Identification of De Novo Germline Mutations in the HRPT2 Gene in Two Apparently Sporadic Cases with Challenging Parathyroid Tumor Diagnoses

Abstract

The diagnosis of parathyroid carcinomas is often difficult. HRPT2 mutations have been identified in familial [hyperparathyroidism-jaw tumor (HPT-JT) syndrome] and sporadic parathyroid carcinomas, supporting that HRPT2 mutations may confer a malignant potential to parathyroid tumors. In this study, we report the clinical, histopathological, and genetic investigation of two unrelated cases, whom had apparently sporadic malignant parathyroid tumors, initially diagnosed as adenomas. In one case, the differential diagnosis was complicated by cervical seeding of parathyroid tumor cells. Genetic studies identified de novo HRPT2 germline mutations in cases 1 (c.518_521delTGTC

Identification of the first germline HRPT2 whole‐gene deletion in a patient with primary hyperparathyroidism

“…HRPT2 mutations are also frequently found in sporadic parathyroid carcinomas (67–100%) and have been described in a few cases of parathyroid adenomas with cystic features 1,9–11 . Approximately 30% of apparently sporadic cases with parathyroid carcinomas have been found to carry mutations at the germline level, and as recently shown by our group, absence of a family history may result from de novo mutations 5,8,12 . Frequent biallelic HRPT2 inactivation in familial and sporadic parathyroid tumours supports a tumour suppressor role for this gene 5,8–12 .…”

“…Germline HRPT2 gene–inactivating mutations, which are associated with parafibromin loss of function, are frequently detected in patients with familial forms of primary hyperparathyroidism, such as HPT‐JT and FIHP, and in cases with apparently sporadic hyperparathyroidism caused by parathyroid carcinomas and cystic adenomas 5,8–12 …”

“…1,[9][10][11] Approximately 30% of apparently sporadic cases with parathyroid carcinomas have been found to carry mutations at the germline level, and as recently shown by our group, absence of a family history may result from de novo mutations. 5,8,12 Frequent biallelic HRPT2 inactivation in familial and sporadic parathyroid tumours supports a tumour suppressor role for this gene. 5,[8][9][10][11][12] Nonetheless, the underlying genetic defects remain undetermined in >20% of HPT-JT families, by conventional techniques (e.g.…”

“…5,8,12 Frequent biallelic HRPT2 inactivation in familial and sporadic parathyroid tumours supports a tumour suppressor role for this gene. 5,[8][9][10][11][12] Nonetheless, the underlying genetic defects remain undetermined in >20% of HPT-JT families, by conventional techniques (e.g. direct sequencing analysis of PCR-amplified DNA).…”

Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel <i>CDC73</i> mutation

“…Although HPT-JT is a rare tumor syndrome, it cannot be overlooked because parathyroid carcinoma develops more frequently in this syndrome than other selected for MEN1 (12 articles, 30 patients) [12][13][14][15][16] and HPT-JT (9 articles, 35 patients) [17][18][19][20]. Serum calcium levels ranged from 10.8 to 17.5 mg/dL (mean 12.3 mg/dL, median 13.2 mg/dL) at 25-35 years old in MEN1 cases, and 12.0 to 16.8 mg/dL (mean 13.7 mg/dL, median 11.5 mg/dL) in HPT-JT cases (Fig.…”