Multiple Endocrine Neoplasia, Type 2A (MEN 2A)
(MEN 2; Multiple Endocrine Adenomatosis, Type 2; Sipple Syndrome)
(See also Overview of Multiple Endocrine Neoplasias (MEN).)
Multiple endocrine neoplasia, type 2A (MEN 2A) is a hereditary syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing 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).
Pheochromocytoma usually 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, 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 MEN 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.
Cutaneous lichen amyloidosis, a pruritic, scaly, papular skin lesion, located in the interscapular region or on extensor surfaces, occurs in some MEN 2A kindreds. Hirschsprung disease is present in 2 to 5% of MEN 2A patients.
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; some experts recommend genetic testing for RET germline mutations in all patients with newly diagnosed MTC (1).
Because pheochromocytoma may be asymptomatic, its exclusion may be difficult. The most sensitive tests are measurement of 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 finding 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. The specific RET mutation also predicts phenotypic characteristics such as age of onset, aggressiveness of MCT, and presence of other endocrinopathies, so is important in clinical management. 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 calcium levels. 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. Laparoscopic adrenalectomy, which has lower morbidity, is preferred to open laparotomy. Because bilateral pheochromocytomas are common, adrenal-sparing surgery may be appropriate in some patients (1).
Surgery for MTC should include total thyroidectomy and central compartment lymph node dissection, with additional lymph node dissection if indicated based on preoperative imaging. Postsurgical assessment for residual or recurrent disease should include measurement of serum calcitonin and imaging with neck ultrasonography and, when indicated, CT or MRI of neck and chest, bone scan, or PET scan.
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. Postoperative adjuvant external beam radiation should be considered in patients at high risk of local recurrence and those at risk for airway obstruction. 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. Depending on the particular mutation, prophylactic thyroidectomy as early as the first months of life may be indicated. MTC can be cured or prevented by early thyroidectomy.
1. Castinetti F, Qi XP, Walz AL, et al: Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromoctyoma associated with multiple endocrine neoplasia type 2: An international retrospective population-based study. Lancet Oncol 15(6):648–655, 2014.
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.