Will somatic gene editing of the thyroid be a future alternative to prophylactic thyroidectomy in patients with the RET (Ret proto-oncogene) 634F mutation and Multiple Endocrine Neoplasia type 2A (MEN2A)?

Somatic Gene Editing for RET634F MEN2A Mutation: Future Prospects vs. Prophylactic Thyroidectomy

Somatic gene editing of the thyroid is unlikely to be a viable alternative to prophylactic thyroidectomy for patients with RET634F MEN2A mutation in the foreseeable future, and prophylactic total thyroidectomy by age 5 remains the gold standard treatment. 1

Current Standard of Care for RET634F Mutation

The American Thyroid Association and National Comprehensive Cancer Network strongly recommend prophylactic total thyroidectomy by age 5 years for children with codon 634 mutations, as this is classified as a high-risk (Level B) mutation 1. This recommendation is based on:

• The high penetrance of medullary thyroid cancer (MTC) in these patients
• The earliest reported MTC with these mutations occurring at age 7 1
• Excellent outcomes with prophylactic surgery, with no evidence of residual or recurrent MTC at three years follow-up 2

Limitations of Gene Editing for RET634F Mutation

Several critical barriers exist that make gene editing unlikely to replace prophylactic thyroidectomy in the near future:

• Technical challenges: Current gene editing technologies lack delivery mechanisms to reach every thyroid C-cell with sufficient efficiency 1
• Molecular complexity: RET mutations in MEN2A cause constitutive activation through disruption of intramolecular disulfide bonds, requiring precise editing of every cell in the thyroid to prevent malignant transformation 1
• Regulatory hurdles: Extensive safety data and regulatory approval would be required, with a realistic timeline for clinical application likely being decades rather than years 1

Risk Stratification and Timing of Prophylactic Thyroidectomy

The risk of MTC development varies by specific RET mutation:

• Highest risk (Level D): Total thyroidectomy during the first year of life (e.g., codons 883,918,922 in MEN2B) 1
• High risk (Level B): Total thyroidectomy by age 5 years (e.g., codons 609,611,618,620,630,634 in MEN2A) 1
• Moderate risk (Level A): Annual calcitonin testing and ultrasound, with thyroidectomy potentially deferred if tests are normal 1

For patients with RET634F specifically:

• The yield of cancer in removed thyroid was 100% for codon 634 mutations (9/9 patients across 5 families) in one study 3
• In the high-risk category (including codon 634), MTC was present in 30% of children aged 3 years or less, 44% aged 4-6 years, and 69% aged 7-12 years 4

Surgical Approach and Outcomes

Prophylactic thyroidectomy for RET634F mutation carriers should include:

• Total thyroidectomy alone for prophylactic surgery 1
• Consideration of central neck dissection only if calcitonin is elevated or ultrasound is abnormal 1
• Surgery performed at tertiary care institutions by high-volume thyroid surgeons 5

Outcomes of prophylactic thyroidectomy are excellent:

• No operative complications in early studies 2
• Postoperative normalization of calcitonin serum levels achieved in 99.1% of children with raised preoperative values 4
• No residual structural disease or recurrence observed in long-term follow-up 4

Comprehensive Management Beyond Surgery

For patients with RET634F mutations, management extends beyond thyroidectomy:

• Annual screening for pheochromocytoma starting at age 10 (every 2 years), as codon 634 variants are associated with higher risks 1
• Annual hyperparathyroidism screening, including serum calcium and PTH monitoring 1
• Postoperative levothyroxine to normalize TSH (not suppress) 1
• Surveillance 2-3 months postoperative including serum calcitonin and CEA monitoring 1

Rare Exceptions

While prophylactic thyroidectomy is strongly recommended, rare cases of late-onset MTC in RET634R carriers have been reported:

• A 71-year-old woman newly diagnosed with hereditary MTC related to a RET C634R germline mutation without distant metastases or other MEN2A manifestations 6

However, these exceptions are extremely rare and do not change the standard recommendation for early prophylactic thyroidectomy.

Conclusion

Despite advances in gene editing technology, prophylactic thyroidectomy remains the gold standard for preventing MTC in patients with RET634F mutations. The technical challenges, molecular complexity, and regulatory hurdles make somatic gene editing an unlikely alternative in the foreseeable future. The excellent outcomes of prophylactic thyroidectomy, with minimal complications when performed by experienced surgeons, further support its continued role as the primary preventive strategy.