Review article

Hyperparathyroidism and multiple endocrine neoplasia

Multiple endocrine neoplasia 1

The constellation of parathyroid, enteropancreatic, pituitary, and adrenal cortical neoplasia is called MEN 1 (Box 1). Earlier descriptions of this syndrome as a clinical and familial entity date to 1954, when it was described independently by two groups and came to be known as Wermer's syndrome [2], [3]. The gene responsible for multiple endocrine neoplasia type 1 (MEN 1) has recently been identified.

Estimates of the prevalence of MEN 1 range from 0.01 to 2.5 per thousand [4], [5].

MEN 1 tumors

Molecular genetics of multiple endocrine neoplasia 1

The MEN 1 gene, MEN1, was localized to chromosome 11q13 and subsequently identified by positional cloning [14], [15]. It contains 10 exons with a 1830–base pair coding region and encodes a 610–amino acid protein called menin [15]. MEN1 is a putative tumor-suppressor gene. A total of 262 germline mutations spanning nine coding exons of the MEN1 gene have been identified [16]. These mutations lead to premature protein truncation. Mutations are usually frame-shift mutations (insertions or

Lack of genotype–phenotype correlation in multiple endocrine neoplasia 1

Well-defined genotype phenotype correlations are lacking in MEN 1. Dissimilar germline mutations with similar phenotypes are well known [23]. Some of the mutations, however, have been observed to occur several times in unrelated families.

Germline MEN1 mutations

Approximately 10% of germline MEN1 mutations arise de novo, and up to 30% of MEN1 mutations are currently undetectable (false negative) [4]. Somatic MEN1 mutations have been reported in 10% to 22% of sporadic parathyroid adenomas, 50% of VIPomas, 25% to 35% of bronchial carcinoids, 25% of gastrinomas, and 10% to 22% of insulinomas. On the other hand, MEN1 germline mutation in tumors presumed sporadic is as follows: parathyroid adenoma (1%), gastrinoma (5%), prolactinoma (1%), foregut carcinoid

Screening in multiple endocrine neoplasia 1

MEN 1 genetic analysis is feasible and is now performed at several centers. Its usefulness is limited, however, because nearly 30% of patients have no detectable mutations. The MEN1 gene is a large gene, and no hot spots exist. At present, no consensus exists regarding MEN1 gene mutation testing. Screening to ascertain carrier status can be performed by MEN1 mutation testing and other methods [13]. Because MEN 1 is autosomal dominant, the diagnosis of MEN 1 in a patient carries important

Hyperparathyroidism in multiple endocrine neooplasia 1

HPT in MEN 1 is largely asymptomatic, but it can also be expressed as parathyroid hormone (PTH)–induced bone abnormalities, nephrolithiasis, myalgias, mental changes, weakness, and marked hypercalcemia. HPT in MEN 1 has earlier onset (typically in the third decade). There is no gender preference, and usually more than one parathyroid gland is affected. Because of earlier onset, there is significant reduction in bone mineralization by the time the patient comes to clinical attention. Because

Molecular pathology of parathyroid tumors

Clonal damage to two groups of normal cellular genes (proto-oncogenes and tumor-suppressor genes) contributes to neoplasia development. The regulation of parathyroid cell proliferation is only partially understood. Phosphate, calcium, and 1,25-dihydroxy vitamin D are regarded as the principal regulators. Exposure to 1,25-dihydroxy vitamin D inhibits cell proliferation, and therefore changes in 1,25-dihydroxy vitamin D or vitamin D receptor (VDR) would be expected to have profound effects on

Surgical management of hyperparathyroidism in multiple endocrine neoplasia 1

Primary HPT is an almost universal finding in patients with MEN 1, and hypercalcemia is usually the initial manifestation of the disease. Currently, surgical intervention is the treatment option of choice for hypercalcemia associated with MEN 1–related primary HPT. The goals of surgical intervention are to restore calcium homeostasis, to achieve long-term normocalcemia, and to prevent permanent hypocalcemia.

The extent of parathyroidectomy and the appropriate timing of surgery remain an on-going

Subtotal parathyroidectomy

The treatment of MEN 1–related HPT by SPX consists of bilateral neck exploration with excision of three and one half glands. An approximately 20-mg to 50-mg remnant of vascularized parathyroid tissue is left intact to maintain normocalcemia [38], [42]. A portion of the excised parathyroid tissue may be cryopreserved for grafting if permanent hypocalcemia develops. The rate of permanent hypocalcemia after SPX ranges between 0% and 24% [38], [39], [40], [41]. In addition to SPX, transcervical

Total parathyroidectomy

Several authors have advocated TPX with grafting of parathyroid tissue to the forearm and cryopreservation of additional parathyroid gland as an alternative treatment strategy to SPX for MEN 1–related HPT [41], [45], [46]. Tissue for autotransplantation into the brachioradialis muscle of the nondominant forearm should be obtained from the smallest normal-appearing parathyroid gland. Cryopreservation of additional parathyroid tissue is important in the event of graft failure. Further details of

Reoperation for recurrent hyperparathyroidism in multiple endocrine neoplasia 1

It is evident that over prolonged periods of time hypercalcemia will recur in the majority of MEN 1 patients treated for HPT. The cause of recurrent HPT in these patients is multifactorial, including

