Men

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INTRODUCTION

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— Multiple endocrine neoplasia type 2 (MEN2) is subclassified into three distinct syndromes: MEN2A; MEN2B; and familial medullary thyroid cancer (FMTC).

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MEN2A

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• autosomal dominant disorder
• medullary thyroid cancer (MTC),
• pheochromocytoma (PC),
• primary parathyroid hyperplasia.

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MEN2B

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• autosomal dominant disorder
• MTC
• PC
• not hyperparathyroidism.
• mucosal neuromas, typically involving the lips and tongue
• intestinal ganglioneuromas.
• envelopment abnormalities
o decreased upper/lower body ratio,
o skeletal deformations (kyphoscoliosis or lordosis),
o joint laxity,
o Marfanoid habitus, and
o myelinated corneal nerves.
• Disturbances of colonic function
o chronic constipation
o Megacolon

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FMTC

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• variant of MEN2A
• strong predisposition to MTC
• not the other clinical manifestations of MEN2A (or 2B).

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MEDULLARY THYROID CANCER

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• neuroendocrine tumor of the parafollicular or C cells of the thyroid gland
• approximately 3 to 5 percent of thyroid cancers.
• A characteristic feature of this tumor is the production of calcitonin.
• Multicentric hyperplasia of the parafollicular C cells is the hallmark of MEN2,
C cells —
• neuroendocrine cells
• derived from the ultimobranchial bodies
• 0.1 percent of the thyroid mass.
• Calcitonin
o important role in regulating blood calcium
o inhibits osteoclast-mediated bone resorption
• MTCs in MEN2 patients are
o multicentric and
o concentrated in the upper third of the thyroid gland

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Relationship to sporadic MTC

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• Most cases of MTC are sporadic
• 25 percent of all MTCs are considered to be familial
• The typical age of presentation of sporadic medullary thyroid cancer is in the fifth or sixth decade.
• germline mutations in the RET proto-oncogene (the underlying defect in MEN2)

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Familial medullary thyroid cancer

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• variant of MEN2A
• rigorous criteria for FMTC should be used in order not to miss a pheochromocytoma :
o More than 10 carriers in the kindred
o Multiple carriers or affected members over the age of 50 years
o An adequate medical history, particularly in older family members

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Clinical manifestations

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• thyroid nodule
• cervical lymphadenopathy.
• search initiated after an associated disease such as pheochromocytoma or hyperparathyroidism
• diarrhea caused by gastrointestinal secretion of fluid and electrolytes
• flushing due to the secretion of other peptides by the tumor.
• Cushing's syndrome due to ectopic production of corticotropin (ACTH).
• Basal serum calcitonin concentrations
o correlate with tumor mass
o almost always high in patients with a palpable tumor
o In patients with small tumors and those with C cell hyperplasia, the values may be normal but rise excessively after calcium infusion
• pentagastrin and calcium stimulation tests were used to stimulate calcitonin secretion by thyroid C-cells, and assess for the diagnosis of MTC.
• RET-mutation screening - lost their clinical significance with respect to diagnosis.
• MTC in MEN2B
o tends to be more aggressive
o surgery is often not curative
o MTC occurred in 50 percent of patients with MEN2B versus 9.7 percent of those with MEN2A
o thyroidectomy as early as the neonatal period may be indicated in patients with MEN2B identified by genetic screening
• Patients with MTC should be evaluated for possible pheochromocytoma.
o A coexisting pheochromocytoma should be removed before thyroidectomy.

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Stimulation tests

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• Other calcitonin secretagogues
o glucocorticoids,
o calcitonin gene-related peptide,
o glucagon, enteroglucagon,
o gastrin, pancreozymin, and
o beta-adrenergic agents.
• Calcium stimulation test —
o rapid infusion of calcium gluconate (2.5 mg/kg over 30 seconds)
o administered to a fasting patient.
o Blood samples for calcitonin are obtained at baseline and 2 and 5 minutes after the stimulus.
o The test is considered positive if the peak plasma calcitonin concentration after stimulation is more than three times the basal concentration or ≥ 300 ng/L [
o There are other patients who have C cell hyperplasia,
• autoimmune thyroid disease or follicular thyroid tumors
• can cause positive calcium stimulation tests but poses
• no risk of progression to MTC.
o Modern screening with molecular methods for the RET proto-oncogene permitting specific diagnosis in patients in whom biochemical tests might be equivocal

