What is the recommended screening protocol for individuals at risk for multiple endocrine neoplasia type 2A (MEN 2A), including germ‑line RET (rearranged during transfection) genetic testing, annual biochemical surveillance (plasma free metanephrines, serum calcitonin, serum calcium and parathyroid hormone), imaging when indicated, and timing of prophylactic total thyroidectomy?

Screening for MEN2A

All individuals at risk for MEN2A should undergo germline RET genetic testing as the primary screening tool, with the timing and intensity of subsequent biochemical surveillance and prophylactic thyroidectomy determined by the specific RET mutation risk category. 1

Genetic Testing Strategy

RET proto-oncogene analysis is the first-choice screening procedure and should be offered to all at-risk family members, as it can be identified in 99% of MEN2 cases and allows for early identification of mutation carriers before clinical disease develops. 2, 3, 4 The de novo mutation rate is approximately 9% in MEN2A, so genetic testing should be considered even without a clear family history. 1, 2

• Genetic assessment should begin at age 5-10 years for known at-risk family members, though some advocate starting as early as age 4 years depending on the specific mutation. 1
• Direct DNA sequencing of RET exons 10,11, and 16 identifies the most common MEN2A mutations, particularly codon 634 variants (C634Y, C634R). 4, 5

Risk Stratification by RET Genotype

The timing of surveillance and prophylactic surgery depends critically on mutation-specific risk categories:

High-Risk Alleles (Codon 634,883)

• Prophylactic total thyroidectomy should be performed by age 5 years, or earlier if calcitonin levels become elevated. 1
• Annual ultrasound and serum calcitonin screening should begin at age 3 years. 1
• Metastatic disease is rare if serum calcitonin remains <40 pg/ml. 1

Moderate-Risk Alleles (Codons 611,620, others)

• Thyroidectomy timing is more variable and should be guided by annual calcitonin trends and family history, as penetrance varies widely (median time to MTC: 19 years for codon 620 vs. 56 years for codon 611). 1
• Surgery is recommended when calcitonin demonstrates an upward trend or if biopsy shows cytological evidence of MTC. 1
• Annual surveillance with serum calcitonin and thyroid ultrasound is mandatory if surgery is delayed. 1

Critical caveat: Ultrasound is less sensitive than calcitonin for MTC diagnosis and should not be used to exclude malignancy or delay surgery. 1

Biochemical Surveillance Protocol

Medullary Thyroid Carcinoma Screening

• Annual serum calcitonin measurement is the primary biochemical marker for MTC surveillance. 1
• Physiological calcitonin levels in infancy may reach 50 pg/ml with a decreasing trend over the first 3 years, limiting utility in very young children. 1
• Annual thyroid ultrasound complements calcitonin screening but cannot replace it. 1

Pheochromocytoma Screening

• Screening should commence at age 11 years for high-risk allele carriers and age 16 years for moderate-risk allele carriers. 1
• Plasma free metanephrines and normetanephrines (or 24-hour urinary fractionated metanephrines) are the recommended screening tests. 1
• Biochemical screening must be performed prior to any planned surgery or pregnancy, regardless of age. 1
• Imaging should only be pursued if biochemical tests are abnormal; MRI of abdomen/pelvis is preferred in pediatric patients to avoid radiation. 1
• Pre-operative alpha-adrenergic blockade is essential before any surgery in patients with biochemically confirmed pheochromocytoma. 1

Hyperparathyroidism Screening

• Screening with serum calcium should begin at age 11 years for high-risk allele carriers and age 16 years for moderate-risk allele carriers. 1
• If hypercalcemia is detected, measure contemporaneous intact parathyroid hormone (iPTH) and consider 25-OH Vitamin D levels. 1
• Hypercalcemia with normal or elevated iPTH is diagnostic of hyperparathyroidism and requires referral to experienced endocrinologist and surgeon. 1

Prophylactic Thyroidectomy Timing

Total thyroidectomy performed by surgeons experienced in MEN2 is the primary preventive strategy and has been shown to be effective in preventing subsequent biochemical evidence of disease. 1

• For highest-risk alleles (p.M918T, associated with MEN2B): Thyroidectomy within the first year of life. 1, 2
• For high-risk alleles (codons 634,883): Thyroidectomy by age 5 years or when calcitonin becomes elevated. 1
• For moderate-risk alleles: Thyroidectomy when calcitonin shows upward trend or cytological evidence of MTC appears. 1

Pre-operative staging with ultrasound or cross-sectional imaging (contrast-enhanced neck CT or MRI) is essential to identify regional lymphadenopathy and facilitate adequate surgical planning. 1

Clinical Outcomes and Benefits

Early identification through RET screening allows significantly improved outcomes: Asymptomatic mutation carriers identified through screening undergo surgery at younger ages (18.1 vs. 39.0 years), have less aggressive MTC (smaller tumors, fewer lymph node metastases), and lower recurrence rates (20% vs. 100%) compared to symptomatic presentations. 6

Biochemical cure rates are substantially higher in MEN2A patients identified through screening (56%) compared to those presenting symptomatically, with cause-specific mortality at 18 years of only 7% versus 23% for sporadic MTC. 7