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

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

Multiple endocrine neoplasia (MEN) type 2 is caused by germline mutations in the RET proto-oncogene, making option (b) the correct answer. 1, 2

Genetic Basis of Different MEN Types

• MEN type 2 (MEN2) results from pathogenic germline variants in the RET proto-oncogene, which is a receptor tyrosine kinase located on chromosome 10q11.21 2
• MEN2 is inherited in an autosomal dominant fashion with high penetrance and striking genotype-phenotype correlations 1
• MEN1, in contrast, is caused by inactivating pathogenic variants in the MEN1 gene, not the RET proto-oncogene 1, 3
• MEN4, which is extremely rare, is associated with mutations in the CDKN1B gene 3

Clinical Subtypes of MEN2

• MEN2 is subdivided into MEN2A and MEN2B based on clinical and genetic characteristics 2
• MEN2A (91% of MEN2 cases) is characterized by:
  • Medullary thyroid carcinoma (MTC) with >95% lifetime risk
  • Pheochromocytoma with 50% risk
  • Primary hyperparathyroidism with 20-30% risk 2, 4
• MEN2B (9% of MEN2 cases) presents with:
  • More aggressive MTC with 100% risk, often in infancy
  • Pheochromocytoma with 50% risk
  • Mucosal neuromas and intestinal ganglioneuromatosis
  • Marfanoid habitus
  • No hyperparathyroidism 1, 2

Genotype-Phenotype Correlations in MEN2

• Strong genotype-phenotype correlations exist in MEN2, with clinical features predictably associated with specific codon mutations 2, 5
• The p.M918T variant in exon 16 is the highest risk variant and is associated with most MEN2B cases 2
• Codon 634 variants are associated with higher risks of pheochromocytoma and hyperparathyroidism than other RET variants 2, 6
• Genetic testing can identify RET mutations in approximately 99% of MEN2 cases 4

Clinical Significance of RET Mutations

• Early identification of RET mutation carriers allows for preventive interventions that significantly reduce morbidity and mortality 2
• Prophylactic thyroidectomy is recommended based on the specific RET mutation:
  • Highest risk mutations (p.M918T): within the first year of life
  • High risk mutations: early childhood
  • Moderate risk mutations: by adolescence 1, 4
• The de novo mutation rate is approximately 9% in MEN2A and as high as 50% in MEN2B 2

Distinguishing from Other Options

• p53 gene (option a) mutations are associated with Li-Fraumeni syndrome, not MEN 5
• N-myc gene (option c) amplification is associated with neuroblastoma, not MEN 7
• APC gene (option d) mutations are associated with familial adenomatous polyposis, not MEN 5

Key Takeaway

• Genetic testing for RET proto-oncogene mutations is essential for diagnosis, risk stratification, and management of MEN2 1, 2, 4
• The specific RET mutation guides clinical management, particularly the timing of prophylactic thyroidectomy to prevent or cure medullary thyroid carcinoma 4