Questions remain concerning the natural history of MEN 2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. For example, a case report documents MTC before age 5 years in two siblings with MEN 2A. Conversely, another case report documents onset of cancer in midlife or later in some families with FMTC, as well as in elderly relatives who carry the FMTC genotype but have not developed cancer. The possibility that certain mutations (e.g., Cys634) might convey a significantly worse prognosis, if confirmed, may permit tailoring intervention based on knowing the specific RET mutation. These clinical observations suggest that the natural history of the MEN 2 syndromes is variable and could be subject to modifying effects related to specific RET mutations, other genes, behavioral factors, or environmental exposures.
Level of evidence: 5
Screening of at-risk individuals for pheochromocytoma
The presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN 2A or MEN 2B. However, childhood pheochromocytomas are rare in MEN 2. The ATA has recommended that annual screening for pheochromocytoma be considered after the age of 8 years in patients with RET mutations in codons 630 and 634 as well as those associated with MEN 2B. In carriers of other MEN 2A RET mutations, ATA recommends that annual screening begin by age 20 years. Patients with RET mutations associated only with FMTC should have periodic screening for pheochromocytoma beginning at age 20 years. MRI or other imaging tests should be ordered only if the biochemical results are abnormal.[130,131] Studies of individuals with sporadic or hereditary pheochromocytoma (including, but not limited to, individuals with MEN 2) have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines, because of the episodic nature of catecholamine excretion.[25,26,27,28,29,30,31,132] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of pheochromocytoma.[31,133] In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized pheochromocytoma. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery.
Level of evidence: 5
Screening of at-risk individuals for hyperparathyroidism
MEN 2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease-which, if left untreated, may become symptomatic. Childhood hyperparathyroidism is rare in MEN 2. Three studies found the median age at diagnosis was about 38 years.[57,134,135] The ATA provides recommendations for annual screening for hyperparathyroidism. Annual screening should begin at age 8 years in carriers of mutations in codons 630 and 634 and at age 20 years for carriers of other MEN 2A RET mutations. Patients with mutations associated only with FMTC should have periodic testing after the age of 20 years. Testing should include albumin-corrected calcium or ionized serum calcium with or without intact PTH measurement.