, it blocks
transcriptional activation by JunD; in fact, loss of
this tumor suppressor interaction is believed to
contribute to the multiple endocrine neoplasia
observed in the setting of MEN1 inactivating
mutations.
On the contrary, the association of wild-type menin
with MLL leads to the formation of a tumor
promoting transcriptional complex in a subset of
leukemias.
Clinical features.
The dominant clinical manifestations of MEN-1 usually
result from the peptide hormones that are overproduced
and include such abnormalities as recurrent
hypoglycemia due to insulinomas, intractable peptic
ulcers in persons with Zollinger-Ellison syndrome,
nephrolithiasis caused by PTH-induced hypercalcemia, or
symptoms of prolactin excess from a pituitary tumor.
Diagnosis.
Genetic testing.
Serum Ca, parathyroid hormone (PTH), gastrin and
prolactin levels
MEN II.
These are sub-classified in to 3 types; MEN II A, MEN II B and
familial medullary thyroid cancer.
MEN-IIA.
MEN-IIA, or Sipple syndrome, is characterized by
pheochromocytoma, medullary carcinoma of the thyroid, and
parathyroid hyperplasia. Medullary carcinomas of the thyroid
occur in almost 100% of patients.
They are usually multifocal and are virtually always associated
with foci of C-cell hyperplasia in the adjacent thyroid. The
medullary carcinomas may elaborate calcitonin and other
active products and are usually clinically aggressive.
 Among individuals with MEN-IIA, 40% to 50% have
pheochromocytomas, which are often bilateral and may
arise in extra-adrenal sites. Parathyroid hyperplasia and
evidence of hypercalcemia or renal stones occur in 10% to
20% of patients.
MEN II A is clinically and genetically distinct from MEN1
and is caused by germline gain of function mutations in the
RET protooncogene on chromosome 10q; the RET proto-
oncogene encodes a receptor tyrosine kinase that binds
glial-derived neurotrophic factor (GDNF) and other ligands
in the GDNF family and transmits growth and differentiation
signals.
Loss-of-function mutations in RET result in intestinal
aganglionosis and Hirschsprung disease. In contrast, in
MEN IIB.
MEN-2B has significant clinical overlap with MEN-2A.
Patients develop medullary thyroid carcinomas, which
are usually multifocal and more aggressive than in MEN-
2A, and pheochromocytomas. However, unlike in MEN-
2A, primary hyperparathyroidism is not present.
In addition, MEN-2B is accompanied by neuromas or
ganglioneuromas involving the skin, oral mucosa, eyes,
respiratory tract, and gastrointestinal tract, and a
marfanoid habitus, with long axial skeletal features and
hyperextensible joints.
A germline mutation leading to a single amino
acid change in RET, distinct from the mutations that
are seen in MEN-2A,seems to be responsible for
virtually all cases of MEN-2B.
This point substitution affects a critical region of
the tyrosine kinase domain of the protein and
leads to constitutive activation of RET in the
absence of ligand.
Of note, approximately a third of sporadic
medullary thyroid carcinomas harbor the identical
mutation, and these cases are associated with
aggressive disease and an adverse prognosis.
Familial medullary thyroid cancer
Is a variant of MEN-2A, in which there is a strong
predisposition to medullary thyroid cancer but not the
other clinical manifestations of MEN-2A or MEN-2B.
A substantial majority of cases of medullary thyroid
cancer are sporadic, but as many as 20% may be
familial.
Familial medullary thyroid cancers develop at an older
age than those occurring in the full-blown MEN-2
syndrome and follow a more indolent course
Mixed syndromes
This include a variety of endocrine neoplastic combinations
which are distinct from those in MEN type 1 and type 2. A few
examples are as under:
Von Hippel-Lindau syndrome from mutation in VHL gene is
association of CNS tumours, renal cell carcinoma,
pheochromocytomas and islet cell tumours.

Type 1 neurofibromatosis from inactivation of neurofibromin

protein and activation of RAS gene, is associated with MEN type
1 or type 2 features.