Multiple Endocrine Neoplasia Type 2

Clinical characteristics Multiple endocrine neoplasia type 2 (MEN 2) includes the following phenotypes: MEN 2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN 2A), and MEN 2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B involve an increased risk for pheochromocytoma; MEN 2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B 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 MEN 2B, early adulthood in MEN 2A, and middle age in FMTC. Diagnosis/testing The diagnosis of MEN 2 is established in a proband who fulfills existing clinical diagnostic criteria. Molecular genetic testing to identify a heterozygous germline RET pathogenic variant is indicated in all individuals with a diagnosis of primary C-cell hyperplasia or MTC or a clinical diagnosis of MEN 2. Identification of a heterozygous germline RET pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. Management Treatment of manifestations: 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 advanced locoregional disease. Kinase inhibitors may be used in metastatic MTC. Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed 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. Prevention of primary manifestations: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant. Prevention of secondary complications: Prior to any surgery in an individual with MEN 2A or MEN 2B, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening. Surveillance: Annual measurement of serum calcitonin concentration to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Monitoring for possible hypoparathyroidism in all those who have undergone thyroidectomy and parathyroid autotransplantation. Annual biochemical screening for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma. Agents/circumstances to avoid: Dopamine D2 receptor antagonists and β-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. Pregnancy management: Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy or as early as possible during an unplanned pregnancy. Genetic counseling All MEN 2 phenotypes are inherited in an autosomal dominant manner. The probability of a de novo pathogenic variant is 5% or less in index cases with MEN 2A and 50% in index cases with MEN 2B. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RET pathogenic variant has been identified in an affected family member.