Multiple Endocrine Neoplasia Type 2

Clinical characteristics: Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features of MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC.

Diagnosis/testing: The diagnosis of MEN2 is established in a proband who fulfills existing clinical diagnostic criteria or by identification of a heterozygous germline gain-of-function variant in RET on molecular genetic testing. Molecular genetic testing is recommended in all individuals with a clinical diagnosis due to genotype-specific surveillance and treatment recommendations and to allow family studies.

Management: Targeted therapy: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant.

Supportive care: Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning pheochromocytoma prior to any surgery in individuals with MEN2A, MEN2B, or FMTC. Adrenalectomy prior to thyroidectomy in any individual with pheochromocytoma identified. Treatment for MTC is surgical removal of the thyroid gland and lymph node dissection. External beam radiation therapy or intensity-modulated radiation therapy can be considered for incomplete tumor resection or extrathyroidal extension with positive margins. Kinase inhibitors may be considered in those with metastatic MTC. Standard treatment for hypothyroidism following thyroidectomy. Treatment of hypertension prior to adrenalectomy or management of hypertension during surgery. Resection of pheochromocytomas by adrenalectomy. Primary hyperparathyroidism is treated with surgery to remove one or more parathyroid glands or, more rarely, with medications to reduce parathyroid hormone secretion.

Surveillance: Annual measurement of serum calcitonin concentration in those who have not had prophylactic thyroidectomy and to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Annual plasma free metanephrines or 24-hour urine for fractionated metanephrines for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma. Annual albumin-corrected calcium or ionized calcium for individuals with MEN2A/FMTC whose initial screening results are negative for hyperparathyroidism. Age of initiation of surveillance for pheochromocytoma and hyperparathyroidism is determined by the specific germline RET pathogenic variant identified.

Agents/circumstances to avoid: Dopamine D₂ receptor antagonists and beta-adrenergic receptor antagonists present a high risk for adverse reactions in individuals with pheochromocytoma.

Evaluation of relatives at risk: RET molecular genetic testing should be offered to all at-risk members of kindreds in which a germline RET pathogenic variant has been identified. When an individual with MEN2 refuses to notify at-risk family members, the physician should consider consulting a clinical ethicist to determine if the physician has the ethical obligation to warn the at-risk family members.

Pregnancy management: Women with MEN2 should be screened for pheochromocytoma prior to a planned pregnancy or as early as possible during an unplanned pregnancy.

Genetic counseling: All MEN2 phenotypes are inherited in an autosomal dominant manner. Up to 95% of individuals diagnosed with MEN2A and 50% of individuals diagnosed with MEN2B have an affected parent. (By definition, individuals with FMTC have multiple family members who are affected.) Approximately 5%-9% of individuals with MEN2A and 50% of individuals with MEN2B have the disorder as the result of a de novo germline pathogenic variant. Each child of an individual with MEN2 has a 50% chance of inheriting the RET pathogenic variant. Once the RET pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk asymptomatic family members and prenatal and preimplantation genetic testing for MEN2 are possible.