Identification of de novo germline mutations in the HRPT2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses

Branca Cavaco, Rita B. Santos, Ana Félix, Davide Carvalho, José Manuel Lopes, Rita Domingues, Marta Sirgado, Nádia Rei, Fernando Fonseca, Jorge Rosa Santos, Luís Sobrinho, Valeriano Leite

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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 [p.Ser174LysfsX27]) and 2 (c.226 C > T [p.Arg76X]), unveiling the hereditary HPT-JT syndrome in both patients. Furthermore, the identification of somatic mutations in the patients parathyroid tumors provided evidence for complete inactivation of the HRPT2 gene, which was consistent with the tumor malignant features. The sensitivity of parafibromin immunostaining to detect HRPT2 mutations was limited. The present data suggests that patients with apparently sporadic parathyroid carcinomas, or parathyroid tumors with atypical histological features, should undergo molecular genetic testing, as it may detect germline HRPT2 mutations. Establishing the diagnosis of hereditary HPT-JT syndrome is relevant for clinical counseling and management of the carriers and their relatives.

Original languageEnglish
Pages (from-to)44-52
Number of pages9
JournalEndocrine Pathology
Issue number1
Publication statusPublished - Mar 2011



  • De novo mutation
  • HRPT2 gene
  • Hyperparathyroidism-jaw tumor syndrome (HPT-JT)
  • Parafibromin
  • Parathyroid carcinoma
  • Tumor seeding

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