Multiple Endocrine Neoplasia Type 2A

Multiple endocrine neoplasia type 2A is an autosomal dominant syndrome caused by activating germline variants in the RET proto oncogene, with medullary thyroid carcinoma, phaeochromocytoma and primary hyperparathyroidism.

Prevalence of MEN2 is about 1 in 35,000. Medullary thyroid carcinoma develops in nearly all carriers, phaeochromocytoma in about 50% (often bilateral) and hyperparathyroidism in 10 to 30%. Cutaneous lichen amyloidosis and Hirschsprung disease occur in some families.

The most common variants affect codon 634 (highest risk category) and other cysteine codons. RET variants are grouped into higher and moderate risk categories that set the timing of thyroidectomy.

Pathophysiology.

Activating RET variants cause constitutive receptor tyrosine kinase signalling, causing C-cell hyperplasia then medullary carcinoma, and adrenal medullary and parathyroid proliferation.

Medullary carcinoma secretes calcitonin and carcinoembryonic antigen, which are used as markers.

• Neck mass or nodule, often with lymphadenopathy; diarrhoea (high calcitonin); flushing.
• Phaeochromocytoma: paroxysmal headache, sweating, palpitations and hypertension (may be silent).
• Hypercalcaemia symptoms (mild). Pruritic scapular lichen amyloidosis. Constipation and megacolon in Hirschsprung disease.

Red flags.

• Hypertensive crisis, arrhythmia or heart failure (phaeochromocytoma).
• Rapidly rising calcitonin, voice change or distant metastases.

• RET sequencing in all patients with medullary thyroid carcinoma and in their first degree relatives; identify the codon to set risk.
• Calcitonin and carcinoembryonic antigen, neck ultrasound and, for larger tumours, staging imaging.
• Phaeochromocytoma: plasma free metanephrines or 24-hour urinary fractionated metanephrines (screen from age 11 in the highest risk category and from age 16 in others), then adrenal CT or MRI.
• Calcium, parathyroid hormone and albumin yearly from age 11 (highest risk) or 16 (others).
• Always exclude phaeochromocytoma before thyroid, parathyroid or other surgery.

Differential diagnosis.

• Sporadic medullary thyroid carcinoma and other causes of raised calcitonin (renal failure, proton pump inhibitor use, other neuroendocrine tumours).
• MEN2B, familial medullary thyroid carcinoma and other hereditary phaeochromocytoma syndromes.
• Sporadic primary hyperparathyroidism.

• Phaeochromocytoma first: alpha blockade for 7 to 14 days (doxazosin 2 to 16 mg daily or phenoxybenzamine 10 mg twice daily increasing as tolerated), then a beta blocker, with generous sodium and fluid intake, then laparoscopic cortical sparing or total adrenalectomy. Replace cortisol after bilateral adrenalectomy.
• Prophylactic total thyroidectomy in carriers: highest risk category (codon 634 and others) at or before age 5; moderate risk when calcitonin rises, usually from age 5 onwards. Central neck dissection if calcitonin is raised or nodes are suspicious.
• After thyroidectomy: levothyroxine about 1.6 micrograms/kg daily (dose by weight in children) to normal thyroid stimulating hormone.
• Primary hyperparathyroidism: parathyroidectomy of enlarged glands, or total with autograft, with attention to preserving parathyroid function.
• Progressive or metastatic medullary carcinoma: selpercatinib 160 mg twice daily (weight 50 kg or more) or pralsetinib 400 mg daily for RET-driven disease; vandetanib 300 mg daily (QT monitoring) or cabozantinib 140 mg daily as alternatives.

Special groups. Children: surgery at a high volume paediatric centre. Pregnancy: control phaeochromocytoma with alpha blockade and plan surgery in the second trimester. Genetic counselling: 50% risk for each child.

Monitoring. Calcitonin and carcinoembryonic antigen 6 months after thyroidectomy, then yearly (or 6 monthly with doubling time assessment). Metanephrines and calcium yearly.

Referral and escalation. Endocrinology with endocrine surgery, oncology and clinical genetics; urgent admission for hypertensive crisis.