Multiple endocrine neoplasia type 2 (MEN2) is an inherited syndrome, caused by a change in the RET gene, in which medullary thyroid cancer (MTC), pheochromocytoma and parathyroid tumors occur in the same person or family. It is one of the main causes of hereditary pheochromocytoma. About 30–40% of all pheochromocytomas and paragangliomas are hereditary, so genetic testing should be offered to every patient with one of these tumors; see our pheochromocytoma genetics page.
Most medullary thyroid cancer cases are sporadic (not inherited) and present as a new thyroid nodule. The workup proceeds similarly to that of non-medullary thyroid cancers. Detailed assessment of personal and family history and physical examination is followed by thyroid ultrasound and FNA (fine-needle aspiration).
All patients with confirmed or suspected medullary thyroid cancer should also have measurements of serum calcitonin and CEA. Calcitonin is useful not only for detection of MTC but for prognosis as well, since very high calcitonin levels correlate with a higher stage of disease. Both CEA and calcitonin are followed after treatment to determine the success of treatment and to monitor for recurrence.
The MEN2 syndromes were originally known as Sipple syndrome when the tumor constellation of pheochromocytoma, medullary thyroid cancer and parathyroid adenoma was first described in 1961. As understanding of this syndrome increased, it became recognized that there are distinct variants of MEN2: MEN2A and MEN2B. Both are caused by pathogenic activating mutations of the proto-oncogene RET. The RET gene is located on chromosome 10q11.2 and codes for a transmembrane receptor tyrosine kinase involved in many cell-signaling pathways. Mutations causing constitutive activation of this kinase promote cell proliferation, survival and migration, often leading to tumorigenesis. The distinct differences between the different variants of MEN2 are largely determined by the location of the mutation.
MEN2A
Based on the American Thyroid Association recommendations on MTC, there are 4 variants of MEN2A: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (MEN2A with CLA), MEN2A with Hirschsprung’s disease (MEN2A with HD), and Familial Medullary Thyroid Cancer (FMTC).
Classical MEN2A Classical MEN2A is the most common variant of MEN2A and represents the phenotype that was originally described by Sipple. It most commonly involves RET mutations in exons 10 or 11. Nearly 100% of patients will develop medullary thyroid cancer, while rates of pheochromocytoma and primary hyperparathyroidism vary based on the specific RET mutation. Codon 634 mutations in exon 11 are associated with higher rates of pheochromocytoma and hyperparathyroidism. Overall, about 50% of patients with classical MEN2A will develop pheochromocytoma and 20-30% will have parathyroid disease.
The parathyroid disease in MEN2A is usually in the form of benign parathyroid adenomas and less often multi-gland hyperplasia. Patients are often asymptomatic or have mild symptoms. Severe clinical hyperparathyroidism is rare in MEN2A. If detected prior to or concurrently with medullary thyroid cancer, most cases of hyperparathyroidism can be treated with parathyroidectomy at the time of surgery for medullary thyroid cancer.
The pheochromocytomas of MEN2A are almost always inside the adrenal glands, are often bilateral (in both glands, at the same time or years apart), and rarely spread (metastasize). Pheochromocytoma can be the first sign of MEN2, and the diagnosis of a pheochromocytoma should prompt testing for a RET mutation. If discovered concurrently with MTC, the pheochromocytoma must be treated first. Before surgery, most patients are prepared with blood-pressure medication (alpha-blockers such as doxazosin or phenoxybenzamine, sometimes other medicines) and good hydration. Occasionally a beta-blocker is added, only after the alpha-blocker has been started, to treat a fast heart rate. The plan is individualized by the team.
Because both adrenal glands are so often affected in MEN2, adrenal-sparing surgery (partial adrenalectomy) is an important option: the tumor is removed but healthy adrenal cortex is preserved, so that many patients avoid lifelong steroid dependence. The trade-off is that a new pheochromocytoma can grow in the remaining tissue; this happened in about 13% of patients in the largest international registry, usually many years later. For this reason, and because new tumors can form in the other gland, follow-up with a metanephrine test every year is lifelong. Read more about surgery for pheochromocytoma and adrenal-sparing surgery.
MEN2B
MEN2B manifests early, usually within the first year of life. Medullary thyroid cancer in MEN2B can develop in infancy and is typically highly aggressive with early metastasis. About 50-75% of MEN2B cases are caused by de novo (new) mutations, and only 25-50% of cases occur within families with an established history of hereditary disease. 95% of MEN2B is caused by the M918T mutation in exon 16. Patients have long and narrow facies and develop lip and tongue mucosal neuromas. Skeletal abnormalities are common resulting in Marfanoid body habitus, chest malformations, scoliosis and joint deformities. Patients are also prone to ganglioneuromas of the gastrointestinal tract that may cause constipation, diarrhea, nausea, and even bowel obstructions that require surgery. Most mortalities result from advanced medullary thyroid cancer and establishing the diagnosis early is essential to timely treatment.
Hereditary pheochromocytoma and paraganglioma
MEN2 is only one of the hereditary causes of pheochromocytoma. The well-established pheochromocytoma and paraganglioma susceptibility genes include RET, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, MAX and FH. An inherited (germline) change in one of these genes is found in most familial cases and also in a meaningful share of patients with no family history. Of these genes, SDHB carries the highest risk of metastatic disease, while the pheochromocytomas of MEN2 have a low risk. Of note, MEN1 syndrome has also been very rarely associated with pheochromocytoma but is more typically linked to adrenocortical tumors.
Detailed personal and family history taking should focus on the presence of syndrome-associated features such as history of medullary thyroid cancer and hyperparathyroidism (MEN2); history of CNS hemangioblastomas and renal cell carcinomas (VHL), and history of GIST, papillary thyroid cancer, pituitary adenomas, and other neuroendocrine tumors (hereditary pheochromocytoma/paraganglioma syndromes). Suspicion for a specific syndrome may be increased or decreased based on the presence of these associated features. Variants in RET and VHL can be detected by single-gene testing, and neurofibromatosis type 1 is usually recognized from its clinical features. In practice, genetic testing is now most often performed with a multigene panel that includes all the known causative genes (RET, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, MAX and others).
Last updated October 2026.