Multiple endocrine neoplasia type 2 (MEN2) is a hereditary condition defined by an increased risk for medullary thyroid carcinoma (MTC). MEN2 is sometimes classified into three subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). MEN2A accounts for 95% of MEN2 cases and also confers an increased risk for parathyroid neoplasms, ranging from benign adenomas to hyperparathyroidism (Wells et al., 2015; Eng, 1999). MEN2A and MEN2B are both associated with pheochromocytoma risk as well. Pathogenic/likely pathogenic (P/LP) variants within the RET gene are associated with all types of MEN2.

In MEN2A, MTC typically occurs in early adulthood and causes an increased risk for pheochromocytoma, parathyroid adenoma, or hyperplasia. Clinical diagnostic criteria for MEN2A include the presence of at least two of the following endocrine tumors: medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia in a single individual or in close relatives (Eng, 1999). Hirschsprung disease (HD) occurs in approximately 7% of individuals with MEN2A, and approximately 2-5% of individuals with HD have MEN2A. MEN2A with HD is almost always due to P/LP variants in exon 10 of the RET oncogene.

A clinical diagnosis of FMTC should be considered in families with at least four diagnoses of MTC and no pheochromocytoma or parathyroid adenoma/hyperplasia (Eng,1999). In FMTC, MTC is usually present in middle age. The most recent recommendations from the American Thyroid Association (ATA) recommend considering FMTC as part of the phenotypic spectrum of MEN2A (Wells et al., 2015). 

In MEN2B, MTC typically occurs in childhood and also predisposes to increased risk for pheochromocytoma (approximately 50%). Early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, and an asthenic ‘marfanoid’ body habitus are diagnostic hallmarks of MEN2B (Eng, 1999). The majority of cases of MEN2B are due to the M918T variant in the RET gene, which is associated with aggressive disease progression (Wasserman, 2017). Rarely MEN2B can have an atypical presentation with onset in the 2nd or 3rd decade. This subset of patients have been shown to harbor two RET germline P/LP variants in tandem within the same allele.

Genetic testing for RET can be considered when an individual meets diagnostic criteria for MEN2 based on clinical findings, and in those with primary C-cell hyperplasia or MTC (Eng et al., 1999).  

Most P/LP variants in the RET gene are found in exons 10, 11, and 13-16 (Eng, 1999). While targeted analysis is preferred as a first step to testing, targeted exon sequencing is no longer widely available. Sequence analysis of RET may be performed if no P/LP variant is found by select exon testing, or if select exon testing is unavailable. Genetic testing for inherited RET P/LP variants is often medically indicated to establish a diagnosis and will likely impact medical management, as the particular variant found in the RET gene may indicate the subtype of MEN2. Wasserman et al (2017) review special considerations for the care of children with MEN2A/B. Genotype and calcitonin levels can help guide timing of thyroidectomy. For those at high risk based on genotype, prophylactic thyroidectomy may be performed as early as the first year of life. Therefore genetic testing has clinical utility in not only confirming the diagnosis, but helping to guide medical management for affected individuals. In addition, recent research has focused on the development of RET-targeted therapies, given that somatic RET P/LP variants are found in a number of different types of more common sporadic cancers (Mulligan, 2018; Redaelli et al., 2018). In 2020, the FDA approved the use of selpercatinib and pralsetinib for certain RET-positive thyroid carcinomas (FDA, 2020).