Multiple Endocrine Neoplasia (MEN)

How do you diagnose MEN 2 and 3?

DNA testing for RET proto-oncogene mutation medullary thyroid carcinoma: *gold standard is thyroid US w/ FNA* serum calcitonin levels TSH w/ reflex to T4 (T4 normal in carcinoma) pheochromocytoma: metanephrine 24hr urine screen CT abdomen for adrenal eval MIBG scintigraphy if (-) CT to look ectopically hyperparathyroidism: serum Ca, PTH

What accounts for the highest morbidity and mortality in MEN type 1?

PUD

What is MEN 3 defined by?

autosomal dominant mutation involving *RET* proto-oncogene leading to hyperplasia and tumor formation/growth *more aggressive/earlier presentation* thyroid c-cell hyperplasia -> medullary thyroid carcinoma that's multifocal and bilat bilat pheochromocytomas *MUCOSAL NEUROMAS AND GI GANGLIONEUROMAS* -> unique to type 3 marfanoid body habitus (tall, long arms and legs)

What are symptoms of MEN 1 with pancreatic islet involvement?

frequently spread to duodenum gastrinoma -> Zollinger-Ellison Syndrome insulinoma -> hypoglycemia glucagonoma -> hyperglyemia vasoactive intestinal peptide tumor (VIPoma) -> watery diarrhea, hypoK pancreatic polypeptide producing tumor (PPoma) -> regulates pancreatic secretion

How do you treat MEN 1?

genetic counseling *diazoxide* to inhibit release of insulin *high dose PPI* targeted at pituitary tumor excess surgery: hyperparathyroidism -> parathyroidectomy w/ cervical thymectomy -> high rate of recurrence removal of pituitary tumor and pancreatic endocrine tumors (pancreas, duodenum, adjacent LNs, high rate of recurrence)

How do you treat MEN 2 and 3?

genetic counseling prophylactic total thyroidectomy bilat adrenalectomy subtotal parathyroidectomy w/ cervical thymectomy -> lower rate of recurrence compared to MEN 1, so only an option with MEN 2 and 3

What is MEN 4 defined by?

autosomal dominant *familial tumor syndrome* mutation involving *CDKN18 -> tumor suppressor gene* defined by: parathyroid adenomas, thyroid adenomas, pituitary adenomas, pancreatic neuroendocrine tumors, adrenal tumors also prone to renal tumors, testicular cancer, neuroendocrine cervical carcinoma, and primary ovarian failure

How does Men 2 present?

medullary thyroid carcinoma -> neck fullness/lump, dysphagia, hoarse voice pheochromocytoma sx hyperparathyroidism (not as common) almost all patients have: HTN, episodic sweating, diarrhea (d/t elevated calcitonin), pruritic skin lesions, neck fullness/lump

What is MEN? What causes it?

multiple endocrine neoplasia *rare* group of syndromes d/t *autosomal dominant* gene mutations mutation in either *menin gene or ret gene* *menin* gene is a tumor suppressor -> *absence leads to tumor formation/growth* *ret* gene is a proto-oncogene -> *presence leads to tumor formation/growth* 4 types

What occurs in MEN type 1? What is it associated with?

mutation of the *menin gene* endocrine tumors develop while teen -> sx delayed for several years cutaneous tumors may develop prior to endocrine tumor symptoms hyperfunctioning of the *parathyroid gland* others may include: pancreatic islets and anterior pituitary can be assoc w/ angiofibromas/collagenomas, lipomas, adrenal cortex (rarely medulla), thymic and bronchial carcinoid tumors, breast cancer

How do you screen for MEN 2 and 3?

screening indicated for 1st and 2nd degree relatives early detection of medullary thyroid carcinoma, pheochromocytomas, or parathyroid lesions reduces morbidity screening beyond genetics: serum calcitonin (thyroid carcinoma) serum Ca (hyperCa) metanephrine 24hr urine screen (pheochromocytoma)

How do you screen for MEN 1?

screening indicated for 1st and 2nd degree relatives (auto dominant) lowers age of detection by 20 years to reduce morbidity by detecting parathyroid, pancreatic, or pituitary lesions screening beyond genetics -> serum Ca (hyperparathyroid), serum fasting gastrin (poss gastrinoma), serum prolactin (hyperprolactinemia)

What are symptoms of MEN 1 generally and in the anterior pituitary?

Hyperparathyroidism d/t hyperplasia -> hypercalcemia, nephrolithiasia *presence of supranumery parathyroid glands MC located in thymus* facial angiofibroma mainly seen on nose and cheeks, discrete papular collagenomas on the upper torso, neck, and shoulders anterior pituitary: possible hyperprolactinema d/t prolactinoma possible somatotropinoma causing excess GH Cushing's syndrome if corticotropinoma mass effect possible (HA, loss of peripheral vision)

Men 1 vs Men 2 vs Men 3

Men 1 -> hyperparathyroidism, menin gene, facial angiofibromas, truncal collagenomas, lipomas Men 2 -> medullary thyroid cancer, RET gene, pruritic papules in scapular region Men 3 -> medullary thyroid cancer, RET gene, mucosal neuromas and GI ganglioneuromas, marfanoid body habitus, earlier age of onset and more aggressive, delayed puberty

What is MEN 2 defined by?

autosomal dominant mutation of *RET* proto-oncogene leading to hyperplasia and tumor formation/growth *thyroid C cell hyperplasia leading to medullary thyroid carcinoma* -> multifocal/bilat bilat pheochromocytomas in 1/2 of cases hyperparathyroidism sometimes (not as common as MEN 1) cutaneous lichen amyloidosis -> *PRURITIC*, hyperpigmented, lichenoid papules in *SCAPULAR REGION*

What are symptoms of thymic and bronchial carcinoid tumors due to MEN 1?

carcinoid syndrome secretion of serotonin and other vasoactive peptides (histamines, kallikrein, prostaglandins) flushing, diarrhea, wheezing, right-sided valvular disease

What may be the first indication of MEN 1?

cutaneous tumors that develop prior to endocrine tumor symptoms OR early onset or recurrent kidney stones

How does MEN 3 present?

earlier presentation sx related to medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism sometimes virtually all patients have: HTN, episodic sweating, diarrhea (elevated calcitonin), neck fullness/lump *delayed puberty* neuromas usually precede medullary thyroid carcinoma and pheo -> appears as *glistening bumps around lips, tongue, lining of mouth or bumps on eyelids* *autonomic nerves of myenteric and submucosal plexi from GI gangliomas -> poor suckling w/ FTT, constipation, diarrhea, recurrent pseudo-obstruction, toxic megacolon* involvement of peripheral motor and sensory nerves can cause *peroneal muscle atrophy* -> weakness w/ *foot and ankle eversion*

How do you diagnose MEN 1?

high level of suspicion -> facial angiofibromas/truncal collagenomas/lipomas w/ hyperparathyroidism AND increased gastric acid secretion (dyspepsia, heartburn, coffee ground emesis or melena) DNA testing for menin mutation CMP- alteration in Ca, blood sugar for insulinoma appropriate hormone studies- PTH, others depending on sx imaging studies to identify tumor -> MR pituitary or MR neck (parathyroid)