Diagnosis
Diagnosis is suspected when a patient with family history of two of the three classical tumors (medullary thyroid cancer, pheochromocytoma, parathyroid adenoma) or MEN2 presents with one of the classical tumors. It is confirmed by genetic testing for mutation in RET gene. Differences in presentation
As noted, all types of MEN2 include pheochromocytoma and medullary thyroid carcinoma. MEN2A is additionally characterized by the presence of parathyroid hyperplasia. MEN2B is additionally characterized by the presence of mucocutaneous neuroma, gastrointestinal symptoms (e.g. constipation and flatulence), and muscular hypotonia. MEN2B can present with a Marfanoid habitus. Classification
Before gene testing was available, the type and location of tumors determined which type of MEN2 a person had. Gene testing now allows a diagnosis before tumors or symptoms develop. A table in the multiple endocrine neoplasia article compares the various MEN syndromes. MEN2 and MEN1 are distinct conditions, despite their similar names. MEN2 includes MEN2A, MEN2B and familial medullary thyroid cancer (FMTC).The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma. A variant of MEAs 2A was described in 1989. This variant also has patches of cutaneous amyloidosis in the mid/upper back and is inherited in an autosomal dominant fashion. Management
Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.
The initial manifestation of MEN2 was medullary thyroid carcinoma in 60% of patients, medullary thyroid carcinoma synchronous with pheochromocytoma in 34% and pheochromocytoma alone in 6%. 72% had bilateral pheochromocytomas. Causes
The table in the multiple endocrine neoplasia article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin. A database of MEN-implicated RET mutations is maintained by the University of Utah Department of Physiology.The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body. MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. OMIM # 164761 lists the syndromes associated with the RET gene. Genetics
When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.