A. Properties

1. Autosomal dominant disorders with variable penetrance
2. One or more genetic alterations
3. Tumors may exist singly or in combinations
4. When any tumor in the list below is found, other abnormalities should be sought
5. Carney complex - adrenal disorder with multiple neoplasia (see below)

B. Multiple Endocrine Neoplasia Type I (Werner Syndrome)

1. Components of MEN 1 Syndrome
   1. Pituitary Adenoma - growth hormone, prolactin frequently
   2. Parathyroid Hyperplasia - hyperparathyroidism (HPT) causing hypercalcemia
   3. Pancreatic Islet Tumor - gastrinoma, insulinoma
2. WRN Mutations cause Typical MEN-1 [1]
   1. WRN mapped to chromosome 11q
   2. WRN codes for a DNA helicase of the RECQ family
   3. Renders cells more susceptible to genotoxic damage
   4. Laminin A (LMNA) mutations can also cause an atypical Werner syndrome [16]
3. Syndrome includes premature aging, "progeroid syndrome" as well
4. Combination of peptic ulcer and hypercalcemia or renal stones suggests MEN I [14]

C. Multiple Endocrine Neoplasia Type 2 [2,3]

1. MEN 2 Syndromes
   1. All include: medullary thyroid cancer (MTC), pheochromocytoma, parathyroid hyperplasia
   2. MTC is ~100% penetrant, nearly always multicentric and bilateral
   3. Diffuse thyroid C-cell hyperplasia is nearly always present (due to RET mutations)
   4. Other clinical findings lead to division into types MEN-2A and MEN-2B
   5. Prevalence is 1:30,000 to 1:45,000
2. MEN Type 2A (Sipple Syndrome)
   1. In addition to above, includes:
   2. Adrenal Mass 5%
   3. Carcinoids <5%
   4. Increased presence of thyroid C-cell disease with RET codon 634 mutation
3. MEN Type 2B
   1. In addition to thyroid, adrenal, parathyroids anomalies above, includes:
   2. Neurofibromatosis (ganglioneuromatosis) must be present
   3. Marfanoid Habitus
4. Genetics of MEN2 [2,3,4]
   1. MEN 2 arises from mutations of the RET gene on chromosome 10q11.2
   2. MEN-2B is usually caused by germ-line mutations in the RET gene
   3. MEN-2A may be caused by non-germ-line mutations in the RET gene
   4. RET mutations cause adrenal medullary hyperlasia and pheochromocytoma
   5. Some families have mutations of von Hippel-Lindau gene and may not have MEN 2 [5]
   6. Deletions in the RET oncogene appear to cause Hirschsprung's Disease [3]
5. Correlation of RET mutations and disease entities [6,7,8]
   1. Any mutation at codon 634 increases risk of pheochromocytoma and/or HPT
   2. Mutations at codons 768 and 804 are only found, thus far, with medullary thyroid Ca
   3. Mutations in codon 918 are specific for MEN 2B
   4. RET mutations should be sought in family members of MEN patients
6. Thyroid Medullary CA (MTC) [3,9,17]
   1. Occurs in >90% of MEN 2 Cases
   2. Usually occurs with amyloid deposition
   3. Generally a very uncommon cancer
   4. May exist alone as familial MTC, or as part of MEN 2 syndromes
   5. Germline RET mutations are not found in patients with sporadic MTC [9]
   6. RET mutations first cause thyroid C cell hyperplasia then conversion to MTC
   7. Thyroid C cells produce calcitonin
   8. Patients with germline RET mutations should have prophylactic thyroidectomy [18]
   9. Follow calcitonin levels after therapy for residual/recurrent disease
   10. Surgery is mainstay of treatment
   11. Radiation therapy for bone and other non-resectable metastases
   12. Chemotherapy is generally ineffective
7. Pheochromocytoma (Adrenal Medullary Carcinoma; see below) [2]
   1. Usually called (see below)
   2. Occurs in 25-50% of MEN 2 Cases
   3. Increased risk of pheochromocytoma with mutations in codon 634 of RET gene [7]
8. Parathyroid Hyperplasia with hyperparathyroidism