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PHEOCHROMOCYTOMA

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• 40 percent of patients with MEN2A and probably a similar percentage in MEN2B
• Sporadic pheochromocytomas are almost always unilateral
• In contrast, pheochromocytomas in MEN2A have been reported to be bilateral in approximately one-third to, in one study from Spain, 100 percent of patients
• bilateral adrenalectomy in the absence of documented bilateral disease is,
o not indicated,
o although controversy exists on this point
• MEN2A-associated pheochromocytomas that are malignant is considerably less than the 10 percent rate of malignancy reported for sporadic pheochromocytomas
• Clinical presentation —
o unusual for pheochromocytoma to precede the development of MTC and be the initial manifestation of MEN2.
o The patients may report
• attacks (paroxysms) of anxiety,
• headache,
• diaphoresis,
• palpitations or
• tachycardia, like patients with sporadic pheochromocytomas.
• Biochemical screening —
o should be performed yearly in MEN2 patients
o RET mutation in sporadic pheochromocytoma —
• Combined data from five studies failed to demonstrate even one example (yield 0/156 cases) of an unsuspected germline RET mutation among unselected patients with apparently sporadic pheochromocytoma
• yield of RET testing in patients with apparently sporadic pheochromocytoma —
 unilateral disease,
 a negative family history, and
 no signs or symptoms of MEN2
• RET testing may be indicated
 who do not meet all three criteria.
• Other causes of familial pheochromocytoma —
o incidence of familial pheochromocytoma - 23 percent [
• a more likely figure is 10 percent.
o Other heritable syndromes associated with pheochromocytoma
• von Hippel-Lindau (vHL) syndrome,
• neurofibromatosis type 1, and
• paraganglioma syndromes
• Phenotype of MEN2 versus vHL syndrome —
 MEN2 patients - adrenergic phenotype with higher rates of epinephrine biosynthesis

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PRIMARY HYPERPARATHYROIDISM

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• Primary hyperparathyroidism in MEN2A is almost always multiglandular.
• It has been reported in 10 to 25 percent of patients
• Etiology and diagnosis —
o consequence of the C-cell abnormalities,
o It seems unlikely that hypercalcitoninemia per se is the stimulus for the parathyroid tumors for the following reasons:
• Hyperparathyroidism is not associated with MEN2B, FMTC, or sporadic MTC, all of which can be characterized by sustained hypercalcitoninemia.
• The RET gene is expressed in MEN2A-associated parathyroid tumors
• A particular RET mutation, Cys to Arg at codon 634, may be preferentially found in MEN2 families that have hyperparathyroidism
• Primary hyperparathyroidism may be the first manifestation of MEN2
The hyperparathyroidism in MEN2A is often clinically occult.

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CUTANEOUS LICHEN AMYLOIDOSIS

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—
• rare skin condition
• sporadically and as a familial disease.
• The skin lesion is usually described as pruritic, scaly, papular, and pigmented, and located in the interscapular region or on the extensor surfaces of the extremities
• Several different RET codon 634 mutations have been described in MEN2A/CLA families

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HIRSCHSPRUNG DISEASE

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• absence of autonomic ganglion cells within the distal colonic parasympathetic plexus resulting in chronic obstruction and megacolon.
• In humans, inactivating mutations of the RET proto-oncogene have been associated with HD.
• familial and in a sporadic form.
• In about 50 percent of familial and 15 to 35 percent of sporadic HD patients,
o mutations in the RET gene are involved.

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DIAGNOSIS

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o Biochemical testing —
• DNA analysis for the detection of mutations in the RET gene
• stimulate calcitonin secretion from malignant or hyperplastic parafollicular C-cells
• if biochemical testing is used, yearly testing until at least age 35 years (or until a positive test occurs) is necessary
o Genetic testing —
• DNA testing becoming the optimal test for their detection.
• Early diagnosis by screening of "at-risk" family members in MEN2 kindreds is essential because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy.
• It provides clinical benefit that should accrue from earlier surgery for known MEN2 gene carriers, as the genotype correlates with the age at initial diagnosis
• It definitively establishes that an individual does not carry the MEN2 mutation and eliminates the need for biochemical testing.
• It avoids unnecessary thyroidectomy in genetically normal subjects in MEN2 families.
o Indications for genetic testing —
• Clinically proven MEN2 syndrome
• MTC or pheochromocytoma and a family member with MTC or pheochromocytoma
• Apparently sporadic MEN2 related tumors and young age (<35 years), multicentric tumors in one organ, and/or two different organs affected
• RET mutation analysis should also be performed in first and second degree family members of MEN2 patients,
• all patients with sporadic MTC.
o Genetic screening of family members
• When, as is usually the case, a RET mutation is found, all subjects of unknown status in that family should then be definitively genotyped.
• RET genotyping requires only a small blood sample, and can therefore be performed at birth or soon thereafter.
• Summary information concerning MEN2 may be useful for counseling patients and affected families. Family alliances can provide such information:
 www.geneclinics.org/profiles/men2
 www.endocrineweb.com/MEN/MEN2.html.
o Genetic screening in apparently sporadic MTC — S
• Germline RET mutations have been identified in small numbers of patients,
• A much higher percentage (approximately 50 percent) of patients with sporadic MTC have somatic (acquired) mutations in the RET gene.
 These mutations are present only in the tumor cells, and are not detected by standard genetic testing,
• Indications for DNA testing for familial MTC in patients with apparently sporadic MTC include:
 age at diagnosis less than 35 years;
 bilateral or multicentric involvement;
 family history positive or suspected.
 All patients with MTC for whom there is clinical suspicion of familial disease should be tested for germline RET gene mutations in blood DNA.
o Timing of surgery —
• prophylactic thyroidectomy in children with a RET germline mutation