What is the hallmark of Multiple Endocrine Neoplasia Type 2 (MEN2) syndromes?

The Hallmark of Multiple Endocrine Neoplasia Type 2 Syndromes

The hallmark of multiple endocrine neoplasia type 2 (MEN2) syndromes is medullary thyroid carcinoma (MTC). 1, 2

Characteristics of MEN2 and Its Subtypes

• MEN2 results from pathogenic germline variants in the RET proto-oncogene and is characterized by a near 100% lifetime risk of developing medullary thyroid carcinoma 1
• MEN2 is subdivided into two main clinical variants: MEN2A and MEN2B, with MTC being the common feature in both subtypes 1, 2
• MEN2A accounts for 91% of MEN2 patients (including those with familial MTC) while MEN2B accounts for the remaining 9% 1

MEN2A Features:

• Characterized by MTC (>95% lifetime risk), pheochromocytoma (50% risk), and primary hyperparathyroidism (20-30% risk) 1, 2
• Can be further classified into "classical MEN2A", MEN2A with cutaneous lichen amyloidosis, and MEN2A with Hirschsprung disease 1
• Familial medullary thyroid carcinoma (FMTC) is now considered a variant of MEN2A with decreased penetrance of pheochromocytoma and hyperparathyroidism 1

MEN2B Features:

• Characterized by MTC (100% risk) that presents earlier and is more aggressive than in MEN2A 1
• Also includes pheochromocytoma (50% risk) but no hyperparathyroidism 1
• Distinguished by additional features such as mucosal neuromas, intestinal ganglioneuromatosis, and marfanoid habitus 1, 2

Genetic Basis and Genotype-Phenotype Correlation

• MEN2 is caused by activating mutations in the RET proto-oncogene located on chromosome 10q11.21 1, 2
• Strong genotype-phenotype correlations exist, with specific mutations predicting disease aggressiveness and component manifestations 1, 2
• The p.M918T variant in exon 16 is considered the highest risk variant and is associated with the majority of MEN2B cases 1, 2
• Variants in exons 10 and 11 comprise 95% of individuals with MEN2A 1

Clinical Management Implications

• Early diagnosis through genetic testing is crucial for at-risk family members 2
• Prophylactic thyroidectomy is recommended based on the specific RET mutation risk category 1, 2
• For patients with highest risk mutations (such as p.M918T in MEN2B), thyroidectomy is advised within the first year of life 1, 2
• For moderate risk mutations, thyroidectomy may be performed at a later age or after abnormal C-cell stimulation test results 1

Common Pitfalls in Diagnosis and Management

• While pheochromocytoma is an important component of MEN2 (present in 10-50% of cases), it is not the hallmark feature that defines the syndrome 1
• Hyperparathyroidism is only present in MEN2A (not MEN2B) and has lower penetrance (20-30%) than MTC 1, 2
• Approximately 50% of MEN2B cases occur de novo, highlighting the importance of clinical recognition even without family history 1
• Delayed diagnosis of MEN2B can lead to metastatic MTC, emphasizing the critical importance of early identification and intervention 1