• •

  Unrecognized MEN-1 syndrome

• •

  Inadequate initial resection of parathyroid tissue

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  Hyperplasia of parathyroid remnant after subtotal parathyroidectomy

• •

  Supernumerary cervical or mediastinal parathyroid glands

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  Local seeding of neck tissue from ruptured or transected parathyroid glands

• •

  Autograft hyperfunction

Preoperative localization studies

HPT in MEN 1 patients is a multiglandular disease, and preoperative localization studies are not necessary at the time of initial surgical intervention. Localization studies, however, have been demonstrated to be useful in certain patients requiring reoperation for recurrent HPT. Shepherd et al [48] prospectively evaluated preoperative ^99mTc sestamibi and single photon emission CT (SPECT) scanning in 13 patients with MEN 1 requiring re-exploration for recurrent HPT after initial SPX (≥3-gland

Intraoperative parathyroid hormone assay

Use of the rapid intraoperative PTH assay has become a valuable diagnostic tool in determining adequacy of resection in the treatment of sporadic HPT caused by a single adenoma. Recently, some investigators have begun to use the rapid intraoperative PTH assay to determine the adequacy of resection in MEN 1 patients undergoing re-exploration or TPX [47], [50]. Tonelli [50] and others have demonstrated a stepwise decrease in intraoperative PTH values during TPX. High-normal PTH values were

Multiple endocrine neoplasia type 2

MEN 2 is characterized by neoplasia involving the thyroid gland, adrenal medulla, and parathyroid gland. MEN 2A is a constellation of medullary thyroid carcinoma (MTC) (95%), pheochromocytoma (50%), and hyperparathyroidism (20%). Several variants of MEN 2A have been described, including familial medullary thyroid carcinoma (FMTC) in which MTC is the sole manifestation [51], MEN 2A associated with cutaneous lichen amyloidosis [52], and MEN 2A associated with Hirshprung's disease [53]. MEN 2B is

Physiologic functions of the RET proto-oncogene

The RET proto-oncogene plays an important role in the development and migration of tissues of neural crest origin. RET is expressed in C cells of the thyroid, adrenal medulla, urogenital tract, parasympathetic, sympathetic, and enteric ganglia [64], [65]. RET is also expressed in branchial arch–derived parathyroid cells and the ureteric bud [65], [66]. RET together with extracellular protein GFR α-1 constitute receptor for glial cell–derived neurotrophic factor (GDNF). GDNF is a member of the

RET proto-oncogene signal transduction and RET proto-oncogene–induced transformation

The RET proto-oncogene—a tyrosine kinase receptor—has two important domains: an extracellular cysteine-rich domain important for receptor dimerization, and an intracellular tyrosine kinase domain (Fig. 6). The receptor uses an elaborate network of interacting proteins through mitogen-activated protein kinases (MAPKs) to transmit extracellular signals to the nucleus. MAPKs have an important role in regulation of cell differentiation, proliferation, and apoptosis. Activation of RET by GDNF or by

RET proto-oncogene genotype–phenotype correlation in multiple endocrine neoplasia 2

The correlation of the RET proto-oncogene genotype with the phenotype is remarkable. In the International RET Mutation Consortium analysis of 477 independent MEN 2 families, more than 95% had RET proto-oncogene mutation [69]. Mutations of the intracellular tyrosine kinase domain are seen in MEN 2B. More than 95% of MEN 2B families have a MET/Thr mutation. It is possible to predict clinical phenotype with reasonable accuracy. Within families, it may even be possible to predict the invasiveness

Role of genetic information and screening in patient management

Genetic information profoundly affects clinical management decisions in MEN 2. The primary goal of this information is to seek candidates for prophylactic thyroidectomy before metastatic disease develops. A further important benefit is to exclude from further screening the 50% of family members who do not have a RET mutation. Most laboratories perform direct DNA sequencing, and several commercial laboratories offer the testing.

Ninety-eight percent of MEN 2 index cases have an identified RET

Hyperparathyroidism in multiple endocrine neoplasia 2

Primary HPT occurs in 20% to 30% of MEN 2A patients, the highest frequency being with codon 634 mutation. HPT is usually asymptomatic and milder than that encountered in MEN 1. The pathogenesis of HPT is unclear, but the mutated RET gene is expressed in parathyroid cells, thus abnormal RET expression in parathyroid cells could contribute to parathyroid tumorigenesis [66].

Surgical management of hyperparathyroidism in multiple endocrine neoplasia 2A

Primary HPT in patients with MEN 2A is characterized by multigland hyperplasia and an increased incidence of ectopic or supernumerary glands. Although the frequency of primary HPT in MEN 2A is much, and the symptoms of hypercalcemia tend to be milder, the surgical treatment options are similar to those for patients with MEN 1. The optimal surgical management scheme remains an area of controversy with arguments and challenges similar to those for MEN 1 [39], [40], [78]. Because symptoms are

Summary

MEN syndromes comprise a group of hereditary disorders resulting in abnormal secretion of multiple peptide hormones from various endocrine organs and a multiplicity of tumors (benign and malignant) in affected organ sites. In MEN 1, primary HPT is the most common and earliest manifestation of the disorder. In MEN 2A, HPT is less common, and symptoms of hypercalcemia are usually less severe. Hypercalcemia is a result of multigland hyperplasia affecting all parathyroid glands including the