Multiple Endocrine Neoplasia

MEN 2 syndrome is an autosomal dominant inherited disease, affecting approximately 500 to 1000 kindreds.23 Medullary thyroid cancer (MTC), pheochromocytomas, and parathyroid hyperplasia are the typical association for patients with MEN 2A. MEN 2B patients present with tumors from the adrenal medulla, intestinal and mucosal ganglioneuromatosis, and a characteristic marfanoid habitus. Other less frequent variants include familial medullary thyroid carcinoma (FMTC), MEN 2A with cutaneous lichen amyloidosis, and MEN 2A or FMTC with Hirschsprung's disease. All variants of MEN 2 show high penetrance for MTC. More than 90% of all MEN 2 carriers show evidence of MTC as a solitary thyroid nodule or as an abnormal elevation of serum thyrocalcitonin in their life span.23

The gene responsible for MEN 2 has been mapped to chromosome 10.23,44,45 The RET gene is located near the centromere and encodes a plasma membrane-bound tyrosine kinase enzyme termed ret. Through an inherited mutation that changes an amino acid, RET is activated, causing oncogenic or transforming changes.

Primary HPT occurs in 20% to 30% of MEN 2A patients.23,29,4647 The relationship between specific mutations and syndromic features has been established. The highest frequency of pheochromocytoma and HPT occurs in those who are found to have a mutation on codon 634, more specifically, C634R.48 The prevalence of HPT is high, however, irrespective of the mutation detected (i.e., C634Y, C634S, C634F, C634G, C634W). It has been suggested that HPT is an earlier component of the syndrome.

Patients are 30 years or older at diagnosis. They occasionally have classic symptoms of HPT, hypercalciuria, or even renal calculi. However, asymptomatic hypercalcemia is usually found during the work-up for a patient with a solitary thyroid nodule or MTC. One or more enlarged glands can be found incidentally during thyroid surgery.

The evolution of HPT is milder than that of its MEN 1 counterparts, and it is rare for patients to develop HPT after the thyroid gland has been removed. A theory of a parathyroid growth-stimulating factor from C cells has been proposed but not proved.

Diagnosis

The diagnostic algorithm for patients with HPT and MEN 2 is the same as that for patients with other forms of HPT. Hypercalcemia and PTH elevation confirm the diagnosis, along with an elevated chloride-to-phosphate ratio and mild hypercalciuria.

Ruling out excessive catecholamine production is mandatory in these patients because of the morbidity and mortality associated with operating on patients with coexistent pheochromocytoma. If the diagnosis is made, pheochromocytoma is dealt with and HPT operated on later.

The treatment of patients with MEN 2A deals primary with the MTC. A total thyroidectomy with central node dissection is performed. Total parathyroidectomy with forearm autotransplantation is recommended by some authors for this reason.29 Disease is milder in these patients, however, and we consider a total resection too aggressive. To date, the rate of postoperative hypoparathyroidism remains high. This may also be the case with the association of parathyroidectomy and thyroidectomy with lymph node excision.

If hyperplasia is encountered during surgery, we recommend identification of the four parathyroid glands and resection of only macroscopically enlarged tissue.16,46,47 A search for ectopic parathyroid tissue and a cervical thymectomy should be added to the procedure. Cryopreservation is done routinely if there is concern about the development of postoperative hypoparathyroidism. This technique is associated with a low rate of persistent or recurrent HPT.

Follow-up and Screening

Because of the other two components of the MEN 2A syndrome, life-long follow-up is mandatory. Serum thyrocalcitonin and calcium levels are measured periodically. Screening for the syndrome in kindreds of patients with MEN 2A involves demonstration of the RET mutation in chromosome 10.49"51 A provocative screening test for thyrocalcitonin has lost its role in the detection of kindreds with MEN 2. Pentagastrin is not always available, and the study is uncomfortable for individuals. Prophylactic surgery is indicated for patients with a positive RET mutation test, even at a young age. Genetic testing in this instance has demonstrated an impact on the clinical course of these patients.

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