Agarwal, Sunita

Abstract Disclosure: R. Tora: None. J. Welch: None. J. Sun: None. S.K. Agarwal: None. D.A. Bell: None. M. Merino: None. L.S. Weinstein: None. W.F. Simonds: None. S. Jha: None. Background: Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism (PHPT) that is associated with tumors in the parathyroid, jaw, kidney, and uterus. We previously presented on the clinical characteristics of primary hyperparathyroidism in our cohort. Methods: We now expand on the report through review of uterine tumors, immunohistochemical staining for parafibromin, sequencing of parathyroid and kidney tumor tissue, and RNA-seq of parathyroid tumors. Results: We identified 68 patients (36 males, 32 females) from 29 kindreds with HPT-JT with median age at last follow-up of 39 [29-53] years. Of these, 7 patients were unaffected (2 males, 5 females). Among females, 12/32 (38%) developed uterine tumors with multiple adenomyomatous polyps, an unusual form of endometrial polyps seen in 10/24 tumors (42%). Given that these types of lesions are very rare in the general population, it is likely that such epithelial-mesenchymal uterine proliferations are a characteristic feature of HPT-JT syndrome.Solid kidney tumors were seen in 4/61 patients (7%). Three had surgery for the tumors - 2/3 were female and had mixed epithelial stromal tumor, while the third patient, a 6-year old male, had metastatic Wilm’s tumor as his initial disease-related manifestation. Among these, two had a germline CDC73 variant at the p.M1 residue while the third patient had the germline variant p.L95P; however, sequencing of his tumor tissue showed a “second hit” at the p.M1 residue resulting in loss of heterozygosity in the tumor. The fourth patient, a female with p.Y55S variant, is being conservatively managed with no kidney surgery yet. All three women with kidney tumors also had a history of uterine tumors. Parafibromin staining of 19 available CDC73 related parathyroid tumors (13 adenomas and 6 carcinoma) did not correlate with histology or genotype. Pathway analysis of 21 parathyroid tumors (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas and 7 sporadic parathyroid carcinoma with wild-type CDC73) showed a significant association of HPT-JT-related parathyroid carcinoma with growth, transmembrane receptor protein tyrosine kinase signaling and mesodermal commitment pathways. Conclusion: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be characteristic of HPT-JT syndrome. Our findings support germline testing at a young age in first-degree relatives of patients with HPT-JT given onset of manifestations as early as 6 years. Variants at M1 residue appear to predispose to genitourinary tumors. At present, there are no therapeutic approaches to compensate for CDC73 inactivation. Future research to identify standards of care and therapeutics targets are warranted for this rare disease. Presentation: Friday, June 16, 2023

Abstract 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