What are the recommended genetic, biochemical, and imaging screenings and the timing of prophylactic total thyroidectomy for individuals with a known RET mutation or a first‑degree relative with multiple endocrine neoplasia type 2?

MEN2 Screening: Comprehensive Protocol for RET Mutation Carriers

All individuals with a known RET mutation or first-degree relatives of MEN2 patients require immediate genetic testing, followed by risk-stratified biochemical surveillance and prophylactic total thyroidectomy timed according to the specific RET codon mutation identified. 1, 2

Genetic Testing Strategy

Germline RET testing is the primary screening tool and should be performed in all at-risk individuals, including those with apparently sporadic medullary thyroid carcinoma (MTC), as approximately 6% of clinically sporadic cases harbor germline mutations. 2

• RET analysis detects pathogenic variants in approximately 95-99% of MEN2 cases, enabling identification of carriers before clinical disease manifests 1, 3
• First-degree relatives of confirmed RET mutation carriers have a 50% probability of inheriting the mutation and must undergo rapid genetic screening 3
• Genetic testing should begin between ages 5-10 years for known at-risk family members, with some experts recommending initiation as early as age 4 years for certain high-risk mutations 1
• The de novo mutation rate is approximately 9% in MEN2A and up to 50% in MEN2B, justifying testing even without known family history 1, 2

Risk Stratification by RET Genotype

The specific RET codon mutation dictates surveillance intensity and surgical timing. Three risk categories exist:

Highest Risk Alleles (Grade 1: codons 883,918,922)

• Prophylactic total thyroidectomy must be performed within the first year of life 1, 2
• The p.M918T variant (exon 16) is associated with MEN2B and represents the most aggressive phenotype 1
• These mutations activate the intracellular tyrosine kinase domain most strongly, resulting in earliest onset and most aggressive disease 1

High Risk Alleles (Grade 2: codons 609,611,620,630,634,804,891)

• Prophylactic total thyroidectomy should be performed by age 5 years, or earlier if serum calcitonin becomes elevated 1, 2
• Annual thyroid ultrasound and serum calcitonin screening commence at age 3 years 1
• Codon 634 mutations carry the highest risk for pheochromocytoma (50%) and hyperparathyroidism (20-30%) among all RET variants 1, 2
• Metastatic disease is uncommon when serum calcitonin remains below 40 pg/mL 1

Moderate Risk Alleles (Grade 3: codon 611,620, others)

• Median age to develop MTC varies significantly: approximately 19 years for codon 620 versus 56 years for codon 611 1
• Surgery is indicated when serum calcitonin shows an upward trend or when fine-needle aspiration confirms MTC 1
• If surgery is delayed, mandatory annual surveillance with serum calcitonin and thyroid ultrasound is required 1

Biochemical Surveillance for Medullary Thyroid Carcinoma

Annual measurement of serum calcitonin is the primary biochemical marker for MTC surveillance and cannot be replaced by imaging. 1

• In infancy, physiological calcitonin levels may reach approximately 50 pg/mL and decline over the first three years, limiting utility in very young children 1
• Annual thyroid ultrasound serves as an adjunct but is less sensitive than calcitonin for detecting MTC and should not be used to exclude malignancy or postpone surgery 1
• Serum carcinoembryonic antigen (CEA) should also be measured as a complementary tumor marker 4

Pheochromocytoma Screening

Biochemical screening for pheochromocytoma must be performed before any planned surgery or pregnancy, regardless of patient age, to prevent hypertensive crisis. 1, 2

• Screening should start at age 11 years for high-risk RET allele carriers and at age 16 years for moderate-risk carriers 1
• Recommended biochemical tests are plasma free metanephrines and normetanephrines, or 24-hour urinary fractionated metanephrines 1
• Imaging is reserved for abnormal biochemical results; magnetic resonance imaging of the abdomen/pelvis is preferred in pediatric patients to avoid ionizing radiation 1
• Pre-operative alpha-adrenergic blockade is essential for patients with biochemically confirmed pheochromocytoma prior to any surgical intervention 1, 2
• Pheochromocytomas occur in approximately 50% of MEN2A and MEN2B patients 2

Hyperparathyroidism Screening

Serum calcium screening should begin at age 11 years for high-risk allele carriers and at age 16 years for moderate-risk carriers. 1

• When hypercalcemia is detected, concurrent measurement of intact parathyroid hormone and assessment of 25-OH vitamin D levels are recommended 1
• Hypercalcemia with normal or elevated intact PTH confirms hyperparathyroidism and warrants referral to an experienced endocrinologist and surgeon 1
• Primary hyperparathyroidism occurs in 20-30% of MEN2A patients, particularly with codon 634 mutations, and does not occur in MEN2B 2

Prophylactic Thyroidectomy: Timing and Surgical Considerations

Total thyroidectomy performed by surgeons experienced in MEN2 is the definitive preventive strategy and effectively prevents subsequent biochemical evidence of disease. 1, 2

Pre-operative Evaluation

• Pre-operative staging with thyroid ultrasound or cross-sectional imaging (contrast-enhanced neck CT or MRI) is essential to identify regional lymphadenopathy and guide surgical planning 2
• Vocal cord mobility must be evaluated before surgery 4
• Coexisting pheochromocytoma must be diagnosed and treated first to avoid hypertensive crisis during thyroid surgery 4, 2

Surgical Timing by Risk Category

• Highest-risk alleles (p.M918T): within the first year of life 1, 2
• High-risk alleles (codons 634,883): by age 5 years or earlier if calcitonin rises 1, 2
• Moderate-risk alleles: when calcitonin demonstrates upward trend or cytology confirms MTC 1

Surgical Outcomes

• The surgical cure rate for MTC is 89% in asymptomatic converters versus only 25% in symptomatic patients presenting with a palpable nodule 2
• Total thyroidectomy with at least central neck lymph node dissection is recommended for patients with clinical or biochemical evidence of MTC 5

Common Pitfalls and Caveats

• Do not rely on thyroid ultrasound alone to exclude MTC or delay surgery—calcitonin is more sensitive 1
• Never proceed with thyroid surgery without first excluding and treating pheochromocytoma—this can be fatal 4, 2
• RET testing is not indicated in apparently sporadic hyperparathyroidism without other clinical suspicion for MEN2 4
• Approximately 25% of unselected individuals with MTC have a RET mutation, emphasizing the importance of universal genetic testing in all MTC cases 4
• Hirschsprung disease can be the initial presentation of MEN2A; genetic screening for RET mutations associated with MEN2A is strongly recommended in patients presenting with Hirschsprung disease 6