Related Experiment Video
Updated: Jul 26, 2025
Generation of Hypoparathyroid Rats via Carbon-Nanoparticle-Assisted Parathyroidectomy
Published on: July 14, 2023
Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome
Rana Tora1, James Welch1, Jian Sun2
1Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Context:
Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease.
Objective:
(1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss.
Design:
Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73).
Results:
We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion.
Conclusions:
Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors.
Clinical Trial Number:
NCT04969926.
Insights
Hyperparathyroidism-jaw tumor (HPT-JT) syndrome patients often develop primary hyperparathyroidism and parathyroid cancer. Uterine polyps are characteristic in females, while specific CDC73 variants predispose to kidney tumors.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a rare inherited disorder characterized by primary hyperparathyroidism and an increased risk of parathyroid cancer, caused by germline mutations in the CDC73 gene.
- Management guidelines for HPT-JT syndrome are limited, necessitating further research into its natural history and molecular underpinnings.
Purpose of the Study:
- To characterize the natural history of HPT-JT syndrome.
- To correlate the genotype and histology of parathyroid tumors with parafibromin (encoded by CDC73) expression.
- To elucidate molecular changes downstream of CDC73 loss in HPT-JT syndrome.
Main Methods:
- Retrospective analysis of 68 patients from 29 kindreds with genetically confirmed HPT-JT syndrome.
- Independent review of uterine tumors from 2 patients and parafibromin immunostaining on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas).
- RNA-sequencing of 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas).
Main Results:
- 81% of patients developed primary hyperparathyroidism, and 31% had parathyroid carcinoma. Uterine tumors occurred in 38% of females, often presenting as rare polypoid lesions.
- Specific CDC73 variants at the p.M1 residue were associated with a predisposition to kidney tumors.
- Parafibromin staining did not correlate with tumor histology or genotype, but RNA-sequencing revealed associations with transmembrane receptor protein tyrosine kinase signaling, mesodermal commitment, and cell-cell adhesion pathways in HPT-JT tumors.
Conclusions:
- Multiple, recurrent atypical adenomyomatous uterine polyps are characteristic of HPT-JT syndrome in women.
- Patients with CDC73 variants at p.M1 residue exhibit a predisposition to developing kidney tumors.
- Understanding the molecular pathways affected by CDC73 loss is crucial for managing HPT-JT syndrome.
More Related Videos
07:13Two Techniques to Create Hypoparathyroid Mice: Parathyroidectomy Using GFP Glands and Diphtheria-Toxin-Mediated Parathyroid Ablation
Published on: March 14, 2017
07:12Establishment of a Simple and Effective Rat Model for Intraoperative Parathyroid Gland Imaging
Published on: August 17, 2022
Related Concept Videos
00:59The Parathyroid Glands
Oxyphil cells, whose functions remain elusive, emerge during late puberty, adding a layer of complexity to the parathyroid gland's intricacies. In contrast, principal parathyroid cells undertake a vital role by...
01:17Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...
01:30Pulmonary Hypertension: Classification and Pathogenesis
There are various classifications for PH, each relating to different underlying causes and also...
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...