What gene is associated with multiple endocrine neoplasia (MEN) due to germline mutation?

Multiple Endocrine Neoplasia is Associated with Germline Mutation in the RET Proto-oncogene

Multiple endocrine neoplasia (MEN) syndromes, particularly MEN2A and MEN2B, are caused by germline mutations in the RET proto-oncogene. 1

Genetic Basis of MEN Syndromes

• MEN2 results from pathogenic germline variants in the RET proto-oncogene, which is a receptor tyrosine kinase located on chromosome 10q11.21 1
• The RET protein has an extracellular binding domain, a transmembrane domain, and an intracellular segment with a split tyrosine kinase domain 1
• Variants that strongly activate the intracellular tyrosine kinase domain are associated with earlier age of onset and more aggressive disease progression 1
• MEN2 is inherited in an autosomal dominant fashion with high penetrance 2

Types of MEN2 and Clinical Manifestations

• MEN2 is subdivided into MEN2A and MEN2B based on clinical and genetic characteristics 1
• MEN2A (91% of MEN2 cases) is characterized by:
  • Medullary thyroid carcinoma (MTC) (>95% lifetime risk) 1
  • Pheochromocytoma (50% risk) 1
  • Primary hyperparathyroidism (20-30% risk with "High" risk alleles) 1
• MEN2B (9% of MEN2 cases) presents with:
  • MTC (100% risk, often in infancy and more aggressive) 1
  • Pheochromocytoma (50% risk) 1
  • Mucosal neuromas and intestinal ganglioneuromatosis 1
  • Marfanoid habitus 1
  • No hyperparathyroidism 1

Genotype-Phenotype Correlations

• Strong genotype-phenotype correlations exist in MEN2, with clinical features predictably associated with specific codon mutations 1, 3
• The p.M918T variant in exon 16 is considered the highest risk variant and is associated with the majority of MEN2B cases 1
• Codon 634 variants are associated with higher risks of pheochromocytoma and hyperparathyroidism than other RET variants 1
• MEN2A with Hirschsprung disease only occurs in patients with variants in codons 609,611,618,620 1
• The age of onset of MTC varies by genotype: early childhood in MEN2B, adolescence/early adulthood in MEN2A 1

Clinical Management Implications

• Early diagnosis and prophylactic thyroidectomy are critical for MEN2B patients, ideally within the first year of life 1, 4
• For patients with the highest risk allele (p.M918T), thyroidectomy is advised within the first year of life 1
• Genetic testing is essential for at-risk family members to guide surveillance and preventive interventions 1, 5
• The timing of thyroidectomy should be based on the specific RET genotype (high-risk mutations within the first year of life, intermediate-risk mutations by 5 years, low-risk mutations by 10 years) 4

Important Distinctions from Other MEN Syndromes

• Unlike MEN2, MEN1 is caused by inactivating mutations in the MEN1 tumor suppressor gene on chromosome 11q13 1
• MEN1 presents with different tumor spectrum: parathyroid adenomas, pituitary adenomas, and pancreatic neuroendocrine tumors 1, 2
• MEN4, which is rare, is related to mutations in the CDKN1B gene 2
• Unlike MEN2, there are no apparent genotype-phenotype correlations in MEN1 1, 2

Clinical Relevance and Testing Recommendations

• Genetic testing for RET mutations should be offered to all patients with MTC or bilateral pheochromocytoma 4
• In 99% of MEN2 cases, a germline RET mutation can be identified by genetic testing 4
• The de novo mutation rate is approximately 9% in MEN2A and as high as 50% in MEN2B 1
• Early identification of mutation carriers allows for preventive interventions that can significantly reduce morbidity and mortality 1