The RET gene (Rearranged during transfection proto-oncogene) encodes for a receptor tyrosine kinase known as RET, that interacts with the glial-derived neurotropic factor (GDNF) family of ligands and activates the MAP kinase pathway [50]. Unlike most inherited cancer syndromes, the mutations in the RET gene do not correspond to the two-hit hypothesis (in which the germline mutation is considered a first “hit” that must be followed by a somatic “hit” in the other allele), rather the mutations are gain-of-function [51]. This leads to a high penetrance (as much as 90 %), and early manifestations of disease [47]. Also, there are strong genotype-phenotype correlations, with certain mutations, especially p.Met918Thr, known to cause the MEN2B subtype [52]. Mutations have been classified into four risk levels, allowing for a more tailored management [49].

The first manifestation of MEN2A is usually MTC . It occurs in greater than 90 % of patients [49]. C-cell hyperplasia can predate the development of the MTC, as seen in specimens of patients who underwent prophylactic surgery [53]. The tumors are aggressive and 70 % of patients have regional node metastasis at the time of diagnosis [54]. The treatment is thyroidectomy with lymph node dissection [49]. Prophylactic thyroidectomy is indicated in patients diagnosed by genetic testing for mutations in RET. In general, the recommendation is for surgery before age 5, except in patients with low risk mutations and who have a family history of less aggressive MTC—these patients can be followed with annual calcitonin measurements and neck ultrasounds [48]. The penetrance of MTC in MEN2B is nearly 100 %. At the time of a new presentation, most patients have metastatic disease [47]. Therefore, if a patient has a high risk mutation associated with MEN2B (whether they have the full phenotype) prophylactic thyroidectomy is indicated at the earliest possible age [48]. After obtaining family history and subsequent definitive genetic testing, multiple family members may be offered prophylactic surgery and spared the significant morbidity and mortality of MEN2.

Pheochromocytomas are also seen in most patients with MEN2A and in 50 % of those with MEN2B [49]. About 4 % become malignant [55]. Unilateral (rather than bilateral) adrenalectomy has become the standard of care [48]. Screening for this manifestation should start at age 8 [49]. Hyperparathyroidism is usually subclinical or mild and typically presents many years after MTC [56]. As with hyperparathyroidism secondary to MEN1, there is no consensus on the optimal surgical management (partial, subtotal, or total parathyroidectomy with or without forearm autograft).

Because of the clear genotype/phenotype correlation, all patients with suspected MEN2 should have genetic testing and all patients with medullary thyroid cancer are candidates for testing regardless of family history. Patients with a pheochromocytoma presenting in childhood, and patients with a pheochromocytoma or parathyroid adenoma and a family history of endocrine tumors should also be considered for genetic testing. If the presentation is a pheochromocytoma, the differential includes the several genes causative of Hereditary Pheochromoctypma/Paraganglioma syndrome. MEN1 and 4 are also potentially in the differential diagnosis. As noted previously, these genetic test results should be interpreted with caution and may be inconclusive.