Journal of Bone and Mineral Research

Abstract

Primary hyperparathyroidism is caused by defects in the parathyroid gland. Investigations have implicated three interesting genes whose mutation can cause primary hyperparathyroidism. Familial hypocalciuric hypercalcemia is believed to be an atypical form of primary hyperparathyroidism with an inherited defect in calcium recognition expressed not only in all parathyroid chief cells (thus a polyclonal defect) but in some renal tubular cells as well. In typical primary hyperparathyroidism a monoclonal parathyroid tumor is usually the central cause. Either of two apparently different genes on the long arm of chromosome 11 has been implicated in development of a parathyroid tumor clone. One gene (D11S287) was shown to have undergone a rearrangement with the parathyroid hormone gene on the short arm of the same chromosome (pericentromeric inversion) in a small fraction of tumors; the D11S287 locus may encode a growth stimulator. Another gene, the locus for familial multiple endocrine neoplasia type 1 (FEMEN1), is likely to encode a growth inhibitor. Inactivation of this gene or another nearby gene by somatic mutation has been indirectly implicated in one-quarter of sporadic parathyroid adenomas and in more than half of parathyroid tumors in FMEN1. In conclusion, studies have suggested three different mechanisms for parathyroid gland dysfunction in primary hyperparathyroidism: (1) a defect in calcium recognition, (2) a monoclonal tumor from overexpression of a growth stimulator, or (3) a monoclonal tumor from inactivation of a growth inhibitor.

Familial Parathyroid Tumors: Diagnosis and Management

“…HPT is the most common and usually the initial endocrine manifestation in patients with MEN1, typically presenting in the third to fifth decade of life, although significant variations exist among affected kindreds [9]. The underlying germline mutation in the MEN1 gene is thought to render the parathyroids more susceptible to expressing a tumor after only one somatic mutation (the second hit) [2, 10]. Thus, it is not surprising that the parathyroid glands are usually asymmetrically enlarged.…”

“…As in the case of HPT in MEN1, HPT is the most common feature of HPT‐JT, occurring in approximately 80% of adults who have the disease, with an early onset (mean age = 32 years). The syndrome is associated with a high incidence of severe hypercalcemia, risk of parathyroid cancer (about 15%), and may be uniglandular [2, 41–44]. In general, HPT may be treated in a similar way as MEN2A, i.e., with resection of grossly enlarged parathyroid glands, unless parathyroid cancer is suspected.…”

“…Primary hyperparathyroidism (HPT) occurs sporadically in the vast majority of cases. However, it may also be part of familial disorders with a high disease penetrance, such as in multiple endocrine neoplasia type 1 (MEN1), MEN2A, the HPT‐jaw tumor syndrome (HPT‐JT), familial isolated hyperparathyroidism (FIHPT), autosomal dominant mild hyperparathyroidism (ADMH), and neonatal severe HPT (NSHPT) [1, 2]. The underlying genetic abnormalities causing the various syndromes have largely been unveiled over the past decade and are summarized in Table 1.…”

Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism

“…I favor classifying FHH as an atypical form of PHPT, and the majority of PHPT needs no conditioning adjective; in this nomenclature, typical may be attached to PHPT occasionally for emphasis. Atypical has been used occasionally in the past to describe FHH and to describe other variations from typical PHPT …”

“…Atypical has been used occasionally in the past to describe FHH and to describe other variations from typical PHPT. (11,18,19) There is wide agreement that FHH and PHPT have both shared yet also distinguishing features. (6) The diversity of approaches to nomenclature reflects an ongoing issue about whether to emphasize shared or distinguishing features in classifying FHH and PHPT.…”