What are the management recommendations for individuals with the RET634F mutation regarding medullary thyroid carcinoma (MTC)?

Management Recommendations for RET634F Mutation and Medullary Thyroid Carcinoma

Prophylactic total thyroidectomy by age 5 years is strongly recommended for individuals with the RET634F mutation, as this is classified as a high-risk (Level B) mutation requiring early intervention to prevent the development of medullary thyroid carcinoma. 1

Risk Profile of RET634F Mutation

The RET634F mutation carries significant implications for medullary thyroid carcinoma (MTC) development:

• C-cell hyperplasia, the precursor to MTC, begins in early childhood in patients with RET634F mutation, with most developing it by age 5 1
• 100% penetrance for MTC development if left untreated in patients with codon 634 mutations 1
• Evidence shows a 100% yield of cancer in removed thyroid specimens for codon 634 mutations 2

Management Algorithm for RET634F Carriers

1. Diagnosis and Screening

• Next-generation sequencing (NGS) is the preferred method to detect RET mutations 1
• For children awaiting surgery:
  • Annual calcitonin measurement starting at age 3 (note: calcitonin may be physiologically elevated in infancy, limiting utility before age 3) 1
  • Annual thyroid ultrasound starting at age 3 1

2. Timing of Prophylactic Surgery

• Prophylactic total thyroidectomy by age 5 years is strongly recommended for RET634F mutation carriers 1
• Do not wait for increases in basal or stimulated calcitonin levels, as this may not guarantee surgery before MTC develops 2

3. Surgical Approach

• Total thyroidectomy alone is recommended for prophylactic surgery 1
• Central neck dissection is generally not required for prophylactic cases when performed at the recommended age 3

4. Postoperative Management

• Normalize (not suppress) TSH with levothyroxine, as C-cells lack TSH receptors 1
• Postoperative surveillance at 2-3 months includes:
  • Serum calcitonin and CEA monitoring
  • Neck imaging if calcitonin is detectable or CEA elevated 1

5. Long-term Surveillance

• Lifelong surveillance for MEN2A-associated conditions:
  • Screening for pheochromocytoma starting at age 10 (every 2 years)
  • Annual hyperparathyroidism screening with serum calcium and PTH monitoring 1

Important Clinical Considerations

• Surgical Outcomes: When performed at the recommended age, prophylactic thyroidectomy has demonstrated excellent outcomes with no permanent hypoparathyroidism or recurrent nerve paralysis in young children 3

• Prognostic Factors: Better prognosis is associated with:

  • Age at diagnosis <40 years
  • Early tumor stage
  • Postoperative undetectable calcitonin levels 1

• Treatment for Advanced Disease: For patients ≥12 years with advanced or metastatic RET-mutant MTC, FDA-approved treatments include:

  • Selpercatinib (objective response rates: 69-73%)
  • Pralsetinib (objective response rates: 60-71%) 1

Pitfalls to Avoid

• Delaying Surgery: Evidence shows that delaying surgery beyond the recommended age increases the risk of MTC development. Studies show that even young children (age 5) with codon 634 mutations can already have MTC 2, 4

• Inadequate Follow-up: Failure to implement lifelong surveillance for other MEN2A-associated conditions can lead to missed diagnoses of pheochromocytoma or hyperparathyroidism 1

• Relying on Calcitonin Alone: While calcitonin is useful for monitoring, normal calcitonin levels do not guarantee absence of disease in RET634F carriers, and should not delay recommended prophylactic surgery 2