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Multiple Endocrine Neoplasia, Type 2A (MEN 2A)
(MEN 2; Multiple Endocrine Adenomatosis, Type 2; Sipple Syndrome)
Multiple endocrine neoplasia, type 2A (MEN 2A) is a hereditary syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, hyperparathyroidism, and occasionally cutaneous lichen amyloidosis. Clinical features depend on the glandular elements affected. Familial medullary thyroid carcinoma is a distinct variant of MEN 2A. Diagnosis involves genetic testing. Hormonal and imaging tests help locate the tumors, which are removed surgically when possible.
Mutations in the RETproto-oncogene on chromosome 10 have been identified in MEN 2A, MEN 2B, and familial medullary thyroid carcinoma. The RET protein is a receptor tyrosine kinase; MEN 2A and familial medullary thyroid carcinoma mutations result in activation of certain intracellular pathways.
Clinical features depend on the type of tumor present (see Table: Conditions Associated With MEN Syndromes).
Almost all patients have medullary thyroid carcinoma (MTC—see Thyroid Cancers : Medullary thyroid carcinoma). The tumor usually develops during childhood and begins with thyroid parafollicular C-cell hyperplasia. Tumors are frequently multicentric.
Pheochromocytoma generally originates in the adrenal glands. Pheochromocytoma occurs in 40 to 50% of patients within a MEN 2A kindred, and in some kindreds pheochromocytoma accounts for 30% of deaths. In contrast to sporadic pheochromocytoma (see Pheochromocytoma), the familial variety within MEN 2A begins with adrenal medullary hyperplasia and is multicentric and bilateral in > 50% of cases. Extra-adrenal pheochromocytomas are rare. Pheochromocytomas are almost always benign, but some tend to recur locally.
Pheochromocytomas that occur with MEN 2A (and 2B) usually produce epinephrine disproportionately to norepinephrine, in contrast to sporadic cases.
Hypertensive crisis secondary to pheochromocytoma is a common manifestation. Hypertension in MEN 2A patients with pheochromocytoma is more often paroxysmal than sustained, in contrast to the usual sporadic case. Patients with pheochromocytomas may have paroxysmal palpitations, anxiety, headaches, or sweating; many are asymptomatic.
Ten to 20% of patients have evidence of hyperparathyroidism (which may be long-standing), with hypercalcemia, nephrolithiasis, nephrocalcinosis, or renal failure. Hyperparathyroidism frequently involves multiple glands as either diffuse hyperplasia or multiple adenomas, and mild abnormalities in parathyroid function may also be present in MEN 2A.
Many cases are identified during screening of family members of known cases. MEN 2A should also be suspected in patients with bilateral pheochromocytoma or at least 2 of its characteristic endocrine manifestations. The diagnosis can be confirmed with genetic testing. Although only 25% of MTC cases are familial, genetic testing of people with apparent sporadic MTC should be considered if patients are < 35 yr, tumors are bilateral or multicentric, or a family history is suspected.
Because pheochromocytoma may be asymptomatic, its exclusion may be difficult (see Pheochromocytoma : Diagnosis). The most sensitive tests are plasma free metanephrines and fractionated urinary catecholamines (particularly epinephrine). CT or MRI is useful in localizing the pheochromocytoma or establishing the presence of bilateral lesions.
Hyperparathyroidism is diagnosed by hypercalcemia, hypophosphatemia, and increased parathyroid hormone level.
Genetic screening of family members of MEN 2A patients is now the diagnostic test of choice; the availability of such testing has made biochemical screening for early MTC largely obsolete. Preimplantation genetic diagnosis and prenatal chorionic villus sampling or amniocentesis have been used for antenatal diagnosis. Among affected family members, annual screening for hyperparathyroidism and pheochromocytoma should begin in early childhood and continue indefinitely. Screening for hyperparathyroidism entails measurement of serum Ca. Screening for pheochromocytoma includes questions about symptoms, measurement of pulse rate and BP, and laboratory testing.
In patients presenting with pheochromocytoma and either MTC or hyperparathyroidism, the pheochromocytoma should be removed first, even if asymptomatic, because it greatly increases risk during other surgeries. Once MTC has metastasized, tyrosine kinase inhibitors, including newly available cabozantinib and vandetanib, can lengthen progression-free survival. Clinical trials of other tyrosine kinase inhibitors for metastatic MTC are ongoing. Cytotoxic chemotherapy and radiation therapy are largely ineffective in lengthening survival but may slow disease progression. Some studies have shown lengthened survival with immunotherapy (eg, tumor-derived vaccines or tumor cell transfectants) and radioimmunotherapy (eg, radioisotope-coupled monoclonal antibodies).
Once genetic testing identifies a child as having a RET mutation, prophylactic thyroidectomy is recommended when the child is ≤ 5 yr; MTC can be cured or prevented by early thyroidectomy.
Most patients have medullary thyroid carcinoma, typically beginning in childhood.
Other manifestations are those of hormone excess, particularly hypertension due to pheochromocytoma and hypercalcemia due to hyperparathyroidism.
Patients should have genetic testing for RET proto-oncogene mutations and clinical evaluation for other tumors of the syndrome.
Tumors are excised when possible, beginning with any pheochromocytoma.
Prophylactic thyroidectomy is recommended.
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