Surgical Management of Familial Hyperparathyroidism

Abstract

In the February 2007 issue of the journal, the members of the Section of Endocrine Surgery at the University of Wisconsin under the leadership of Dr. Herb Chen report their experience with radioguided parathyroidectomy in 19 patients with familial hyperparathyroidism (HPT). The cause of HPT was multiple endocrine neoplasia type 1 (MEN1) in 11 patients, multiple endocrine neoplasia type 2 (MEN2) in 1, and presumed nonsyndromic or familial isolated HPT (FIHPT) in 7. The gamma probe accurately localized all hyperplastic parathyroid glands and when combined with the intraoperative parathyroid hormone (IOPTH) assay resulted in the correction of hypercalcemia (at least in the short term) in all 19 patients. Such excellent results require accurate intraoperative identification of the parathyroid glands, including those that may exist in ectopic locations, as well as a thorough understanding of the natural history of the familial syndromes associated with HPT to allow for the proper management of the parathyroids once they are identified. Finding the parathyroid glands is of value only if one knows how many to remove, when to cryopreserve, and when and where to autograft; the gamma probe is just one piece of the puzzle necessary to generate the results as seen from the University of Wisconsin. Familial HPT is caused by several known inherited disorders, but it may also occur in nonsyndromic form with autosomal dominant inheritance or familial tendency. Syndromic disorders in which HPT is a central feature include MEN1 and MEN2A, hyperparathyroidism jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). The genetic basis of nonsyndromic HPT or FIHPT is unknown, but recent evidence suggests that a causative gene for FIHPT may reside on chromosome 2. Patients with MEN1 typically develop HPT due to hyperplasia of multiple parathyroid glands in early adulthood and essentially all are affected by age 50, though HPT may go undiagnosed for years. Most patients with MEN1 have one or more affected relatives with autosomal dominant transmission of disease. In 75% to 90% of affected families, a causative germline mutation has been identified in the putative tumor suppressor gene, MEN1, located on chromosome 11q13. More than 400 different germline mutations in MEN1 have been reported and are scattered throughout the coding region (exons 2 through 10) as well as in splice sites within noncoding introns. Most mutations are unique to individual families without marked clustering or correspondence to protein functional domains that would suggest genotype-phenotype correlations. Several functional roles for menin (protein product of the MEN1 gene) have been proposed, including regulation of DNA replication and repair, transcriptional activation, and chromatin modification. Patients with MEN1 also commonly develop functioning and nonfunctioning tumors of the pancreatic islet cells and duodenum, and the anterior pituitary gland. Less commonly, they may develop bronchial and thymic carcinoid tumors, adrenal tumors, thyroid neoplasms, and/or meningiomas. Received October 31, 2006; accepted October 31, 2006; published online: February 7, 2007. Address correspondence and reprint requests to: Douglas B. Evans, M.D.; E-mail: devans@mdanderson.org