Background: At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. Methods: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. Conclusions: 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after ...

/pdf/diagnosis-of-asymptomatic-primary-hyperparathyroidism-1hb0zdc3tb.pdf

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop.

https://www.cell.com/molecular-cell/pdf/S1097-2765(05)01646-1.pdf

Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation.

Background We looked for mutations of the HRPT2 gene, which encodes the parafibromin protein, in sporadic parathyroid carcinoma because germ-line inactivating HRPT2 mutations have been found in a type of familial hyperparathyroidism — hyperparathyroidism–jaw tumor (HPT-JT) syndrome — that carries an increased risk of parathyroid cancer. Methods We directly sequenced the full coding and flanking splice-junctional regions of the HRPT2 gene in 21 parathyroid carcinomas from 15 patients who had no known family history of primary hyperparathyroidism or the HPT-JT syndrome at presentation. We also sought to confirm the somatic nature of the identified mutations and tested the carcinomas for tumor-specific loss of heterozygosity at HRPT2. Results Parathyroid carcinomas from 10 of the 15 patients had HRPT2 mutations, all of which were predicted to inactivate the encoded parafibromin protein. Two distinct HRPT2 mutations were found in tumors from five patients, and biallelic inactivation as a result of a mutation ...

Somatic and Germ-Line Mutations of the HRPT2 Gene in Sporadic Parathyroid Carcinoma

Background: Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2 , in parathyroid tumorigenesis. Methods: Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours. Results: HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. “Two-hits” (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours. Conclusions: The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.

https://jmg.bmj.com/content/jmedgenet/40/9/657.full.pdf

HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours

Parafibromin/Hyrax Activates Wnt/Wg Target Gene Transcription by Direct Association With beta-catenin/Armadillo

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

P.D. Leotlela

Papers

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome