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

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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 [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.

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Acknowledgments

We are grateful to the Pathology Departments from Instituto Português de Oncologia de Lisboa Francisco Gentil, Hospital SAMS, Lisboa and Hospital de São João, Porto. We are thankful to Prof. DeLellis for revising the histopathology features of case 1.

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Authors and Affiliations

  1. Centro de Investigação de Patobiologia Molecular (CIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023, Lisboa, Portugal

    Branca Maria Cavaco, Rita Domingues, Nádia Rei, Luís Sobrinho & Valeriano Leite

  2. Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023, Lisboa, Portugal

    Rita Santos, Luís Sobrinho & Valeriano Leite

  3. Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023, Lisboa, Portugal

    Ana Félix & Marta Sirgado

  4. Serviço de Cirurgia de Cabeça e Pescoço, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023, Lisboa, Portugal

    Jorge Rosa Santos

  5. Centro de Estudos de Doenças Crónicas (CEDOC), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal

    Branca Maria Cavaco, Ana Félix, Rita Domingues & Valeriano Leite

  6. Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de São João, 4200-319, Porto, Portugal

    Davide Carvalho

  7. Serviço de Anatomia Patológica, Hospital de São João, 4200-319, Porto, Portugal

    José Manuel Lopes

  8. Faculdade de Medicina, Universidade do Porto, 4200-319, Porto, Portugal

    Davide Carvalho & José Manuel Lopes

  9. Instituto de Patologia e Imunologia, Universidade do Porto, 4200-465, Porto, Portugal

    José Manuel Lopes

  10. Serviço de Endocrinologia, Hospital Curry Cabral, 1069-639, Lisboa, Portugal

    Fernando Fonseca

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  1. Branca Maria Cavaco
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  2. Rita Santos
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  3. Ana Félix
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  10. Jorge Rosa Santos
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  12. Valeriano Leite
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Correspondence to Branca Maria Cavaco.

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Cavaco, B.M., Santos, R., Félix, A. et al. Identification of De Novo Germline Mutations in the HRPT2 Gene in Two Apparently Sporadic Cases with Challenging Parathyroid Tumor Diagnoses. Endocr Pathol 22, 44–52 (2011). https://doi.org/10.1007/s12022-011-9151-1

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