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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 RET proto-oncogene on chromosome 10, have been identified in MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The RET protein is a receptor tyrosine kinase; MEN 2A and FMTC mutations result in activation of certain intracellular pathways.
Symptoms and Signs
Clinical features depend on the type of tumor present (Table 1: Multiple Endocrine Neoplasia (MEN) Syndromes: Conditions Associated With MEN Syndromes ).
Thyroid
Almost all patients have medullary thyroid carcinoma (MTC—see Thyroid Disorders: Medullary Carcinoma). The tumor usually develops during childhood and begins with thyroid parafollicular C-cell hyperplasia. Tumors are frequently multicentric.
Adrenal
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 (see Adrenal Disorders: 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 presentation. 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.
Parathyroid
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.
Other manifestations
Cutaneous lichen amyloidosis, a pruritic, scaly, papular skin lesion, located in the interscapular region or on extensor surfaces, occurs in some MEN 2A kindreds. Increased incidence of Hirschsprung's disease has been reported in children in at least one MEN 2A kindred.
Diagnosis
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 Adrenal Disorders: 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.
Screening
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. Among affected family members, annual screening for hyperparathyroidism and pheochromocytoma should begin in early childhood and continue indefinitely. Screening for hyperparathyroidism is with measurement of serum Ca. Screening for pheochromocytoma includes questions about symptoms, measurement of BP, and laboratory testing.
Treatment
In patients presenting with pheochromocytoma and either MTC or hyperparathyroidism, the pheochromocytoma should be removed first; even if asymptomatic, it greatly increases risk of other surgeries. Once MTC has metastasized, chemotherapy and radiation therapy are largely ineffective in lengthening survival but may slow disease progression. Radioimmunotherapy has improved survival in initial studies.
Once genetic testing identifies a person as having a RET mutation, prophylactic thyroidectomy is recommended, generally when the child is between 4 and 6 yr; this potentially fatal condition can be cured or prevented by early thyroidectomy.
Last full review/revision June 2008 by Patricia A. Daly, MD; Lewis Landsberg, MD
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