These data indicate that a significant proportion of individuals presenting with apparently sporadic pheochromocytoma are carriers of germline genetic mutations. Since testing for mutations in five different genes in every patient may not be feasible or cost-effective, clinical and genetic screening algorithms have been proposed to assist clinicians in deciding which genes to test and in which order.[31,37,38,39,40,41]
Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the 6th decade of life. Approximately 80% of cases are the results of a single adenoma. PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:
- Multiple Endocrine Neoplasia type 1.
- Hyperparathyroidism-Jaw Tumor syndrome.
- Familial Isolated Hyperparathyroidism.
- MEN 2.[43,44,45]
Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.
Incidence and Prevalence
The prevalence of MEN 2 has been estimated to be 1 in 35,000. The vast majority of MEN 2 cases are MEN 2A. In the United States, an estimated 360 cases of MEN 2-related MTC are diagnosed per year.
Clinical Diagnosis of MEN 2 Subtypes
The diagnosis of the three MEN 2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11.2).
MEN 2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma and/or hyperplasia) in a single individual or in close relatives.
The MEN 2A subtype makes up about 60% to 90% of MEN 2 cases. The MEN 2A subtype was initially called Sipple syndrome. Since genetic testing for RET mutations has become available, it has become apparent that about 95% of individuals with MEN 2A will develop MTC, about 50% will develop pheochromocytoma, and about 15% to 30% will develop hyperparathyroidism.[13,49,50,51]
MTC is generally the first manifestation of MEN 2A. In asymptomatic at-risk individuals, provocative testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[13,50] In families with MEN 2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean 15 years). If presymptomatic screening is not done, MTC typically presents as a neck mass or neck pain at about age 5 to 20 years. More than 50% of such patients have cervical lymph node metastases. Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma calcitonin level of greater than 10 ng/mL and implies a poor prognosis. Up to 30% of patients with MTC present with diarrhea and advanced disease.