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Multiple endocrine neoplasia type 2
Multiple endocrine neoplasia type 2 (MEN2) is a multiple endocrine neoplasia (see this term), a polyglandular cancer syndrome characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma (PCC; see these terms), in one variant, primary hyperparathyroidism (PHPT). There are three forms: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) (see these terms).
The total prevalence of all MEN2 variants is approximately 1/35,000. Of the three MEN2 subtypes, MEN2A accounts for about 70%-80% of cases, familial medullary thyroid carcinoma (FMTC) for 10-20%, and MEN2B for 5%.
The clinical manifestations of MEN2 are related to the syndrome subtypes and depend on the specific mutation in the RET gene. MEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A and FMTC). MTC is seen in all forms of MEN2, is usually the first manifestation of the disease, and arises in the lateral thyroid lobes. In MEN2A, MTC is associated in 50% of cases with pheochromocytoma and in 20-30% with hyperparathyroidism. MEN2B is characterized by MTC and in 50% of cases includes PCC, but unlike MEN2A, PHPT is not present. Patients instead exhibit mucosal neuromas of the lips and tongue, bumpy lips, ganglioneuromatosis of the gastrointestinal tract and marfanoid habitus. Patients with PCC have additional symptoms of headache, palpitations, nervousness, hypertension and tachycardia. If PHPT is present, symptoms such as depression, muscle weakness and fatigue may be found. MTC can remain in the thyroid gland or can spread to distant sites in the more aggressive forms of the disease, leading to bone pain and diarrhea from increased calcitonin (Ct).
MEN2 is caused by a germline activating mutation in the RET proto-oncogene (10q11.2). The specific RET mutations are directly related to the MEN2 subtypes, to the specific clinical phenotype, tumor manifestation and severity, particularly the aggressiveness of MTC.
Diagnosis involves identification of MTC, PCC, and eventually PHPT. For the diagnosis of MTC, a thyroid scan is performed and plasma Ct is measured. Elevated basal Ct (>10pg/ml) is specific to this disease. PCC is diagnosed by measuring plasma and/or 24h urinary excretion of catecholamines and metanephrines along with MRI imaging. Molecular genetic testing confirms the diagnosis.
Differential diagnoses include MTC and Hirschsprung disease (see these terms).
Prenatal diagnosis is possible and can identify mutations in the RET gene of offspring.
MEN2 is an autosomal-dominant syndrome and parents have a 50% chance of passing on the RET gene mutation to their offspring. Screening of all first-degree relatives should be performed in order to identify RET mutated gene carriers.
Management and treatment
Specific RET codon mutations correlate with the MEN2 variants and are used to guide treatment plans. Management of MEN2 involves treatment of MTC, PCC and PHPT. Total thyroidectomy with systematic dissection of all lymph nodes is the standard surgery. For patients with PCC, endoscopic adrenal-sparing surgery has become the treatment of choice. PCC can be fatal and should be removed before a thyroidectomy or any other surgical intervention. In MEN2A, PHPT can be treated by excising enlarged parathyroid glands while leaving at least one intact. A prophylactic thyroidectomy is recommended for all patients with an identified RET mutation, but the timing of this surgery is controversial. It has been recommended that this be performed in the first year of life for children with MEN2B and between the ages of 2-5 in patients with MEN2A or FMTC. Lifelong thyroid hormone supplementation is needed.
The prognosis depends on the stage at which MTC is diagnosed and quality of initial surgical treatment. Early diagnosis and complete initial resection of tumors increases life expectancy.