Does Genotype-Specific Phenotype in Patients with Multiple Endocrine Neoplasia Type 2 Occur as Current Guidelines Predict?

Simple Summary Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant inherited orphan disease, caused by activating germline mutations of the RET gene. This syndrome is mainly characterized by the occurrence of medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. The frequency and occurrence of the mentioned manifestations depend on the respective pathogenic variant of the RET gene. Recommendations for treatment and follow-up of individuals are currently derived from studies characterizing the genotype-dependent phenotype. In this analysis, we examined the clinical presentation of a cohort of 158 MEN2 patients with different mutations, comparing these findings with the risk profiles of the respective mutation in current guidelines. The results are quite consistent, thereby reinforcing the foundations for optimal clinical management.Abstract The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively analyze the individual, genotype-dependent clinical manifestations of a large cohort of MEN2 patients. By comparing their clinical profile with currently existing evidence-based knowledge, an optimal therapy and prevention strategy in terms of prophylactic thyroidectomy and clinical follow-up could be ensured. This is a retrospective single-center study of 158 MEN2 patients who were diagnosed and/or surgically treated at a tertiary referral care center between 1990 and 2022. All participants were categorized according to their pathogenic variant of the RET proto-oncogene. Subsequently, the clinical manifestation of the disease and its time of occurrence was documented. Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.