Multiple Endocrine Neoplasia Type 2B

Multiple endocrine neoplasia type 2B is an autosomal dominant syndrome caused by activating RET variants, almost always M918T. It causes very early and aggressive medullary thyroid carcinoma, phaeochromocytoma and a characteristic physical phenotype, without hyperparathyroidism.

It is the rarest and most aggressive form of MEN2 (about 5% of cases), and about 75% of cases are new variants. Medullary carcinoma can develop in infancy and metastasise early. Phaeochromocytoma occurs in about 50%.

Diagnosis is often delayed until the carcinoma has spread. Recognition of the phenotype allows early thyroidectomy.

Pathophysiology.

The M918T variant causes constitutive RET activation with altered substrate specificity, giving more aggressive C-cell transformation than in type 2A. Ganglioneuromatosis and neuromas result from neural crest overgrowth.

• Mucosal neuromas of lips and tongue (thick, bumpy lips), eyelid margin thickening and medullated corneal nerve fibres.
• Marfanoid habitus with long limbs, joint laxity and kyphoscoliosis.
• Intestinal ganglioneuromatosis: constipation, diarrhoea, megacolon and abdominal pain from infancy.
• Neck mass, flushing and diarrhoea (medullary carcinoma). Paroxysmal hypertension (phaeochromocytoma).

Red flags.

• Infant with feeding or bowel problems and the characteristic face.
• Hypertensive crisis and distant metastases.

• RET sequencing for M918T (and other variants) in the patient and relatives; early test in infants of carriers.
• Calcitonin and carcinoembryonic antigen, neck ultrasound and staging imaging (chest and liver CT, MRI) once the carcinoma is established.
• Plasma free metanephrines or 24-hour urinary fractionated metanephrines from age 11 and before any surgery.
• Calcium and parathyroid hormone are normal.

Differential diagnosis.

• MEN2A and Marfan syndrome.
• Neurofibromatosis, Hirschsprung disease and other causes of intestinal pseudo obstruction.
• Sporadic medullary thyroid carcinoma.

• Total thyroidectomy as early as possible, ideally in the first year of life, by an experienced paediatric surgeon. Central neck dissection when feasible without compromising the parathyroid glands.
• Phaeochromocytoma: alpha blockade (doxazosin 2 to 16 mg daily or phenoxybenzamine 10 mg twice daily increasing as tolerated), then a beta blocker, then adrenalectomy. Always exclude phaeochromocytoma before any other surgery.
• Levothyroxine about 1.6 micrograms/kg daily (adjust by weight in children) after thyroidectomy.
• 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 or cabozantinib 140 mg daily as alternatives.
• Gastrointestinal symptoms: dietary fibre, laxatives and surgical review for obstruction.

Special groups. Pregnancy: control phaeochromocytoma with alpha blockade before and during pregnancy. Genetic counselling: 50% risk to children; prenatal diagnosis is possible.

Monitoring. Calcitonin and carcinoembryonic antigen 3 to 6 months after surgery and then every 6 to 12 months. Metanephrines yearly. Growth and parathyroid function.

Referral and escalation. Paediatric or adult endocrine surgery and oncology at a specialist centre; clinical genetics.