Is termination of the fetus recommended due to the presence of the RET634F gene associated with Multiple Endocrine Neoplasia type 2A (MEN2A)?

Management of Pregnancy with RET634F Gene Associated with MEN2A

Pregnancy termination is not routinely recommended solely based on the presence of the RET634F gene associated with Multiple Endocrine Neoplasia type 2A (MEN2A), as this condition is treatable with appropriate medical intervention and surveillance.

Understanding RET634F and MEN2A

The RET634F gene mutation is associated with MEN2A, which is characterized by:

• Medullary thyroid carcinoma (MTC) - 95% risk
• Pheochromocytoma - 10-50% risk depending on genotype
• Hyperparathyroidism - lower risk
• Occasionally cutaneous lichen amyloidosis and Hirschsprung disease

Codon 634 variants are classified as "high-risk" RET mutations 1 and are associated with higher risks of pheochromocytoma and hyperparathyroidism than other RET variants 1.

Risk Assessment and Management Approach

For the Fetus/Child:

• The RET634F mutation is inherited in an autosomal dominant pattern
• Early prophylactic thyroidectomy is the standard preventive measure for MTC risk
• For children with "high-risk" alleles (including codon 634), thyroidectomy is recommended before age 5 1
• This intervention is highly effective in preventing subsequent disease when performed by experienced surgeons 1

For the Pregnant Woman:

• If the pregnant woman carries the mutation, monitoring for pheochromocytoma is essential during pregnancy
• Undiagnosed pheochromocytoma can complicate pregnancy, but complications are rare when MEN2A is diagnosed before pregnancy and appropriate monitoring is instituted 2

Current Guidelines on Pregnancy Management

Current clinical guidelines do not recommend pregnancy termination based solely on the presence of the RET634F gene. The British Thyroid Association and American Thyroid Association guidelines focus on appropriate timing of risk-reducing thyroidectomy based on the specific RET mutation, not on pregnancy termination 1.

The UK guidelines on risk-reducing surgery for individuals with cancer-predisposing germline pathogenic variants specifically address RET mutations, stating that:

• Risk-reducing thyroidectomy is an option for carriers of RET gene pathogenic variants
• For high-risk RET variants (codon 634 changes), risk-reducing surgery is recommended before age five 1
• There is no recommendation for pregnancy termination based on RET mutation status

Considerations for Genetic Counseling

When counseling a pregnant woman carrying a fetus with the RET634F mutation:

1. Discuss that MEN2A is a treatable condition with excellent outcomes when managed appropriately
2. Explain the timing of prophylactic thyroidectomy (before age 5 for codon 634 mutations)
3. Review the surveillance protocols for other MEN2A-associated conditions
4. Discuss the availability of prenatal genetic testing for future pregnancies

Conclusion

The presence of the RET634F gene mutation alone does not warrant pregnancy termination. With appropriate medical management including prophylactic thyroidectomy at the recommended age and ongoing surveillance, individuals with MEN2A can have normal life expectancy and quality of life. Genetic counseling should be provided to discuss management options and address any concerns the family may have.