History and exam
Key diagnostic factors
common
young age (MEN1/2)
Germline defects are likely in young patients presenting with syndromal tumors (e.g., multigland primary hyperparathyroidism, medullary thyroid cancer, or pheochromocytoma).
MEN2 medullary thyroid cancer typically presents before 20 years of age.
Primary hyperparathyroidism in MEN1 typically presents several decades earlier than in sporadic cases.
positive family history (MEN1/2)
Most mutations are inherited.
Family history of thyroid tumors or sudden death in index cases suggests MEN2.
Family history of kidney stones, pancreatic disease, or gastrointestinal problems (such as ulcers and chronic diarrhea) in index cases suggests MEN1.
episodic triad of sweating, palpitations, and headache (MEN2)
Pheochromocytomas with episodic hypersecretion of catecholamines cause classic spells of sweating, palpitations, and headache.
clinical features of kidney stones (MEN1/2)
Excess parathyroid hormone (from parathyroid hyperplasia) results in hypercalciuria and can cause nephrolithiasis.
facial angiofibromas or collagenomas (MEN1)
Multiple lesions (>5) are present in 40% to 80% of patients with MEN1.[41]
mucosal neuromas (MEN2B)
Part of the characteristic phenotype of MEN2B patients. Patients may complain of "bumpy" lips. Mucosal neuromas are seen on the lips, tongue, and eyelids.
arm span and upper-to-lower-body-segment ratio (MEN2B)
Marfanoid body habitus is part of the characteristic phenotype of MEN2B patients.
uncommon
irregular menses (MEN1)
Prolactin or cortisol elevation (from prolactinomas or other pituitary adenomas causing hypersecretion of cortisol) can affect menses, while mass effects in the pituitary can cause central hypogonadism.
visual changes (MEN1)
Bitemporal hemianopia is associated with compression of the optic chiasm from pituitary masses.
unexplained flushing (MEN2)
May result from peptide hypersecretion from enterochromaffin-like cell tumors such as gastrinoma and carcinoid.
May also result from hypersecretion of calcitonin due to medullary thyroid cancer.
infertility (MEN1)
May result from hypersecretion of prolactin from prolactinomas, or suppression of gonadotropins due to large functioning, or nonfunctioning, pituitary adenomas.
clinical features of acromegaly (MEN1)
Examination findings, including oversized hands, feet, and face, and excess sweating, may result from hypersecretion of growth hormone from pituitary adenomas.
clinical features of thyrotoxicosis (MEN1)
Tachycardia, lid lag, tremor, and warm skin may result from hypersecretion of thyroid-stimulating hormone from pituitary adenomas.
Other diagnostic factors
common
weight changes (MEN1/2)
Weight gain may result from insulinomas (causing hypoglycemia, which patients often self-treat with frequent meals), pituitary adenomas (causing hypersecretion of cortisol) or late-stage medullary thyroid cancer (causing Cushing syndrome).
Weight loss may result from pituitary adenomas that result in thyrotoxicosis, pheochromocytomas, and malignancy.
hypertension (MEN1/2)
Pheochromocytomas with chronic hypersecretion of catecholamines cause chronic hypertension.
Patients with hyperparathyroidism, hypercortisolism, acromegaly, or thyrotoxicosis (from pituitary adenoma hypersecretion) may also have hypertension.
abdominal pain (MEN1/2)
Epigastric pain and dyspepsia may result from peptic ulceration (due to Zollinger-Ellison syndrome manifestations of gastrinomas).
uncommon
headache (MEN1/2)
Pituitary masses and pheochromocytoma can be associated with headaches. Pheochromocytoma headaches tend to be episodic and can present as a triad with palpitations and hypertension.
low-trauma fractures (MEN1)
Osteoporotic fractures at a young age may result from parathyroid adenomas causing hyperparathyroidism or from hypersecretion of cortisol causing Cushing syndrome.
altered bowel habit (MEN1/2)
Various hormonal excesses affect the gastrointestinal tract. Constipation may result from elevated calcium associated with hyperparathyroidism.
Diarrhea may result from elevated calcitonin associated with medullary thyroid cancer or elevated gastrin associated with gastrinomas.
Ganglioneuromas are present in the gastrointestinal tract of up to 40% of patients with MEN2B and can result in constipation, diarrhea, abdominal pain, and bowel obstruction.[50]
palpitations (MEN1/2)
May be present with pheochromocytomas as a result of episodic elevations in catecholamine levels.
May also be present with insulinomas as a result of episodic fasting hypoglycemia. The responsive counterregulatory hormonal surges to this hypoglycemia (including adrenal hormones) can cause episodic palpitations, which may be accompanied by diaphoresis and tremor.
May also be present with thyrotoxicosis as a result of thyroid-stimulating-hormone-producing pituitary adenomas.
easy bruising (MEN1/2)
May result from hypersecretion of cortisol from pituitary adenomas.
slow wound healing (MEN1/2)
May result from hypersecretion of cortisol from pituitary adenomas.
erectile dysfunction (MEN1)
Resulting from hypogonadotropic hypogonadism due to mass effect of a pituitary adenoma, or hyperprolactinemia caused by a prolactinoma.
clinical features of hypercortisolism/Cushing syndrome (MEN1/2)
Moon facies, thin skin, proximal myopathy, and central obesity may result from hypersecretion of cortisol from pituitary adenomas.
Late stages of medullary thyroid cancer may also cause hypersecretion of adrenocorticotropic hormone causing Cushing syndrome.
Adrenal carcinomas can also cause Cushing syndrome.
anxiety (MEN1/2)
May result from hypersecretion of thyroid-stimulating hormone from pituitary adenomas or of catecholamines from pheochromocytoma.
heat intolerance (MEN1)
May result from hypersecretion of thyroid-stimulating hormone from pituitary adenomas.
confusion (MEN1/2)
May result from a severe case of hyperparathyroidism (from parathyroid hyperplasia) when serum and urine calcium levels are grossly elevated. Confusion can also occur in the context of hypoglycemia (due to insulinomas) and severe Cushing syndrome
dehydration (MEN1/2)
May result from a severe case of hyperparathyroidism (from parathyroid adenomas) when serum and urine calcium levels are grossly elevated.
gastrointestinal bleeding (MEN2)
Coffee-ground vomit or melena may be presenting features of Zollinger-Ellison syndrome manifestations of gastrinomas.
hepatomegaly (MEN2)
May be present if liver metastasis has occurred.
Risk factors
strong
familial cases of MEN
MEN1 and MEN2 are hereditary cancer syndromes of autosomal-dominant patterns and variable penetrance. Patients are considered to have familial cases if they have ≥1 first-degree relatives with symptoms.[37]
RET proto-oncogene mutation
All variants of MEN2 have been mapped to distinct RET proto-oncogene mutations.[27] Different mutations confer different risks of medullary thyroid cancer aggressiveness and pheochromocytoma penetrance. For example, mutations in codons 806, 883, and 918 confer high risks of early aggressive medullary thyroid cancer in MEN2B, and mutations in codon 634 are associated with early pheochromocytoma.[5] Codons 630, 768, 791, and 891 have not been associated with pheochromocytoma at all.[29]
MEN1 (menin) mutation
MEN1 gene mutations have been identified in 80% to 90% of patients clinically classified as having MEN1.[37]
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