MEN 2-associated pheochromocytomas are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[53,54,55] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[53,56] MEN 2-associated pheochromocytomas usually present after MTC, typically with intractable hypertension.
Unlike the PHPT seen in MEN 1, hyperparathyroidism in individuals with MEN 2 is typically asymptomatic or associated with only mild elevations in calcium.[52,57] A series of 56 patients with MEN 2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group. The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN 2. This is in sharp contrast to MEN 1, in which the vast majority of patients (87%-99%) initially present with primary hyperparathyroidism.[58,59,60] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, four double adenomas, and 25 hyperplastic glands.
A small number of families with MEN 2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[61,62]
Familial medullary thyroid carcinoma (FMTC)
The FMTC subtype makes up from 5% to 35% of MEN 2 cases and is defined as families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. Families with two or three cases of MTC and incompletely documented screening for pheochromocytoma and parathyroid disease may actually represent MEN 2A; it has been suggested that these families should be considered unclassified.[7,63] Misclassification of families with MEN 2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN 2A) may result in overlooking the risk of pheochromocytoma, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN 2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN 2A syndrome. Some authors recommended, therefore, that patients thought to have pure FMTC also be screened for pheochromoctyoma and hyperparathyroidism. (Refer to the sections on Screening of at-risk individuals for pheochromocytoma and Screening of at-risk individuals for hyperparathyroidism in this summary for more information.)
MEN 2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[65,66,67]