D. Pheochromocytoma (Pheo) [2,10]

1. Types
   1. Spontaneous (more common)
   2. Associated with MEN 2 or Von-Hippel Lindau Syndrome (see below)
2. Tumor Type
   1. Neuroendocrine etiology
   2. Chromaffin cells which produce catecholamines
   3. About 90% of tumors are associated with adrenal glands
3. Typically presents as paroxysms of symptoms and signs
   1. Intermittent symptoms and signs means clinical diagnosis is difficult
   2. Headaches (most common), diaphoresis, palpitations, hot flashes less common than palor
   3. Major sign is hypertension (HTN): 65% sustained, 25% paroxysmal, 4% pregnancy
   4. Mean age of patients at presentation is around 42 years (depends on etiology)
4. Screening for Pheo [15]
   1. Metanephrines are 0-methylated metabolites of catecholamines
   2. Metanephrines include normetanephrine and metanephrine
   3. Plasma combined metanephrine levels are the best screening tests for Pheo [15]
   4. Normal plasma free metanephrines exclude the diagnosis of phenochromocytoma
5. Localization of the Tumor [2]
   1. CT scan typically used for diagnosis and is good for visualizing adrenals
   2. MRI is better than CT for non-adrenal Pheo with bright T2 signal of tumor
   3. 10% of tumors are extra-abdominal
   4. 10% bilateral adrenal
   5. 10% other abdominal (non-adrenal)
   6. 10% malignant
   7. 10% familial
6. Associated Diseases
   1. Neurofibromatosis (20% have pheochromocytoma)
   2. Von-Hippel-Lindau Syndrome (40%)
   3. Multiple Endocrine Neoplasia Type IIb
7. Treatment [2]
   1. Surgery without medical stabilization associated with high risk for mortality
   2. Alpha-methyl-para-tyrosine (metyrosine) is used for 2-3 weeks to deplete catecholamines
   3. Alpha adrenergic blockade with phenyoxybenzamine is then given prior to ß-blockers
   4. Intravascular volume is maintained high to reduce orthostatic hypotension
   5. Salt intake is also increased to maintain intravascular volume
   6. ß-blockers are then given to prevent reflex tachycardia due to alpha-blockers
   7. Hypertensive crisis is treated with nitroprusside, labetolol, phentolamine (alpha blockade)
   8. Surgical Resection either with open or laparoscopic proceedure is carried out

E. Von Hippel-Lindau (VHL) Syndrome [2]

1. Prevalence is similar to MEN 2: 1:30,000 to 1:45,000
2. Mutations in gene for VHL
   1. Normal VHL functions as a transcription elongation inhibitor
   2. It also plays a role in hypoxia-regulated ubiquitin ligase complex
   3. VHL is a tumor suppressor gene
   4. Missense mutations typically associated with pheochromocytoma development
3. Marked phenotypic heterogeneity present in patients with VHL mutations
4. Components of Syndrome
   1. Early onset, often bilateral Renal Cysts and Renal Tumors
   2. Pheochromocytoma (~40%)
   3. Retinal Angiomas
   4. Cerebellar and spinal hemangioblastomas
   5. Pancreatic cysts and tumors
   6. Epididymal cystadenomas
   7. Endolymphatic sac canal tumors of inner ear can cause insidious hearing loss [19]
   8. Intralabyrinthine hemorrhage (~50% of tumors) can cause acute hearing loss [19]
5. Pheo with VHL has reduced incidence of HTN and lower metanephrine levels than spontaneous

F. Carney Complex [12,13]

1. Bilateral micronodular adrenal disorder with multiple endocrine and non-endocrine cancers
2. Adrenal disorder called primary pigmented nodular adrenocortical disease (PPNAD)
3. Skin Lentigines
4. Cardiac myxomas
5. Non-endocrine and endocrine tumors

References

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2. Pacak K, Linehan WM, Eisenhofer G, et al. 2001. Ann Intern Med. 134(4):315
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4. Ledger GA, et al. 1995. Ann Intern Med. 122(2):118
5. Neumann HPH, Eng C, Mulligan LM, et al. 1995. JAMA. 274(14):1149
6. Eng C, Clayton D, Schuffenecker I, et al. 1996. JAMA. 276(19):1575
7. Heshmati HM, Gharib H, Khosla S, et al. 1997. Mayo Clin Proc. 72:430
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12. Stratakis CA, Sarlis N, Kirchner LS, et al. 1999. Ann Intern Med. 131(8):585
13. Carney JA and Young WF. 1992. Endocrinologist. 2:6
14. Broadus AE and Braaten KM. 2002. NEJM. 346(9):694 (Case Record)
15. Lenders JWM, Pacak K, Walther MM, et al. 2002. JAMA. 287(11):1427
16. Chen L, Lee L, Kudlow BA, et al. 2003. Lancet. 362(9382):440
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